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What was the outcome of reaction 'Progressive multifocal leukoencephalopathy'?
|
Early Pathological JC Virus Lesions in a Patient without Any MRI-based Indications.
A 70-year-old woman with a human T-cell leukemia virus type 1 infection without any focal neurological symptoms showed age-related atherosclerotic changes in the white matter without any suspicious signal changes suggestive of progressive multifocal leukoencephalopathy (PML) based on the findings of MRI. Viral polymerase chain reaction (PCR) revealed 6,700 copies/mL of the JC virus genome in the cerebrospinal fluid (CSF). An immuno-pathological examination of the autopsied brain revealed JC virus capsid proteins, and in situ hybridization confirmed a JC virus infection, indicating that an active infection begins at the radiologically indistinguishable phase of PML. An early JC virus infection is probably associated with small, scattered demyelinating lesions around the cortico-medullary area of the cortex.
Introduction
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease induced by an opportunistic JC polyomavirus infection of the central nervous system (CNS). Accumulating evidence has indicated that the development of PML is also an adverse effect of the administration of immunomodulatory agents to patients with autoimmune diseases (1). The clinical diagnostic criteria for PML have recently been published (2), and cerebrospinal fluid polymerase chain reaction (CSF PCR) for the detection of the JC virus genome is considered to be an important biomarker. However, the detection of the JC virus in the CSF via PCR is not infallible (3-5). It is rare for patients with a JC virus in the CSF to exhibit a lack of MR image findings compatible with PML. The clinical criteria for PML (2) recommend MR image scanning as the first step of screening for a JC virus infection in the CNS. Knowledge of the distinct pathophysiology of radiologically asymptomatic PML may aid in diagnosing such patients.
Case Report
A 70-year-old Japanese woman was admitted to our hospital with general fatigue and appetite loss. The patient had previously been diagnosed with a smoldering form of adult T-cell leukemia (ATL), but had experienced no symptoms since five years ago. In previous year, positron emission tomography (PET) revealed an abnormal accumulation in multiple lymph nodes of the patient's body, including the spleen. At the end of previous year, treatment was initiated using the modified lymphoma study group 15 method. In next year, the patient successfully underwent umbilical cord blood stem cell transplantation and was discharged in September. Gastric and skin graft-versus-host disease (GVHD) was observed as an adverse effect of the transplantation, resolving after continuous treatment with a combination of cyclosporine and prednisolone.
However, the patient reported experiencing general fatigue soon after discharge and was thus re-admitted to the hospital. Although the patient experienced no disturbance of consciousness, she complained of easy fatigability for maintaining sufficient concentration to complete cognitive examinations, but she exhibited no focal neurological disturbance.
MR images of the brain revealed an apparent progressive enlargement of the ventricles during the preceding 10 months (Fig. 1). A slight enlargement of mild ischemic changes was observed in the periventricular white matter on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images, although there were no signal changes suggestive of PML, such as punctate lesions, the Milky Way sign, or a scalloped appearance (2,6,7), even on diffusion-weighted images (Fig. 1, lower panels). The patient tested negative for HIV, and a CSF examination yielded the following results: 1 cell/μL and 56 mg/dL of total protein. A PCR analysis revealed that the CSF was positive for JC virus DNA (6,700 copies/mL). A pathological examination of the CSF revealed no malignant cells. The patient died of pneumonia nine days after the last MRI examination, and an autopsy was performed 34 hours after the patient's death.
Figure 1. Sequential MRI over a 10-month period. MRI brain scans without contrast enhancement were performed. Images were acquired on a 1.5 Tesla MRI (Toshiba). The parameters of first and second T2-weighted imaging were as follows: repetition time (TR), 4,080 and 4,460 ms; echo time (TE), 100.608 and 100.928 ms; flip angle, 90° both; slice thickness, 6 mm both; interslice gap, 1.5 mm; field of view (FOV), 100 mm both; number of excitations (NEX), 2 and 1; acquisition matrix, 352×352 or 256×256, respectively. T2-weighted axial MR images obtained 10 months prior to admission (upper panels) reveal slight cortical atrophy and mild age-related white matter hyperintensities. Compared with the previous MRI results, T2-weighted MR images obtained at the time of admission (middle panels) indicate progressive cortical atrophy, mild enlargement of the ventricles, and mild widening of the white matter hyperintensities. Diffusion-weighted MR images [lower panels-TR, 5,600 ms; TE, 83 ms; flip angle, 90°; slice thickness, 5 mm; interslice gap, 6 mm; field of view (FOV), 100 mm; number of excitations (NEX), 1; acquisition matrix, 128×160] demonstrated no abnormal signals. White rectangles in the middle panels indicate the tissue area excised for histological analyses. R: right, L: left
Pathological findings
The total brain weighed 1,335 g, and enlargement of the third ventricle and anterior horns of the lateral ventricles without ventricle obstruction were observed. The brain was fixed in 10% buffered formalin. Specimens for histopathological examination were resected from areas with radiologically normal appearance or mild white matter high-signal lesions according to MRI (Fig. 1, white rectangles). Using low microscopic magnification, numerous small, patchy demyelinating lesions were observed in the cerebral cortex and white matter, predominantly around the cortico-medullary junction (Fig. 2A, C), which were associated with infiltration of CD163-positive macrophages (Fig. 2B, E) and an apparent reduction of glial fibrillary acidic protein-positive cells (Fig. 2D). Oligodendroglia-like cells, which were negative for CD45 and glial fibrillary acidic protein, were also observed. These cells exhibited swollen nuclei of various sizes, and some exhibited intranuclear full or dot-shaped inclusions (Fig. 2B). Immunohistochemistry using antibodies specifically recognizing the JC virus capsid proteins VP1 and VP2/3 (Fig. 2F) yielded positive results (8), and in situ hybridization detected JC virus-positive cells around the demyelinating lesions (Fig. 2G). Inflammatory reactions occurred sparsely, and a few CD8-positive anaplastic cells were identified (Supplementary material). Based on these findings, the patient was found to be a pathologically confirmed case of PML.
Figure 2. Histopathological findings of demyelinating lesions around the cortico-medullary junction of the cerebrum. Klüver-Barrera (KB) staining (A) of brain specimens shows numerous small-sized, patchy demyelinating lesions in the cerebral cortex and white matter, predominantly at the cortico-medullary junction. Hematoxylin and Eosin staining (B) shows a mildly affected lesion, where oligodendroglia-like cells with swollen nuclei containing full or dot-shaped inclusions can be identified (inset). Serial sections were subjected to KB staining (C), and immunohistochemistry using anti-glial fibrillary acidic protein (GFAP) (D) or anti-CD163 antibodies (E), showing decreased GFAP signals and infiltration of macrophages. Immunohistochemistry with antibodies specific to JC virus capsid proteins VP2/3 (F) demonstrates JC virus-infected cells (browned nuclei). In situ hybridization for the detection of JC virus DNA (G) identifies oligodendroglia-like cells to be JC virus-positive (browned nuclei). Scale bar=1,000 μm (A), 100 μm (B, F, G), and 500 μm (C, D, E)
Discussion
The neuropathological findings represented the condition of the brain at the time of the second MRI, as the autopsy of the patient was performed only 10 days after the MRI. Surprisingly, numerous small, patchy demyelinating lesions were detected around the cortico-medullary junction, infiltrated by numerous macrophages, and these lesions were surrounded by reactive glial cells that expressed JC virus capsid proteins, some of which additionally exhibited intranuclear JC virus inclusions, even on specimens obtained from areas with a radiologically normal appearance.
Immunologically, the patient was at risk of developing PML due to umbilical cord blood stem cell transplantation, ATL, old age, and the use of cyclosporine and prednisolone for the treatment of GVHD. Viremia and viral mutations likely occurred when the patient was treated with these immunosuppressive agents, thus leading to the virus slowly infiltrating the brain. Alternatively, it may have been present in the brain prior to the treatment, and pathological mutations may have disrupted the immunosurveillance system, causing the virus to spread in the CNS (9). Some malignant cases have been reported to respond to immune-checkpoint inhibitor therapy for immune status enhancement; intervention should be considered in such cases to prevent the onset of PML.
A recent study reported that, among patients with multiple sclerosis diagnosed with natalizumab-associated PML, those with lesions detected early by MRI who remained asymptomatic had a better prognosis (10). However, no previous reports have discussed whether a JC virus infection can be observed in the CNS in minimally symptomatic patients with negative radiological findings and those with positive CSF PCR results. Nonetheless, such cases are defined as possible PML cases based on the clinical diagnostic criteria (2). To our knowledge, the present study is the first to demonstrate that the radiologically asymptomatic phase of PML with minimal symptoms occurs prior to the radiologically symptomatic phase in the course of active JC virus infection in the CNS. Moreover, our findings indicate that an early JC virus infection is associated with small, scattered demyelinating lesions around the cortico-medullary area of the cortex. Thus, it may be beneficial to evaluate the presence of the JC virus DNA in the CSF of patients likely to carry the virus in the CNS during immunosuppressive treatment, even in cases of negative MRI findings, as this would allow physicians to detect the earliest phase possible (i.e., minimally symptomatic and radiologically negative phase). In particular, the high prevalence of JC virus copies in the CSF strongly suggests an active JC virus infection because individuals with false-positive JC virus PCR results in the CSF usually feature copy numbers that are one or two orders of magnitude lower than in this PCR. Early discontinuation of immunosuppressive agents is currently the best treatment available for drug-associated PML because there are no agents that can enhance the immunosurveillance system in patients undergoing immunosuppressive treatment.
In conclusion, this study highlights that an early active JC virus infection begins at the radiologically indistinguishable phase of PML and is associated with small, scattered demyelinating lesions around the cortico-medullary area of the cortex.
This study was approved by the ethics committee of Tokyo Medical and Dental University Hospital. Written informed consent was obtained from the patient's legal representative.
The authors state that they have no Conflict of Interest (COI).
Financial Support
This work was funded by a Grant-in-Aid from the Research Committee of Prion Disease and Slow Virus Infection of the Ministry of Health, Labour, and Welfare of Japan, Program Grant Number JPMH-H29-Nanchitou-Ippan-036 (NS and YS-H). This work was partly supported by JSPS KAKENHI, Grant Number 18K07397 (YS-H). Funding contributed to the pathological analysis of this study.
Supplementary Material
Immunocytochemistry evaluation of lymphocyte markers. Immunohistochemistry staining of lymphocytic surface markers revealed no CD3-, CD4-, and CD20-positive cells; a faint immunopositivity for CD8 in anaplastic cells around the JC virus-positive lesions was observed. Scale bar = 100 μm
Click here for additional data file.
Acknowledgement
We thank the attending physicians for their cooperation.
|
Not recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33162483
| 19,962,956
|
2021-04-15
|
What is the weight of the patient?
|
Coronary Artery Spasm During Catheter Ablation Caused by the Intravenous Infusion of Isoproterenol.
Radiofrequency ablation is an established treatment for atrial fibrillation (AF). However, coronary artery spasm (CAS) is a rare but a potentially lethal complication associated with this procedure. A 54-year-old man with paroxysmal AF underwent pulmonary vein isolation. The procedure was completed and AF could not be induced after burst pacing and the administration of isoproterenol. Suddenly, ST-segment elevation developed in the anterior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation. The diagnosis of CAS was made by urgent coronary angiography. We identified isoproterenol as a potential cause of CAS. Physicians should be aware of this potentially lethal side effect.
Introduction
Radiofrequency (RF) ablation has become a standard treatment modality for atrial fibrillation (AF), and it is generally considered to be a safe procedure. However, serious complications can occur. Case reports demonstrating coronary artery spasm (CAS) as a potential lethal complication of catheter ablation for AF have been published (1, 2). The occurrence of CAS during RF ablation is probably multifactorial, and its underlying mechanisms have not yet been fully determined. We herein report a patient who experienced severe CAS during RF ablation for AF due to the intravenous infusion of isoproterenol.
Case Report
A 54-year-old Caucasian man with history of hypertension, atrial flutter, nicotine dependence, and alcohol abuse was referred to our institution for RF ablation of paroxysmal AF. He previously underwent cavo-tricuspid isthmus ablation of atrial flutter and had isoproterenol infusion post ablation without any complications. The patient had been implanted with a loop recorder eighteen months prior to this presentation. His height was 180 cm and body weight was 90.4 kg. He had no known allergies or family history of sudden death or cardiac disease. He had no prior resting or exercising angina, and a pharmacologic nuclear stress test demonstrated normal myocardial perfusion with normal wall motion prior to the procedure.
The ablation strategy employed pulmonary vein isolation under general anesthesia. There was no hemodynamic instability nor hypoxemia during the procedure. The sheath was removed from left atrium. AF could not be induced after burst pacing and the administration of isoproterenol at 5 μg/min. Therefore, the procedure was concluded.
Six minutes after stopping isoproterenol, the 12 lead surface electrocardiogram showed ST-segment elevation in the anterior and inferior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation (Fig. 1A). Urgent coronary angiography was performed which showed an occluded mid-left anterior descending artery and moderate-severe narrowing of left circumflex artery and right coronary artery (Fig. 1B). After the intracoronary administration of 200 μg nitroglycerin, the coronary narrowing and ST-segment elevation resolved (Fig. 2A, B). Diltiazem was added to the patient's medical regimen and he was discharged the following day without any complications. Smoking and alcohol intake were strictly prohibited.
Figure 1. The 12-lead surface electrocardiogram showed ST-segment elevation in the anterior and inferior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation (A). Coronary angiography showed an occluded mid-left anterior descending artery (arrow) and moderate-severe narrowing of left circumflex artery and right coronary artery (B).
Figure 2. After the intracoronary administration of nitroglycerin, the 12-lead surface electrocardiogram showed an improvement of ST-segment elevation (A), and angiographic stenosis (B).
Discussion
RF ablation is an established treatment for AF in terms of efficacy and safety. However, coronary artery related complications have been reported after RF ablation; these include direct thermal injury by RF energy (3), embolus (4) and CAS (1, 2, 5). To the best of our knowledge, this is the first case which showed severe CAS on angiography caused by isoproterenol during catheter ablation.
Patients with paroxysmal AF have high positive rates of drug-provoked CAS (6). Although the underlying mechanism responsible for CAS remains unclear, CAS during and after catheter ablation has been attributed to several different mechanisms such as direct thermal damage from RF energy to coronary artery (7), indirect effects via cryoenergy-induced blood cooling (8), an imbalance in the autonomic nervous system activity caused by the affected ganglionated plexus through a thermal or cooling injury (1), and an imbalance in the autonomic discharge, such as stimulation of α-2 adrenergic receptors induced by dexmedetomidine (9). The CAS in the present case occurred after the ablation procedure. Moreover, neither cryoballoon nor dexmedetomidine was used. The present case was a rare case which showed CAS caused by isoproterenol infusion. The use of isoproterenol in the electrophysiology lab to study triggers of AF is well established (10). The mechanisms which isoproterenol induces AF may include an increase in intracellular calcium that facilitates abnormal automaticity or early after depolarizations and triggered activity. Accentuated antagonism leading to enhanced parasympathetic tone also may play a role in the inducibility of AF by isoproterenol (11). The relationship between the autonomic nervous system and CAS is complex. Although the parasympathetic activity is well known to be a trigger of CAS, sympathetic stimuli may also play a role. CAS has been shown to occur more frequently during the rapid eye movement phase of sleep at night when there is a reduction in vagal activity and an increase in adrenergic activity (12), suggesting that CAS is not necessarily induced by parasympathetic activity. Moreover, several case reports have suggested that CAS can be induced by various sympathetic related stimuli (13, 14). Hung et al. showed that a head-up tilt test with isoproterenol can provoke CAS, which suggests that the induction of CAS is associated with a rapid elevation of sympathetic activity during augmented parasympathetic activity (15). The present case report describes the intravenous administration of isoproterenol, a non-selective β adrenoreceptor agonist, as a potential cause of CAS during catheter ablation for AF. Physicians should be aware of this potentially lethal side effect. A through a preoperative history should be taken to determine whether a patient has a risk of CAS. The main risk factors for CAS are age, a smoking history, Japanese ethnicity, hypertension, and diabetes mellitus, and it can be precipitated by various factors such as mental exercise, cold exposure, hyperventilation, or alcohol consumption (16). Although this patient was Caucasian and did not have alcohol flushing syndrome, the present case had history of nicotine dependence and alcohol abuse. Mizuno et al. reported that East Asian variants of the aldehyde dehydrogenase 2 genotype was associated with CAS in Japanese (17). The administration of a calcium channel blocker and smoking cessation before RF ablation may avoid CAS during these procedures. The 12-lead electrocardiogram should be continuously monitored throughout the procedure with special attention to ischemic changes. Moreover, coronary angiography and the administration of coronary vasodilator should be performed when ST changes are observed.
Conclusions
Isoproterenol administration during AF ablation may provoke severe CAS, possibly due to an autonomic nervous system imbalance. This is a rare complication of AF ablation and it should be considered when performing these procedures.
The authors state that they have no Conflict of Interest (COI).
|
90.4 kg.
|
Weight
|
CC BY-NC-ND
|
33162486
| 18,549,615
|
2021-04-15
|
What was the administration route of drug 'ISOPROTERENOL HYDROCHLORIDE'?
|
Coronary Artery Spasm During Catheter Ablation Caused by the Intravenous Infusion of Isoproterenol.
Radiofrequency ablation is an established treatment for atrial fibrillation (AF). However, coronary artery spasm (CAS) is a rare but a potentially lethal complication associated with this procedure. A 54-year-old man with paroxysmal AF underwent pulmonary vein isolation. The procedure was completed and AF could not be induced after burst pacing and the administration of isoproterenol. Suddenly, ST-segment elevation developed in the anterior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation. The diagnosis of CAS was made by urgent coronary angiography. We identified isoproterenol as a potential cause of CAS. Physicians should be aware of this potentially lethal side effect.
Introduction
Radiofrequency (RF) ablation has become a standard treatment modality for atrial fibrillation (AF), and it is generally considered to be a safe procedure. However, serious complications can occur. Case reports demonstrating coronary artery spasm (CAS) as a potential lethal complication of catheter ablation for AF have been published (1, 2). The occurrence of CAS during RF ablation is probably multifactorial, and its underlying mechanisms have not yet been fully determined. We herein report a patient who experienced severe CAS during RF ablation for AF due to the intravenous infusion of isoproterenol.
Case Report
A 54-year-old Caucasian man with history of hypertension, atrial flutter, nicotine dependence, and alcohol abuse was referred to our institution for RF ablation of paroxysmal AF. He previously underwent cavo-tricuspid isthmus ablation of atrial flutter and had isoproterenol infusion post ablation without any complications. The patient had been implanted with a loop recorder eighteen months prior to this presentation. His height was 180 cm and body weight was 90.4 kg. He had no known allergies or family history of sudden death or cardiac disease. He had no prior resting or exercising angina, and a pharmacologic nuclear stress test demonstrated normal myocardial perfusion with normal wall motion prior to the procedure.
The ablation strategy employed pulmonary vein isolation under general anesthesia. There was no hemodynamic instability nor hypoxemia during the procedure. The sheath was removed from left atrium. AF could not be induced after burst pacing and the administration of isoproterenol at 5 μg/min. Therefore, the procedure was concluded.
Six minutes after stopping isoproterenol, the 12 lead surface electrocardiogram showed ST-segment elevation in the anterior and inferior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation (Fig. 1A). Urgent coronary angiography was performed which showed an occluded mid-left anterior descending artery and moderate-severe narrowing of left circumflex artery and right coronary artery (Fig. 1B). After the intracoronary administration of 200 μg nitroglycerin, the coronary narrowing and ST-segment elevation resolved (Fig. 2A, B). Diltiazem was added to the patient's medical regimen and he was discharged the following day without any complications. Smoking and alcohol intake were strictly prohibited.
Figure 1. The 12-lead surface electrocardiogram showed ST-segment elevation in the anterior and inferior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation (A). Coronary angiography showed an occluded mid-left anterior descending artery (arrow) and moderate-severe narrowing of left circumflex artery and right coronary artery (B).
Figure 2. After the intracoronary administration of nitroglycerin, the 12-lead surface electrocardiogram showed an improvement of ST-segment elevation (A), and angiographic stenosis (B).
Discussion
RF ablation is an established treatment for AF in terms of efficacy and safety. However, coronary artery related complications have been reported after RF ablation; these include direct thermal injury by RF energy (3), embolus (4) and CAS (1, 2, 5). To the best of our knowledge, this is the first case which showed severe CAS on angiography caused by isoproterenol during catheter ablation.
Patients with paroxysmal AF have high positive rates of drug-provoked CAS (6). Although the underlying mechanism responsible for CAS remains unclear, CAS during and after catheter ablation has been attributed to several different mechanisms such as direct thermal damage from RF energy to coronary artery (7), indirect effects via cryoenergy-induced blood cooling (8), an imbalance in the autonomic nervous system activity caused by the affected ganglionated plexus through a thermal or cooling injury (1), and an imbalance in the autonomic discharge, such as stimulation of α-2 adrenergic receptors induced by dexmedetomidine (9). The CAS in the present case occurred after the ablation procedure. Moreover, neither cryoballoon nor dexmedetomidine was used. The present case was a rare case which showed CAS caused by isoproterenol infusion. The use of isoproterenol in the electrophysiology lab to study triggers of AF is well established (10). The mechanisms which isoproterenol induces AF may include an increase in intracellular calcium that facilitates abnormal automaticity or early after depolarizations and triggered activity. Accentuated antagonism leading to enhanced parasympathetic tone also may play a role in the inducibility of AF by isoproterenol (11). The relationship between the autonomic nervous system and CAS is complex. Although the parasympathetic activity is well known to be a trigger of CAS, sympathetic stimuli may also play a role. CAS has been shown to occur more frequently during the rapid eye movement phase of sleep at night when there is a reduction in vagal activity and an increase in adrenergic activity (12), suggesting that CAS is not necessarily induced by parasympathetic activity. Moreover, several case reports have suggested that CAS can be induced by various sympathetic related stimuli (13, 14). Hung et al. showed that a head-up tilt test with isoproterenol can provoke CAS, which suggests that the induction of CAS is associated with a rapid elevation of sympathetic activity during augmented parasympathetic activity (15). The present case report describes the intravenous administration of isoproterenol, a non-selective β adrenoreceptor agonist, as a potential cause of CAS during catheter ablation for AF. Physicians should be aware of this potentially lethal side effect. A through a preoperative history should be taken to determine whether a patient has a risk of CAS. The main risk factors for CAS are age, a smoking history, Japanese ethnicity, hypertension, and diabetes mellitus, and it can be precipitated by various factors such as mental exercise, cold exposure, hyperventilation, or alcohol consumption (16). Although this patient was Caucasian and did not have alcohol flushing syndrome, the present case had history of nicotine dependence and alcohol abuse. Mizuno et al. reported that East Asian variants of the aldehyde dehydrogenase 2 genotype was associated with CAS in Japanese (17). The administration of a calcium channel blocker and smoking cessation before RF ablation may avoid CAS during these procedures. The 12-lead electrocardiogram should be continuously monitored throughout the procedure with special attention to ischemic changes. Moreover, coronary angiography and the administration of coronary vasodilator should be performed when ST changes are observed.
Conclusions
Isoproterenol administration during AF ablation may provoke severe CAS, possibly due to an autonomic nervous system imbalance. This is a rare complication of AF ablation and it should be considered when performing these procedures.
The authors state that they have no Conflict of Interest (COI).
|
Intravenous (not otherwise specified)
|
DrugAdministrationRoute
|
CC BY-NC-ND
|
33162486
| 18,549,615
|
2021-04-15
|
What was the administration route of drug 'ISOPROTERENOL'?
|
Coronary Artery Spasm During Catheter Ablation Caused by the Intravenous Infusion of Isoproterenol.
Radiofrequency ablation is an established treatment for atrial fibrillation (AF). However, coronary artery spasm (CAS) is a rare but a potentially lethal complication associated with this procedure. A 54-year-old man with paroxysmal AF underwent pulmonary vein isolation. The procedure was completed and AF could not be induced after burst pacing and the administration of isoproterenol. Suddenly, ST-segment elevation developed in the anterior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation. The diagnosis of CAS was made by urgent coronary angiography. We identified isoproterenol as a potential cause of CAS. Physicians should be aware of this potentially lethal side effect.
Introduction
Radiofrequency (RF) ablation has become a standard treatment modality for atrial fibrillation (AF), and it is generally considered to be a safe procedure. However, serious complications can occur. Case reports demonstrating coronary artery spasm (CAS) as a potential lethal complication of catheter ablation for AF have been published (1, 2). The occurrence of CAS during RF ablation is probably multifactorial, and its underlying mechanisms have not yet been fully determined. We herein report a patient who experienced severe CAS during RF ablation for AF due to the intravenous infusion of isoproterenol.
Case Report
A 54-year-old Caucasian man with history of hypertension, atrial flutter, nicotine dependence, and alcohol abuse was referred to our institution for RF ablation of paroxysmal AF. He previously underwent cavo-tricuspid isthmus ablation of atrial flutter and had isoproterenol infusion post ablation without any complications. The patient had been implanted with a loop recorder eighteen months prior to this presentation. His height was 180 cm and body weight was 90.4 kg. He had no known allergies or family history of sudden death or cardiac disease. He had no prior resting or exercising angina, and a pharmacologic nuclear stress test demonstrated normal myocardial perfusion with normal wall motion prior to the procedure.
The ablation strategy employed pulmonary vein isolation under general anesthesia. There was no hemodynamic instability nor hypoxemia during the procedure. The sheath was removed from left atrium. AF could not be induced after burst pacing and the administration of isoproterenol at 5 μg/min. Therefore, the procedure was concluded.
Six minutes after stopping isoproterenol, the 12 lead surface electrocardiogram showed ST-segment elevation in the anterior and inferior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation (Fig. 1A). Urgent coronary angiography was performed which showed an occluded mid-left anterior descending artery and moderate-severe narrowing of left circumflex artery and right coronary artery (Fig. 1B). After the intracoronary administration of 200 μg nitroglycerin, the coronary narrowing and ST-segment elevation resolved (Fig. 2A, B). Diltiazem was added to the patient's medical regimen and he was discharged the following day without any complications. Smoking and alcohol intake were strictly prohibited.
Figure 1. The 12-lead surface electrocardiogram showed ST-segment elevation in the anterior and inferior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation (A). Coronary angiography showed an occluded mid-left anterior descending artery (arrow) and moderate-severe narrowing of left circumflex artery and right coronary artery (B).
Figure 2. After the intracoronary administration of nitroglycerin, the 12-lead surface electrocardiogram showed an improvement of ST-segment elevation (A), and angiographic stenosis (B).
Discussion
RF ablation is an established treatment for AF in terms of efficacy and safety. However, coronary artery related complications have been reported after RF ablation; these include direct thermal injury by RF energy (3), embolus (4) and CAS (1, 2, 5). To the best of our knowledge, this is the first case which showed severe CAS on angiography caused by isoproterenol during catheter ablation.
Patients with paroxysmal AF have high positive rates of drug-provoked CAS (6). Although the underlying mechanism responsible for CAS remains unclear, CAS during and after catheter ablation has been attributed to several different mechanisms such as direct thermal damage from RF energy to coronary artery (7), indirect effects via cryoenergy-induced blood cooling (8), an imbalance in the autonomic nervous system activity caused by the affected ganglionated plexus through a thermal or cooling injury (1), and an imbalance in the autonomic discharge, such as stimulation of α-2 adrenergic receptors induced by dexmedetomidine (9). The CAS in the present case occurred after the ablation procedure. Moreover, neither cryoballoon nor dexmedetomidine was used. The present case was a rare case which showed CAS caused by isoproterenol infusion. The use of isoproterenol in the electrophysiology lab to study triggers of AF is well established (10). The mechanisms which isoproterenol induces AF may include an increase in intracellular calcium that facilitates abnormal automaticity or early after depolarizations and triggered activity. Accentuated antagonism leading to enhanced parasympathetic tone also may play a role in the inducibility of AF by isoproterenol (11). The relationship between the autonomic nervous system and CAS is complex. Although the parasympathetic activity is well known to be a trigger of CAS, sympathetic stimuli may also play a role. CAS has been shown to occur more frequently during the rapid eye movement phase of sleep at night when there is a reduction in vagal activity and an increase in adrenergic activity (12), suggesting that CAS is not necessarily induced by parasympathetic activity. Moreover, several case reports have suggested that CAS can be induced by various sympathetic related stimuli (13, 14). Hung et al. showed that a head-up tilt test with isoproterenol can provoke CAS, which suggests that the induction of CAS is associated with a rapid elevation of sympathetic activity during augmented parasympathetic activity (15). The present case report describes the intravenous administration of isoproterenol, a non-selective β adrenoreceptor agonist, as a potential cause of CAS during catheter ablation for AF. Physicians should be aware of this potentially lethal side effect. A through a preoperative history should be taken to determine whether a patient has a risk of CAS. The main risk factors for CAS are age, a smoking history, Japanese ethnicity, hypertension, and diabetes mellitus, and it can be precipitated by various factors such as mental exercise, cold exposure, hyperventilation, or alcohol consumption (16). Although this patient was Caucasian and did not have alcohol flushing syndrome, the present case had history of nicotine dependence and alcohol abuse. Mizuno et al. reported that East Asian variants of the aldehyde dehydrogenase 2 genotype was associated with CAS in Japanese (17). The administration of a calcium channel blocker and smoking cessation before RF ablation may avoid CAS during these procedures. The 12-lead electrocardiogram should be continuously monitored throughout the procedure with special attention to ischemic changes. Moreover, coronary angiography and the administration of coronary vasodilator should be performed when ST changes are observed.
Conclusions
Isoproterenol administration during AF ablation may provoke severe CAS, possibly due to an autonomic nervous system imbalance. This is a rare complication of AF ablation and it should be considered when performing these procedures.
The authors state that they have no Conflict of Interest (COI).
|
Intravenous (not otherwise specified)
|
DrugAdministrationRoute
|
CC BY-NC-ND
|
33162486
| 18,563,630
|
2021-04-15
|
What was the dosage of drug 'ISOPROTERENOL HYDROCHLORIDE'?
|
Coronary Artery Spasm During Catheter Ablation Caused by the Intravenous Infusion of Isoproterenol.
Radiofrequency ablation is an established treatment for atrial fibrillation (AF). However, coronary artery spasm (CAS) is a rare but a potentially lethal complication associated with this procedure. A 54-year-old man with paroxysmal AF underwent pulmonary vein isolation. The procedure was completed and AF could not be induced after burst pacing and the administration of isoproterenol. Suddenly, ST-segment elevation developed in the anterior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation. The diagnosis of CAS was made by urgent coronary angiography. We identified isoproterenol as a potential cause of CAS. Physicians should be aware of this potentially lethal side effect.
Introduction
Radiofrequency (RF) ablation has become a standard treatment modality for atrial fibrillation (AF), and it is generally considered to be a safe procedure. However, serious complications can occur. Case reports demonstrating coronary artery spasm (CAS) as a potential lethal complication of catheter ablation for AF have been published (1, 2). The occurrence of CAS during RF ablation is probably multifactorial, and its underlying mechanisms have not yet been fully determined. We herein report a patient who experienced severe CAS during RF ablation for AF due to the intravenous infusion of isoproterenol.
Case Report
A 54-year-old Caucasian man with history of hypertension, atrial flutter, nicotine dependence, and alcohol abuse was referred to our institution for RF ablation of paroxysmal AF. He previously underwent cavo-tricuspid isthmus ablation of atrial flutter and had isoproterenol infusion post ablation without any complications. The patient had been implanted with a loop recorder eighteen months prior to this presentation. His height was 180 cm and body weight was 90.4 kg. He had no known allergies or family history of sudden death or cardiac disease. He had no prior resting or exercising angina, and a pharmacologic nuclear stress test demonstrated normal myocardial perfusion with normal wall motion prior to the procedure.
The ablation strategy employed pulmonary vein isolation under general anesthesia. There was no hemodynamic instability nor hypoxemia during the procedure. The sheath was removed from left atrium. AF could not be induced after burst pacing and the administration of isoproterenol at 5 μg/min. Therefore, the procedure was concluded.
Six minutes after stopping isoproterenol, the 12 lead surface electrocardiogram showed ST-segment elevation in the anterior and inferior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation (Fig. 1A). Urgent coronary angiography was performed which showed an occluded mid-left anterior descending artery and moderate-severe narrowing of left circumflex artery and right coronary artery (Fig. 1B). After the intracoronary administration of 200 μg nitroglycerin, the coronary narrowing and ST-segment elevation resolved (Fig. 2A, B). Diltiazem was added to the patient's medical regimen and he was discharged the following day without any complications. Smoking and alcohol intake were strictly prohibited.
Figure 1. The 12-lead surface electrocardiogram showed ST-segment elevation in the anterior and inferior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation (A). Coronary angiography showed an occluded mid-left anterior descending artery (arrow) and moderate-severe narrowing of left circumflex artery and right coronary artery (B).
Figure 2. After the intracoronary administration of nitroglycerin, the 12-lead surface electrocardiogram showed an improvement of ST-segment elevation (A), and angiographic stenosis (B).
Discussion
RF ablation is an established treatment for AF in terms of efficacy and safety. However, coronary artery related complications have been reported after RF ablation; these include direct thermal injury by RF energy (3), embolus (4) and CAS (1, 2, 5). To the best of our knowledge, this is the first case which showed severe CAS on angiography caused by isoproterenol during catheter ablation.
Patients with paroxysmal AF have high positive rates of drug-provoked CAS (6). Although the underlying mechanism responsible for CAS remains unclear, CAS during and after catheter ablation has been attributed to several different mechanisms such as direct thermal damage from RF energy to coronary artery (7), indirect effects via cryoenergy-induced blood cooling (8), an imbalance in the autonomic nervous system activity caused by the affected ganglionated plexus through a thermal or cooling injury (1), and an imbalance in the autonomic discharge, such as stimulation of α-2 adrenergic receptors induced by dexmedetomidine (9). The CAS in the present case occurred after the ablation procedure. Moreover, neither cryoballoon nor dexmedetomidine was used. The present case was a rare case which showed CAS caused by isoproterenol infusion. The use of isoproterenol in the electrophysiology lab to study triggers of AF is well established (10). The mechanisms which isoproterenol induces AF may include an increase in intracellular calcium that facilitates abnormal automaticity or early after depolarizations and triggered activity. Accentuated antagonism leading to enhanced parasympathetic tone also may play a role in the inducibility of AF by isoproterenol (11). The relationship between the autonomic nervous system and CAS is complex. Although the parasympathetic activity is well known to be a trigger of CAS, sympathetic stimuli may also play a role. CAS has been shown to occur more frequently during the rapid eye movement phase of sleep at night when there is a reduction in vagal activity and an increase in adrenergic activity (12), suggesting that CAS is not necessarily induced by parasympathetic activity. Moreover, several case reports have suggested that CAS can be induced by various sympathetic related stimuli (13, 14). Hung et al. showed that a head-up tilt test with isoproterenol can provoke CAS, which suggests that the induction of CAS is associated with a rapid elevation of sympathetic activity during augmented parasympathetic activity (15). The present case report describes the intravenous administration of isoproterenol, a non-selective β adrenoreceptor agonist, as a potential cause of CAS during catheter ablation for AF. Physicians should be aware of this potentially lethal side effect. A through a preoperative history should be taken to determine whether a patient has a risk of CAS. The main risk factors for CAS are age, a smoking history, Japanese ethnicity, hypertension, and diabetes mellitus, and it can be precipitated by various factors such as mental exercise, cold exposure, hyperventilation, or alcohol consumption (16). Although this patient was Caucasian and did not have alcohol flushing syndrome, the present case had history of nicotine dependence and alcohol abuse. Mizuno et al. reported that East Asian variants of the aldehyde dehydrogenase 2 genotype was associated with CAS in Japanese (17). The administration of a calcium channel blocker and smoking cessation before RF ablation may avoid CAS during these procedures. The 12-lead electrocardiogram should be continuously monitored throughout the procedure with special attention to ischemic changes. Moreover, coronary angiography and the administration of coronary vasodilator should be performed when ST changes are observed.
Conclusions
Isoproterenol administration during AF ablation may provoke severe CAS, possibly due to an autonomic nervous system imbalance. This is a rare complication of AF ablation and it should be considered when performing these procedures.
The authors state that they have no Conflict of Interest (COI).
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5 µg (micrograms).
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DrugDosage
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CC BY-NC-ND
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33162486
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2021-04-15
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What was the outcome of reaction 'Arteriospasm coronary'?
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Coronary Artery Spasm During Catheter Ablation Caused by the Intravenous Infusion of Isoproterenol.
Radiofrequency ablation is an established treatment for atrial fibrillation (AF). However, coronary artery spasm (CAS) is a rare but a potentially lethal complication associated with this procedure. A 54-year-old man with paroxysmal AF underwent pulmonary vein isolation. The procedure was completed and AF could not be induced after burst pacing and the administration of isoproterenol. Suddenly, ST-segment elevation developed in the anterior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation. The diagnosis of CAS was made by urgent coronary angiography. We identified isoproterenol as a potential cause of CAS. Physicians should be aware of this potentially lethal side effect.
Introduction
Radiofrequency (RF) ablation has become a standard treatment modality for atrial fibrillation (AF), and it is generally considered to be a safe procedure. However, serious complications can occur. Case reports demonstrating coronary artery spasm (CAS) as a potential lethal complication of catheter ablation for AF have been published (1, 2). The occurrence of CAS during RF ablation is probably multifactorial, and its underlying mechanisms have not yet been fully determined. We herein report a patient who experienced severe CAS during RF ablation for AF due to the intravenous infusion of isoproterenol.
Case Report
A 54-year-old Caucasian man with history of hypertension, atrial flutter, nicotine dependence, and alcohol abuse was referred to our institution for RF ablation of paroxysmal AF. He previously underwent cavo-tricuspid isthmus ablation of atrial flutter and had isoproterenol infusion post ablation without any complications. The patient had been implanted with a loop recorder eighteen months prior to this presentation. His height was 180 cm and body weight was 90.4 kg. He had no known allergies or family history of sudden death or cardiac disease. He had no prior resting or exercising angina, and a pharmacologic nuclear stress test demonstrated normal myocardial perfusion with normal wall motion prior to the procedure.
The ablation strategy employed pulmonary vein isolation under general anesthesia. There was no hemodynamic instability nor hypoxemia during the procedure. The sheath was removed from left atrium. AF could not be induced after burst pacing and the administration of isoproterenol at 5 μg/min. Therefore, the procedure was concluded.
Six minutes after stopping isoproterenol, the 12 lead surface electrocardiogram showed ST-segment elevation in the anterior and inferior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation (Fig. 1A). Urgent coronary angiography was performed which showed an occluded mid-left anterior descending artery and moderate-severe narrowing of left circumflex artery and right coronary artery (Fig. 1B). After the intracoronary administration of 200 μg nitroglycerin, the coronary narrowing and ST-segment elevation resolved (Fig. 2A, B). Diltiazem was added to the patient's medical regimen and he was discharged the following day without any complications. Smoking and alcohol intake were strictly prohibited.
Figure 1. The 12-lead surface electrocardiogram showed ST-segment elevation in the anterior and inferior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation (A). Coronary angiography showed an occluded mid-left anterior descending artery (arrow) and moderate-severe narrowing of left circumflex artery and right coronary artery (B).
Figure 2. After the intracoronary administration of nitroglycerin, the 12-lead surface electrocardiogram showed an improvement of ST-segment elevation (A), and angiographic stenosis (B).
Discussion
RF ablation is an established treatment for AF in terms of efficacy and safety. However, coronary artery related complications have been reported after RF ablation; these include direct thermal injury by RF energy (3), embolus (4) and CAS (1, 2, 5). To the best of our knowledge, this is the first case which showed severe CAS on angiography caused by isoproterenol during catheter ablation.
Patients with paroxysmal AF have high positive rates of drug-provoked CAS (6). Although the underlying mechanism responsible for CAS remains unclear, CAS during and after catheter ablation has been attributed to several different mechanisms such as direct thermal damage from RF energy to coronary artery (7), indirect effects via cryoenergy-induced blood cooling (8), an imbalance in the autonomic nervous system activity caused by the affected ganglionated plexus through a thermal or cooling injury (1), and an imbalance in the autonomic discharge, such as stimulation of α-2 adrenergic receptors induced by dexmedetomidine (9). The CAS in the present case occurred after the ablation procedure. Moreover, neither cryoballoon nor dexmedetomidine was used. The present case was a rare case which showed CAS caused by isoproterenol infusion. The use of isoproterenol in the electrophysiology lab to study triggers of AF is well established (10). The mechanisms which isoproterenol induces AF may include an increase in intracellular calcium that facilitates abnormal automaticity or early after depolarizations and triggered activity. Accentuated antagonism leading to enhanced parasympathetic tone also may play a role in the inducibility of AF by isoproterenol (11). The relationship between the autonomic nervous system and CAS is complex. Although the parasympathetic activity is well known to be a trigger of CAS, sympathetic stimuli may also play a role. CAS has been shown to occur more frequently during the rapid eye movement phase of sleep at night when there is a reduction in vagal activity and an increase in adrenergic activity (12), suggesting that CAS is not necessarily induced by parasympathetic activity. Moreover, several case reports have suggested that CAS can be induced by various sympathetic related stimuli (13, 14). Hung et al. showed that a head-up tilt test with isoproterenol can provoke CAS, which suggests that the induction of CAS is associated with a rapid elevation of sympathetic activity during augmented parasympathetic activity (15). The present case report describes the intravenous administration of isoproterenol, a non-selective β adrenoreceptor agonist, as a potential cause of CAS during catheter ablation for AF. Physicians should be aware of this potentially lethal side effect. A through a preoperative history should be taken to determine whether a patient has a risk of CAS. The main risk factors for CAS are age, a smoking history, Japanese ethnicity, hypertension, and diabetes mellitus, and it can be precipitated by various factors such as mental exercise, cold exposure, hyperventilation, or alcohol consumption (16). Although this patient was Caucasian and did not have alcohol flushing syndrome, the present case had history of nicotine dependence and alcohol abuse. Mizuno et al. reported that East Asian variants of the aldehyde dehydrogenase 2 genotype was associated with CAS in Japanese (17). The administration of a calcium channel blocker and smoking cessation before RF ablation may avoid CAS during these procedures. The 12-lead electrocardiogram should be continuously monitored throughout the procedure with special attention to ischemic changes. Moreover, coronary angiography and the administration of coronary vasodilator should be performed when ST changes are observed.
Conclusions
Isoproterenol administration during AF ablation may provoke severe CAS, possibly due to an autonomic nervous system imbalance. This is a rare complication of AF ablation and it should be considered when performing these procedures.
The authors state that they have no Conflict of Interest (COI).
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Recovered
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ReactionOutcome
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CC BY-NC-ND
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33162486
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2021-04-15
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'No adverse event'.
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Acceptability, Feasibility, and Utility of Integrating Pharmacogenetic Testing into a Child Psychiatry Clinic.
Pharmacogenetic (PGx) testing is a tool to identify patients at a higher risk of adverse events or treatment failure. The concern for unwanted side effects can limit medication adherence, particularly in children and adolescents. We conducted a pragmatic study to evaluate the acceptability and feasibility and gather pilot data on the utility of PGx testing in a child and adolescent psychiatry clinic. Both physicians and families participated in the study and answered pre-survey and post-survey questionnaires to examine their attitudes toward PGx testing. Patients were randomized into implementation (N = 25) and control groups (N = 24) and underwent PGx testing at the beginning or end of the study, respectively. Clinical consult notes with genotype-guided recommendations were provided to physicians for their consideration in clinical decisions. Patient-reported symptom severity and antidepressant-related side effects were assessed at baseline and for 12 weeks. Both participating physicians and families agreed that PGx testing is a useful tool to improve medication selection. The time from sample collection to having PGx test results was ~ 10 days and 15 days to having consult notes available, which may have impaired test utility in clinical decision making. There were no differences in any clinical end point between the implementation and control arms; however, there were higher antidepressant side effect scores for CYP2D6 poor and intermediate metabolizers after the eighth week of treatment. Our findings revealed benefits and pitfalls with the use of PGx testing in the real-world clinical setting, which may inform the methodology of a larger trial focused on outcomes.
Study Highlights
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
☑ Previous studies have demonstrated that differences in CYP2D6 and CYP2C19 explains variability in drug response of psychiatric medications in adults. There is a need to assess the acceptability, feasibility, and clinical utility of psychiatric medications among the pediatric population in the real clinical setting. WHAT QUESTION DID THIS STUDY ADDRESS?
☑ This study aimed to address whether pharmacogenetic (PGx) testing is accepted among parents and physicians, is feasible in a real world clinical setting, and is useful to choose optimal medications to treat depression in the pediatric population. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
☑ This study found that PGx testing is feasible and well‐accepted among physicians and families of children with depression and anxiety and has the potential to identify patients at higher risk of experiencing side effects after 8 weeks of treatment. Our study also identified challenges for PGx testing implementation for treatment of pediatric psychiatric disorders in the real‐world clinical setting. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
☑ Our findings informed the methodology for a large randomized clinical trial investigating PGx testing in both children and adults with psychiatric disorders.
Approximately one in every six children and adolescents suffers from a psychiatric illness, the most common being anxiety and depression. 1 , 2 Although psychosocial interventions are effective, pharmacological therapy is needed in more severe cases. The use of selective serotonin reuptake inhibitors (SSRIs) and serotonin‐norepinephrine reuptake inhibitors either alone 3 or in combination with cognitive behavioral therapy 4 is beneficial for the treatment of depression and anxiety disorders in children and adolescents. Nevertheless, these medications also carry a substantial potential side effect burden.
Optimization of antidepressant therapy in children can be challenging given the potential for adverse events, particularly in the first few days of treatment, 5 consequently impacting treatment adherence. In fact, experiencing physical adverse events related to antidepressants is not uncommon in the pediatric population and may lead to visits to the emergency department. 6 Adherence may also be impacted by parents’ perceptions that the treatment may cause more harm than benefit. 7 Thus, identifying a medication that is most likely to be effective and/or has a lower risk of potential side effects in advance of treatment initiation could lead to an improvement in outcomes.
One potential way to optimize medication choice and dosage is the use of pharmacogenetics (PGx), which involves testing specific variants in genes encoding for drug metabolizing enzymes (pharmacokinetics) or target proteins (pharmacodynamics). 8 CYP2D6 and CYP2C19 are the primary enzymes responsible for the metabolism of SSRIs, one of the most commonly used classes of antidepressants in adults and children. Polymorphisms in the genes that encode for CYP2D6 and CYP2C19 may contribute to interindividual differences in the pharmacokinetics of SSRIs. 9 The CYP2D6 and CYP2C19 genes are highly polymorphic, conferring normal metabolizer (NM), intermediate metabolizer (IM), poor metabolizer (PM), and rapid or ultra‐rapid metabolizer phenotypes (RM and UM, respectively). Although the sample size in most PGx association studies conducted in the pediatric population is limited, 10 several studies have shown an association between CYP2D6 and CYP2C19 genotypes and antidepressants response. 11 , 12 , 13 , 14 Nevertheless, there is still much work to be done regarding assessing the acceptability, feasibility, and utility of PGx testing in children with psychiatric disorders, particularly in the outpatient setting.
This study was a prospective, randomized, pragmatic clinical trial comparing antidepressant therapy in children and adolescents using a genotype‐guided approach vs. the standard of care. The primary aim was to assess the acceptability and feasibility of PGx testing in a child psychiatry clinic. Our primary outcomes were: (i) attitudes of parents and physicians towards PGx testing (acceptability), and (ii) ease of and barriers to the implementation of PGx testing in a child psychiatry clinic (feasibility). As secondary outcomes, we evaluated the utility of PGx testing by measuring clinical end points related to medication response and psychiatric adverse events in the PGx implementation vs. the control arm (usual treatment).
METHODS
Study setting and design
This study was conducted at the University of Florida (UF) Health outpatient Pediatric Psychiatry Clinic and was approved by the institutional review board and registered on ClinicalTrials.gov (NCT02855580). The clinic provides evaluation and treatment for children and adolescents up to age 20 years. The study procedure is summarized in Figure 1 .
Figure 1 Diagram of the study procedure. PGx, pharmacogenetics; UF, University of Florida.
Healthcare providers
Physicians in the UF Health Pediatric Psychiatry Clinic (faculty and fellows) were consented to participate in the study to evaluate the acceptability of PGx testing for their patients and use of PGx results in prescribing decisions. A pharmacist from the UF Health Precision Medicine Program (PMP) conducted an in‐person educational session on psychiatric PGx using written and oral educational materials and case discussions. The training incorporated patient cases and included discussion of topics, such as ordering a PGx test at UF, genes included in the testing, interpretation of results, understanding the association between PGx profiles and treatment outcomes, and applying PGx results to prescribing decisions for antidepressant therapy.
Patients
Participating physicians referred eligible patients to the study but did not consent them to avoid selection bias. Nonparticipating physicians also referred patients to the study. Families were consented by study investigators; parents provided informed parental permission, whereas children of age 12 years and under provided assent and adolescents (ages 13–18 years) provided consent. Patients under age 20 years in whom initiation or dosage change of an SSRI was being considered for treatment for a depressive, anxiety, or obsessive‐compulsive disorder were eligible for participation. Children or adolescents with primary diagnoses of autism or psychotic disorders or at high risk of suicide were excluded to avoid a delay in starting or changing therapy and potential harm in these populations. Patients were assessed for baseline demographics (age, sex, race, and ethnicity) and clinical characteristics (psychiatric diagnosis, medication use, and symptom scores), and randomized by the investigators 1:1 to the PGx implementation or the control group (usual treatment). All participants received CYP2D6 and CYP2C19 genotyping independent of their study arm.
Assessment of PGx testing acceptability
Attitudes toward PGx testing in study participants (physicians, parents, and adolescents older than age 12 years) were assessed at week 0 (pre‐survey) and week 15 (post‐survey). The surveys asked participants to rate their responses on a scale of 1 (strongly disagree) to 5 (strongly agree). The family survey assessed views regarding the use of antidepressants, willingness to undergo genetic testing and/or delay treatment until receiving test results, perceived risks (e.g., insurance coverage and discrimination based on PGx test results), and willingness to pay for PGx testing. Physician surveys assessed knowledge about CYP2D6 and CYP2C19 variability and its impact on antidepressant therapy, confidence in using PGx testing for their patients, views about integrating PGx to their clinical practice, and the benefits of PGx testing to choose medications for their patients.
Assessment of PGx testing feasibility
DNA from the implementation group was sent for PGx testing as soon as collected; in the control group, DNA was stored, and testing occurred after week 12 of the study. DNA was collected from blood samples, as at the time of the study, this was the only validated collection method in the UF Health Pathology Laboratory, which is accredited by the College of American Pathologists and certified by the Clinical Laboratory Improvement Amendments of 1988 (CLIA).
CYP2D6 genotype was determined using Luminex xTAG CYP2D6 Kit version 3 (Luminex, Austin, TX), as previously described. 15 Each allele was assigned an activity value to obtain an activity score. Translation from activity score to CYP2D6 phenotype followed recommendations from the Clinical Pharmacogenomics Implementation Consortium (CPIC) guidelines available at the time the study was conducted, 16 however, we acknowledge updated translation is available. 17 Drug‐induced phenoconversion of CYP2D6 was determined in individuals taking a strong CYP2D6 inhibitor (e.g., bupropion), and were considered as PMs in the analyses, as previously described. 15
CYP2C19 genotypes were determined using the GenMark Dx (Carlsbad, CA) platform, as previously described. 15 Individuals with two no‐function alleles (e.g., *2 through *6) were assigned the PM phenotype, those with one no‐function allele were assigned the IM phenotype, and those with one normal (*1) and one increased function allele (*17) or two were assigned the RM (*1/*17) or UM (*17/*17) phenotype, respectively.
Once PGx test results of both CYP2D6 and CYP2C19 were available for individuals in the implementation group, a UF Health PMP pharmacist provided a clinical consult note that included an interpretation of the results and genotype‐guided recommendations (see Table S1 ). The note was routed via message to the ordering provider in the Epic Electronic Health Record (EHR). In addition to the consult notes, Best Practice Advisory alerts were introduced about halfway through the study. In the presence of genotype results in the EHR, an active alert would fire if the provider ordered a medication that was not recommended based on the individual’s genotype (e.g., CYP2C19*17/*17 or UM and escitalopram). The healthcare provider was able to order a change in medication based on phenotype information at his/her discretion. The number of physicians who acknowledged the PGx test results for dosing recommendations and/or referred to the results in progress notes was recorded.
Assessment of PGx testing utility
The number of times that a medication was concordant (or consistent) with an actionable phenotype was determined. Concordance was defined as starting or continuing an SSRI or switching to a different one not metabolized by the relevant enzyme (CYP2D6 or CYP2C19) or appropriately increasing/decreasing the dose of the SSRI based on actionable phenotype.
Actionable phenotypes were defined in two fashions: as either standard or extended. The standard definition considers UM/RM or PM as actionable phenotypes for either CYP2D6 and/or CYP2C19 consistent with the CPIC guidelines. 16 The extended definition included IM as an actionable phenotype based on evidence suggesting that reduced activity may lead to increased effective drug doses and thus affect treatment outcomes. 18 As the CPIC guidelines do not define these phenotypes as actionable, the extended definition was not examined with regard to medication concordance; this definition was only used in analyses examining participant outcomes by phenotype. Actionable phenotypes were assigned for both CYP2C19 and CYP2D6 separately.
A secondary outcome of this study was to evaluate the utility of PGx testing by measuring clinical end points to gather preliminary data to inform a larger trial of the efficacy of genotype‐guided antidepressant therapy. Participants (for children under age 12 years, together with their parents) completed surveys to assess psychiatric symptoms, severity, and side effects of the medications in each study arm at weeks 0, 1, 2, 4, 8, and 12. Global measures of impairment were assessed using the Columbia Impairment Scale (CIS), this questionnaire targets performance of the individual in his/her school or job, interpersonal relationships, use of free time, and psychopathological domains. 19 The presence of side‐effects was assessed using the Antidepressant Side‐Effect Checklist (ASEC) that includes physical symptoms commonly experienced with the use of antidepressants. 20 We did not assess medication safety, such as rashes. Depressive symptoms were measured using the Children’s Depression Inventory (CDI), which is a self‐report scale designed for young individuals from 7–17 years of age. 21 Obsessive compulsive and anxiety symptoms were self‐reported with the Obsessive Compulsive Inventory‐Revised (OCI‐R) 22 and the Screen for Child Anxiety Related Emotional Disorders (SCARED), 23 respectively. Overall, higher scores were indicative of worse disease severity (CDI, OCI‐R, SCARED, and CIS) and higher number of side effects (ASEC).
Data analysis
Baseline characteristics of participants in the control vs. the implementation group were compared using a χ2 test or t‐test, as appropriate. If participants were missing data, their data were not included in the relevant analyses. The acceptability of PGx testing was analyzed by comparing the proportion of participants who agreed with each item in the pre‐survey vs. the post‐survey using a χ2 test. Although the study was not powered to detect meaningful clinical changes, analyses examining differences in patient outcomes using the CIS and ASEC between study arms were also conducted to assess the utility of PGx testing. Finally, trajectories of the clinical end points across study arms and phenotypes were explored as post hoc analyses.
For the clinical end points (utility) analyses, we used a mixed linear model that relied on maximum likelihood estimation and variance components structure to estimate fixed and random effects. This model tested longitudinal effects of study arm and genotype differences, including potential group‐by‐time and phenotype‐by‐time interactions, on each of the clinical end points. Phenotypes were collapsed into three main categories to facilitate the analysis: PM/IM, NM, and RM/UM. Two hierarchical models were tested that incorporated the fixed effects of randomization groups (implementation vs. control) or phenotypes (PM/IM vs. NM vs. RM/UM), as well as fixed effects of group‐by‐linear time and group‐by‐quadratic time interactions. Analyses evaluating −2 log likelihood statistic, Akaike’s Information Criterion, and Schwarz’s Bayesian Criterion fit statistics against the null model were conducted to determine the best fitting model; χ2 analyses were run to determine if there were significant changes in −2 log likelihood. All statistical results for exploratory analyses were reported without correction for multiple testing.
RESULTS
Study participants
A total of 17 physicians participated in the study and referred the majority of patients (N = 40), whereas nonparticipating physicians referred the remaining study participants. A total of 77 eligible families were invited to participate, of which 55 consented. Two patients declined to participate further and four withdrew because of the need for venipuncture for sample collection (Figure 1 ). The ages of the patients ranged from 8 to 20 years. Forty‐nine patients were randomized into the implementation (N = 25) or the control (N = 24) groups. Of these 49 participants, 38 (77%) were on a medication at baseline and were considering a medication change, primarily due to side effects (63%, N = 24), whereas 11 (23%) were considering starting a medication. The baseline characteristics of the participants are available in Table 1 . There were no differences in baseline CIS or ASEC scores between those on medication at baseline and those not on a medication, after controlling for age and sex.
Table 1 Baseline characteristics of patients
Characteristic Control (N = 24) Implementation (N = 25) P value
Age, mean ± SD 14.8 ± 3.2 years 14.5 ± 3.6 years Pr(|T|> |t|) = 0.78
Sex, n (%)
Female 12 (50.0) 19 (76.0) 0.06
Race, n (%) 1.00
White 21 (87.5) 21 (84.0)
Other a 3 (12.5) 4 (16.0)
Ethnicity, n (%) 1.00
Hispanic or Latino 3 (12.5) 4 (16.0)
Non‐Hispanic or Latino 21 (87.5) 21 (84.0)
Primary diagnosis, n (%) 0.49
ADHD 1 (4.2) 0 (0.0)
Anxiety 6 (25.0) 8 (32.0)
Depression 11 (45.8) 14 (56.0)
OCD 6 (25.0) 3 (12.0)
Medications, n (%) 0.74
SSRIs
Citalopram 1 (4.2) 0 (0.0)
Escitalopram 5 (20.8) 4 (16.0)
Fluoxetine 4 (16.7) 4 (16.0)
Fluvoxamine 3 (8.3) 1 (4.0)
Sertraline 7 (29.2) 6 (24.0)
No SSRI/other antidepressant 2 (8.3) 5 (20.0)
Non‐SSRIs antidepressants 1 (4.2) 0 (0.0)
Other antidepressants b 0.88
Bupropion 2 (8.3) 1 (4.0)
Doxepin 1 (4.2) 1 (4.0)
Quetiapine 1 (4.2) 0 (0.0)
Trazodone 1 (4.2) 1 (4.0)
Other psychiatric medications c
Amphetamine 0 (0.0) 1 (4.0) 1.00
Aripiprazole 5 (20.8) 0 (0.0) 0.02
Atomoxetine 2 (8.3) 1 (4.0) 0.61
Benztropine 2 (8.3) 0 (0.0) 0.23
Buspirone 1 (4.2) 1 (4.0) 1.00
Clonidine 1 (4.2) 0 (0.0) 1.00
Dexmethylphenidate 1 (4.2) 0 (0.0) 1.00
Diazepam 1 (4.2) 0 (0.0) 1.00
Guanfacine 2 (8.3) 3 (12.0) 1.00
Hydroxyzine 1 (4.2) 0 (0.0) 1.00
Lamotrigine 0 (0.0) 1 (4.0) 1.00
Lisdexamfetamine 0 (0.0) 2 (8.0) 0.23
Methylphenidate 5 (20.8) 1 (4.0) 0.09
Naltrexone 1 (4.2) 0 (0.0) 1.00
Olanzapine 1 (4.2) 0 (0.0) 1.00
Perphenazine 1 (4.2) 0 (0.0) 1.00
Propanolol 1 (4.2) 1 (4.0) 1.00
Risperidone 3 (12.5) 2 (8.0) 1.00
Topiramate 1 (4.2) 1 (4.0) 1.00
Medication plan, n (%) 0.74
Start medication 5 (20.8) 7 (28.0)
Switch medication 19 (79.2) 18 (72.0)
Symptom scores, mean ± SD
ASEC score 12.6 ± 9.3 15.4 ± 2.6 Pr(|T|> |t|) = 0.392
CDI score 45.0 ± 10.2 44.7 ± 13.8 Pr(|T|> |t|) = 0.927
CIS score 22.1 ± 9.9 22.6 ± 7.5 Pr(|T|> |t|) = 0.825
SCARED score 32.6 ± 16.3 35.0 ± 18.8 Pr(|T|> |t|) = 0.622
OCI‐R 13.1 ± 7.4 12.9 ± 9.1 Pr(|T|> |t|) = 0.945
ADHD, attention deficit hyperactivity disorder; ASEC, Antidepressant Side‐Effect Checklist; CDI, Children’s Depression Inventory; CIS, Columbia Impairment Scale; OCD, obsessive‐compulsive disorder; OCI‐R, Obsessive Compulsive Inventory‐Revised; SCARED, Screen for Child Anxiety Related Emotional Disorders; SSRI, selective serotonin reuptake inhibitor.
a Other includes African Americans and American Indian or Alaskan.
b Other non‐SSRIs antidepressants that were used alone or in combination with SSRIs.
c One individual may have more than one medication and each medication can be used either alone or in combination with SSRIs and/or other antidepressants.
John Wiley & Sons, Ltd
Acceptability of PGx testing
Healthcare providers
Thirteen of the 17 (76%) providers completed the surveys (Table 2 ). More than 90% of the physicians felt confident using PGx testing results at the post‐survey in comparison with only 46.2% at the beginning of the study. The number of physicians who endorsed PGx testing as a tool that fits in their way of managing their patients doubled from pre‐survey to post‐survey. Moreover, 100% of the physicians reported that using genetic data to guide therapeutic choices improved their ability to select medications at the end of the study (post‐survey) compared with 61.5% at the pre‐survey. Physicians were willing to wait an average of 2 weeks for PGx testing results prior to starting patients on a medication.
Table 2 Attitudes about PGx testing among physicians
Survey question Pre‐survey: “agree” or “strongly agree”
N = 12
Post‐survey: “agree” or “strongly agree”
N = 13
Understand the role of CYP2D6 and CYP2C19 genotype testing in prescribing medications 12 (92.3%) 13 (100%)
In favor of adding genotype ordering process 10 (76.9%) 13 (100%)
Confident in ability to use results of genotype testing 6 (46.2%) 12 (92.3%)
Genotype testing is important for patient care 8 (61.5%) 11 (84.6%)
EHR alerts are effective in supporting mood/anxiety management based on genotype 8 (61.5%) 10 (76.9%)
Genotype testing fits in well with how I already manage patients 5 (38.5%) 11 (84.6%)
My training has prepared me to use genotype information 4 (30.8%) 9 (69.2%)
Using genetic data to guide therapeutic choices improves my ability to prescribe medicine 8 (61.5%) 13 (100%)
Genotype testing improves ability to care for patients 8 (61.5%) 12 (92.3%)
Genotype testing is relevant to my clinical practice 10 (76.9%) 13 (100%)
I can find reliable sources of information about CYP2D6 and CYP2C19 genotype testing 6 (46.2%) 10 (76.9%)
CYP2D6 and CYP2C19 genotype testing should be available for clinical care 10 (76.9%) 11 (84.6%)
I have enough time to use genotype testing in clinical practice 6 (46.2%) 10 (76.9%)
I have trouble talking to my patients about CYP2D6 and CYP2C19 genotype testing 3 (23.1%) 0 (0%)
EHR, electronic health record; PGx, pharmacogenetics.
John Wiley & Sons, Ltd
Patients
Twenty‐five of 49 (51%) participating families completed the post‐survey questionnaire (Figure 1 ). In the pre‐survey (N = 49), parents expressed concerns related primarily to ethical and economic issues. Twenty percent (n = 10) of parents were concerned that PGx testing may hurt their child’s ability to get health or other insurance (e.g., life or disability insurance). Additionally, 16% (n = 8) of parents responding expressed concerns that PGx testing may affect their child’s employment opportunities in the future. Another concern from parents was that PGx testing might reveal a risk for certain disease (n = 10, 20%) and a few (n = 3, 6%) felt that the results could have the potential to adversely affect their family. However, none of the responders endorsed this concern in the post‐survey.
Most parents indicated in the pre‐survey that they were willing to cover expenses for PGx testing. The average cost parents were willing to pay was $235; 24% (n = 12) of parents endorsed paying $500 or more, whereas 14% (n = 7) stated that they would not be willing to pay anything for the test. In the post‐survey completed by 11 parents, 18% (n = 2) endorsed being willing to pay $500 or more for PGx testing, whereas most of the parents (72.7%, n = 8), endorsed paying $200 or less.
Most parents (94%, n = 46), agreed or strongly agreed that PGx testing could help their providers to choose better and safer medications for their child in the pre‐survey vs. 91% (n = 10) in the post‐survey, whereas 8% were neutral about this question (see Table S2 ). Fewer than half of respondents (47%, n = 23), at the beginning of the study were interested in PGx testing for future medications vs. 73% (n = 8) in the post‐survey.
Feasibility of PGx testing
Medication recommendations based on PGx testing results
Both the PGx testing results and the consult notes with recommendations from PMP pharmacists were available in the EHR. The mean time for obtaining PGx test results for the implementation arm was longer for CYP2D6 (11.4 days ± 10.4 days) than for CYP2C19 (8.4 days ± 8.8 days; t = 1.1, Pr(T> t) = 0.142). The mean time to having the consult notes with genotype‐guided recommendations in the EHR was 15 days (± 8.9 days). Physicians referred to PGx test results in their progress notes for 18 patients in the implementation group (72%). Only one physician did not acknowledge PGx test results for treatment decisions.
Utility of PGx testing
The distribution of CYP2D6 and CYP2C19 phenotypes are available in Table 3 . Three patients who were using bupropion (strong CYPD6 inhibitor) were phenoconverted to PMs. Twelve (48%) of patients in the implementation arm and 9 (37.5%) in the control arm had at least one actionable phenotype under the standard definition (i.e., PM or RM/UM; Table 4 ). Eleven of the patients with an actionable phenotype in the implementation arm had an SSRI prescription during the trial and 100% of these prescriptions or medication changes were concordant with their phenotype. Eight of the patients with an actionable phenotype in the control arm had an SSRI prescription and 75% were concordant. There was no difference in concordance rates between implementation and control arms (P = 0.16).
Table 3 CYP2D6 and CYP2C19 phenotypes distribution across randomization groups
Phenotype CYP2D6, N (%) CYP2C19, N (%)
Control (n = 24) Implementation (n = 25) Control (n = 24) Implementation (n = 25)
Poor metabolizer a 4 (16.6) 1 (4.0) 1 (4.2) 0 (0)
Intermediate metabolizer 1 (4.2) 2 (8.0) 10 (41.7) 6 (24.0)
Normal metabolizer 18 (75.0) 20 (80.0) 9 (37.5) 10 (40.0)
Rapid metabolizer – – 4 (16.7) 7 (28.0)
Ultra‐rapid metabolizer 1 (4.2) 2 (8.0) b 0 (0) 2 (8.0)
a Three individuals (one in the implementation and two in the control groups) were considered poor metabolizers as they were using a strong CYP2D6 inhibitor (bupropion).
b One individual was a range phenotype (normal to ultra‐rapid metabolizer) but treated clinically as ultra‐rapid metabolizer.
John Wiley & Sons, Ltd
Table 4 Concordance rates across groups based on actionable phenotypes and use of SSRIs
Controls (N = 24) Implementation (N = 25)
CYP2D6, N (%) CYPC19, N (%) CYP2D6, N (%) CYP2C19, N (%)
Total N (% of total) with potentially actionable phenotypes 5 a (20.8) 5 a (20.8) 3 (12.0) 9 (36.0)
Total N (% of actionable) with concordant medication changes if prescribed a medication 2 (50.0) d 4 (80.0) 3 (100.0) 8 (100.0) d
Total N with discordant actionable phenotypes in relation to medications taken at baseline. Note: total N on medications at baseline = 38 1 3 0 4
Medication change, N
Medication metabolized by the other CYP enzyme; no change required 2 1 3 4
Medication changed to one metabolized by the other CYP enzyme 0 1 b 0 1 c
Dose of medication changed 0 2 0 3
SSRIs, selective serotonin reuptake inhibitors.
a One patient had both an actionable phenotype for CYP2D6 and for CYP2C19.
b Rapid metabolizer originally on escitalopram, switched to fluoxetine.
c Ultra‐rapid metabolizer originally on sertraline, switched to duloxetine.
d One individual never prescribed an SSRI throughout the study and was not counted as being concordant nor discordant.
John Wiley & Sons, Ltd
None of the clinical end points examined, either for the secondary outcomes (CIS and ASEC scores), or the post hoc analyses (CDI and SCARED scores), showed significant differences between the control and implementation arms at 12 weeks (Figure S1 ). Nonetheless, there were interesting observations across the whole cohort. Baseline mixed linear models (i.e., linear and quadratic time with group as the overall number of actionable phenotypes (0, 1, or 2) across both CYP2D6 and CYP2C19) revealed a statistically significant improvement in global impairment (CIS linear: −0.63, SE = 0.11, P < 0.01 and CIS quadratic: 0.07, SE = 0.02, P = 0.001) and antidepressant‐related side effects (ASEC linear: −0.51, SE = 0.11, P < 0.01 and ASEC quadratic 0.11, SE = 0.02, P < 0.001) from baseline to the eighth week, followed by a worsening for the next 4 weeks. Across the best fitting models, CYP2D6 PM/IM phenotypes experienced a steeper rate of improvement of ASEC scores (i.e., fewer side effects) from baseline to the eighth week, followed by a steeper rate of worsening for the next 4 weeks when compared with NMs and RM/UMs (ASEC linear*phenotype: 0.66, SE = 0.24, P = 0.01 and ASEC quadratic*phenotype: −0.17, SE = 0.04, P < 0.01; Figure 2 ). Similarly, CYP2C19 PM/IM phenotypes showed improvement in antidepressant‐related side effects as measured by the ASEC scores compared with NM, and to RM/UM phenotypes, who actually worsened with time (ASEC linear*phenotype: 0.32, SE = 0.14, P = 0.02; Figure 3 ). The models examining changes in impairment using CIS scores were further indicative of improvements in global impairments over time (CIS linear: −0.62, SE = 0.11, P < 0.01 and CIS quadratic: 0.07, SE = 0.02, P = 0.002), although, for this measure, the effects were not moderated by either CYP2D6 or CYP2C19 phenotypes.
Figure 2 Antidepressant‐related adverse events as measured by mean Antidepressant Side‐Effect Checklist (ASEC) scores over time for CYP2D6. Higher scores indicate higher number of adverse events related to antidepressant medications. This predictive model shows that from week 0 to week 4, poor metabolizers (PMs) and intermediate metabolizers (IMs) showed a steeper rate of decrease in ASEC scores. From the fourth week to the eighth week, scores are relatively stable independent of CYP2D6 phenotype. PMs and IMs showed the highest change in ASEC scores (worsening) from week 8 to week 12, whereas there is only a slight increase in normal metabolizers (NMs). RM, rapid metabolizer; UM, ultra‐rapid metabolizer.
Figure 3 Antidepressant‐related adverse events as measured by mean Antidepressant Side‐Effect Checklist (ASEC) scores over time for CYP2C19. Higher scores indicate higher number of adverse events related to antidepressant medications. This predictive model shows that from week 0 to week 4, ASEC scores decrease independent of the CY2C19 phenotype and remain relatively stable from week 4 to week 8. Although the scores increase for all CYP2C19 phenotypes after the eighth week, the scores remain relatively higher for RMs and UMs. IM, intermediate metabolizer; NM, normal metabolizer; PM, poor metabolizer; RM, rapid metabolizer; UM, ultra‐rapid metabolizer.
DISCUSSION
Main findings
The findings of this study suggest that the implementation of PGx in a pediatric psychiatry clinic is both feasible and well accepted by families and physicians. Although parents were concerned at the beginning of the study about the societal and ethical implications of genetic testing, most agreed that PGx testing may help providers to choose more effective and safer medications for their children by the end of the study. Furthermore, most parents were willing to pay $100 to $200 for PGx testing. Unanimously, the physicians agreed in the post‐survey that having genetic data available improved their ability to select medications for their patients. The vast majority of physicians reported feeling confident in using genetic information.
There are several factors that may limit the feasibility of PGx testing, such as the lack of PGx education and/or knowledge of PGx testing availability, and how to apply genotype results to prescribing decisions. 24 Studies have consistently identified the need of physicians to receive education about PGx in order to interpret testing results and answer their patients’ questions. 25 , 26 For this study, participating physicians were enabled to use genetic information to guide their medical decisions through both formal education and ongoing clinical support provided by UF Health PMP pharmacists. Most of the participant physicians acknowledged the results from PGx testing and followed pharmacist‐provided recommendations based on genetic information.
Challenges and solutions
However, efficient provision of PGx results and consult notes with genotype‐guided recommendations was a major challenge in our study. The length of time required to obtain the results and place consult notes by pharmacists may have delayed or impeded the utilization of the results for medical decision making. Consequently, physicians may have started or changed a medication for their patients prior to genetic information being available. Genotype turnaround time has been identified as a feasibility concern of PGx testing in psychiatry because physicians may require the results in a short period of time for patients with severe clinical presentations. 27 We have subsequently reduced the total turnaround time; beginning in July 2019, our consult notes are placed between 1 to 3 days (average 3.85 days ± 6.91 days, median: 1.5 days) after the PGx test results are ready. Similarly, as a result of this study, which confirmed that children are often averse to invasive sample collection methods (e.g., blood draws), we have validated PGx testing using DNA from buccal swabs, 15 further facilitating the testing process.
Overall, we did not find statistically significant differences in any of the secondary clinical end points between the implementation and the control arms, although we observed some interesting differences by genotype. Perhaps most importantly, in our study, CYP2D6 PMs and IMs showed a rapid decrease in antidepressant‐related side effects up to week 8, whereas CYP2C19 PMs and IMs experienced a decrease throughout the weeks of the study compared with NMs and RMs and UMs. As the majority of participants were on medications prior to starting the study, the ASEC cannot effectively differentiate between baseline medication side effects and similar symptoms caused by the underlying mood or anxiety disorder. Future studies are needed to distinguish these effects from one another. However, in context of this study, the ASEC can be thought of as a global measure of symptom severity (regardless of etiology).
Consistent with our findings, Oshikoya and colleagues found that children with CYP2D6 PM and IM phenotypes had more adverse events when taking risperidone, 28 another CYP2D6 substrate. Similarly, Strawn and colleagues used a pharmacokinetics approach to demonstrate that CYP2C19 PM and IM pediatric patients had longer half‐lives and higher maximum plasma concentrations of escitalopram and sertraline. 29 Aldrich et al. found that the CYP2C19 PM and IM phenotypes were associated with a higher proportion of side effects and higher frequency of treatment (escitalopram and citalopram) discontinuation in youths. 11 Together, our findings underscore the potential opportunity for identifying patients through PGx testing who may experience antidepressant‐related adverse events with CYP2D6 and CYP2C19 substrate medications resulting in treatment discontinuation.
Limitations
There are several limitations for our study. First, our sample size was small given the pilot nature of the trial, and therefore was underpowered to detect significant differences in clinical outcomes between study arms; we were also underpowered to include concordance/discordance between PGx phenotype and baseline medications in the analyses. Second, only half of the participant families completed the post‐survey, and, therefore, the responses may not necessarily represent the attitudes of the whole cohort toward PGx testing. Nonetheless, the responses to the post‐survey overwhelmingly favored PGx testing. Third, as this study required a long follow‐up period (12 weeks), some of the intervening self‐reported clinical surveys to quantify symptoms severity and adverse events were not completed by the participant families and, consequently, some data were missing. Finally, the majority of participants were on medications at baseline, and we were not able to distinguish between changes in underlying disease symptomatology and medication side effects, which can often, especially in a pediatric population, overlap.
Significance and future projections
Our findings suggest that families and physicians have positive attitudes toward PGx testing to assist with selection of antidepressant medications for children and adolescents. However, the results of PGx testing should ideally be available early, before medication is started, to be considered by physicians in the treatment selection or dose adjustment and to maximize its potential for improving medication efficacy and reducing side effects. The findings from this small pragmatic trial were nevertheless important to informing the methodology of the National Human Genome Research Institute (NHGRI)‐funded Implementing GeNomics In pracTicE (IGNITE) Pragmatic Clinical Trials Network, 30 a multi‐site trial funded by the NHGRI. There are three pharmacogenetic trials being conducted by IGNITE, including one that aims to investigate the use of PGx testing to guide SSRI prescribing in adult and pediatric populations.
Funding
This study was funded by the National Institutes of Health IGNITE Network (NIH grant U01 HG007269 to Dr. Julie Johnson) and the UF Clinical and Translational Science Institute (CTSI), which is supported by the NIH National Center for Advancing Translational Sciences (NCATS) (UL1TR001427). Dr. Karla Claudio‐Campos is supported by T32HG008958 by the National Genome Research Institute (NHGRI).
Conflict of Interest
The authors declared no competing interests for this work.
Author Contributions
K.C., A.P., G.J., and E.J.C. wrote the manuscript. C.A.M., L.H.C., and K.W. designed the research. J.N., R.N., A.M., D.M.S., Y.S., and M.M. performed the research. A.P. and K.C. analyzed the data.
Supporting information
FigS1
Click here for additional data file.
TableS1
Click here for additional data file.
TableS2
Click here for additional data file.
Acknowledgments
The authors thank the participants and families who contributed their information and time so that this study could be conducted. We would like to acknowledge the trainee Dr. Benjamin Duong who contributed to this study by writing consult notes. We also would like to acknowledge Dr. Julie Johnson for her support to our research group.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arrhythmia'.
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Real-world experience of carfilzomib-associated cardiovascular adverse events: SEER-Medicare data set analysis.
Carfilzomib was approved for the treatment of multiple myeloma in 2012 and since then there have been concerns for cardiovascular toxicity from its use. With this study, we aim to further study the hazards and underlying risk factors for cardiovascular adverse events associated with carfilzomib. This study was conducted using Surveillance, Epidemiology, and End Results (SEER)-Medicare data set of multiple myeloma from 2001 to 2015. Data were analyzed for hazards ratio of cardiovascular adverse events between carfilzomib users and nonusers. We identified 7330 patients with multiple myeloma of whom 815 were carfilzomib users. Carfilzomib users had a statistically significant hazard ratio of 1.41 with p < 0.0001 for all cardiovascular adverse events as compared to nonusers. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Carfilzomib users were at higher risk of new-onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers. Age above 75 years, preexisting cardiovascular disease, obesity, and twice a week carfilzomib schedule were significant risk factors associated with cardiovascular adverse events in carfilzomib users. The median time of the onset for all cardiovascular adverse events was 3.1 months. This study has identified a significantly higher likelihood of cardiovascular adverse events in elderly Medicare patients receiving carfilzomib.
1 BACKGROUND
Proteasome inhibitors (PI) comprise an important class of drugs for treating multiple myeloma (MM). Currently, three drugs are approved in this class, bortezomib, carfilzomib, and ixazomib. Carfilzomib is a second‐generation, highly selective and irreversible PI which received accelerated approval by the United States Food and Drug Administration (FDA) in July 2012.
1
This approval was based on a phase II study where carfilzomib demonstrated an overall response rate (ORR) of about 23% for relapsed and refractory multiple myeloma (RRMM).
2
Since then carfilzomib has been approved for multiple other indications for the treatment of MM. Presently, as per the National Comprehensive Cancer Network (NCCN) guidelines, carfilzomib is recommended for primary therapy of MM in transplant‐eligible as well as transplant‐ineligible patients. In the RRMM, carfilzomib is recommended as a preferred regimen either as a single agent or in combination with other agents.
Since its approval, cardiovascular adverse events (CVAEs) from carfilzomib has been a concern. Initially, carfilzomib associated CVAEs were reported in about 22% patients from the grouped data of four phase II studies in 2013.
3
Meta‐analyses of clinical trials have shown that up to 18% of patients experienced CVAEs.
4
,
5
,
6
,
7
These studies reported CVAEs with variable rates and the most common CVAEs were hypertension (18.5%) and heart failure (6.7%). Arrhythmia (2.4%) and ischemic events (3.7%) were observed less commonly. Other significant CVAEs were dyspnea (31.9%) and edema (24.7%).
6
,
7
Multiple studies have tried to identify risk factors for Carfilzomib associated cardiotoxicity. Retrospective studies from single institutions have reported prior cardiac history as a risk factor for carfilzomib associated cardiotoxicity.
8
,
9
,
10
Most of CVAEs have been reported to occur soon after carfilzomib use, rarely beyond 12 cycles and the systolic dysfunction is usually reversible.
9
,
11
,
12
Current evidence is not clear for an association of CVAEs with the dose or the duration of carfilzomib use but re‐challenge with reduced dose has been recommended.
4
,
11
,
13
The prospective observational study by Cornell et al reported that 51% of patients treated with carfilzomib developed CVAEs including heart failure (41%), hypertension (23%), arrhythmia (7%), an acute coronary syndrome in (6%), and also reported chest pain in 9% of patients.
14
There was no association between drug dose, infusion time, and concurrent drugs or fluids administered with carfilzomib but elevated natriuretic peptide was associated with increased risk of CVAEs. Similarly, 33% of patients experienced CVAEs in the study by Bruno et al and baseline uncontrolled blood pressure, left ventricular hypertrophy, and higher pulse‐wave velocity were identified as risk factors.
15
Cardiovascular adverse events remains the drug limiting toxicity of carfilzomib and NCCN also alerts for potential carfilzomib related cardiac and pulmonary toxicity, especially in elderly patients. As the median age for diagnosis of MM is 70 years, nearly two‐thirds of patients have preexisting cardiovascular disease at baseline, hence, at risk of developing carfilzomib associated CVAEs.
16
We have enough scientific evidence about CVAEs from the use of carfilzomib which is mainly obtained through pooled analysis of data from clinical trials. Clinical trials usually exclude patients with preexisting cardiac conditions and the enrolled patients are usually monitored diligently as per clinical trial protocols. Therefore, a clinical trial setting is not the representative of the most commonly encountered scenario in the community clinical practice. This study aims to identify the incidence and risk factors for CVAEs associated with carfilzomib for the treatment of MM using Surveillance Epidemiology and Endpoint Research (SEER)‐Medicare data set, which gives a real‐world experience of carfilzomib.
2 METHODS
This study is a retrospective study completed through the SEER‐Medicare data set. The SEER program, supported by the National Cancer Institute (NCI), contains cancer patients’ demographic and tumor characteristics for approximately 34% of the U.S. population. The Medicare data set, maintained by the Centers for Medicare and Medicaid Services, contains health care claims and payment information, for over 97% of the U.S. population aged 65 years or older. We used this linked SEER‐Medicare data set, which captures treatment information after a cancer diagnosis from the Medicare insurance program along with individual patient‐level demographic and survival data from the SEER cancer registry program.
2.1 Study population
This study included patients age ≥ 65 years‐old with the diagnosis of MM between 2001 and 2015. To capture the prior history or risk factors for cardiovascular events, only patients who were enrolled in Medicare for at least 1 year before diagnosis were included. Patients were identified using International Classification of Diseases for Oncology, third edition (ICD‐O‐3) codes from the SEER database. We excluded patients with amyloidosis as those patients can have cardiac dysfunction and can be a confounding factor.
ICD 9/10 codes were used to identify past medical history and the new cardiovascular diagnosis after treatment with carfilzomib. Basic demographic data were collected for sex, race/ethnicity, Nicotine/tobacco use, obesity, and Charleston comorbidity index (CCI) among others. Various cardiovascular diagnoses including ischemic heart disease, congestive heart failure, conduction disorders (arrhythmia and blocks) were identified using ICD9/10. We also identified hazards of edema, chest pain, dyspnea, and syncope which are reported separately and not included in CVAEs. Treatment details were identified using Healthcare Common Procedure Coding System (HCPCS) and National Drug Code (NDC) drug codes. Data from Medicare claims for linked patients are available for a year after, up to 2016. Details of the diagnostic codes used for study are available as Table S1.
The primary endpoint of the study was the hazard of the all‐new CVAEs associated with carfilzomib use in the entire study cohort of myeloma patients. The secondary endpoint of the study includes risk factors for CVAEs and hazard of different categories of CVAEs in carfilzomib users. We analyzed the potential risk factors for CVAEs the entire study cohort of myeloma patients and then separately for sub‐group of carfilzomib users. The study focuses mainly on risk factors in carfilzomib users. Impact of carfilzomib use pattern and use of other drugs for treatment of myeloma on were also analyzed. We also calculated the hazard of dyspnea, chest pain, edema, and syncope in carfilzomib users versus nonusers.
2.2 Statistical analysis
Patients were divided into two cohorts; carfilzomib users and nonusers. Patient‐, disease‐, and treatment‐related factors were compared using the Chi‐square test for categorical and the Kruskal–Wallis test for continuous variables. A Cox proportional‐hazards model was constructed to determine the relationship between CVAEs and carfilzomib therapy and was controlled for various variables including age, sex, race/ethnicity, previous autologous transplant, CCI, preexisting conditions including body mass index (BMI), nicotine/tobacco use, preexisting diabetes, preexisting hypertension, preexisting cardiovascular conditions, and previous anthracycline use. The goodness of fit was assessed using the method of Hosmer and Lemeshow. Within the treatment group, we also used Cox proportional‐hazards models to examine how the preexisting conditions predicted the newly diagnosed CVAEs. Cox models were also adjusted for the aforementioned patients' characteristics. All statistical tests were two‐sided and statistical significance was defined as p < 0.05. Analyses were conducted using SAS version 9.4 software (SAS Institute).
3 RESULTS
3.1 Patient characteristics
A total of 7330 patients with multiple myeloma were included in the study; 815 (11.1%) carfilzomib users and 6515 (88.9%) carfilzomib nonusers. Figure 1 shows the flowsheet for the study cohort derivation.
FIGURE 1 Flowsheet detailing cohort derivation from the SEER‐Medicare data set. HCPCS, Healthcare Common Procedure Coding System; HMO, Health Maintenance Organization
Baseline characteristics of the entire cohort including carfilzomib users and nonusers are shown in Table 1. Carfilzomib‐user cohort was younger, white race, had lower CCI compare to nonusers. A higher proportion of carfilzomib users had a history of hypertension or pre‐existing cardiovascular diseases. Furthermore, Carfilzomib use was higher in patients with relapsed myeloma and prior history of stem cell transplant (Table S2). No significant differences were observed between the two groups in terms of sex and pre‐existing history of diabetes. The study model was controlled for these different variables.
TABLE 1 Patient demographics and clinical characteristics of carfilzomib users and non‐users
Characteristics Total Carfilzomib use
p‐value
Yes % No %
Year of diagnosis
2001–2012 4459 537 12.0 3922 88.0 0.0001
2013 1088 121 11.1 967 88.9
2014 856 92 10.7 764 89.3
2015 927 65 7.0 862 93.0
Age groups
66–69 1813 286 15.8 1527 84.2 <0.0001
70–74 2015 291 14.4 1724 85.6
75–79 1627 146 9.0 1481 91.0
80+ 1875 92 4.9 1783 95.1
Sex
Male 3846 429 11.2 3417 88.8 0.9185
Female 3484 386 11.1 3098 88.9
Race/ethnicity
Non‐Hispanic white 5332 640 12.0 4692 88.0 <0.0001
Non‐Hispanic black 1076 98 9.1 978 90.9
Other 400 29 7.3 371 92.8
Hispanic 522 48 9.2 474 90.8
Myeloma
New 5621 355 6.3 5266 93.7 <0.0001
Relapsed 1709 460 26.9 1249 73.1
Previous transplant
No 6483 606 9.3 5877 90.7 <0.0001
Yes 847 209 24.7 638 75.3
Charleston comorbidity index
0 4788 613 12.8 4175 87.2 <0.0001
1 1293 129 10.0 1164 90.0
2 631 41 6.5 590 93.5
3+ 618 32 5.2 586 94.8
Body mass index
Other 6775 693 10.2 6082 89.8 <0.0001
Overweight 60 15 25.0 45 75.0
Obesity 495 107 21.6 388 78.4
Nicotine/tobacco use
Never 6565 557 8.5 6008 91.5 <0.0001
Current/former 765 258 33.7 507 66.3
Pre‐existing diabetes
No 4311 465 10.8 3846 89.2 0.2795
Yes 3019 350 11.6 2669 88.4
Pre‐existing hypertension
No 6682 584 8.7 6098 91.3 <0.0001
Yes 648 231 35.6 417 64.4
Pre‐existing cardiovascular conditions
No 3452 302 8.7 3150 91.3 <0.0001
Yes 3878 513 13.2 3365 86.8
Previous anthracycline use
No 7177 755 10.5 6422 89.5 <0.0001
Yes 153 60 39.2 93 60.8
John Wiley & Sons, Ltd3.2 Risk factors associated with CVAEs in the entire study cohort of myeloma patients, including carfilzomib users and nonusers
Based on the multivariate analysis, carfilzomib use was independently associated with an increase in the risk of development of CVAEs in the entire study cohort of MM patients. Compared to carfilzomib nonusers, the HR for CVAEs for carfilzomib users was 1.41 (95% CI 1.26–1.58, p < 0.0001). In addition to exposure to carfilzomib, advancing age, male sex, white race, higher CCI, higher BMI, nicotine/tobacco use, preexisting hypertension, and other cardiovascular diagnosis were associated with an increased risk for CVAEs. Pre‐existing diabetes and previous anthracycline use were not associated with higher CVAEs. Please see Table S3 for results of multivariable analysis of the entire study cohort.
3.3 Risk factors associated with CVAEs in sub‐group of carfilzomib users
Based on the multivariate analysis, age 75–79 years (HR 1.35, p = 0.0394) and above 80 (HR 1.53, p = 0.0118) were associated with a significantly higher risk of CVAEs compared to patients aged 65–69 years. Whereas obesity (HR 1.57, p = 0.0006), pre‐existing hypertension (HR 1.57, p = 0.0006), and preexisting other cardiovascular diagnoses (HR 2.75, p < 0.0001) were also significant risk factors. Patient's sex, race/ethnicity, nicotine/tobacco use, preexisting diabetes, previous anthracycline use, and history of the previous autologous transplant were not associated with higher CVAEs. Please see Figure 2 for details. Among all carfilzomib users, 57.6% (n = 469) were noted to have one or more CVAEs. The median time to onset of these CVAEs was 3.1 months.
FIGURE 2 Adjusted hazard ratios for cardiovascular adverse events in carfilzomib users (n = 815). CI, confidence interval; HR, hazards ratio; NH, non‐Hispanic
3.4 Categories of CVAEs
The study cohort was then analyzed for the hazards of various categories of new‐onset CVAEs. Cardiovascular events were categorized into ischemic heart disease, heart failure, conduction disorders (arrhythmia and heart blocks), and hypertension. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Please see Figure 3 for details.
FIGURE 3 Adjusted hazard ratios of patient using carfilzomib in cardiovascular adverse effects. CI, confidence interval; HR, hazards ratio
3.5 Symptoms
Hazards of certain new‐onset symptoms were also studied in the entire study cohort. Carfilzomib users were at higher risk of new‐onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers (Figure 4).
FIGURE 4 Hazards of new‐onset symptoms in carfilzomib users as compared to nonusers. CI, confidence interval; HR, hazards ratio
3.6 Carfilzomib use pattern
The SEER‐Medicare data set has limited information about drug doses. We analyzed carfilzomib usage information based on reimbursement patterns. Although, not perfect but this does provide some insight into the pattern of carfilzomib use and associated toxicity. The multivariate logistic regression model was used after controlling various variables as described previously.
The overall median duration of carfilzomib therapy was 3.6 months and the median number of carfilzomib doses used was 24. The median interval between the two doses was 4.5 days. Patients receiving twice a week carfilzomib were identified as a treatment interval of fewer than 4 days. Carfilzomib was used once a week in 38% of patients while in rest 62% of patients; carfilzomib was used twice a week. Weekly infusion of carfilzomib was associated with a lower risk of cardiovascular toxicity compare to twice‐weekly infusions (HR 0.76, 95% CI: 0.62–0.92, p = 0.0051).
Carfilzomib was used as a single agent in 61% (n = 496) and in combination with other drugs in 39% (n = 319) of patients. When prescribed in combination, carfilzomib was most commonly used with cyclophosphamide in 27.7% (n = 218) followed by daratumumab in 8.3% (n = 68) and Lenalidomide in 2.7% (n = 22). Combination use with Pomalidomide or Thalidomide was minimal. In comparison to single‐agent carfilzomib, combined use with cyclophosphamide, daratumumab, lenalidomide, pomalidomide, or thalidomide was not associated with increased risk for CVAEs.
4 DISCUSSION
Our study is an extensive review of carfilzomib associated CVAEs using the SEER‐Medicare data set that approximately includes 34% of the U.S. population and represents a commonly encountered patient population as compared to selective patients enrolled through clinical trials. We identified a significantly increased risk of CVAEs with carfilzomib therapy, even after controlling for multiple variables. The incidence of CVAEs (57.6%) was higher as compared to previously reported incidence through pooled analysis but these rates are closer to the prospective study done by Cornell et al to identify the incidence of CVAEs.
14
Similar to previous retrospective studies, we found that pre‐existing hypertension and other cardiovascular diagnoses were associated with a higher risk of CVAEs after carfilzomib use. Elderly patients above age 75 years and obesity were at higher risk for CVAEs from carfilzomib use. The majority of MM patients who received carfilzomib had relapsed disease and were likely to have received previous treatments or underwent an autologous transplant. Our study did not find that patients with either relapsed disease or previous autologous transplant had higher CVAEs after carfilzomib use.
As previously reported in the literature, we also identified highly significant HR for heart failure, ischemic heart disease, and hypertension while there was no association with conduction disorders (arrhythmia and blocks). Conduction disorders have been reported with carfilzomib use, but the literature review was not consistent with this toxicity. Like other studies
6
,
12
our study also identified that carfilzomib users had significant hazards of new‐onset dyspnea, chest pain, edema, and syncope, as compared to nonusers. Although these symptoms are not specific, we recommend careful monitoring of these symptoms as it might help in the early detection of CVAEs.
Our study did not identify any combination regimens to be associated with a higher risk for CVAEs as compared to the use of carfilzomib alone. Once a week use was associated with lower CVAEs as compared to twice a week use of carfilzomib. A study by Moreau et al reported prolonged progression‐free survival and fewer cardiac failure events with the once weekly schedule as compared to a twice‐weekly schedule.
17
Since studies so far have not shown any clear evidence of dose‐dependent cardiovascular toxicity form carfilzomib, this finding suggests that quicker frequency may be related to higher toxicity. Although this finding is significant, we advise caution in clinical interpretation in the absence of exact dosages information, which unfortunately is a known limitation of the SEER‐Medicare data set.
Various preventative and management strategies have been proposed for carfilzomib‐induced cardiotoxicity by single‐center studies.
18
,
19
These include baseline cardiac function evaluation, optimizing underlying hypertension and cardiac conditions, careful fluid management, and symptom directed workup while on carfilzomib therapy. Although faster infusion rates of carfilzomib have been reported to be associated with higher CVAEs the prospective observational study by Cornell et al did not find any such association.
14
,
20
Cautious re‐challenge with a reduced dose of carfilzomib after the resolution of cardiac events has also been recommended. European Myeloma network and the Italian society of arterial hypertension also released a consensus paper with a scoring system based on risk factors and management recommendations for patients using carfilzomib.
21
In summary, with our study results and previous data, we can assertively say that there is enough evidence to strongly associate the significant risk of CVAEs with the use of carfilzomib. As such, there is a need for identifying patients at higher risk, cautious monitoring, prompt identification, and management of carfilzomib associated CVAEs. Patients with pre‐existing cardiovascular conditions should be monitored closely by a multidisciplinary team from cardiology and oncology which is also a recommendation from the International Cardio‐Oncology Society (ICOS).
22
This is absolutely necessary until we have a full understanding of all the risk factors, preventative measures, and long‐term toxicity from carfilzomib use.
5 CONCLUSIONS
This study from a large SEER‐Medicare data set provides further evidence of carfilzomib‐associated CVAEs and identifies potential risk factors.
5.1 Study limitations
This study has an inherent limitation of retrospective design and thus we infer association and not direct causation. Although the SEER database includes data from 19 different geographical areas covering approximately 34% of the U.S. population from diverse demographics and locations it cannot be ascertained that every population group has proper representation. Authors caution that results might be affected by various local risk factors, including access to health care, and should be considered for an individual patient The SEER‐Medicare database does not contain clinical measures of disease severity, information regarding chemotherapy dosage and schedule or management of cardiovascular toxicity. In addition, this study included elderly patients with age ≥ 65 years and prone to reporting bias. Therefore, the results may not be generalizable to younger populations or those not covered by Medicare. We have included nicotine/tobacco use and BMI in analyses based on ICD‐9/10 diagnoses codes from Medicare data. However, the sensitivity of these codes is low. Even considering these limitations, studies from SEER‐Medicare data sets have provided clinically relevant information, which often is not feasible from clinical trials.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The Institution Review Board (IRB) at the University of Florida, Gainesville FL, approved this study and all standard ethical guidelines were followed. A full waiver of informed consent was obtained.
CONSENT TO PUBLICATION
Not applicable. The manuscript does not contain any individual patients' data.
Supporting information
Table S1‐S3
Click here for additional data file.
ACKNOWLEDGEMENTS
None.
DATA AVAILABILITY STATEMENT
The data sets used for the current study are available from SEER‐Medicare. This study used the linked SEER‐Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER‐Medicare database.
|
CARFILZOMIB
|
DrugsGivenReaction
|
CC BY
|
33169938
| 18,544,063
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Atrioventricular block'.
|
Real-world experience of carfilzomib-associated cardiovascular adverse events: SEER-Medicare data set analysis.
Carfilzomib was approved for the treatment of multiple myeloma in 2012 and since then there have been concerns for cardiovascular toxicity from its use. With this study, we aim to further study the hazards and underlying risk factors for cardiovascular adverse events associated with carfilzomib. This study was conducted using Surveillance, Epidemiology, and End Results (SEER)-Medicare data set of multiple myeloma from 2001 to 2015. Data were analyzed for hazards ratio of cardiovascular adverse events between carfilzomib users and nonusers. We identified 7330 patients with multiple myeloma of whom 815 were carfilzomib users. Carfilzomib users had a statistically significant hazard ratio of 1.41 with p < 0.0001 for all cardiovascular adverse events as compared to nonusers. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Carfilzomib users were at higher risk of new-onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers. Age above 75 years, preexisting cardiovascular disease, obesity, and twice a week carfilzomib schedule were significant risk factors associated with cardiovascular adverse events in carfilzomib users. The median time of the onset for all cardiovascular adverse events was 3.1 months. This study has identified a significantly higher likelihood of cardiovascular adverse events in elderly Medicare patients receiving carfilzomib.
1 BACKGROUND
Proteasome inhibitors (PI) comprise an important class of drugs for treating multiple myeloma (MM). Currently, three drugs are approved in this class, bortezomib, carfilzomib, and ixazomib. Carfilzomib is a second‐generation, highly selective and irreversible PI which received accelerated approval by the United States Food and Drug Administration (FDA) in July 2012.
1
This approval was based on a phase II study where carfilzomib demonstrated an overall response rate (ORR) of about 23% for relapsed and refractory multiple myeloma (RRMM).
2
Since then carfilzomib has been approved for multiple other indications for the treatment of MM. Presently, as per the National Comprehensive Cancer Network (NCCN) guidelines, carfilzomib is recommended for primary therapy of MM in transplant‐eligible as well as transplant‐ineligible patients. In the RRMM, carfilzomib is recommended as a preferred regimen either as a single agent or in combination with other agents.
Since its approval, cardiovascular adverse events (CVAEs) from carfilzomib has been a concern. Initially, carfilzomib associated CVAEs were reported in about 22% patients from the grouped data of four phase II studies in 2013.
3
Meta‐analyses of clinical trials have shown that up to 18% of patients experienced CVAEs.
4
,
5
,
6
,
7
These studies reported CVAEs with variable rates and the most common CVAEs were hypertension (18.5%) and heart failure (6.7%). Arrhythmia (2.4%) and ischemic events (3.7%) were observed less commonly. Other significant CVAEs were dyspnea (31.9%) and edema (24.7%).
6
,
7
Multiple studies have tried to identify risk factors for Carfilzomib associated cardiotoxicity. Retrospective studies from single institutions have reported prior cardiac history as a risk factor for carfilzomib associated cardiotoxicity.
8
,
9
,
10
Most of CVAEs have been reported to occur soon after carfilzomib use, rarely beyond 12 cycles and the systolic dysfunction is usually reversible.
9
,
11
,
12
Current evidence is not clear for an association of CVAEs with the dose or the duration of carfilzomib use but re‐challenge with reduced dose has been recommended.
4
,
11
,
13
The prospective observational study by Cornell et al reported that 51% of patients treated with carfilzomib developed CVAEs including heart failure (41%), hypertension (23%), arrhythmia (7%), an acute coronary syndrome in (6%), and also reported chest pain in 9% of patients.
14
There was no association between drug dose, infusion time, and concurrent drugs or fluids administered with carfilzomib but elevated natriuretic peptide was associated with increased risk of CVAEs. Similarly, 33% of patients experienced CVAEs in the study by Bruno et al and baseline uncontrolled blood pressure, left ventricular hypertrophy, and higher pulse‐wave velocity were identified as risk factors.
15
Cardiovascular adverse events remains the drug limiting toxicity of carfilzomib and NCCN also alerts for potential carfilzomib related cardiac and pulmonary toxicity, especially in elderly patients. As the median age for diagnosis of MM is 70 years, nearly two‐thirds of patients have preexisting cardiovascular disease at baseline, hence, at risk of developing carfilzomib associated CVAEs.
16
We have enough scientific evidence about CVAEs from the use of carfilzomib which is mainly obtained through pooled analysis of data from clinical trials. Clinical trials usually exclude patients with preexisting cardiac conditions and the enrolled patients are usually monitored diligently as per clinical trial protocols. Therefore, a clinical trial setting is not the representative of the most commonly encountered scenario in the community clinical practice. This study aims to identify the incidence and risk factors for CVAEs associated with carfilzomib for the treatment of MM using Surveillance Epidemiology and Endpoint Research (SEER)‐Medicare data set, which gives a real‐world experience of carfilzomib.
2 METHODS
This study is a retrospective study completed through the SEER‐Medicare data set. The SEER program, supported by the National Cancer Institute (NCI), contains cancer patients’ demographic and tumor characteristics for approximately 34% of the U.S. population. The Medicare data set, maintained by the Centers for Medicare and Medicaid Services, contains health care claims and payment information, for over 97% of the U.S. population aged 65 years or older. We used this linked SEER‐Medicare data set, which captures treatment information after a cancer diagnosis from the Medicare insurance program along with individual patient‐level demographic and survival data from the SEER cancer registry program.
2.1 Study population
This study included patients age ≥ 65 years‐old with the diagnosis of MM between 2001 and 2015. To capture the prior history or risk factors for cardiovascular events, only patients who were enrolled in Medicare for at least 1 year before diagnosis were included. Patients were identified using International Classification of Diseases for Oncology, third edition (ICD‐O‐3) codes from the SEER database. We excluded patients with amyloidosis as those patients can have cardiac dysfunction and can be a confounding factor.
ICD 9/10 codes were used to identify past medical history and the new cardiovascular diagnosis after treatment with carfilzomib. Basic demographic data were collected for sex, race/ethnicity, Nicotine/tobacco use, obesity, and Charleston comorbidity index (CCI) among others. Various cardiovascular diagnoses including ischemic heart disease, congestive heart failure, conduction disorders (arrhythmia and blocks) were identified using ICD9/10. We also identified hazards of edema, chest pain, dyspnea, and syncope which are reported separately and not included in CVAEs. Treatment details were identified using Healthcare Common Procedure Coding System (HCPCS) and National Drug Code (NDC) drug codes. Data from Medicare claims for linked patients are available for a year after, up to 2016. Details of the diagnostic codes used for study are available as Table S1.
The primary endpoint of the study was the hazard of the all‐new CVAEs associated with carfilzomib use in the entire study cohort of myeloma patients. The secondary endpoint of the study includes risk factors for CVAEs and hazard of different categories of CVAEs in carfilzomib users. We analyzed the potential risk factors for CVAEs the entire study cohort of myeloma patients and then separately for sub‐group of carfilzomib users. The study focuses mainly on risk factors in carfilzomib users. Impact of carfilzomib use pattern and use of other drugs for treatment of myeloma on were also analyzed. We also calculated the hazard of dyspnea, chest pain, edema, and syncope in carfilzomib users versus nonusers.
2.2 Statistical analysis
Patients were divided into two cohorts; carfilzomib users and nonusers. Patient‐, disease‐, and treatment‐related factors were compared using the Chi‐square test for categorical and the Kruskal–Wallis test for continuous variables. A Cox proportional‐hazards model was constructed to determine the relationship between CVAEs and carfilzomib therapy and was controlled for various variables including age, sex, race/ethnicity, previous autologous transplant, CCI, preexisting conditions including body mass index (BMI), nicotine/tobacco use, preexisting diabetes, preexisting hypertension, preexisting cardiovascular conditions, and previous anthracycline use. The goodness of fit was assessed using the method of Hosmer and Lemeshow. Within the treatment group, we also used Cox proportional‐hazards models to examine how the preexisting conditions predicted the newly diagnosed CVAEs. Cox models were also adjusted for the aforementioned patients' characteristics. All statistical tests were two‐sided and statistical significance was defined as p < 0.05. Analyses were conducted using SAS version 9.4 software (SAS Institute).
3 RESULTS
3.1 Patient characteristics
A total of 7330 patients with multiple myeloma were included in the study; 815 (11.1%) carfilzomib users and 6515 (88.9%) carfilzomib nonusers. Figure 1 shows the flowsheet for the study cohort derivation.
FIGURE 1 Flowsheet detailing cohort derivation from the SEER‐Medicare data set. HCPCS, Healthcare Common Procedure Coding System; HMO, Health Maintenance Organization
Baseline characteristics of the entire cohort including carfilzomib users and nonusers are shown in Table 1. Carfilzomib‐user cohort was younger, white race, had lower CCI compare to nonusers. A higher proportion of carfilzomib users had a history of hypertension or pre‐existing cardiovascular diseases. Furthermore, Carfilzomib use was higher in patients with relapsed myeloma and prior history of stem cell transplant (Table S2). No significant differences were observed between the two groups in terms of sex and pre‐existing history of diabetes. The study model was controlled for these different variables.
TABLE 1 Patient demographics and clinical characteristics of carfilzomib users and non‐users
Characteristics Total Carfilzomib use
p‐value
Yes % No %
Year of diagnosis
2001–2012 4459 537 12.0 3922 88.0 0.0001
2013 1088 121 11.1 967 88.9
2014 856 92 10.7 764 89.3
2015 927 65 7.0 862 93.0
Age groups
66–69 1813 286 15.8 1527 84.2 <0.0001
70–74 2015 291 14.4 1724 85.6
75–79 1627 146 9.0 1481 91.0
80+ 1875 92 4.9 1783 95.1
Sex
Male 3846 429 11.2 3417 88.8 0.9185
Female 3484 386 11.1 3098 88.9
Race/ethnicity
Non‐Hispanic white 5332 640 12.0 4692 88.0 <0.0001
Non‐Hispanic black 1076 98 9.1 978 90.9
Other 400 29 7.3 371 92.8
Hispanic 522 48 9.2 474 90.8
Myeloma
New 5621 355 6.3 5266 93.7 <0.0001
Relapsed 1709 460 26.9 1249 73.1
Previous transplant
No 6483 606 9.3 5877 90.7 <0.0001
Yes 847 209 24.7 638 75.3
Charleston comorbidity index
0 4788 613 12.8 4175 87.2 <0.0001
1 1293 129 10.0 1164 90.0
2 631 41 6.5 590 93.5
3+ 618 32 5.2 586 94.8
Body mass index
Other 6775 693 10.2 6082 89.8 <0.0001
Overweight 60 15 25.0 45 75.0
Obesity 495 107 21.6 388 78.4
Nicotine/tobacco use
Never 6565 557 8.5 6008 91.5 <0.0001
Current/former 765 258 33.7 507 66.3
Pre‐existing diabetes
No 4311 465 10.8 3846 89.2 0.2795
Yes 3019 350 11.6 2669 88.4
Pre‐existing hypertension
No 6682 584 8.7 6098 91.3 <0.0001
Yes 648 231 35.6 417 64.4
Pre‐existing cardiovascular conditions
No 3452 302 8.7 3150 91.3 <0.0001
Yes 3878 513 13.2 3365 86.8
Previous anthracycline use
No 7177 755 10.5 6422 89.5 <0.0001
Yes 153 60 39.2 93 60.8
John Wiley & Sons, Ltd3.2 Risk factors associated with CVAEs in the entire study cohort of myeloma patients, including carfilzomib users and nonusers
Based on the multivariate analysis, carfilzomib use was independently associated with an increase in the risk of development of CVAEs in the entire study cohort of MM patients. Compared to carfilzomib nonusers, the HR for CVAEs for carfilzomib users was 1.41 (95% CI 1.26–1.58, p < 0.0001). In addition to exposure to carfilzomib, advancing age, male sex, white race, higher CCI, higher BMI, nicotine/tobacco use, preexisting hypertension, and other cardiovascular diagnosis were associated with an increased risk for CVAEs. Pre‐existing diabetes and previous anthracycline use were not associated with higher CVAEs. Please see Table S3 for results of multivariable analysis of the entire study cohort.
3.3 Risk factors associated with CVAEs in sub‐group of carfilzomib users
Based on the multivariate analysis, age 75–79 years (HR 1.35, p = 0.0394) and above 80 (HR 1.53, p = 0.0118) were associated with a significantly higher risk of CVAEs compared to patients aged 65–69 years. Whereas obesity (HR 1.57, p = 0.0006), pre‐existing hypertension (HR 1.57, p = 0.0006), and preexisting other cardiovascular diagnoses (HR 2.75, p < 0.0001) were also significant risk factors. Patient's sex, race/ethnicity, nicotine/tobacco use, preexisting diabetes, previous anthracycline use, and history of the previous autologous transplant were not associated with higher CVAEs. Please see Figure 2 for details. Among all carfilzomib users, 57.6% (n = 469) were noted to have one or more CVAEs. The median time to onset of these CVAEs was 3.1 months.
FIGURE 2 Adjusted hazard ratios for cardiovascular adverse events in carfilzomib users (n = 815). CI, confidence interval; HR, hazards ratio; NH, non‐Hispanic
3.4 Categories of CVAEs
The study cohort was then analyzed for the hazards of various categories of new‐onset CVAEs. Cardiovascular events were categorized into ischemic heart disease, heart failure, conduction disorders (arrhythmia and heart blocks), and hypertension. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Please see Figure 3 for details.
FIGURE 3 Adjusted hazard ratios of patient using carfilzomib in cardiovascular adverse effects. CI, confidence interval; HR, hazards ratio
3.5 Symptoms
Hazards of certain new‐onset symptoms were also studied in the entire study cohort. Carfilzomib users were at higher risk of new‐onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers (Figure 4).
FIGURE 4 Hazards of new‐onset symptoms in carfilzomib users as compared to nonusers. CI, confidence interval; HR, hazards ratio
3.6 Carfilzomib use pattern
The SEER‐Medicare data set has limited information about drug doses. We analyzed carfilzomib usage information based on reimbursement patterns. Although, not perfect but this does provide some insight into the pattern of carfilzomib use and associated toxicity. The multivariate logistic regression model was used after controlling various variables as described previously.
The overall median duration of carfilzomib therapy was 3.6 months and the median number of carfilzomib doses used was 24. The median interval between the two doses was 4.5 days. Patients receiving twice a week carfilzomib were identified as a treatment interval of fewer than 4 days. Carfilzomib was used once a week in 38% of patients while in rest 62% of patients; carfilzomib was used twice a week. Weekly infusion of carfilzomib was associated with a lower risk of cardiovascular toxicity compare to twice‐weekly infusions (HR 0.76, 95% CI: 0.62–0.92, p = 0.0051).
Carfilzomib was used as a single agent in 61% (n = 496) and in combination with other drugs in 39% (n = 319) of patients. When prescribed in combination, carfilzomib was most commonly used with cyclophosphamide in 27.7% (n = 218) followed by daratumumab in 8.3% (n = 68) and Lenalidomide in 2.7% (n = 22). Combination use with Pomalidomide or Thalidomide was minimal. In comparison to single‐agent carfilzomib, combined use with cyclophosphamide, daratumumab, lenalidomide, pomalidomide, or thalidomide was not associated with increased risk for CVAEs.
4 DISCUSSION
Our study is an extensive review of carfilzomib associated CVAEs using the SEER‐Medicare data set that approximately includes 34% of the U.S. population and represents a commonly encountered patient population as compared to selective patients enrolled through clinical trials. We identified a significantly increased risk of CVAEs with carfilzomib therapy, even after controlling for multiple variables. The incidence of CVAEs (57.6%) was higher as compared to previously reported incidence through pooled analysis but these rates are closer to the prospective study done by Cornell et al to identify the incidence of CVAEs.
14
Similar to previous retrospective studies, we found that pre‐existing hypertension and other cardiovascular diagnoses were associated with a higher risk of CVAEs after carfilzomib use. Elderly patients above age 75 years and obesity were at higher risk for CVAEs from carfilzomib use. The majority of MM patients who received carfilzomib had relapsed disease and were likely to have received previous treatments or underwent an autologous transplant. Our study did not find that patients with either relapsed disease or previous autologous transplant had higher CVAEs after carfilzomib use.
As previously reported in the literature, we also identified highly significant HR for heart failure, ischemic heart disease, and hypertension while there was no association with conduction disorders (arrhythmia and blocks). Conduction disorders have been reported with carfilzomib use, but the literature review was not consistent with this toxicity. Like other studies
6
,
12
our study also identified that carfilzomib users had significant hazards of new‐onset dyspnea, chest pain, edema, and syncope, as compared to nonusers. Although these symptoms are not specific, we recommend careful monitoring of these symptoms as it might help in the early detection of CVAEs.
Our study did not identify any combination regimens to be associated with a higher risk for CVAEs as compared to the use of carfilzomib alone. Once a week use was associated with lower CVAEs as compared to twice a week use of carfilzomib. A study by Moreau et al reported prolonged progression‐free survival and fewer cardiac failure events with the once weekly schedule as compared to a twice‐weekly schedule.
17
Since studies so far have not shown any clear evidence of dose‐dependent cardiovascular toxicity form carfilzomib, this finding suggests that quicker frequency may be related to higher toxicity. Although this finding is significant, we advise caution in clinical interpretation in the absence of exact dosages information, which unfortunately is a known limitation of the SEER‐Medicare data set.
Various preventative and management strategies have been proposed for carfilzomib‐induced cardiotoxicity by single‐center studies.
18
,
19
These include baseline cardiac function evaluation, optimizing underlying hypertension and cardiac conditions, careful fluid management, and symptom directed workup while on carfilzomib therapy. Although faster infusion rates of carfilzomib have been reported to be associated with higher CVAEs the prospective observational study by Cornell et al did not find any such association.
14
,
20
Cautious re‐challenge with a reduced dose of carfilzomib after the resolution of cardiac events has also been recommended. European Myeloma network and the Italian society of arterial hypertension also released a consensus paper with a scoring system based on risk factors and management recommendations for patients using carfilzomib.
21
In summary, with our study results and previous data, we can assertively say that there is enough evidence to strongly associate the significant risk of CVAEs with the use of carfilzomib. As such, there is a need for identifying patients at higher risk, cautious monitoring, prompt identification, and management of carfilzomib associated CVAEs. Patients with pre‐existing cardiovascular conditions should be monitored closely by a multidisciplinary team from cardiology and oncology which is also a recommendation from the International Cardio‐Oncology Society (ICOS).
22
This is absolutely necessary until we have a full understanding of all the risk factors, preventative measures, and long‐term toxicity from carfilzomib use.
5 CONCLUSIONS
This study from a large SEER‐Medicare data set provides further evidence of carfilzomib‐associated CVAEs and identifies potential risk factors.
5.1 Study limitations
This study has an inherent limitation of retrospective design and thus we infer association and not direct causation. Although the SEER database includes data from 19 different geographical areas covering approximately 34% of the U.S. population from diverse demographics and locations it cannot be ascertained that every population group has proper representation. Authors caution that results might be affected by various local risk factors, including access to health care, and should be considered for an individual patient The SEER‐Medicare database does not contain clinical measures of disease severity, information regarding chemotherapy dosage and schedule or management of cardiovascular toxicity. In addition, this study included elderly patients with age ≥ 65 years and prone to reporting bias. Therefore, the results may not be generalizable to younger populations or those not covered by Medicare. We have included nicotine/tobacco use and BMI in analyses based on ICD‐9/10 diagnoses codes from Medicare data. However, the sensitivity of these codes is low. Even considering these limitations, studies from SEER‐Medicare data sets have provided clinically relevant information, which often is not feasible from clinical trials.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The Institution Review Board (IRB) at the University of Florida, Gainesville FL, approved this study and all standard ethical guidelines were followed. A full waiver of informed consent was obtained.
CONSENT TO PUBLICATION
Not applicable. The manuscript does not contain any individual patients' data.
Supporting information
Table S1‐S3
Click here for additional data file.
ACKNOWLEDGEMENTS
None.
DATA AVAILABILITY STATEMENT
The data sets used for the current study are available from SEER‐Medicare. This study used the linked SEER‐Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER‐Medicare database.
|
CARFILZOMIB
|
DrugsGivenReaction
|
CC BY
|
33169938
| 18,544,063
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure'.
|
Real-world experience of carfilzomib-associated cardiovascular adverse events: SEER-Medicare data set analysis.
Carfilzomib was approved for the treatment of multiple myeloma in 2012 and since then there have been concerns for cardiovascular toxicity from its use. With this study, we aim to further study the hazards and underlying risk factors for cardiovascular adverse events associated with carfilzomib. This study was conducted using Surveillance, Epidemiology, and End Results (SEER)-Medicare data set of multiple myeloma from 2001 to 2015. Data were analyzed for hazards ratio of cardiovascular adverse events between carfilzomib users and nonusers. We identified 7330 patients with multiple myeloma of whom 815 were carfilzomib users. Carfilzomib users had a statistically significant hazard ratio of 1.41 with p < 0.0001 for all cardiovascular adverse events as compared to nonusers. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Carfilzomib users were at higher risk of new-onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers. Age above 75 years, preexisting cardiovascular disease, obesity, and twice a week carfilzomib schedule were significant risk factors associated with cardiovascular adverse events in carfilzomib users. The median time of the onset for all cardiovascular adverse events was 3.1 months. This study has identified a significantly higher likelihood of cardiovascular adverse events in elderly Medicare patients receiving carfilzomib.
1 BACKGROUND
Proteasome inhibitors (PI) comprise an important class of drugs for treating multiple myeloma (MM). Currently, three drugs are approved in this class, bortezomib, carfilzomib, and ixazomib. Carfilzomib is a second‐generation, highly selective and irreversible PI which received accelerated approval by the United States Food and Drug Administration (FDA) in July 2012.
1
This approval was based on a phase II study where carfilzomib demonstrated an overall response rate (ORR) of about 23% for relapsed and refractory multiple myeloma (RRMM).
2
Since then carfilzomib has been approved for multiple other indications for the treatment of MM. Presently, as per the National Comprehensive Cancer Network (NCCN) guidelines, carfilzomib is recommended for primary therapy of MM in transplant‐eligible as well as transplant‐ineligible patients. In the RRMM, carfilzomib is recommended as a preferred regimen either as a single agent or in combination with other agents.
Since its approval, cardiovascular adverse events (CVAEs) from carfilzomib has been a concern. Initially, carfilzomib associated CVAEs were reported in about 22% patients from the grouped data of four phase II studies in 2013.
3
Meta‐analyses of clinical trials have shown that up to 18% of patients experienced CVAEs.
4
,
5
,
6
,
7
These studies reported CVAEs with variable rates and the most common CVAEs were hypertension (18.5%) and heart failure (6.7%). Arrhythmia (2.4%) and ischemic events (3.7%) were observed less commonly. Other significant CVAEs were dyspnea (31.9%) and edema (24.7%).
6
,
7
Multiple studies have tried to identify risk factors for Carfilzomib associated cardiotoxicity. Retrospective studies from single institutions have reported prior cardiac history as a risk factor for carfilzomib associated cardiotoxicity.
8
,
9
,
10
Most of CVAEs have been reported to occur soon after carfilzomib use, rarely beyond 12 cycles and the systolic dysfunction is usually reversible.
9
,
11
,
12
Current evidence is not clear for an association of CVAEs with the dose or the duration of carfilzomib use but re‐challenge with reduced dose has been recommended.
4
,
11
,
13
The prospective observational study by Cornell et al reported that 51% of patients treated with carfilzomib developed CVAEs including heart failure (41%), hypertension (23%), arrhythmia (7%), an acute coronary syndrome in (6%), and also reported chest pain in 9% of patients.
14
There was no association between drug dose, infusion time, and concurrent drugs or fluids administered with carfilzomib but elevated natriuretic peptide was associated with increased risk of CVAEs. Similarly, 33% of patients experienced CVAEs in the study by Bruno et al and baseline uncontrolled blood pressure, left ventricular hypertrophy, and higher pulse‐wave velocity were identified as risk factors.
15
Cardiovascular adverse events remains the drug limiting toxicity of carfilzomib and NCCN also alerts for potential carfilzomib related cardiac and pulmonary toxicity, especially in elderly patients. As the median age for diagnosis of MM is 70 years, nearly two‐thirds of patients have preexisting cardiovascular disease at baseline, hence, at risk of developing carfilzomib associated CVAEs.
16
We have enough scientific evidence about CVAEs from the use of carfilzomib which is mainly obtained through pooled analysis of data from clinical trials. Clinical trials usually exclude patients with preexisting cardiac conditions and the enrolled patients are usually monitored diligently as per clinical trial protocols. Therefore, a clinical trial setting is not the representative of the most commonly encountered scenario in the community clinical practice. This study aims to identify the incidence and risk factors for CVAEs associated with carfilzomib for the treatment of MM using Surveillance Epidemiology and Endpoint Research (SEER)‐Medicare data set, which gives a real‐world experience of carfilzomib.
2 METHODS
This study is a retrospective study completed through the SEER‐Medicare data set. The SEER program, supported by the National Cancer Institute (NCI), contains cancer patients’ demographic and tumor characteristics for approximately 34% of the U.S. population. The Medicare data set, maintained by the Centers for Medicare and Medicaid Services, contains health care claims and payment information, for over 97% of the U.S. population aged 65 years or older. We used this linked SEER‐Medicare data set, which captures treatment information after a cancer diagnosis from the Medicare insurance program along with individual patient‐level demographic and survival data from the SEER cancer registry program.
2.1 Study population
This study included patients age ≥ 65 years‐old with the diagnosis of MM between 2001 and 2015. To capture the prior history or risk factors for cardiovascular events, only patients who were enrolled in Medicare for at least 1 year before diagnosis were included. Patients were identified using International Classification of Diseases for Oncology, third edition (ICD‐O‐3) codes from the SEER database. We excluded patients with amyloidosis as those patients can have cardiac dysfunction and can be a confounding factor.
ICD 9/10 codes were used to identify past medical history and the new cardiovascular diagnosis after treatment with carfilzomib. Basic demographic data were collected for sex, race/ethnicity, Nicotine/tobacco use, obesity, and Charleston comorbidity index (CCI) among others. Various cardiovascular diagnoses including ischemic heart disease, congestive heart failure, conduction disorders (arrhythmia and blocks) were identified using ICD9/10. We also identified hazards of edema, chest pain, dyspnea, and syncope which are reported separately and not included in CVAEs. Treatment details were identified using Healthcare Common Procedure Coding System (HCPCS) and National Drug Code (NDC) drug codes. Data from Medicare claims for linked patients are available for a year after, up to 2016. Details of the diagnostic codes used for study are available as Table S1.
The primary endpoint of the study was the hazard of the all‐new CVAEs associated with carfilzomib use in the entire study cohort of myeloma patients. The secondary endpoint of the study includes risk factors for CVAEs and hazard of different categories of CVAEs in carfilzomib users. We analyzed the potential risk factors for CVAEs the entire study cohort of myeloma patients and then separately for sub‐group of carfilzomib users. The study focuses mainly on risk factors in carfilzomib users. Impact of carfilzomib use pattern and use of other drugs for treatment of myeloma on were also analyzed. We also calculated the hazard of dyspnea, chest pain, edema, and syncope in carfilzomib users versus nonusers.
2.2 Statistical analysis
Patients were divided into two cohorts; carfilzomib users and nonusers. Patient‐, disease‐, and treatment‐related factors were compared using the Chi‐square test for categorical and the Kruskal–Wallis test for continuous variables. A Cox proportional‐hazards model was constructed to determine the relationship between CVAEs and carfilzomib therapy and was controlled for various variables including age, sex, race/ethnicity, previous autologous transplant, CCI, preexisting conditions including body mass index (BMI), nicotine/tobacco use, preexisting diabetes, preexisting hypertension, preexisting cardiovascular conditions, and previous anthracycline use. The goodness of fit was assessed using the method of Hosmer and Lemeshow. Within the treatment group, we also used Cox proportional‐hazards models to examine how the preexisting conditions predicted the newly diagnosed CVAEs. Cox models were also adjusted for the aforementioned patients' characteristics. All statistical tests were two‐sided and statistical significance was defined as p < 0.05. Analyses were conducted using SAS version 9.4 software (SAS Institute).
3 RESULTS
3.1 Patient characteristics
A total of 7330 patients with multiple myeloma were included in the study; 815 (11.1%) carfilzomib users and 6515 (88.9%) carfilzomib nonusers. Figure 1 shows the flowsheet for the study cohort derivation.
FIGURE 1 Flowsheet detailing cohort derivation from the SEER‐Medicare data set. HCPCS, Healthcare Common Procedure Coding System; HMO, Health Maintenance Organization
Baseline characteristics of the entire cohort including carfilzomib users and nonusers are shown in Table 1. Carfilzomib‐user cohort was younger, white race, had lower CCI compare to nonusers. A higher proportion of carfilzomib users had a history of hypertension or pre‐existing cardiovascular diseases. Furthermore, Carfilzomib use was higher in patients with relapsed myeloma and prior history of stem cell transplant (Table S2). No significant differences were observed between the two groups in terms of sex and pre‐existing history of diabetes. The study model was controlled for these different variables.
TABLE 1 Patient demographics and clinical characteristics of carfilzomib users and non‐users
Characteristics Total Carfilzomib use
p‐value
Yes % No %
Year of diagnosis
2001–2012 4459 537 12.0 3922 88.0 0.0001
2013 1088 121 11.1 967 88.9
2014 856 92 10.7 764 89.3
2015 927 65 7.0 862 93.0
Age groups
66–69 1813 286 15.8 1527 84.2 <0.0001
70–74 2015 291 14.4 1724 85.6
75–79 1627 146 9.0 1481 91.0
80+ 1875 92 4.9 1783 95.1
Sex
Male 3846 429 11.2 3417 88.8 0.9185
Female 3484 386 11.1 3098 88.9
Race/ethnicity
Non‐Hispanic white 5332 640 12.0 4692 88.0 <0.0001
Non‐Hispanic black 1076 98 9.1 978 90.9
Other 400 29 7.3 371 92.8
Hispanic 522 48 9.2 474 90.8
Myeloma
New 5621 355 6.3 5266 93.7 <0.0001
Relapsed 1709 460 26.9 1249 73.1
Previous transplant
No 6483 606 9.3 5877 90.7 <0.0001
Yes 847 209 24.7 638 75.3
Charleston comorbidity index
0 4788 613 12.8 4175 87.2 <0.0001
1 1293 129 10.0 1164 90.0
2 631 41 6.5 590 93.5
3+ 618 32 5.2 586 94.8
Body mass index
Other 6775 693 10.2 6082 89.8 <0.0001
Overweight 60 15 25.0 45 75.0
Obesity 495 107 21.6 388 78.4
Nicotine/tobacco use
Never 6565 557 8.5 6008 91.5 <0.0001
Current/former 765 258 33.7 507 66.3
Pre‐existing diabetes
No 4311 465 10.8 3846 89.2 0.2795
Yes 3019 350 11.6 2669 88.4
Pre‐existing hypertension
No 6682 584 8.7 6098 91.3 <0.0001
Yes 648 231 35.6 417 64.4
Pre‐existing cardiovascular conditions
No 3452 302 8.7 3150 91.3 <0.0001
Yes 3878 513 13.2 3365 86.8
Previous anthracycline use
No 7177 755 10.5 6422 89.5 <0.0001
Yes 153 60 39.2 93 60.8
John Wiley & Sons, Ltd3.2 Risk factors associated with CVAEs in the entire study cohort of myeloma patients, including carfilzomib users and nonusers
Based on the multivariate analysis, carfilzomib use was independently associated with an increase in the risk of development of CVAEs in the entire study cohort of MM patients. Compared to carfilzomib nonusers, the HR for CVAEs for carfilzomib users was 1.41 (95% CI 1.26–1.58, p < 0.0001). In addition to exposure to carfilzomib, advancing age, male sex, white race, higher CCI, higher BMI, nicotine/tobacco use, preexisting hypertension, and other cardiovascular diagnosis were associated with an increased risk for CVAEs. Pre‐existing diabetes and previous anthracycline use were not associated with higher CVAEs. Please see Table S3 for results of multivariable analysis of the entire study cohort.
3.3 Risk factors associated with CVAEs in sub‐group of carfilzomib users
Based on the multivariate analysis, age 75–79 years (HR 1.35, p = 0.0394) and above 80 (HR 1.53, p = 0.0118) were associated with a significantly higher risk of CVAEs compared to patients aged 65–69 years. Whereas obesity (HR 1.57, p = 0.0006), pre‐existing hypertension (HR 1.57, p = 0.0006), and preexisting other cardiovascular diagnoses (HR 2.75, p < 0.0001) were also significant risk factors. Patient's sex, race/ethnicity, nicotine/tobacco use, preexisting diabetes, previous anthracycline use, and history of the previous autologous transplant were not associated with higher CVAEs. Please see Figure 2 for details. Among all carfilzomib users, 57.6% (n = 469) were noted to have one or more CVAEs. The median time to onset of these CVAEs was 3.1 months.
FIGURE 2 Adjusted hazard ratios for cardiovascular adverse events in carfilzomib users (n = 815). CI, confidence interval; HR, hazards ratio; NH, non‐Hispanic
3.4 Categories of CVAEs
The study cohort was then analyzed for the hazards of various categories of new‐onset CVAEs. Cardiovascular events were categorized into ischemic heart disease, heart failure, conduction disorders (arrhythmia and heart blocks), and hypertension. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Please see Figure 3 for details.
FIGURE 3 Adjusted hazard ratios of patient using carfilzomib in cardiovascular adverse effects. CI, confidence interval; HR, hazards ratio
3.5 Symptoms
Hazards of certain new‐onset symptoms were also studied in the entire study cohort. Carfilzomib users were at higher risk of new‐onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers (Figure 4).
FIGURE 4 Hazards of new‐onset symptoms in carfilzomib users as compared to nonusers. CI, confidence interval; HR, hazards ratio
3.6 Carfilzomib use pattern
The SEER‐Medicare data set has limited information about drug doses. We analyzed carfilzomib usage information based on reimbursement patterns. Although, not perfect but this does provide some insight into the pattern of carfilzomib use and associated toxicity. The multivariate logistic regression model was used after controlling various variables as described previously.
The overall median duration of carfilzomib therapy was 3.6 months and the median number of carfilzomib doses used was 24. The median interval between the two doses was 4.5 days. Patients receiving twice a week carfilzomib were identified as a treatment interval of fewer than 4 days. Carfilzomib was used once a week in 38% of patients while in rest 62% of patients; carfilzomib was used twice a week. Weekly infusion of carfilzomib was associated with a lower risk of cardiovascular toxicity compare to twice‐weekly infusions (HR 0.76, 95% CI: 0.62–0.92, p = 0.0051).
Carfilzomib was used as a single agent in 61% (n = 496) and in combination with other drugs in 39% (n = 319) of patients. When prescribed in combination, carfilzomib was most commonly used with cyclophosphamide in 27.7% (n = 218) followed by daratumumab in 8.3% (n = 68) and Lenalidomide in 2.7% (n = 22). Combination use with Pomalidomide or Thalidomide was minimal. In comparison to single‐agent carfilzomib, combined use with cyclophosphamide, daratumumab, lenalidomide, pomalidomide, or thalidomide was not associated with increased risk for CVAEs.
4 DISCUSSION
Our study is an extensive review of carfilzomib associated CVAEs using the SEER‐Medicare data set that approximately includes 34% of the U.S. population and represents a commonly encountered patient population as compared to selective patients enrolled through clinical trials. We identified a significantly increased risk of CVAEs with carfilzomib therapy, even after controlling for multiple variables. The incidence of CVAEs (57.6%) was higher as compared to previously reported incidence through pooled analysis but these rates are closer to the prospective study done by Cornell et al to identify the incidence of CVAEs.
14
Similar to previous retrospective studies, we found that pre‐existing hypertension and other cardiovascular diagnoses were associated with a higher risk of CVAEs after carfilzomib use. Elderly patients above age 75 years and obesity were at higher risk for CVAEs from carfilzomib use. The majority of MM patients who received carfilzomib had relapsed disease and were likely to have received previous treatments or underwent an autologous transplant. Our study did not find that patients with either relapsed disease or previous autologous transplant had higher CVAEs after carfilzomib use.
As previously reported in the literature, we also identified highly significant HR for heart failure, ischemic heart disease, and hypertension while there was no association with conduction disorders (arrhythmia and blocks). Conduction disorders have been reported with carfilzomib use, but the literature review was not consistent with this toxicity. Like other studies
6
,
12
our study also identified that carfilzomib users had significant hazards of new‐onset dyspnea, chest pain, edema, and syncope, as compared to nonusers. Although these symptoms are not specific, we recommend careful monitoring of these symptoms as it might help in the early detection of CVAEs.
Our study did not identify any combination regimens to be associated with a higher risk for CVAEs as compared to the use of carfilzomib alone. Once a week use was associated with lower CVAEs as compared to twice a week use of carfilzomib. A study by Moreau et al reported prolonged progression‐free survival and fewer cardiac failure events with the once weekly schedule as compared to a twice‐weekly schedule.
17
Since studies so far have not shown any clear evidence of dose‐dependent cardiovascular toxicity form carfilzomib, this finding suggests that quicker frequency may be related to higher toxicity. Although this finding is significant, we advise caution in clinical interpretation in the absence of exact dosages information, which unfortunately is a known limitation of the SEER‐Medicare data set.
Various preventative and management strategies have been proposed for carfilzomib‐induced cardiotoxicity by single‐center studies.
18
,
19
These include baseline cardiac function evaluation, optimizing underlying hypertension and cardiac conditions, careful fluid management, and symptom directed workup while on carfilzomib therapy. Although faster infusion rates of carfilzomib have been reported to be associated with higher CVAEs the prospective observational study by Cornell et al did not find any such association.
14
,
20
Cautious re‐challenge with a reduced dose of carfilzomib after the resolution of cardiac events has also been recommended. European Myeloma network and the Italian society of arterial hypertension also released a consensus paper with a scoring system based on risk factors and management recommendations for patients using carfilzomib.
21
In summary, with our study results and previous data, we can assertively say that there is enough evidence to strongly associate the significant risk of CVAEs with the use of carfilzomib. As such, there is a need for identifying patients at higher risk, cautious monitoring, prompt identification, and management of carfilzomib associated CVAEs. Patients with pre‐existing cardiovascular conditions should be monitored closely by a multidisciplinary team from cardiology and oncology which is also a recommendation from the International Cardio‐Oncology Society (ICOS).
22
This is absolutely necessary until we have a full understanding of all the risk factors, preventative measures, and long‐term toxicity from carfilzomib use.
5 CONCLUSIONS
This study from a large SEER‐Medicare data set provides further evidence of carfilzomib‐associated CVAEs and identifies potential risk factors.
5.1 Study limitations
This study has an inherent limitation of retrospective design and thus we infer association and not direct causation. Although the SEER database includes data from 19 different geographical areas covering approximately 34% of the U.S. population from diverse demographics and locations it cannot be ascertained that every population group has proper representation. Authors caution that results might be affected by various local risk factors, including access to health care, and should be considered for an individual patient The SEER‐Medicare database does not contain clinical measures of disease severity, information regarding chemotherapy dosage and schedule or management of cardiovascular toxicity. In addition, this study included elderly patients with age ≥ 65 years and prone to reporting bias. Therefore, the results may not be generalizable to younger populations or those not covered by Medicare. We have included nicotine/tobacco use and BMI in analyses based on ICD‐9/10 diagnoses codes from Medicare data. However, the sensitivity of these codes is low. Even considering these limitations, studies from SEER‐Medicare data sets have provided clinically relevant information, which often is not feasible from clinical trials.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The Institution Review Board (IRB) at the University of Florida, Gainesville FL, approved this study and all standard ethical guidelines were followed. A full waiver of informed consent was obtained.
CONSENT TO PUBLICATION
Not applicable. The manuscript does not contain any individual patients' data.
Supporting information
Table S1‐S3
Click here for additional data file.
ACKNOWLEDGEMENTS
None.
DATA AVAILABILITY STATEMENT
The data sets used for the current study are available from SEER‐Medicare. This study used the linked SEER‐Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER‐Medicare database.
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CARFILZOMIB
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DrugsGivenReaction
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CC BY
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33169938
| 18,544,063
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2021-01
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chest pain'.
|
Real-world experience of carfilzomib-associated cardiovascular adverse events: SEER-Medicare data set analysis.
Carfilzomib was approved for the treatment of multiple myeloma in 2012 and since then there have been concerns for cardiovascular toxicity from its use. With this study, we aim to further study the hazards and underlying risk factors for cardiovascular adverse events associated with carfilzomib. This study was conducted using Surveillance, Epidemiology, and End Results (SEER)-Medicare data set of multiple myeloma from 2001 to 2015. Data were analyzed for hazards ratio of cardiovascular adverse events between carfilzomib users and nonusers. We identified 7330 patients with multiple myeloma of whom 815 were carfilzomib users. Carfilzomib users had a statistically significant hazard ratio of 1.41 with p < 0.0001 for all cardiovascular adverse events as compared to nonusers. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Carfilzomib users were at higher risk of new-onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers. Age above 75 years, preexisting cardiovascular disease, obesity, and twice a week carfilzomib schedule were significant risk factors associated with cardiovascular adverse events in carfilzomib users. The median time of the onset for all cardiovascular adverse events was 3.1 months. This study has identified a significantly higher likelihood of cardiovascular adverse events in elderly Medicare patients receiving carfilzomib.
1 BACKGROUND
Proteasome inhibitors (PI) comprise an important class of drugs for treating multiple myeloma (MM). Currently, three drugs are approved in this class, bortezomib, carfilzomib, and ixazomib. Carfilzomib is a second‐generation, highly selective and irreversible PI which received accelerated approval by the United States Food and Drug Administration (FDA) in July 2012.
1
This approval was based on a phase II study where carfilzomib demonstrated an overall response rate (ORR) of about 23% for relapsed and refractory multiple myeloma (RRMM).
2
Since then carfilzomib has been approved for multiple other indications for the treatment of MM. Presently, as per the National Comprehensive Cancer Network (NCCN) guidelines, carfilzomib is recommended for primary therapy of MM in transplant‐eligible as well as transplant‐ineligible patients. In the RRMM, carfilzomib is recommended as a preferred regimen either as a single agent or in combination with other agents.
Since its approval, cardiovascular adverse events (CVAEs) from carfilzomib has been a concern. Initially, carfilzomib associated CVAEs were reported in about 22% patients from the grouped data of four phase II studies in 2013.
3
Meta‐analyses of clinical trials have shown that up to 18% of patients experienced CVAEs.
4
,
5
,
6
,
7
These studies reported CVAEs with variable rates and the most common CVAEs were hypertension (18.5%) and heart failure (6.7%). Arrhythmia (2.4%) and ischemic events (3.7%) were observed less commonly. Other significant CVAEs were dyspnea (31.9%) and edema (24.7%).
6
,
7
Multiple studies have tried to identify risk factors for Carfilzomib associated cardiotoxicity. Retrospective studies from single institutions have reported prior cardiac history as a risk factor for carfilzomib associated cardiotoxicity.
8
,
9
,
10
Most of CVAEs have been reported to occur soon after carfilzomib use, rarely beyond 12 cycles and the systolic dysfunction is usually reversible.
9
,
11
,
12
Current evidence is not clear for an association of CVAEs with the dose or the duration of carfilzomib use but re‐challenge with reduced dose has been recommended.
4
,
11
,
13
The prospective observational study by Cornell et al reported that 51% of patients treated with carfilzomib developed CVAEs including heart failure (41%), hypertension (23%), arrhythmia (7%), an acute coronary syndrome in (6%), and also reported chest pain in 9% of patients.
14
There was no association between drug dose, infusion time, and concurrent drugs or fluids administered with carfilzomib but elevated natriuretic peptide was associated with increased risk of CVAEs. Similarly, 33% of patients experienced CVAEs in the study by Bruno et al and baseline uncontrolled blood pressure, left ventricular hypertrophy, and higher pulse‐wave velocity were identified as risk factors.
15
Cardiovascular adverse events remains the drug limiting toxicity of carfilzomib and NCCN also alerts for potential carfilzomib related cardiac and pulmonary toxicity, especially in elderly patients. As the median age for diagnosis of MM is 70 years, nearly two‐thirds of patients have preexisting cardiovascular disease at baseline, hence, at risk of developing carfilzomib associated CVAEs.
16
We have enough scientific evidence about CVAEs from the use of carfilzomib which is mainly obtained through pooled analysis of data from clinical trials. Clinical trials usually exclude patients with preexisting cardiac conditions and the enrolled patients are usually monitored diligently as per clinical trial protocols. Therefore, a clinical trial setting is not the representative of the most commonly encountered scenario in the community clinical practice. This study aims to identify the incidence and risk factors for CVAEs associated with carfilzomib for the treatment of MM using Surveillance Epidemiology and Endpoint Research (SEER)‐Medicare data set, which gives a real‐world experience of carfilzomib.
2 METHODS
This study is a retrospective study completed through the SEER‐Medicare data set. The SEER program, supported by the National Cancer Institute (NCI), contains cancer patients’ demographic and tumor characteristics for approximately 34% of the U.S. population. The Medicare data set, maintained by the Centers for Medicare and Medicaid Services, contains health care claims and payment information, for over 97% of the U.S. population aged 65 years or older. We used this linked SEER‐Medicare data set, which captures treatment information after a cancer diagnosis from the Medicare insurance program along with individual patient‐level demographic and survival data from the SEER cancer registry program.
2.1 Study population
This study included patients age ≥ 65 years‐old with the diagnosis of MM between 2001 and 2015. To capture the prior history or risk factors for cardiovascular events, only patients who were enrolled in Medicare for at least 1 year before diagnosis were included. Patients were identified using International Classification of Diseases for Oncology, third edition (ICD‐O‐3) codes from the SEER database. We excluded patients with amyloidosis as those patients can have cardiac dysfunction and can be a confounding factor.
ICD 9/10 codes were used to identify past medical history and the new cardiovascular diagnosis after treatment with carfilzomib. Basic demographic data were collected for sex, race/ethnicity, Nicotine/tobacco use, obesity, and Charleston comorbidity index (CCI) among others. Various cardiovascular diagnoses including ischemic heart disease, congestive heart failure, conduction disorders (arrhythmia and blocks) were identified using ICD9/10. We also identified hazards of edema, chest pain, dyspnea, and syncope which are reported separately and not included in CVAEs. Treatment details were identified using Healthcare Common Procedure Coding System (HCPCS) and National Drug Code (NDC) drug codes. Data from Medicare claims for linked patients are available for a year after, up to 2016. Details of the diagnostic codes used for study are available as Table S1.
The primary endpoint of the study was the hazard of the all‐new CVAEs associated with carfilzomib use in the entire study cohort of myeloma patients. The secondary endpoint of the study includes risk factors for CVAEs and hazard of different categories of CVAEs in carfilzomib users. We analyzed the potential risk factors for CVAEs the entire study cohort of myeloma patients and then separately for sub‐group of carfilzomib users. The study focuses mainly on risk factors in carfilzomib users. Impact of carfilzomib use pattern and use of other drugs for treatment of myeloma on were also analyzed. We also calculated the hazard of dyspnea, chest pain, edema, and syncope in carfilzomib users versus nonusers.
2.2 Statistical analysis
Patients were divided into two cohorts; carfilzomib users and nonusers. Patient‐, disease‐, and treatment‐related factors were compared using the Chi‐square test for categorical and the Kruskal–Wallis test for continuous variables. A Cox proportional‐hazards model was constructed to determine the relationship between CVAEs and carfilzomib therapy and was controlled for various variables including age, sex, race/ethnicity, previous autologous transplant, CCI, preexisting conditions including body mass index (BMI), nicotine/tobacco use, preexisting diabetes, preexisting hypertension, preexisting cardiovascular conditions, and previous anthracycline use. The goodness of fit was assessed using the method of Hosmer and Lemeshow. Within the treatment group, we also used Cox proportional‐hazards models to examine how the preexisting conditions predicted the newly diagnosed CVAEs. Cox models were also adjusted for the aforementioned patients' characteristics. All statistical tests were two‐sided and statistical significance was defined as p < 0.05. Analyses were conducted using SAS version 9.4 software (SAS Institute).
3 RESULTS
3.1 Patient characteristics
A total of 7330 patients with multiple myeloma were included in the study; 815 (11.1%) carfilzomib users and 6515 (88.9%) carfilzomib nonusers. Figure 1 shows the flowsheet for the study cohort derivation.
FIGURE 1 Flowsheet detailing cohort derivation from the SEER‐Medicare data set. HCPCS, Healthcare Common Procedure Coding System; HMO, Health Maintenance Organization
Baseline characteristics of the entire cohort including carfilzomib users and nonusers are shown in Table 1. Carfilzomib‐user cohort was younger, white race, had lower CCI compare to nonusers. A higher proportion of carfilzomib users had a history of hypertension or pre‐existing cardiovascular diseases. Furthermore, Carfilzomib use was higher in patients with relapsed myeloma and prior history of stem cell transplant (Table S2). No significant differences were observed between the two groups in terms of sex and pre‐existing history of diabetes. The study model was controlled for these different variables.
TABLE 1 Patient demographics and clinical characteristics of carfilzomib users and non‐users
Characteristics Total Carfilzomib use
p‐value
Yes % No %
Year of diagnosis
2001–2012 4459 537 12.0 3922 88.0 0.0001
2013 1088 121 11.1 967 88.9
2014 856 92 10.7 764 89.3
2015 927 65 7.0 862 93.0
Age groups
66–69 1813 286 15.8 1527 84.2 <0.0001
70–74 2015 291 14.4 1724 85.6
75–79 1627 146 9.0 1481 91.0
80+ 1875 92 4.9 1783 95.1
Sex
Male 3846 429 11.2 3417 88.8 0.9185
Female 3484 386 11.1 3098 88.9
Race/ethnicity
Non‐Hispanic white 5332 640 12.0 4692 88.0 <0.0001
Non‐Hispanic black 1076 98 9.1 978 90.9
Other 400 29 7.3 371 92.8
Hispanic 522 48 9.2 474 90.8
Myeloma
New 5621 355 6.3 5266 93.7 <0.0001
Relapsed 1709 460 26.9 1249 73.1
Previous transplant
No 6483 606 9.3 5877 90.7 <0.0001
Yes 847 209 24.7 638 75.3
Charleston comorbidity index
0 4788 613 12.8 4175 87.2 <0.0001
1 1293 129 10.0 1164 90.0
2 631 41 6.5 590 93.5
3+ 618 32 5.2 586 94.8
Body mass index
Other 6775 693 10.2 6082 89.8 <0.0001
Overweight 60 15 25.0 45 75.0
Obesity 495 107 21.6 388 78.4
Nicotine/tobacco use
Never 6565 557 8.5 6008 91.5 <0.0001
Current/former 765 258 33.7 507 66.3
Pre‐existing diabetes
No 4311 465 10.8 3846 89.2 0.2795
Yes 3019 350 11.6 2669 88.4
Pre‐existing hypertension
No 6682 584 8.7 6098 91.3 <0.0001
Yes 648 231 35.6 417 64.4
Pre‐existing cardiovascular conditions
No 3452 302 8.7 3150 91.3 <0.0001
Yes 3878 513 13.2 3365 86.8
Previous anthracycline use
No 7177 755 10.5 6422 89.5 <0.0001
Yes 153 60 39.2 93 60.8
John Wiley & Sons, Ltd3.2 Risk factors associated with CVAEs in the entire study cohort of myeloma patients, including carfilzomib users and nonusers
Based on the multivariate analysis, carfilzomib use was independently associated with an increase in the risk of development of CVAEs in the entire study cohort of MM patients. Compared to carfilzomib nonusers, the HR for CVAEs for carfilzomib users was 1.41 (95% CI 1.26–1.58, p < 0.0001). In addition to exposure to carfilzomib, advancing age, male sex, white race, higher CCI, higher BMI, nicotine/tobacco use, preexisting hypertension, and other cardiovascular diagnosis were associated with an increased risk for CVAEs. Pre‐existing diabetes and previous anthracycline use were not associated with higher CVAEs. Please see Table S3 for results of multivariable analysis of the entire study cohort.
3.3 Risk factors associated with CVAEs in sub‐group of carfilzomib users
Based on the multivariate analysis, age 75–79 years (HR 1.35, p = 0.0394) and above 80 (HR 1.53, p = 0.0118) were associated with a significantly higher risk of CVAEs compared to patients aged 65–69 years. Whereas obesity (HR 1.57, p = 0.0006), pre‐existing hypertension (HR 1.57, p = 0.0006), and preexisting other cardiovascular diagnoses (HR 2.75, p < 0.0001) were also significant risk factors. Patient's sex, race/ethnicity, nicotine/tobacco use, preexisting diabetes, previous anthracycline use, and history of the previous autologous transplant were not associated with higher CVAEs. Please see Figure 2 for details. Among all carfilzomib users, 57.6% (n = 469) were noted to have one or more CVAEs. The median time to onset of these CVAEs was 3.1 months.
FIGURE 2 Adjusted hazard ratios for cardiovascular adverse events in carfilzomib users (n = 815). CI, confidence interval; HR, hazards ratio; NH, non‐Hispanic
3.4 Categories of CVAEs
The study cohort was then analyzed for the hazards of various categories of new‐onset CVAEs. Cardiovascular events were categorized into ischemic heart disease, heart failure, conduction disorders (arrhythmia and heart blocks), and hypertension. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Please see Figure 3 for details.
FIGURE 3 Adjusted hazard ratios of patient using carfilzomib in cardiovascular adverse effects. CI, confidence interval; HR, hazards ratio
3.5 Symptoms
Hazards of certain new‐onset symptoms were also studied in the entire study cohort. Carfilzomib users were at higher risk of new‐onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers (Figure 4).
FIGURE 4 Hazards of new‐onset symptoms in carfilzomib users as compared to nonusers. CI, confidence interval; HR, hazards ratio
3.6 Carfilzomib use pattern
The SEER‐Medicare data set has limited information about drug doses. We analyzed carfilzomib usage information based on reimbursement patterns. Although, not perfect but this does provide some insight into the pattern of carfilzomib use and associated toxicity. The multivariate logistic regression model was used after controlling various variables as described previously.
The overall median duration of carfilzomib therapy was 3.6 months and the median number of carfilzomib doses used was 24. The median interval between the two doses was 4.5 days. Patients receiving twice a week carfilzomib were identified as a treatment interval of fewer than 4 days. Carfilzomib was used once a week in 38% of patients while in rest 62% of patients; carfilzomib was used twice a week. Weekly infusion of carfilzomib was associated with a lower risk of cardiovascular toxicity compare to twice‐weekly infusions (HR 0.76, 95% CI: 0.62–0.92, p = 0.0051).
Carfilzomib was used as a single agent in 61% (n = 496) and in combination with other drugs in 39% (n = 319) of patients. When prescribed in combination, carfilzomib was most commonly used with cyclophosphamide in 27.7% (n = 218) followed by daratumumab in 8.3% (n = 68) and Lenalidomide in 2.7% (n = 22). Combination use with Pomalidomide or Thalidomide was minimal. In comparison to single‐agent carfilzomib, combined use with cyclophosphamide, daratumumab, lenalidomide, pomalidomide, or thalidomide was not associated with increased risk for CVAEs.
4 DISCUSSION
Our study is an extensive review of carfilzomib associated CVAEs using the SEER‐Medicare data set that approximately includes 34% of the U.S. population and represents a commonly encountered patient population as compared to selective patients enrolled through clinical trials. We identified a significantly increased risk of CVAEs with carfilzomib therapy, even after controlling for multiple variables. The incidence of CVAEs (57.6%) was higher as compared to previously reported incidence through pooled analysis but these rates are closer to the prospective study done by Cornell et al to identify the incidence of CVAEs.
14
Similar to previous retrospective studies, we found that pre‐existing hypertension and other cardiovascular diagnoses were associated with a higher risk of CVAEs after carfilzomib use. Elderly patients above age 75 years and obesity were at higher risk for CVAEs from carfilzomib use. The majority of MM patients who received carfilzomib had relapsed disease and were likely to have received previous treatments or underwent an autologous transplant. Our study did not find that patients with either relapsed disease or previous autologous transplant had higher CVAEs after carfilzomib use.
As previously reported in the literature, we also identified highly significant HR for heart failure, ischemic heart disease, and hypertension while there was no association with conduction disorders (arrhythmia and blocks). Conduction disorders have been reported with carfilzomib use, but the literature review was not consistent with this toxicity. Like other studies
6
,
12
our study also identified that carfilzomib users had significant hazards of new‐onset dyspnea, chest pain, edema, and syncope, as compared to nonusers. Although these symptoms are not specific, we recommend careful monitoring of these symptoms as it might help in the early detection of CVAEs.
Our study did not identify any combination regimens to be associated with a higher risk for CVAEs as compared to the use of carfilzomib alone. Once a week use was associated with lower CVAEs as compared to twice a week use of carfilzomib. A study by Moreau et al reported prolonged progression‐free survival and fewer cardiac failure events with the once weekly schedule as compared to a twice‐weekly schedule.
17
Since studies so far have not shown any clear evidence of dose‐dependent cardiovascular toxicity form carfilzomib, this finding suggests that quicker frequency may be related to higher toxicity. Although this finding is significant, we advise caution in clinical interpretation in the absence of exact dosages information, which unfortunately is a known limitation of the SEER‐Medicare data set.
Various preventative and management strategies have been proposed for carfilzomib‐induced cardiotoxicity by single‐center studies.
18
,
19
These include baseline cardiac function evaluation, optimizing underlying hypertension and cardiac conditions, careful fluid management, and symptom directed workup while on carfilzomib therapy. Although faster infusion rates of carfilzomib have been reported to be associated with higher CVAEs the prospective observational study by Cornell et al did not find any such association.
14
,
20
Cautious re‐challenge with a reduced dose of carfilzomib after the resolution of cardiac events has also been recommended. European Myeloma network and the Italian society of arterial hypertension also released a consensus paper with a scoring system based on risk factors and management recommendations for patients using carfilzomib.
21
In summary, with our study results and previous data, we can assertively say that there is enough evidence to strongly associate the significant risk of CVAEs with the use of carfilzomib. As such, there is a need for identifying patients at higher risk, cautious monitoring, prompt identification, and management of carfilzomib associated CVAEs. Patients with pre‐existing cardiovascular conditions should be monitored closely by a multidisciplinary team from cardiology and oncology which is also a recommendation from the International Cardio‐Oncology Society (ICOS).
22
This is absolutely necessary until we have a full understanding of all the risk factors, preventative measures, and long‐term toxicity from carfilzomib use.
5 CONCLUSIONS
This study from a large SEER‐Medicare data set provides further evidence of carfilzomib‐associated CVAEs and identifies potential risk factors.
5.1 Study limitations
This study has an inherent limitation of retrospective design and thus we infer association and not direct causation. Although the SEER database includes data from 19 different geographical areas covering approximately 34% of the U.S. population from diverse demographics and locations it cannot be ascertained that every population group has proper representation. Authors caution that results might be affected by various local risk factors, including access to health care, and should be considered for an individual patient The SEER‐Medicare database does not contain clinical measures of disease severity, information regarding chemotherapy dosage and schedule or management of cardiovascular toxicity. In addition, this study included elderly patients with age ≥ 65 years and prone to reporting bias. Therefore, the results may not be generalizable to younger populations or those not covered by Medicare. We have included nicotine/tobacco use and BMI in analyses based on ICD‐9/10 diagnoses codes from Medicare data. However, the sensitivity of these codes is low. Even considering these limitations, studies from SEER‐Medicare data sets have provided clinically relevant information, which often is not feasible from clinical trials.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The Institution Review Board (IRB) at the University of Florida, Gainesville FL, approved this study and all standard ethical guidelines were followed. A full waiver of informed consent was obtained.
CONSENT TO PUBLICATION
Not applicable. The manuscript does not contain any individual patients' data.
Supporting information
Table S1‐S3
Click here for additional data file.
ACKNOWLEDGEMENTS
None.
DATA AVAILABILITY STATEMENT
The data sets used for the current study are available from SEER‐Medicare. This study used the linked SEER‐Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER‐Medicare database.
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CARFILZOMIB
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DrugsGivenReaction
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CC BY
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33169938
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dyspnoea'.
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Real-world experience of carfilzomib-associated cardiovascular adverse events: SEER-Medicare data set analysis.
Carfilzomib was approved for the treatment of multiple myeloma in 2012 and since then there have been concerns for cardiovascular toxicity from its use. With this study, we aim to further study the hazards and underlying risk factors for cardiovascular adverse events associated with carfilzomib. This study was conducted using Surveillance, Epidemiology, and End Results (SEER)-Medicare data set of multiple myeloma from 2001 to 2015. Data were analyzed for hazards ratio of cardiovascular adverse events between carfilzomib users and nonusers. We identified 7330 patients with multiple myeloma of whom 815 were carfilzomib users. Carfilzomib users had a statistically significant hazard ratio of 1.41 with p < 0.0001 for all cardiovascular adverse events as compared to nonusers. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Carfilzomib users were at higher risk of new-onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers. Age above 75 years, preexisting cardiovascular disease, obesity, and twice a week carfilzomib schedule were significant risk factors associated with cardiovascular adverse events in carfilzomib users. The median time of the onset for all cardiovascular adverse events was 3.1 months. This study has identified a significantly higher likelihood of cardiovascular adverse events in elderly Medicare patients receiving carfilzomib.
1 BACKGROUND
Proteasome inhibitors (PI) comprise an important class of drugs for treating multiple myeloma (MM). Currently, three drugs are approved in this class, bortezomib, carfilzomib, and ixazomib. Carfilzomib is a second‐generation, highly selective and irreversible PI which received accelerated approval by the United States Food and Drug Administration (FDA) in July 2012.
1
This approval was based on a phase II study where carfilzomib demonstrated an overall response rate (ORR) of about 23% for relapsed and refractory multiple myeloma (RRMM).
2
Since then carfilzomib has been approved for multiple other indications for the treatment of MM. Presently, as per the National Comprehensive Cancer Network (NCCN) guidelines, carfilzomib is recommended for primary therapy of MM in transplant‐eligible as well as transplant‐ineligible patients. In the RRMM, carfilzomib is recommended as a preferred regimen either as a single agent or in combination with other agents.
Since its approval, cardiovascular adverse events (CVAEs) from carfilzomib has been a concern. Initially, carfilzomib associated CVAEs were reported in about 22% patients from the grouped data of four phase II studies in 2013.
3
Meta‐analyses of clinical trials have shown that up to 18% of patients experienced CVAEs.
4
,
5
,
6
,
7
These studies reported CVAEs with variable rates and the most common CVAEs were hypertension (18.5%) and heart failure (6.7%). Arrhythmia (2.4%) and ischemic events (3.7%) were observed less commonly. Other significant CVAEs were dyspnea (31.9%) and edema (24.7%).
6
,
7
Multiple studies have tried to identify risk factors for Carfilzomib associated cardiotoxicity. Retrospective studies from single institutions have reported prior cardiac history as a risk factor for carfilzomib associated cardiotoxicity.
8
,
9
,
10
Most of CVAEs have been reported to occur soon after carfilzomib use, rarely beyond 12 cycles and the systolic dysfunction is usually reversible.
9
,
11
,
12
Current evidence is not clear for an association of CVAEs with the dose or the duration of carfilzomib use but re‐challenge with reduced dose has been recommended.
4
,
11
,
13
The prospective observational study by Cornell et al reported that 51% of patients treated with carfilzomib developed CVAEs including heart failure (41%), hypertension (23%), arrhythmia (7%), an acute coronary syndrome in (6%), and also reported chest pain in 9% of patients.
14
There was no association between drug dose, infusion time, and concurrent drugs or fluids administered with carfilzomib but elevated natriuretic peptide was associated with increased risk of CVAEs. Similarly, 33% of patients experienced CVAEs in the study by Bruno et al and baseline uncontrolled blood pressure, left ventricular hypertrophy, and higher pulse‐wave velocity were identified as risk factors.
15
Cardiovascular adverse events remains the drug limiting toxicity of carfilzomib and NCCN also alerts for potential carfilzomib related cardiac and pulmonary toxicity, especially in elderly patients. As the median age for diagnosis of MM is 70 years, nearly two‐thirds of patients have preexisting cardiovascular disease at baseline, hence, at risk of developing carfilzomib associated CVAEs.
16
We have enough scientific evidence about CVAEs from the use of carfilzomib which is mainly obtained through pooled analysis of data from clinical trials. Clinical trials usually exclude patients with preexisting cardiac conditions and the enrolled patients are usually monitored diligently as per clinical trial protocols. Therefore, a clinical trial setting is not the representative of the most commonly encountered scenario in the community clinical practice. This study aims to identify the incidence and risk factors for CVAEs associated with carfilzomib for the treatment of MM using Surveillance Epidemiology and Endpoint Research (SEER)‐Medicare data set, which gives a real‐world experience of carfilzomib.
2 METHODS
This study is a retrospective study completed through the SEER‐Medicare data set. The SEER program, supported by the National Cancer Institute (NCI), contains cancer patients’ demographic and tumor characteristics for approximately 34% of the U.S. population. The Medicare data set, maintained by the Centers for Medicare and Medicaid Services, contains health care claims and payment information, for over 97% of the U.S. population aged 65 years or older. We used this linked SEER‐Medicare data set, which captures treatment information after a cancer diagnosis from the Medicare insurance program along with individual patient‐level demographic and survival data from the SEER cancer registry program.
2.1 Study population
This study included patients age ≥ 65 years‐old with the diagnosis of MM between 2001 and 2015. To capture the prior history or risk factors for cardiovascular events, only patients who were enrolled in Medicare for at least 1 year before diagnosis were included. Patients were identified using International Classification of Diseases for Oncology, third edition (ICD‐O‐3) codes from the SEER database. We excluded patients with amyloidosis as those patients can have cardiac dysfunction and can be a confounding factor.
ICD 9/10 codes were used to identify past medical history and the new cardiovascular diagnosis after treatment with carfilzomib. Basic demographic data were collected for sex, race/ethnicity, Nicotine/tobacco use, obesity, and Charleston comorbidity index (CCI) among others. Various cardiovascular diagnoses including ischemic heart disease, congestive heart failure, conduction disorders (arrhythmia and blocks) were identified using ICD9/10. We also identified hazards of edema, chest pain, dyspnea, and syncope which are reported separately and not included in CVAEs. Treatment details were identified using Healthcare Common Procedure Coding System (HCPCS) and National Drug Code (NDC) drug codes. Data from Medicare claims for linked patients are available for a year after, up to 2016. Details of the diagnostic codes used for study are available as Table S1.
The primary endpoint of the study was the hazard of the all‐new CVAEs associated with carfilzomib use in the entire study cohort of myeloma patients. The secondary endpoint of the study includes risk factors for CVAEs and hazard of different categories of CVAEs in carfilzomib users. We analyzed the potential risk factors for CVAEs the entire study cohort of myeloma patients and then separately for sub‐group of carfilzomib users. The study focuses mainly on risk factors in carfilzomib users. Impact of carfilzomib use pattern and use of other drugs for treatment of myeloma on were also analyzed. We also calculated the hazard of dyspnea, chest pain, edema, and syncope in carfilzomib users versus nonusers.
2.2 Statistical analysis
Patients were divided into two cohorts; carfilzomib users and nonusers. Patient‐, disease‐, and treatment‐related factors were compared using the Chi‐square test for categorical and the Kruskal–Wallis test for continuous variables. A Cox proportional‐hazards model was constructed to determine the relationship between CVAEs and carfilzomib therapy and was controlled for various variables including age, sex, race/ethnicity, previous autologous transplant, CCI, preexisting conditions including body mass index (BMI), nicotine/tobacco use, preexisting diabetes, preexisting hypertension, preexisting cardiovascular conditions, and previous anthracycline use. The goodness of fit was assessed using the method of Hosmer and Lemeshow. Within the treatment group, we also used Cox proportional‐hazards models to examine how the preexisting conditions predicted the newly diagnosed CVAEs. Cox models were also adjusted for the aforementioned patients' characteristics. All statistical tests were two‐sided and statistical significance was defined as p < 0.05. Analyses were conducted using SAS version 9.4 software (SAS Institute).
3 RESULTS
3.1 Patient characteristics
A total of 7330 patients with multiple myeloma were included in the study; 815 (11.1%) carfilzomib users and 6515 (88.9%) carfilzomib nonusers. Figure 1 shows the flowsheet for the study cohort derivation.
FIGURE 1 Flowsheet detailing cohort derivation from the SEER‐Medicare data set. HCPCS, Healthcare Common Procedure Coding System; HMO, Health Maintenance Organization
Baseline characteristics of the entire cohort including carfilzomib users and nonusers are shown in Table 1. Carfilzomib‐user cohort was younger, white race, had lower CCI compare to nonusers. A higher proportion of carfilzomib users had a history of hypertension or pre‐existing cardiovascular diseases. Furthermore, Carfilzomib use was higher in patients with relapsed myeloma and prior history of stem cell transplant (Table S2). No significant differences were observed between the two groups in terms of sex and pre‐existing history of diabetes. The study model was controlled for these different variables.
TABLE 1 Patient demographics and clinical characteristics of carfilzomib users and non‐users
Characteristics Total Carfilzomib use
p‐value
Yes % No %
Year of diagnosis
2001–2012 4459 537 12.0 3922 88.0 0.0001
2013 1088 121 11.1 967 88.9
2014 856 92 10.7 764 89.3
2015 927 65 7.0 862 93.0
Age groups
66–69 1813 286 15.8 1527 84.2 <0.0001
70–74 2015 291 14.4 1724 85.6
75–79 1627 146 9.0 1481 91.0
80+ 1875 92 4.9 1783 95.1
Sex
Male 3846 429 11.2 3417 88.8 0.9185
Female 3484 386 11.1 3098 88.9
Race/ethnicity
Non‐Hispanic white 5332 640 12.0 4692 88.0 <0.0001
Non‐Hispanic black 1076 98 9.1 978 90.9
Other 400 29 7.3 371 92.8
Hispanic 522 48 9.2 474 90.8
Myeloma
New 5621 355 6.3 5266 93.7 <0.0001
Relapsed 1709 460 26.9 1249 73.1
Previous transplant
No 6483 606 9.3 5877 90.7 <0.0001
Yes 847 209 24.7 638 75.3
Charleston comorbidity index
0 4788 613 12.8 4175 87.2 <0.0001
1 1293 129 10.0 1164 90.0
2 631 41 6.5 590 93.5
3+ 618 32 5.2 586 94.8
Body mass index
Other 6775 693 10.2 6082 89.8 <0.0001
Overweight 60 15 25.0 45 75.0
Obesity 495 107 21.6 388 78.4
Nicotine/tobacco use
Never 6565 557 8.5 6008 91.5 <0.0001
Current/former 765 258 33.7 507 66.3
Pre‐existing diabetes
No 4311 465 10.8 3846 89.2 0.2795
Yes 3019 350 11.6 2669 88.4
Pre‐existing hypertension
No 6682 584 8.7 6098 91.3 <0.0001
Yes 648 231 35.6 417 64.4
Pre‐existing cardiovascular conditions
No 3452 302 8.7 3150 91.3 <0.0001
Yes 3878 513 13.2 3365 86.8
Previous anthracycline use
No 7177 755 10.5 6422 89.5 <0.0001
Yes 153 60 39.2 93 60.8
John Wiley & Sons, Ltd3.2 Risk factors associated with CVAEs in the entire study cohort of myeloma patients, including carfilzomib users and nonusers
Based on the multivariate analysis, carfilzomib use was independently associated with an increase in the risk of development of CVAEs in the entire study cohort of MM patients. Compared to carfilzomib nonusers, the HR for CVAEs for carfilzomib users was 1.41 (95% CI 1.26–1.58, p < 0.0001). In addition to exposure to carfilzomib, advancing age, male sex, white race, higher CCI, higher BMI, nicotine/tobacco use, preexisting hypertension, and other cardiovascular diagnosis were associated with an increased risk for CVAEs. Pre‐existing diabetes and previous anthracycline use were not associated with higher CVAEs. Please see Table S3 for results of multivariable analysis of the entire study cohort.
3.3 Risk factors associated with CVAEs in sub‐group of carfilzomib users
Based on the multivariate analysis, age 75–79 years (HR 1.35, p = 0.0394) and above 80 (HR 1.53, p = 0.0118) were associated with a significantly higher risk of CVAEs compared to patients aged 65–69 years. Whereas obesity (HR 1.57, p = 0.0006), pre‐existing hypertension (HR 1.57, p = 0.0006), and preexisting other cardiovascular diagnoses (HR 2.75, p < 0.0001) were also significant risk factors. Patient's sex, race/ethnicity, nicotine/tobacco use, preexisting diabetes, previous anthracycline use, and history of the previous autologous transplant were not associated with higher CVAEs. Please see Figure 2 for details. Among all carfilzomib users, 57.6% (n = 469) were noted to have one or more CVAEs. The median time to onset of these CVAEs was 3.1 months.
FIGURE 2 Adjusted hazard ratios for cardiovascular adverse events in carfilzomib users (n = 815). CI, confidence interval; HR, hazards ratio; NH, non‐Hispanic
3.4 Categories of CVAEs
The study cohort was then analyzed for the hazards of various categories of new‐onset CVAEs. Cardiovascular events were categorized into ischemic heart disease, heart failure, conduction disorders (arrhythmia and heart blocks), and hypertension. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Please see Figure 3 for details.
FIGURE 3 Adjusted hazard ratios of patient using carfilzomib in cardiovascular adverse effects. CI, confidence interval; HR, hazards ratio
3.5 Symptoms
Hazards of certain new‐onset symptoms were also studied in the entire study cohort. Carfilzomib users were at higher risk of new‐onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers (Figure 4).
FIGURE 4 Hazards of new‐onset symptoms in carfilzomib users as compared to nonusers. CI, confidence interval; HR, hazards ratio
3.6 Carfilzomib use pattern
The SEER‐Medicare data set has limited information about drug doses. We analyzed carfilzomib usage information based on reimbursement patterns. Although, not perfect but this does provide some insight into the pattern of carfilzomib use and associated toxicity. The multivariate logistic regression model was used after controlling various variables as described previously.
The overall median duration of carfilzomib therapy was 3.6 months and the median number of carfilzomib doses used was 24. The median interval between the two doses was 4.5 days. Patients receiving twice a week carfilzomib were identified as a treatment interval of fewer than 4 days. Carfilzomib was used once a week in 38% of patients while in rest 62% of patients; carfilzomib was used twice a week. Weekly infusion of carfilzomib was associated with a lower risk of cardiovascular toxicity compare to twice‐weekly infusions (HR 0.76, 95% CI: 0.62–0.92, p = 0.0051).
Carfilzomib was used as a single agent in 61% (n = 496) and in combination with other drugs in 39% (n = 319) of patients. When prescribed in combination, carfilzomib was most commonly used with cyclophosphamide in 27.7% (n = 218) followed by daratumumab in 8.3% (n = 68) and Lenalidomide in 2.7% (n = 22). Combination use with Pomalidomide or Thalidomide was minimal. In comparison to single‐agent carfilzomib, combined use with cyclophosphamide, daratumumab, lenalidomide, pomalidomide, or thalidomide was not associated with increased risk for CVAEs.
4 DISCUSSION
Our study is an extensive review of carfilzomib associated CVAEs using the SEER‐Medicare data set that approximately includes 34% of the U.S. population and represents a commonly encountered patient population as compared to selective patients enrolled through clinical trials. We identified a significantly increased risk of CVAEs with carfilzomib therapy, even after controlling for multiple variables. The incidence of CVAEs (57.6%) was higher as compared to previously reported incidence through pooled analysis but these rates are closer to the prospective study done by Cornell et al to identify the incidence of CVAEs.
14
Similar to previous retrospective studies, we found that pre‐existing hypertension and other cardiovascular diagnoses were associated with a higher risk of CVAEs after carfilzomib use. Elderly patients above age 75 years and obesity were at higher risk for CVAEs from carfilzomib use. The majority of MM patients who received carfilzomib had relapsed disease and were likely to have received previous treatments or underwent an autologous transplant. Our study did not find that patients with either relapsed disease or previous autologous transplant had higher CVAEs after carfilzomib use.
As previously reported in the literature, we also identified highly significant HR for heart failure, ischemic heart disease, and hypertension while there was no association with conduction disorders (arrhythmia and blocks). Conduction disorders have been reported with carfilzomib use, but the literature review was not consistent with this toxicity. Like other studies
6
,
12
our study also identified that carfilzomib users had significant hazards of new‐onset dyspnea, chest pain, edema, and syncope, as compared to nonusers. Although these symptoms are not specific, we recommend careful monitoring of these symptoms as it might help in the early detection of CVAEs.
Our study did not identify any combination regimens to be associated with a higher risk for CVAEs as compared to the use of carfilzomib alone. Once a week use was associated with lower CVAEs as compared to twice a week use of carfilzomib. A study by Moreau et al reported prolonged progression‐free survival and fewer cardiac failure events with the once weekly schedule as compared to a twice‐weekly schedule.
17
Since studies so far have not shown any clear evidence of dose‐dependent cardiovascular toxicity form carfilzomib, this finding suggests that quicker frequency may be related to higher toxicity. Although this finding is significant, we advise caution in clinical interpretation in the absence of exact dosages information, which unfortunately is a known limitation of the SEER‐Medicare data set.
Various preventative and management strategies have been proposed for carfilzomib‐induced cardiotoxicity by single‐center studies.
18
,
19
These include baseline cardiac function evaluation, optimizing underlying hypertension and cardiac conditions, careful fluid management, and symptom directed workup while on carfilzomib therapy. Although faster infusion rates of carfilzomib have been reported to be associated with higher CVAEs the prospective observational study by Cornell et al did not find any such association.
14
,
20
Cautious re‐challenge with a reduced dose of carfilzomib after the resolution of cardiac events has also been recommended. European Myeloma network and the Italian society of arterial hypertension also released a consensus paper with a scoring system based on risk factors and management recommendations for patients using carfilzomib.
21
In summary, with our study results and previous data, we can assertively say that there is enough evidence to strongly associate the significant risk of CVAEs with the use of carfilzomib. As such, there is a need for identifying patients at higher risk, cautious monitoring, prompt identification, and management of carfilzomib associated CVAEs. Patients with pre‐existing cardiovascular conditions should be monitored closely by a multidisciplinary team from cardiology and oncology which is also a recommendation from the International Cardio‐Oncology Society (ICOS).
22
This is absolutely necessary until we have a full understanding of all the risk factors, preventative measures, and long‐term toxicity from carfilzomib use.
5 CONCLUSIONS
This study from a large SEER‐Medicare data set provides further evidence of carfilzomib‐associated CVAEs and identifies potential risk factors.
5.1 Study limitations
This study has an inherent limitation of retrospective design and thus we infer association and not direct causation. Although the SEER database includes data from 19 different geographical areas covering approximately 34% of the U.S. population from diverse demographics and locations it cannot be ascertained that every population group has proper representation. Authors caution that results might be affected by various local risk factors, including access to health care, and should be considered for an individual patient The SEER‐Medicare database does not contain clinical measures of disease severity, information regarding chemotherapy dosage and schedule or management of cardiovascular toxicity. In addition, this study included elderly patients with age ≥ 65 years and prone to reporting bias. Therefore, the results may not be generalizable to younger populations or those not covered by Medicare. We have included nicotine/tobacco use and BMI in analyses based on ICD‐9/10 diagnoses codes from Medicare data. However, the sensitivity of these codes is low. Even considering these limitations, studies from SEER‐Medicare data sets have provided clinically relevant information, which often is not feasible from clinical trials.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The Institution Review Board (IRB) at the University of Florida, Gainesville FL, approved this study and all standard ethical guidelines were followed. A full waiver of informed consent was obtained.
CONSENT TO PUBLICATION
Not applicable. The manuscript does not contain any individual patients' data.
Supporting information
Table S1‐S3
Click here for additional data file.
ACKNOWLEDGEMENTS
None.
DATA AVAILABILITY STATEMENT
The data sets used for the current study are available from SEER‐Medicare. This study used the linked SEER‐Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER‐Medicare database.
|
CARFILZOMIB
|
DrugsGivenReaction
|
CC BY
|
33169938
| 18,544,063
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypertension'.
|
Real-world experience of carfilzomib-associated cardiovascular adverse events: SEER-Medicare data set analysis.
Carfilzomib was approved for the treatment of multiple myeloma in 2012 and since then there have been concerns for cardiovascular toxicity from its use. With this study, we aim to further study the hazards and underlying risk factors for cardiovascular adverse events associated with carfilzomib. This study was conducted using Surveillance, Epidemiology, and End Results (SEER)-Medicare data set of multiple myeloma from 2001 to 2015. Data were analyzed for hazards ratio of cardiovascular adverse events between carfilzomib users and nonusers. We identified 7330 patients with multiple myeloma of whom 815 were carfilzomib users. Carfilzomib users had a statistically significant hazard ratio of 1.41 with p < 0.0001 for all cardiovascular adverse events as compared to nonusers. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Carfilzomib users were at higher risk of new-onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers. Age above 75 years, preexisting cardiovascular disease, obesity, and twice a week carfilzomib schedule were significant risk factors associated with cardiovascular adverse events in carfilzomib users. The median time of the onset for all cardiovascular adverse events was 3.1 months. This study has identified a significantly higher likelihood of cardiovascular adverse events in elderly Medicare patients receiving carfilzomib.
1 BACKGROUND
Proteasome inhibitors (PI) comprise an important class of drugs for treating multiple myeloma (MM). Currently, three drugs are approved in this class, bortezomib, carfilzomib, and ixazomib. Carfilzomib is a second‐generation, highly selective and irreversible PI which received accelerated approval by the United States Food and Drug Administration (FDA) in July 2012.
1
This approval was based on a phase II study where carfilzomib demonstrated an overall response rate (ORR) of about 23% for relapsed and refractory multiple myeloma (RRMM).
2
Since then carfilzomib has been approved for multiple other indications for the treatment of MM. Presently, as per the National Comprehensive Cancer Network (NCCN) guidelines, carfilzomib is recommended for primary therapy of MM in transplant‐eligible as well as transplant‐ineligible patients. In the RRMM, carfilzomib is recommended as a preferred regimen either as a single agent or in combination with other agents.
Since its approval, cardiovascular adverse events (CVAEs) from carfilzomib has been a concern. Initially, carfilzomib associated CVAEs were reported in about 22% patients from the grouped data of four phase II studies in 2013.
3
Meta‐analyses of clinical trials have shown that up to 18% of patients experienced CVAEs.
4
,
5
,
6
,
7
These studies reported CVAEs with variable rates and the most common CVAEs were hypertension (18.5%) and heart failure (6.7%). Arrhythmia (2.4%) and ischemic events (3.7%) were observed less commonly. Other significant CVAEs were dyspnea (31.9%) and edema (24.7%).
6
,
7
Multiple studies have tried to identify risk factors for Carfilzomib associated cardiotoxicity. Retrospective studies from single institutions have reported prior cardiac history as a risk factor for carfilzomib associated cardiotoxicity.
8
,
9
,
10
Most of CVAEs have been reported to occur soon after carfilzomib use, rarely beyond 12 cycles and the systolic dysfunction is usually reversible.
9
,
11
,
12
Current evidence is not clear for an association of CVAEs with the dose or the duration of carfilzomib use but re‐challenge with reduced dose has been recommended.
4
,
11
,
13
The prospective observational study by Cornell et al reported that 51% of patients treated with carfilzomib developed CVAEs including heart failure (41%), hypertension (23%), arrhythmia (7%), an acute coronary syndrome in (6%), and also reported chest pain in 9% of patients.
14
There was no association between drug dose, infusion time, and concurrent drugs or fluids administered with carfilzomib but elevated natriuretic peptide was associated with increased risk of CVAEs. Similarly, 33% of patients experienced CVAEs in the study by Bruno et al and baseline uncontrolled blood pressure, left ventricular hypertrophy, and higher pulse‐wave velocity were identified as risk factors.
15
Cardiovascular adverse events remains the drug limiting toxicity of carfilzomib and NCCN also alerts for potential carfilzomib related cardiac and pulmonary toxicity, especially in elderly patients. As the median age for diagnosis of MM is 70 years, nearly two‐thirds of patients have preexisting cardiovascular disease at baseline, hence, at risk of developing carfilzomib associated CVAEs.
16
We have enough scientific evidence about CVAEs from the use of carfilzomib which is mainly obtained through pooled analysis of data from clinical trials. Clinical trials usually exclude patients with preexisting cardiac conditions and the enrolled patients are usually monitored diligently as per clinical trial protocols. Therefore, a clinical trial setting is not the representative of the most commonly encountered scenario in the community clinical practice. This study aims to identify the incidence and risk factors for CVAEs associated with carfilzomib for the treatment of MM using Surveillance Epidemiology and Endpoint Research (SEER)‐Medicare data set, which gives a real‐world experience of carfilzomib.
2 METHODS
This study is a retrospective study completed through the SEER‐Medicare data set. The SEER program, supported by the National Cancer Institute (NCI), contains cancer patients’ demographic and tumor characteristics for approximately 34% of the U.S. population. The Medicare data set, maintained by the Centers for Medicare and Medicaid Services, contains health care claims and payment information, for over 97% of the U.S. population aged 65 years or older. We used this linked SEER‐Medicare data set, which captures treatment information after a cancer diagnosis from the Medicare insurance program along with individual patient‐level demographic and survival data from the SEER cancer registry program.
2.1 Study population
This study included patients age ≥ 65 years‐old with the diagnosis of MM between 2001 and 2015. To capture the prior history or risk factors for cardiovascular events, only patients who were enrolled in Medicare for at least 1 year before diagnosis were included. Patients were identified using International Classification of Diseases for Oncology, third edition (ICD‐O‐3) codes from the SEER database. We excluded patients with amyloidosis as those patients can have cardiac dysfunction and can be a confounding factor.
ICD 9/10 codes were used to identify past medical history and the new cardiovascular diagnosis after treatment with carfilzomib. Basic demographic data were collected for sex, race/ethnicity, Nicotine/tobacco use, obesity, and Charleston comorbidity index (CCI) among others. Various cardiovascular diagnoses including ischemic heart disease, congestive heart failure, conduction disorders (arrhythmia and blocks) were identified using ICD9/10. We also identified hazards of edema, chest pain, dyspnea, and syncope which are reported separately and not included in CVAEs. Treatment details were identified using Healthcare Common Procedure Coding System (HCPCS) and National Drug Code (NDC) drug codes. Data from Medicare claims for linked patients are available for a year after, up to 2016. Details of the diagnostic codes used for study are available as Table S1.
The primary endpoint of the study was the hazard of the all‐new CVAEs associated with carfilzomib use in the entire study cohort of myeloma patients. The secondary endpoint of the study includes risk factors for CVAEs and hazard of different categories of CVAEs in carfilzomib users. We analyzed the potential risk factors for CVAEs the entire study cohort of myeloma patients and then separately for sub‐group of carfilzomib users. The study focuses mainly on risk factors in carfilzomib users. Impact of carfilzomib use pattern and use of other drugs for treatment of myeloma on were also analyzed. We also calculated the hazard of dyspnea, chest pain, edema, and syncope in carfilzomib users versus nonusers.
2.2 Statistical analysis
Patients were divided into two cohorts; carfilzomib users and nonusers. Patient‐, disease‐, and treatment‐related factors were compared using the Chi‐square test for categorical and the Kruskal–Wallis test for continuous variables. A Cox proportional‐hazards model was constructed to determine the relationship between CVAEs and carfilzomib therapy and was controlled for various variables including age, sex, race/ethnicity, previous autologous transplant, CCI, preexisting conditions including body mass index (BMI), nicotine/tobacco use, preexisting diabetes, preexisting hypertension, preexisting cardiovascular conditions, and previous anthracycline use. The goodness of fit was assessed using the method of Hosmer and Lemeshow. Within the treatment group, we also used Cox proportional‐hazards models to examine how the preexisting conditions predicted the newly diagnosed CVAEs. Cox models were also adjusted for the aforementioned patients' characteristics. All statistical tests were two‐sided and statistical significance was defined as p < 0.05. Analyses were conducted using SAS version 9.4 software (SAS Institute).
3 RESULTS
3.1 Patient characteristics
A total of 7330 patients with multiple myeloma were included in the study; 815 (11.1%) carfilzomib users and 6515 (88.9%) carfilzomib nonusers. Figure 1 shows the flowsheet for the study cohort derivation.
FIGURE 1 Flowsheet detailing cohort derivation from the SEER‐Medicare data set. HCPCS, Healthcare Common Procedure Coding System; HMO, Health Maintenance Organization
Baseline characteristics of the entire cohort including carfilzomib users and nonusers are shown in Table 1. Carfilzomib‐user cohort was younger, white race, had lower CCI compare to nonusers. A higher proportion of carfilzomib users had a history of hypertension or pre‐existing cardiovascular diseases. Furthermore, Carfilzomib use was higher in patients with relapsed myeloma and prior history of stem cell transplant (Table S2). No significant differences were observed between the two groups in terms of sex and pre‐existing history of diabetes. The study model was controlled for these different variables.
TABLE 1 Patient demographics and clinical characteristics of carfilzomib users and non‐users
Characteristics Total Carfilzomib use
p‐value
Yes % No %
Year of diagnosis
2001–2012 4459 537 12.0 3922 88.0 0.0001
2013 1088 121 11.1 967 88.9
2014 856 92 10.7 764 89.3
2015 927 65 7.0 862 93.0
Age groups
66–69 1813 286 15.8 1527 84.2 <0.0001
70–74 2015 291 14.4 1724 85.6
75–79 1627 146 9.0 1481 91.0
80+ 1875 92 4.9 1783 95.1
Sex
Male 3846 429 11.2 3417 88.8 0.9185
Female 3484 386 11.1 3098 88.9
Race/ethnicity
Non‐Hispanic white 5332 640 12.0 4692 88.0 <0.0001
Non‐Hispanic black 1076 98 9.1 978 90.9
Other 400 29 7.3 371 92.8
Hispanic 522 48 9.2 474 90.8
Myeloma
New 5621 355 6.3 5266 93.7 <0.0001
Relapsed 1709 460 26.9 1249 73.1
Previous transplant
No 6483 606 9.3 5877 90.7 <0.0001
Yes 847 209 24.7 638 75.3
Charleston comorbidity index
0 4788 613 12.8 4175 87.2 <0.0001
1 1293 129 10.0 1164 90.0
2 631 41 6.5 590 93.5
3+ 618 32 5.2 586 94.8
Body mass index
Other 6775 693 10.2 6082 89.8 <0.0001
Overweight 60 15 25.0 45 75.0
Obesity 495 107 21.6 388 78.4
Nicotine/tobacco use
Never 6565 557 8.5 6008 91.5 <0.0001
Current/former 765 258 33.7 507 66.3
Pre‐existing diabetes
No 4311 465 10.8 3846 89.2 0.2795
Yes 3019 350 11.6 2669 88.4
Pre‐existing hypertension
No 6682 584 8.7 6098 91.3 <0.0001
Yes 648 231 35.6 417 64.4
Pre‐existing cardiovascular conditions
No 3452 302 8.7 3150 91.3 <0.0001
Yes 3878 513 13.2 3365 86.8
Previous anthracycline use
No 7177 755 10.5 6422 89.5 <0.0001
Yes 153 60 39.2 93 60.8
John Wiley & Sons, Ltd3.2 Risk factors associated with CVAEs in the entire study cohort of myeloma patients, including carfilzomib users and nonusers
Based on the multivariate analysis, carfilzomib use was independently associated with an increase in the risk of development of CVAEs in the entire study cohort of MM patients. Compared to carfilzomib nonusers, the HR for CVAEs for carfilzomib users was 1.41 (95% CI 1.26–1.58, p < 0.0001). In addition to exposure to carfilzomib, advancing age, male sex, white race, higher CCI, higher BMI, nicotine/tobacco use, preexisting hypertension, and other cardiovascular diagnosis were associated with an increased risk for CVAEs. Pre‐existing diabetes and previous anthracycline use were not associated with higher CVAEs. Please see Table S3 for results of multivariable analysis of the entire study cohort.
3.3 Risk factors associated with CVAEs in sub‐group of carfilzomib users
Based on the multivariate analysis, age 75–79 years (HR 1.35, p = 0.0394) and above 80 (HR 1.53, p = 0.0118) were associated with a significantly higher risk of CVAEs compared to patients aged 65–69 years. Whereas obesity (HR 1.57, p = 0.0006), pre‐existing hypertension (HR 1.57, p = 0.0006), and preexisting other cardiovascular diagnoses (HR 2.75, p < 0.0001) were also significant risk factors. Patient's sex, race/ethnicity, nicotine/tobacco use, preexisting diabetes, previous anthracycline use, and history of the previous autologous transplant were not associated with higher CVAEs. Please see Figure 2 for details. Among all carfilzomib users, 57.6% (n = 469) were noted to have one or more CVAEs. The median time to onset of these CVAEs was 3.1 months.
FIGURE 2 Adjusted hazard ratios for cardiovascular adverse events in carfilzomib users (n = 815). CI, confidence interval; HR, hazards ratio; NH, non‐Hispanic
3.4 Categories of CVAEs
The study cohort was then analyzed for the hazards of various categories of new‐onset CVAEs. Cardiovascular events were categorized into ischemic heart disease, heart failure, conduction disorders (arrhythmia and heart blocks), and hypertension. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Please see Figure 3 for details.
FIGURE 3 Adjusted hazard ratios of patient using carfilzomib in cardiovascular adverse effects. CI, confidence interval; HR, hazards ratio
3.5 Symptoms
Hazards of certain new‐onset symptoms were also studied in the entire study cohort. Carfilzomib users were at higher risk of new‐onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers (Figure 4).
FIGURE 4 Hazards of new‐onset symptoms in carfilzomib users as compared to nonusers. CI, confidence interval; HR, hazards ratio
3.6 Carfilzomib use pattern
The SEER‐Medicare data set has limited information about drug doses. We analyzed carfilzomib usage information based on reimbursement patterns. Although, not perfect but this does provide some insight into the pattern of carfilzomib use and associated toxicity. The multivariate logistic regression model was used after controlling various variables as described previously.
The overall median duration of carfilzomib therapy was 3.6 months and the median number of carfilzomib doses used was 24. The median interval between the two doses was 4.5 days. Patients receiving twice a week carfilzomib were identified as a treatment interval of fewer than 4 days. Carfilzomib was used once a week in 38% of patients while in rest 62% of patients; carfilzomib was used twice a week. Weekly infusion of carfilzomib was associated with a lower risk of cardiovascular toxicity compare to twice‐weekly infusions (HR 0.76, 95% CI: 0.62–0.92, p = 0.0051).
Carfilzomib was used as a single agent in 61% (n = 496) and in combination with other drugs in 39% (n = 319) of patients. When prescribed in combination, carfilzomib was most commonly used with cyclophosphamide in 27.7% (n = 218) followed by daratumumab in 8.3% (n = 68) and Lenalidomide in 2.7% (n = 22). Combination use with Pomalidomide or Thalidomide was minimal. In comparison to single‐agent carfilzomib, combined use with cyclophosphamide, daratumumab, lenalidomide, pomalidomide, or thalidomide was not associated with increased risk for CVAEs.
4 DISCUSSION
Our study is an extensive review of carfilzomib associated CVAEs using the SEER‐Medicare data set that approximately includes 34% of the U.S. population and represents a commonly encountered patient population as compared to selective patients enrolled through clinical trials. We identified a significantly increased risk of CVAEs with carfilzomib therapy, even after controlling for multiple variables. The incidence of CVAEs (57.6%) was higher as compared to previously reported incidence through pooled analysis but these rates are closer to the prospective study done by Cornell et al to identify the incidence of CVAEs.
14
Similar to previous retrospective studies, we found that pre‐existing hypertension and other cardiovascular diagnoses were associated with a higher risk of CVAEs after carfilzomib use. Elderly patients above age 75 years and obesity were at higher risk for CVAEs from carfilzomib use. The majority of MM patients who received carfilzomib had relapsed disease and were likely to have received previous treatments or underwent an autologous transplant. Our study did not find that patients with either relapsed disease or previous autologous transplant had higher CVAEs after carfilzomib use.
As previously reported in the literature, we also identified highly significant HR for heart failure, ischemic heart disease, and hypertension while there was no association with conduction disorders (arrhythmia and blocks). Conduction disorders have been reported with carfilzomib use, but the literature review was not consistent with this toxicity. Like other studies
6
,
12
our study also identified that carfilzomib users had significant hazards of new‐onset dyspnea, chest pain, edema, and syncope, as compared to nonusers. Although these symptoms are not specific, we recommend careful monitoring of these symptoms as it might help in the early detection of CVAEs.
Our study did not identify any combination regimens to be associated with a higher risk for CVAEs as compared to the use of carfilzomib alone. Once a week use was associated with lower CVAEs as compared to twice a week use of carfilzomib. A study by Moreau et al reported prolonged progression‐free survival and fewer cardiac failure events with the once weekly schedule as compared to a twice‐weekly schedule.
17
Since studies so far have not shown any clear evidence of dose‐dependent cardiovascular toxicity form carfilzomib, this finding suggests that quicker frequency may be related to higher toxicity. Although this finding is significant, we advise caution in clinical interpretation in the absence of exact dosages information, which unfortunately is a known limitation of the SEER‐Medicare data set.
Various preventative and management strategies have been proposed for carfilzomib‐induced cardiotoxicity by single‐center studies.
18
,
19
These include baseline cardiac function evaluation, optimizing underlying hypertension and cardiac conditions, careful fluid management, and symptom directed workup while on carfilzomib therapy. Although faster infusion rates of carfilzomib have been reported to be associated with higher CVAEs the prospective observational study by Cornell et al did not find any such association.
14
,
20
Cautious re‐challenge with a reduced dose of carfilzomib after the resolution of cardiac events has also been recommended. European Myeloma network and the Italian society of arterial hypertension also released a consensus paper with a scoring system based on risk factors and management recommendations for patients using carfilzomib.
21
In summary, with our study results and previous data, we can assertively say that there is enough evidence to strongly associate the significant risk of CVAEs with the use of carfilzomib. As such, there is a need for identifying patients at higher risk, cautious monitoring, prompt identification, and management of carfilzomib associated CVAEs. Patients with pre‐existing cardiovascular conditions should be monitored closely by a multidisciplinary team from cardiology and oncology which is also a recommendation from the International Cardio‐Oncology Society (ICOS).
22
This is absolutely necessary until we have a full understanding of all the risk factors, preventative measures, and long‐term toxicity from carfilzomib use.
5 CONCLUSIONS
This study from a large SEER‐Medicare data set provides further evidence of carfilzomib‐associated CVAEs and identifies potential risk factors.
5.1 Study limitations
This study has an inherent limitation of retrospective design and thus we infer association and not direct causation. Although the SEER database includes data from 19 different geographical areas covering approximately 34% of the U.S. population from diverse demographics and locations it cannot be ascertained that every population group has proper representation. Authors caution that results might be affected by various local risk factors, including access to health care, and should be considered for an individual patient The SEER‐Medicare database does not contain clinical measures of disease severity, information regarding chemotherapy dosage and schedule or management of cardiovascular toxicity. In addition, this study included elderly patients with age ≥ 65 years and prone to reporting bias. Therefore, the results may not be generalizable to younger populations or those not covered by Medicare. We have included nicotine/tobacco use and BMI in analyses based on ICD‐9/10 diagnoses codes from Medicare data. However, the sensitivity of these codes is low. Even considering these limitations, studies from SEER‐Medicare data sets have provided clinically relevant information, which often is not feasible from clinical trials.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The Institution Review Board (IRB) at the University of Florida, Gainesville FL, approved this study and all standard ethical guidelines were followed. A full waiver of informed consent was obtained.
CONSENT TO PUBLICATION
Not applicable. The manuscript does not contain any individual patients' data.
Supporting information
Table S1‐S3
Click here for additional data file.
ACKNOWLEDGEMENTS
None.
DATA AVAILABILITY STATEMENT
The data sets used for the current study are available from SEER‐Medicare. This study used the linked SEER‐Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER‐Medicare database.
|
CARFILZOMIB
|
DrugsGivenReaction
|
CC BY
|
33169938
| 18,544,063
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myocardial ischaemia'.
|
Real-world experience of carfilzomib-associated cardiovascular adverse events: SEER-Medicare data set analysis.
Carfilzomib was approved for the treatment of multiple myeloma in 2012 and since then there have been concerns for cardiovascular toxicity from its use. With this study, we aim to further study the hazards and underlying risk factors for cardiovascular adverse events associated with carfilzomib. This study was conducted using Surveillance, Epidemiology, and End Results (SEER)-Medicare data set of multiple myeloma from 2001 to 2015. Data were analyzed for hazards ratio of cardiovascular adverse events between carfilzomib users and nonusers. We identified 7330 patients with multiple myeloma of whom 815 were carfilzomib users. Carfilzomib users had a statistically significant hazard ratio of 1.41 with p < 0.0001 for all cardiovascular adverse events as compared to nonusers. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Carfilzomib users were at higher risk of new-onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers. Age above 75 years, preexisting cardiovascular disease, obesity, and twice a week carfilzomib schedule were significant risk factors associated with cardiovascular adverse events in carfilzomib users. The median time of the onset for all cardiovascular adverse events was 3.1 months. This study has identified a significantly higher likelihood of cardiovascular adverse events in elderly Medicare patients receiving carfilzomib.
1 BACKGROUND
Proteasome inhibitors (PI) comprise an important class of drugs for treating multiple myeloma (MM). Currently, three drugs are approved in this class, bortezomib, carfilzomib, and ixazomib. Carfilzomib is a second‐generation, highly selective and irreversible PI which received accelerated approval by the United States Food and Drug Administration (FDA) in July 2012.
1
This approval was based on a phase II study where carfilzomib demonstrated an overall response rate (ORR) of about 23% for relapsed and refractory multiple myeloma (RRMM).
2
Since then carfilzomib has been approved for multiple other indications for the treatment of MM. Presently, as per the National Comprehensive Cancer Network (NCCN) guidelines, carfilzomib is recommended for primary therapy of MM in transplant‐eligible as well as transplant‐ineligible patients. In the RRMM, carfilzomib is recommended as a preferred regimen either as a single agent or in combination with other agents.
Since its approval, cardiovascular adverse events (CVAEs) from carfilzomib has been a concern. Initially, carfilzomib associated CVAEs were reported in about 22% patients from the grouped data of four phase II studies in 2013.
3
Meta‐analyses of clinical trials have shown that up to 18% of patients experienced CVAEs.
4
,
5
,
6
,
7
These studies reported CVAEs with variable rates and the most common CVAEs were hypertension (18.5%) and heart failure (6.7%). Arrhythmia (2.4%) and ischemic events (3.7%) were observed less commonly. Other significant CVAEs were dyspnea (31.9%) and edema (24.7%).
6
,
7
Multiple studies have tried to identify risk factors for Carfilzomib associated cardiotoxicity. Retrospective studies from single institutions have reported prior cardiac history as a risk factor for carfilzomib associated cardiotoxicity.
8
,
9
,
10
Most of CVAEs have been reported to occur soon after carfilzomib use, rarely beyond 12 cycles and the systolic dysfunction is usually reversible.
9
,
11
,
12
Current evidence is not clear for an association of CVAEs with the dose or the duration of carfilzomib use but re‐challenge with reduced dose has been recommended.
4
,
11
,
13
The prospective observational study by Cornell et al reported that 51% of patients treated with carfilzomib developed CVAEs including heart failure (41%), hypertension (23%), arrhythmia (7%), an acute coronary syndrome in (6%), and also reported chest pain in 9% of patients.
14
There was no association between drug dose, infusion time, and concurrent drugs or fluids administered with carfilzomib but elevated natriuretic peptide was associated with increased risk of CVAEs. Similarly, 33% of patients experienced CVAEs in the study by Bruno et al and baseline uncontrolled blood pressure, left ventricular hypertrophy, and higher pulse‐wave velocity were identified as risk factors.
15
Cardiovascular adverse events remains the drug limiting toxicity of carfilzomib and NCCN also alerts for potential carfilzomib related cardiac and pulmonary toxicity, especially in elderly patients. As the median age for diagnosis of MM is 70 years, nearly two‐thirds of patients have preexisting cardiovascular disease at baseline, hence, at risk of developing carfilzomib associated CVAEs.
16
We have enough scientific evidence about CVAEs from the use of carfilzomib which is mainly obtained through pooled analysis of data from clinical trials. Clinical trials usually exclude patients with preexisting cardiac conditions and the enrolled patients are usually monitored diligently as per clinical trial protocols. Therefore, a clinical trial setting is not the representative of the most commonly encountered scenario in the community clinical practice. This study aims to identify the incidence and risk factors for CVAEs associated with carfilzomib for the treatment of MM using Surveillance Epidemiology and Endpoint Research (SEER)‐Medicare data set, which gives a real‐world experience of carfilzomib.
2 METHODS
This study is a retrospective study completed through the SEER‐Medicare data set. The SEER program, supported by the National Cancer Institute (NCI), contains cancer patients’ demographic and tumor characteristics for approximately 34% of the U.S. population. The Medicare data set, maintained by the Centers for Medicare and Medicaid Services, contains health care claims and payment information, for over 97% of the U.S. population aged 65 years or older. We used this linked SEER‐Medicare data set, which captures treatment information after a cancer diagnosis from the Medicare insurance program along with individual patient‐level demographic and survival data from the SEER cancer registry program.
2.1 Study population
This study included patients age ≥ 65 years‐old with the diagnosis of MM between 2001 and 2015. To capture the prior history or risk factors for cardiovascular events, only patients who were enrolled in Medicare for at least 1 year before diagnosis were included. Patients were identified using International Classification of Diseases for Oncology, third edition (ICD‐O‐3) codes from the SEER database. We excluded patients with amyloidosis as those patients can have cardiac dysfunction and can be a confounding factor.
ICD 9/10 codes were used to identify past medical history and the new cardiovascular diagnosis after treatment with carfilzomib. Basic demographic data were collected for sex, race/ethnicity, Nicotine/tobacco use, obesity, and Charleston comorbidity index (CCI) among others. Various cardiovascular diagnoses including ischemic heart disease, congestive heart failure, conduction disorders (arrhythmia and blocks) were identified using ICD9/10. We also identified hazards of edema, chest pain, dyspnea, and syncope which are reported separately and not included in CVAEs. Treatment details were identified using Healthcare Common Procedure Coding System (HCPCS) and National Drug Code (NDC) drug codes. Data from Medicare claims for linked patients are available for a year after, up to 2016. Details of the diagnostic codes used for study are available as Table S1.
The primary endpoint of the study was the hazard of the all‐new CVAEs associated with carfilzomib use in the entire study cohort of myeloma patients. The secondary endpoint of the study includes risk factors for CVAEs and hazard of different categories of CVAEs in carfilzomib users. We analyzed the potential risk factors for CVAEs the entire study cohort of myeloma patients and then separately for sub‐group of carfilzomib users. The study focuses mainly on risk factors in carfilzomib users. Impact of carfilzomib use pattern and use of other drugs for treatment of myeloma on were also analyzed. We also calculated the hazard of dyspnea, chest pain, edema, and syncope in carfilzomib users versus nonusers.
2.2 Statistical analysis
Patients were divided into two cohorts; carfilzomib users and nonusers. Patient‐, disease‐, and treatment‐related factors were compared using the Chi‐square test for categorical and the Kruskal–Wallis test for continuous variables. A Cox proportional‐hazards model was constructed to determine the relationship between CVAEs and carfilzomib therapy and was controlled for various variables including age, sex, race/ethnicity, previous autologous transplant, CCI, preexisting conditions including body mass index (BMI), nicotine/tobacco use, preexisting diabetes, preexisting hypertension, preexisting cardiovascular conditions, and previous anthracycline use. The goodness of fit was assessed using the method of Hosmer and Lemeshow. Within the treatment group, we also used Cox proportional‐hazards models to examine how the preexisting conditions predicted the newly diagnosed CVAEs. Cox models were also adjusted for the aforementioned patients' characteristics. All statistical tests were two‐sided and statistical significance was defined as p < 0.05. Analyses were conducted using SAS version 9.4 software (SAS Institute).
3 RESULTS
3.1 Patient characteristics
A total of 7330 patients with multiple myeloma were included in the study; 815 (11.1%) carfilzomib users and 6515 (88.9%) carfilzomib nonusers. Figure 1 shows the flowsheet for the study cohort derivation.
FIGURE 1 Flowsheet detailing cohort derivation from the SEER‐Medicare data set. HCPCS, Healthcare Common Procedure Coding System; HMO, Health Maintenance Organization
Baseline characteristics of the entire cohort including carfilzomib users and nonusers are shown in Table 1. Carfilzomib‐user cohort was younger, white race, had lower CCI compare to nonusers. A higher proportion of carfilzomib users had a history of hypertension or pre‐existing cardiovascular diseases. Furthermore, Carfilzomib use was higher in patients with relapsed myeloma and prior history of stem cell transplant (Table S2). No significant differences were observed between the two groups in terms of sex and pre‐existing history of diabetes. The study model was controlled for these different variables.
TABLE 1 Patient demographics and clinical characteristics of carfilzomib users and non‐users
Characteristics Total Carfilzomib use
p‐value
Yes % No %
Year of diagnosis
2001–2012 4459 537 12.0 3922 88.0 0.0001
2013 1088 121 11.1 967 88.9
2014 856 92 10.7 764 89.3
2015 927 65 7.0 862 93.0
Age groups
66–69 1813 286 15.8 1527 84.2 <0.0001
70–74 2015 291 14.4 1724 85.6
75–79 1627 146 9.0 1481 91.0
80+ 1875 92 4.9 1783 95.1
Sex
Male 3846 429 11.2 3417 88.8 0.9185
Female 3484 386 11.1 3098 88.9
Race/ethnicity
Non‐Hispanic white 5332 640 12.0 4692 88.0 <0.0001
Non‐Hispanic black 1076 98 9.1 978 90.9
Other 400 29 7.3 371 92.8
Hispanic 522 48 9.2 474 90.8
Myeloma
New 5621 355 6.3 5266 93.7 <0.0001
Relapsed 1709 460 26.9 1249 73.1
Previous transplant
No 6483 606 9.3 5877 90.7 <0.0001
Yes 847 209 24.7 638 75.3
Charleston comorbidity index
0 4788 613 12.8 4175 87.2 <0.0001
1 1293 129 10.0 1164 90.0
2 631 41 6.5 590 93.5
3+ 618 32 5.2 586 94.8
Body mass index
Other 6775 693 10.2 6082 89.8 <0.0001
Overweight 60 15 25.0 45 75.0
Obesity 495 107 21.6 388 78.4
Nicotine/tobacco use
Never 6565 557 8.5 6008 91.5 <0.0001
Current/former 765 258 33.7 507 66.3
Pre‐existing diabetes
No 4311 465 10.8 3846 89.2 0.2795
Yes 3019 350 11.6 2669 88.4
Pre‐existing hypertension
No 6682 584 8.7 6098 91.3 <0.0001
Yes 648 231 35.6 417 64.4
Pre‐existing cardiovascular conditions
No 3452 302 8.7 3150 91.3 <0.0001
Yes 3878 513 13.2 3365 86.8
Previous anthracycline use
No 7177 755 10.5 6422 89.5 <0.0001
Yes 153 60 39.2 93 60.8
John Wiley & Sons, Ltd3.2 Risk factors associated with CVAEs in the entire study cohort of myeloma patients, including carfilzomib users and nonusers
Based on the multivariate analysis, carfilzomib use was independently associated with an increase in the risk of development of CVAEs in the entire study cohort of MM patients. Compared to carfilzomib nonusers, the HR for CVAEs for carfilzomib users was 1.41 (95% CI 1.26–1.58, p < 0.0001). In addition to exposure to carfilzomib, advancing age, male sex, white race, higher CCI, higher BMI, nicotine/tobacco use, preexisting hypertension, and other cardiovascular diagnosis were associated with an increased risk for CVAEs. Pre‐existing diabetes and previous anthracycline use were not associated with higher CVAEs. Please see Table S3 for results of multivariable analysis of the entire study cohort.
3.3 Risk factors associated with CVAEs in sub‐group of carfilzomib users
Based on the multivariate analysis, age 75–79 years (HR 1.35, p = 0.0394) and above 80 (HR 1.53, p = 0.0118) were associated with a significantly higher risk of CVAEs compared to patients aged 65–69 years. Whereas obesity (HR 1.57, p = 0.0006), pre‐existing hypertension (HR 1.57, p = 0.0006), and preexisting other cardiovascular diagnoses (HR 2.75, p < 0.0001) were also significant risk factors. Patient's sex, race/ethnicity, nicotine/tobacco use, preexisting diabetes, previous anthracycline use, and history of the previous autologous transplant were not associated with higher CVAEs. Please see Figure 2 for details. Among all carfilzomib users, 57.6% (n = 469) were noted to have one or more CVAEs. The median time to onset of these CVAEs was 3.1 months.
FIGURE 2 Adjusted hazard ratios for cardiovascular adverse events in carfilzomib users (n = 815). CI, confidence interval; HR, hazards ratio; NH, non‐Hispanic
3.4 Categories of CVAEs
The study cohort was then analyzed for the hazards of various categories of new‐onset CVAEs. Cardiovascular events were categorized into ischemic heart disease, heart failure, conduction disorders (arrhythmia and heart blocks), and hypertension. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Please see Figure 3 for details.
FIGURE 3 Adjusted hazard ratios of patient using carfilzomib in cardiovascular adverse effects. CI, confidence interval; HR, hazards ratio
3.5 Symptoms
Hazards of certain new‐onset symptoms were also studied in the entire study cohort. Carfilzomib users were at higher risk of new‐onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers (Figure 4).
FIGURE 4 Hazards of new‐onset symptoms in carfilzomib users as compared to nonusers. CI, confidence interval; HR, hazards ratio
3.6 Carfilzomib use pattern
The SEER‐Medicare data set has limited information about drug doses. We analyzed carfilzomib usage information based on reimbursement patterns. Although, not perfect but this does provide some insight into the pattern of carfilzomib use and associated toxicity. The multivariate logistic regression model was used after controlling various variables as described previously.
The overall median duration of carfilzomib therapy was 3.6 months and the median number of carfilzomib doses used was 24. The median interval between the two doses was 4.5 days. Patients receiving twice a week carfilzomib were identified as a treatment interval of fewer than 4 days. Carfilzomib was used once a week in 38% of patients while in rest 62% of patients; carfilzomib was used twice a week. Weekly infusion of carfilzomib was associated with a lower risk of cardiovascular toxicity compare to twice‐weekly infusions (HR 0.76, 95% CI: 0.62–0.92, p = 0.0051).
Carfilzomib was used as a single agent in 61% (n = 496) and in combination with other drugs in 39% (n = 319) of patients. When prescribed in combination, carfilzomib was most commonly used with cyclophosphamide in 27.7% (n = 218) followed by daratumumab in 8.3% (n = 68) and Lenalidomide in 2.7% (n = 22). Combination use with Pomalidomide or Thalidomide was minimal. In comparison to single‐agent carfilzomib, combined use with cyclophosphamide, daratumumab, lenalidomide, pomalidomide, or thalidomide was not associated with increased risk for CVAEs.
4 DISCUSSION
Our study is an extensive review of carfilzomib associated CVAEs using the SEER‐Medicare data set that approximately includes 34% of the U.S. population and represents a commonly encountered patient population as compared to selective patients enrolled through clinical trials. We identified a significantly increased risk of CVAEs with carfilzomib therapy, even after controlling for multiple variables. The incidence of CVAEs (57.6%) was higher as compared to previously reported incidence through pooled analysis but these rates are closer to the prospective study done by Cornell et al to identify the incidence of CVAEs.
14
Similar to previous retrospective studies, we found that pre‐existing hypertension and other cardiovascular diagnoses were associated with a higher risk of CVAEs after carfilzomib use. Elderly patients above age 75 years and obesity were at higher risk for CVAEs from carfilzomib use. The majority of MM patients who received carfilzomib had relapsed disease and were likely to have received previous treatments or underwent an autologous transplant. Our study did not find that patients with either relapsed disease or previous autologous transplant had higher CVAEs after carfilzomib use.
As previously reported in the literature, we also identified highly significant HR for heart failure, ischemic heart disease, and hypertension while there was no association with conduction disorders (arrhythmia and blocks). Conduction disorders have been reported with carfilzomib use, but the literature review was not consistent with this toxicity. Like other studies
6
,
12
our study also identified that carfilzomib users had significant hazards of new‐onset dyspnea, chest pain, edema, and syncope, as compared to nonusers. Although these symptoms are not specific, we recommend careful monitoring of these symptoms as it might help in the early detection of CVAEs.
Our study did not identify any combination regimens to be associated with a higher risk for CVAEs as compared to the use of carfilzomib alone. Once a week use was associated with lower CVAEs as compared to twice a week use of carfilzomib. A study by Moreau et al reported prolonged progression‐free survival and fewer cardiac failure events with the once weekly schedule as compared to a twice‐weekly schedule.
17
Since studies so far have not shown any clear evidence of dose‐dependent cardiovascular toxicity form carfilzomib, this finding suggests that quicker frequency may be related to higher toxicity. Although this finding is significant, we advise caution in clinical interpretation in the absence of exact dosages information, which unfortunately is a known limitation of the SEER‐Medicare data set.
Various preventative and management strategies have been proposed for carfilzomib‐induced cardiotoxicity by single‐center studies.
18
,
19
These include baseline cardiac function evaluation, optimizing underlying hypertension and cardiac conditions, careful fluid management, and symptom directed workup while on carfilzomib therapy. Although faster infusion rates of carfilzomib have been reported to be associated with higher CVAEs the prospective observational study by Cornell et al did not find any such association.
14
,
20
Cautious re‐challenge with a reduced dose of carfilzomib after the resolution of cardiac events has also been recommended. European Myeloma network and the Italian society of arterial hypertension also released a consensus paper with a scoring system based on risk factors and management recommendations for patients using carfilzomib.
21
In summary, with our study results and previous data, we can assertively say that there is enough evidence to strongly associate the significant risk of CVAEs with the use of carfilzomib. As such, there is a need for identifying patients at higher risk, cautious monitoring, prompt identification, and management of carfilzomib associated CVAEs. Patients with pre‐existing cardiovascular conditions should be monitored closely by a multidisciplinary team from cardiology and oncology which is also a recommendation from the International Cardio‐Oncology Society (ICOS).
22
This is absolutely necessary until we have a full understanding of all the risk factors, preventative measures, and long‐term toxicity from carfilzomib use.
5 CONCLUSIONS
This study from a large SEER‐Medicare data set provides further evidence of carfilzomib‐associated CVAEs and identifies potential risk factors.
5.1 Study limitations
This study has an inherent limitation of retrospective design and thus we infer association and not direct causation. Although the SEER database includes data from 19 different geographical areas covering approximately 34% of the U.S. population from diverse demographics and locations it cannot be ascertained that every population group has proper representation. Authors caution that results might be affected by various local risk factors, including access to health care, and should be considered for an individual patient The SEER‐Medicare database does not contain clinical measures of disease severity, information regarding chemotherapy dosage and schedule or management of cardiovascular toxicity. In addition, this study included elderly patients with age ≥ 65 years and prone to reporting bias. Therefore, the results may not be generalizable to younger populations or those not covered by Medicare. We have included nicotine/tobacco use and BMI in analyses based on ICD‐9/10 diagnoses codes from Medicare data. However, the sensitivity of these codes is low. Even considering these limitations, studies from SEER‐Medicare data sets have provided clinically relevant information, which often is not feasible from clinical trials.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The Institution Review Board (IRB) at the University of Florida, Gainesville FL, approved this study and all standard ethical guidelines were followed. A full waiver of informed consent was obtained.
CONSENT TO PUBLICATION
Not applicable. The manuscript does not contain any individual patients' data.
Supporting information
Table S1‐S3
Click here for additional data file.
ACKNOWLEDGEMENTS
None.
DATA AVAILABILITY STATEMENT
The data sets used for the current study are available from SEER‐Medicare. This study used the linked SEER‐Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER‐Medicare database.
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CARFILZOMIB
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DrugsGivenReaction
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CC BY
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33169938
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2021-01
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Oedema'.
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Real-world experience of carfilzomib-associated cardiovascular adverse events: SEER-Medicare data set analysis.
Carfilzomib was approved for the treatment of multiple myeloma in 2012 and since then there have been concerns for cardiovascular toxicity from its use. With this study, we aim to further study the hazards and underlying risk factors for cardiovascular adverse events associated with carfilzomib. This study was conducted using Surveillance, Epidemiology, and End Results (SEER)-Medicare data set of multiple myeloma from 2001 to 2015. Data were analyzed for hazards ratio of cardiovascular adverse events between carfilzomib users and nonusers. We identified 7330 patients with multiple myeloma of whom 815 were carfilzomib users. Carfilzomib users had a statistically significant hazard ratio of 1.41 with p < 0.0001 for all cardiovascular adverse events as compared to nonusers. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Carfilzomib users were at higher risk of new-onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers. Age above 75 years, preexisting cardiovascular disease, obesity, and twice a week carfilzomib schedule were significant risk factors associated with cardiovascular adverse events in carfilzomib users. The median time of the onset for all cardiovascular adverse events was 3.1 months. This study has identified a significantly higher likelihood of cardiovascular adverse events in elderly Medicare patients receiving carfilzomib.
1 BACKGROUND
Proteasome inhibitors (PI) comprise an important class of drugs for treating multiple myeloma (MM). Currently, three drugs are approved in this class, bortezomib, carfilzomib, and ixazomib. Carfilzomib is a second‐generation, highly selective and irreversible PI which received accelerated approval by the United States Food and Drug Administration (FDA) in July 2012.
1
This approval was based on a phase II study where carfilzomib demonstrated an overall response rate (ORR) of about 23% for relapsed and refractory multiple myeloma (RRMM).
2
Since then carfilzomib has been approved for multiple other indications for the treatment of MM. Presently, as per the National Comprehensive Cancer Network (NCCN) guidelines, carfilzomib is recommended for primary therapy of MM in transplant‐eligible as well as transplant‐ineligible patients. In the RRMM, carfilzomib is recommended as a preferred regimen either as a single agent or in combination with other agents.
Since its approval, cardiovascular adverse events (CVAEs) from carfilzomib has been a concern. Initially, carfilzomib associated CVAEs were reported in about 22% patients from the grouped data of four phase II studies in 2013.
3
Meta‐analyses of clinical trials have shown that up to 18% of patients experienced CVAEs.
4
,
5
,
6
,
7
These studies reported CVAEs with variable rates and the most common CVAEs were hypertension (18.5%) and heart failure (6.7%). Arrhythmia (2.4%) and ischemic events (3.7%) were observed less commonly. Other significant CVAEs were dyspnea (31.9%) and edema (24.7%).
6
,
7
Multiple studies have tried to identify risk factors for Carfilzomib associated cardiotoxicity. Retrospective studies from single institutions have reported prior cardiac history as a risk factor for carfilzomib associated cardiotoxicity.
8
,
9
,
10
Most of CVAEs have been reported to occur soon after carfilzomib use, rarely beyond 12 cycles and the systolic dysfunction is usually reversible.
9
,
11
,
12
Current evidence is not clear for an association of CVAEs with the dose or the duration of carfilzomib use but re‐challenge with reduced dose has been recommended.
4
,
11
,
13
The prospective observational study by Cornell et al reported that 51% of patients treated with carfilzomib developed CVAEs including heart failure (41%), hypertension (23%), arrhythmia (7%), an acute coronary syndrome in (6%), and also reported chest pain in 9% of patients.
14
There was no association between drug dose, infusion time, and concurrent drugs or fluids administered with carfilzomib but elevated natriuretic peptide was associated with increased risk of CVAEs. Similarly, 33% of patients experienced CVAEs in the study by Bruno et al and baseline uncontrolled blood pressure, left ventricular hypertrophy, and higher pulse‐wave velocity were identified as risk factors.
15
Cardiovascular adverse events remains the drug limiting toxicity of carfilzomib and NCCN also alerts for potential carfilzomib related cardiac and pulmonary toxicity, especially in elderly patients. As the median age for diagnosis of MM is 70 years, nearly two‐thirds of patients have preexisting cardiovascular disease at baseline, hence, at risk of developing carfilzomib associated CVAEs.
16
We have enough scientific evidence about CVAEs from the use of carfilzomib which is mainly obtained through pooled analysis of data from clinical trials. Clinical trials usually exclude patients with preexisting cardiac conditions and the enrolled patients are usually monitored diligently as per clinical trial protocols. Therefore, a clinical trial setting is not the representative of the most commonly encountered scenario in the community clinical practice. This study aims to identify the incidence and risk factors for CVAEs associated with carfilzomib for the treatment of MM using Surveillance Epidemiology and Endpoint Research (SEER)‐Medicare data set, which gives a real‐world experience of carfilzomib.
2 METHODS
This study is a retrospective study completed through the SEER‐Medicare data set. The SEER program, supported by the National Cancer Institute (NCI), contains cancer patients’ demographic and tumor characteristics for approximately 34% of the U.S. population. The Medicare data set, maintained by the Centers for Medicare and Medicaid Services, contains health care claims and payment information, for over 97% of the U.S. population aged 65 years or older. We used this linked SEER‐Medicare data set, which captures treatment information after a cancer diagnosis from the Medicare insurance program along with individual patient‐level demographic and survival data from the SEER cancer registry program.
2.1 Study population
This study included patients age ≥ 65 years‐old with the diagnosis of MM between 2001 and 2015. To capture the prior history or risk factors for cardiovascular events, only patients who were enrolled in Medicare for at least 1 year before diagnosis were included. Patients were identified using International Classification of Diseases for Oncology, third edition (ICD‐O‐3) codes from the SEER database. We excluded patients with amyloidosis as those patients can have cardiac dysfunction and can be a confounding factor.
ICD 9/10 codes were used to identify past medical history and the new cardiovascular diagnosis after treatment with carfilzomib. Basic demographic data were collected for sex, race/ethnicity, Nicotine/tobacco use, obesity, and Charleston comorbidity index (CCI) among others. Various cardiovascular diagnoses including ischemic heart disease, congestive heart failure, conduction disorders (arrhythmia and blocks) were identified using ICD9/10. We also identified hazards of edema, chest pain, dyspnea, and syncope which are reported separately and not included in CVAEs. Treatment details were identified using Healthcare Common Procedure Coding System (HCPCS) and National Drug Code (NDC) drug codes. Data from Medicare claims for linked patients are available for a year after, up to 2016. Details of the diagnostic codes used for study are available as Table S1.
The primary endpoint of the study was the hazard of the all‐new CVAEs associated with carfilzomib use in the entire study cohort of myeloma patients. The secondary endpoint of the study includes risk factors for CVAEs and hazard of different categories of CVAEs in carfilzomib users. We analyzed the potential risk factors for CVAEs the entire study cohort of myeloma patients and then separately for sub‐group of carfilzomib users. The study focuses mainly on risk factors in carfilzomib users. Impact of carfilzomib use pattern and use of other drugs for treatment of myeloma on were also analyzed. We also calculated the hazard of dyspnea, chest pain, edema, and syncope in carfilzomib users versus nonusers.
2.2 Statistical analysis
Patients were divided into two cohorts; carfilzomib users and nonusers. Patient‐, disease‐, and treatment‐related factors were compared using the Chi‐square test for categorical and the Kruskal–Wallis test for continuous variables. A Cox proportional‐hazards model was constructed to determine the relationship between CVAEs and carfilzomib therapy and was controlled for various variables including age, sex, race/ethnicity, previous autologous transplant, CCI, preexisting conditions including body mass index (BMI), nicotine/tobacco use, preexisting diabetes, preexisting hypertension, preexisting cardiovascular conditions, and previous anthracycline use. The goodness of fit was assessed using the method of Hosmer and Lemeshow. Within the treatment group, we also used Cox proportional‐hazards models to examine how the preexisting conditions predicted the newly diagnosed CVAEs. Cox models were also adjusted for the aforementioned patients' characteristics. All statistical tests were two‐sided and statistical significance was defined as p < 0.05. Analyses were conducted using SAS version 9.4 software (SAS Institute).
3 RESULTS
3.1 Patient characteristics
A total of 7330 patients with multiple myeloma were included in the study; 815 (11.1%) carfilzomib users and 6515 (88.9%) carfilzomib nonusers. Figure 1 shows the flowsheet for the study cohort derivation.
FIGURE 1 Flowsheet detailing cohort derivation from the SEER‐Medicare data set. HCPCS, Healthcare Common Procedure Coding System; HMO, Health Maintenance Organization
Baseline characteristics of the entire cohort including carfilzomib users and nonusers are shown in Table 1. Carfilzomib‐user cohort was younger, white race, had lower CCI compare to nonusers. A higher proportion of carfilzomib users had a history of hypertension or pre‐existing cardiovascular diseases. Furthermore, Carfilzomib use was higher in patients with relapsed myeloma and prior history of stem cell transplant (Table S2). No significant differences were observed between the two groups in terms of sex and pre‐existing history of diabetes. The study model was controlled for these different variables.
TABLE 1 Patient demographics and clinical characteristics of carfilzomib users and non‐users
Characteristics Total Carfilzomib use
p‐value
Yes % No %
Year of diagnosis
2001–2012 4459 537 12.0 3922 88.0 0.0001
2013 1088 121 11.1 967 88.9
2014 856 92 10.7 764 89.3
2015 927 65 7.0 862 93.0
Age groups
66–69 1813 286 15.8 1527 84.2 <0.0001
70–74 2015 291 14.4 1724 85.6
75–79 1627 146 9.0 1481 91.0
80+ 1875 92 4.9 1783 95.1
Sex
Male 3846 429 11.2 3417 88.8 0.9185
Female 3484 386 11.1 3098 88.9
Race/ethnicity
Non‐Hispanic white 5332 640 12.0 4692 88.0 <0.0001
Non‐Hispanic black 1076 98 9.1 978 90.9
Other 400 29 7.3 371 92.8
Hispanic 522 48 9.2 474 90.8
Myeloma
New 5621 355 6.3 5266 93.7 <0.0001
Relapsed 1709 460 26.9 1249 73.1
Previous transplant
No 6483 606 9.3 5877 90.7 <0.0001
Yes 847 209 24.7 638 75.3
Charleston comorbidity index
0 4788 613 12.8 4175 87.2 <0.0001
1 1293 129 10.0 1164 90.0
2 631 41 6.5 590 93.5
3+ 618 32 5.2 586 94.8
Body mass index
Other 6775 693 10.2 6082 89.8 <0.0001
Overweight 60 15 25.0 45 75.0
Obesity 495 107 21.6 388 78.4
Nicotine/tobacco use
Never 6565 557 8.5 6008 91.5 <0.0001
Current/former 765 258 33.7 507 66.3
Pre‐existing diabetes
No 4311 465 10.8 3846 89.2 0.2795
Yes 3019 350 11.6 2669 88.4
Pre‐existing hypertension
No 6682 584 8.7 6098 91.3 <0.0001
Yes 648 231 35.6 417 64.4
Pre‐existing cardiovascular conditions
No 3452 302 8.7 3150 91.3 <0.0001
Yes 3878 513 13.2 3365 86.8
Previous anthracycline use
No 7177 755 10.5 6422 89.5 <0.0001
Yes 153 60 39.2 93 60.8
John Wiley & Sons, Ltd3.2 Risk factors associated with CVAEs in the entire study cohort of myeloma patients, including carfilzomib users and nonusers
Based on the multivariate analysis, carfilzomib use was independently associated with an increase in the risk of development of CVAEs in the entire study cohort of MM patients. Compared to carfilzomib nonusers, the HR for CVAEs for carfilzomib users was 1.41 (95% CI 1.26–1.58, p < 0.0001). In addition to exposure to carfilzomib, advancing age, male sex, white race, higher CCI, higher BMI, nicotine/tobacco use, preexisting hypertension, and other cardiovascular diagnosis were associated with an increased risk for CVAEs. Pre‐existing diabetes and previous anthracycline use were not associated with higher CVAEs. Please see Table S3 for results of multivariable analysis of the entire study cohort.
3.3 Risk factors associated with CVAEs in sub‐group of carfilzomib users
Based on the multivariate analysis, age 75–79 years (HR 1.35, p = 0.0394) and above 80 (HR 1.53, p = 0.0118) were associated with a significantly higher risk of CVAEs compared to patients aged 65–69 years. Whereas obesity (HR 1.57, p = 0.0006), pre‐existing hypertension (HR 1.57, p = 0.0006), and preexisting other cardiovascular diagnoses (HR 2.75, p < 0.0001) were also significant risk factors. Patient's sex, race/ethnicity, nicotine/tobacco use, preexisting diabetes, previous anthracycline use, and history of the previous autologous transplant were not associated with higher CVAEs. Please see Figure 2 for details. Among all carfilzomib users, 57.6% (n = 469) were noted to have one or more CVAEs. The median time to onset of these CVAEs was 3.1 months.
FIGURE 2 Adjusted hazard ratios for cardiovascular adverse events in carfilzomib users (n = 815). CI, confidence interval; HR, hazards ratio; NH, non‐Hispanic
3.4 Categories of CVAEs
The study cohort was then analyzed for the hazards of various categories of new‐onset CVAEs. Cardiovascular events were categorized into ischemic heart disease, heart failure, conduction disorders (arrhythmia and heart blocks), and hypertension. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Please see Figure 3 for details.
FIGURE 3 Adjusted hazard ratios of patient using carfilzomib in cardiovascular adverse effects. CI, confidence interval; HR, hazards ratio
3.5 Symptoms
Hazards of certain new‐onset symptoms were also studied in the entire study cohort. Carfilzomib users were at higher risk of new‐onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers (Figure 4).
FIGURE 4 Hazards of new‐onset symptoms in carfilzomib users as compared to nonusers. CI, confidence interval; HR, hazards ratio
3.6 Carfilzomib use pattern
The SEER‐Medicare data set has limited information about drug doses. We analyzed carfilzomib usage information based on reimbursement patterns. Although, not perfect but this does provide some insight into the pattern of carfilzomib use and associated toxicity. The multivariate logistic regression model was used after controlling various variables as described previously.
The overall median duration of carfilzomib therapy was 3.6 months and the median number of carfilzomib doses used was 24. The median interval between the two doses was 4.5 days. Patients receiving twice a week carfilzomib were identified as a treatment interval of fewer than 4 days. Carfilzomib was used once a week in 38% of patients while in rest 62% of patients; carfilzomib was used twice a week. Weekly infusion of carfilzomib was associated with a lower risk of cardiovascular toxicity compare to twice‐weekly infusions (HR 0.76, 95% CI: 0.62–0.92, p = 0.0051).
Carfilzomib was used as a single agent in 61% (n = 496) and in combination with other drugs in 39% (n = 319) of patients. When prescribed in combination, carfilzomib was most commonly used with cyclophosphamide in 27.7% (n = 218) followed by daratumumab in 8.3% (n = 68) and Lenalidomide in 2.7% (n = 22). Combination use with Pomalidomide or Thalidomide was minimal. In comparison to single‐agent carfilzomib, combined use with cyclophosphamide, daratumumab, lenalidomide, pomalidomide, or thalidomide was not associated with increased risk for CVAEs.
4 DISCUSSION
Our study is an extensive review of carfilzomib associated CVAEs using the SEER‐Medicare data set that approximately includes 34% of the U.S. population and represents a commonly encountered patient population as compared to selective patients enrolled through clinical trials. We identified a significantly increased risk of CVAEs with carfilzomib therapy, even after controlling for multiple variables. The incidence of CVAEs (57.6%) was higher as compared to previously reported incidence through pooled analysis but these rates are closer to the prospective study done by Cornell et al to identify the incidence of CVAEs.
14
Similar to previous retrospective studies, we found that pre‐existing hypertension and other cardiovascular diagnoses were associated with a higher risk of CVAEs after carfilzomib use. Elderly patients above age 75 years and obesity were at higher risk for CVAEs from carfilzomib use. The majority of MM patients who received carfilzomib had relapsed disease and were likely to have received previous treatments or underwent an autologous transplant. Our study did not find that patients with either relapsed disease or previous autologous transplant had higher CVAEs after carfilzomib use.
As previously reported in the literature, we also identified highly significant HR for heart failure, ischemic heart disease, and hypertension while there was no association with conduction disorders (arrhythmia and blocks). Conduction disorders have been reported with carfilzomib use, but the literature review was not consistent with this toxicity. Like other studies
6
,
12
our study also identified that carfilzomib users had significant hazards of new‐onset dyspnea, chest pain, edema, and syncope, as compared to nonusers. Although these symptoms are not specific, we recommend careful monitoring of these symptoms as it might help in the early detection of CVAEs.
Our study did not identify any combination regimens to be associated with a higher risk for CVAEs as compared to the use of carfilzomib alone. Once a week use was associated with lower CVAEs as compared to twice a week use of carfilzomib. A study by Moreau et al reported prolonged progression‐free survival and fewer cardiac failure events with the once weekly schedule as compared to a twice‐weekly schedule.
17
Since studies so far have not shown any clear evidence of dose‐dependent cardiovascular toxicity form carfilzomib, this finding suggests that quicker frequency may be related to higher toxicity. Although this finding is significant, we advise caution in clinical interpretation in the absence of exact dosages information, which unfortunately is a known limitation of the SEER‐Medicare data set.
Various preventative and management strategies have been proposed for carfilzomib‐induced cardiotoxicity by single‐center studies.
18
,
19
These include baseline cardiac function evaluation, optimizing underlying hypertension and cardiac conditions, careful fluid management, and symptom directed workup while on carfilzomib therapy. Although faster infusion rates of carfilzomib have been reported to be associated with higher CVAEs the prospective observational study by Cornell et al did not find any such association.
14
,
20
Cautious re‐challenge with a reduced dose of carfilzomib after the resolution of cardiac events has also been recommended. European Myeloma network and the Italian society of arterial hypertension also released a consensus paper with a scoring system based on risk factors and management recommendations for patients using carfilzomib.
21
In summary, with our study results and previous data, we can assertively say that there is enough evidence to strongly associate the significant risk of CVAEs with the use of carfilzomib. As such, there is a need for identifying patients at higher risk, cautious monitoring, prompt identification, and management of carfilzomib associated CVAEs. Patients with pre‐existing cardiovascular conditions should be monitored closely by a multidisciplinary team from cardiology and oncology which is also a recommendation from the International Cardio‐Oncology Society (ICOS).
22
This is absolutely necessary until we have a full understanding of all the risk factors, preventative measures, and long‐term toxicity from carfilzomib use.
5 CONCLUSIONS
This study from a large SEER‐Medicare data set provides further evidence of carfilzomib‐associated CVAEs and identifies potential risk factors.
5.1 Study limitations
This study has an inherent limitation of retrospective design and thus we infer association and not direct causation. Although the SEER database includes data from 19 different geographical areas covering approximately 34% of the U.S. population from diverse demographics and locations it cannot be ascertained that every population group has proper representation. Authors caution that results might be affected by various local risk factors, including access to health care, and should be considered for an individual patient The SEER‐Medicare database does not contain clinical measures of disease severity, information regarding chemotherapy dosage and schedule or management of cardiovascular toxicity. In addition, this study included elderly patients with age ≥ 65 years and prone to reporting bias. Therefore, the results may not be generalizable to younger populations or those not covered by Medicare. We have included nicotine/tobacco use and BMI in analyses based on ICD‐9/10 diagnoses codes from Medicare data. However, the sensitivity of these codes is low. Even considering these limitations, studies from SEER‐Medicare data sets have provided clinically relevant information, which often is not feasible from clinical trials.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The Institution Review Board (IRB) at the University of Florida, Gainesville FL, approved this study and all standard ethical guidelines were followed. A full waiver of informed consent was obtained.
CONSENT TO PUBLICATION
Not applicable. The manuscript does not contain any individual patients' data.
Supporting information
Table S1‐S3
Click here for additional data file.
ACKNOWLEDGEMENTS
None.
DATA AVAILABILITY STATEMENT
The data sets used for the current study are available from SEER‐Medicare. This study used the linked SEER‐Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER‐Medicare database.
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CARFILZOMIB
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DrugsGivenReaction
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CC BY
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33169938
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2021-01
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Syncope'.
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Real-world experience of carfilzomib-associated cardiovascular adverse events: SEER-Medicare data set analysis.
Carfilzomib was approved for the treatment of multiple myeloma in 2012 and since then there have been concerns for cardiovascular toxicity from its use. With this study, we aim to further study the hazards and underlying risk factors for cardiovascular adverse events associated with carfilzomib. This study was conducted using Surveillance, Epidemiology, and End Results (SEER)-Medicare data set of multiple myeloma from 2001 to 2015. Data were analyzed for hazards ratio of cardiovascular adverse events between carfilzomib users and nonusers. We identified 7330 patients with multiple myeloma of whom 815 were carfilzomib users. Carfilzomib users had a statistically significant hazard ratio of 1.41 with p < 0.0001 for all cardiovascular adverse events as compared to nonusers. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Carfilzomib users were at higher risk of new-onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers. Age above 75 years, preexisting cardiovascular disease, obesity, and twice a week carfilzomib schedule were significant risk factors associated with cardiovascular adverse events in carfilzomib users. The median time of the onset for all cardiovascular adverse events was 3.1 months. This study has identified a significantly higher likelihood of cardiovascular adverse events in elderly Medicare patients receiving carfilzomib.
1 BACKGROUND
Proteasome inhibitors (PI) comprise an important class of drugs for treating multiple myeloma (MM). Currently, three drugs are approved in this class, bortezomib, carfilzomib, and ixazomib. Carfilzomib is a second‐generation, highly selective and irreversible PI which received accelerated approval by the United States Food and Drug Administration (FDA) in July 2012.
1
This approval was based on a phase II study where carfilzomib demonstrated an overall response rate (ORR) of about 23% for relapsed and refractory multiple myeloma (RRMM).
2
Since then carfilzomib has been approved for multiple other indications for the treatment of MM. Presently, as per the National Comprehensive Cancer Network (NCCN) guidelines, carfilzomib is recommended for primary therapy of MM in transplant‐eligible as well as transplant‐ineligible patients. In the RRMM, carfilzomib is recommended as a preferred regimen either as a single agent or in combination with other agents.
Since its approval, cardiovascular adverse events (CVAEs) from carfilzomib has been a concern. Initially, carfilzomib associated CVAEs were reported in about 22% patients from the grouped data of four phase II studies in 2013.
3
Meta‐analyses of clinical trials have shown that up to 18% of patients experienced CVAEs.
4
,
5
,
6
,
7
These studies reported CVAEs with variable rates and the most common CVAEs were hypertension (18.5%) and heart failure (6.7%). Arrhythmia (2.4%) and ischemic events (3.7%) were observed less commonly. Other significant CVAEs were dyspnea (31.9%) and edema (24.7%).
6
,
7
Multiple studies have tried to identify risk factors for Carfilzomib associated cardiotoxicity. Retrospective studies from single institutions have reported prior cardiac history as a risk factor for carfilzomib associated cardiotoxicity.
8
,
9
,
10
Most of CVAEs have been reported to occur soon after carfilzomib use, rarely beyond 12 cycles and the systolic dysfunction is usually reversible.
9
,
11
,
12
Current evidence is not clear for an association of CVAEs with the dose or the duration of carfilzomib use but re‐challenge with reduced dose has been recommended.
4
,
11
,
13
The prospective observational study by Cornell et al reported that 51% of patients treated with carfilzomib developed CVAEs including heart failure (41%), hypertension (23%), arrhythmia (7%), an acute coronary syndrome in (6%), and also reported chest pain in 9% of patients.
14
There was no association between drug dose, infusion time, and concurrent drugs or fluids administered with carfilzomib but elevated natriuretic peptide was associated with increased risk of CVAEs. Similarly, 33% of patients experienced CVAEs in the study by Bruno et al and baseline uncontrolled blood pressure, left ventricular hypertrophy, and higher pulse‐wave velocity were identified as risk factors.
15
Cardiovascular adverse events remains the drug limiting toxicity of carfilzomib and NCCN also alerts for potential carfilzomib related cardiac and pulmonary toxicity, especially in elderly patients. As the median age for diagnosis of MM is 70 years, nearly two‐thirds of patients have preexisting cardiovascular disease at baseline, hence, at risk of developing carfilzomib associated CVAEs.
16
We have enough scientific evidence about CVAEs from the use of carfilzomib which is mainly obtained through pooled analysis of data from clinical trials. Clinical trials usually exclude patients with preexisting cardiac conditions and the enrolled patients are usually monitored diligently as per clinical trial protocols. Therefore, a clinical trial setting is not the representative of the most commonly encountered scenario in the community clinical practice. This study aims to identify the incidence and risk factors for CVAEs associated with carfilzomib for the treatment of MM using Surveillance Epidemiology and Endpoint Research (SEER)‐Medicare data set, which gives a real‐world experience of carfilzomib.
2 METHODS
This study is a retrospective study completed through the SEER‐Medicare data set. The SEER program, supported by the National Cancer Institute (NCI), contains cancer patients’ demographic and tumor characteristics for approximately 34% of the U.S. population. The Medicare data set, maintained by the Centers for Medicare and Medicaid Services, contains health care claims and payment information, for over 97% of the U.S. population aged 65 years or older. We used this linked SEER‐Medicare data set, which captures treatment information after a cancer diagnosis from the Medicare insurance program along with individual patient‐level demographic and survival data from the SEER cancer registry program.
2.1 Study population
This study included patients age ≥ 65 years‐old with the diagnosis of MM between 2001 and 2015. To capture the prior history or risk factors for cardiovascular events, only patients who were enrolled in Medicare for at least 1 year before diagnosis were included. Patients were identified using International Classification of Diseases for Oncology, third edition (ICD‐O‐3) codes from the SEER database. We excluded patients with amyloidosis as those patients can have cardiac dysfunction and can be a confounding factor.
ICD 9/10 codes were used to identify past medical history and the new cardiovascular diagnosis after treatment with carfilzomib. Basic demographic data were collected for sex, race/ethnicity, Nicotine/tobacco use, obesity, and Charleston comorbidity index (CCI) among others. Various cardiovascular diagnoses including ischemic heart disease, congestive heart failure, conduction disorders (arrhythmia and blocks) were identified using ICD9/10. We also identified hazards of edema, chest pain, dyspnea, and syncope which are reported separately and not included in CVAEs. Treatment details were identified using Healthcare Common Procedure Coding System (HCPCS) and National Drug Code (NDC) drug codes. Data from Medicare claims for linked patients are available for a year after, up to 2016. Details of the diagnostic codes used for study are available as Table S1.
The primary endpoint of the study was the hazard of the all‐new CVAEs associated with carfilzomib use in the entire study cohort of myeloma patients. The secondary endpoint of the study includes risk factors for CVAEs and hazard of different categories of CVAEs in carfilzomib users. We analyzed the potential risk factors for CVAEs the entire study cohort of myeloma patients and then separately for sub‐group of carfilzomib users. The study focuses mainly on risk factors in carfilzomib users. Impact of carfilzomib use pattern and use of other drugs for treatment of myeloma on were also analyzed. We also calculated the hazard of dyspnea, chest pain, edema, and syncope in carfilzomib users versus nonusers.
2.2 Statistical analysis
Patients were divided into two cohorts; carfilzomib users and nonusers. Patient‐, disease‐, and treatment‐related factors were compared using the Chi‐square test for categorical and the Kruskal–Wallis test for continuous variables. A Cox proportional‐hazards model was constructed to determine the relationship between CVAEs and carfilzomib therapy and was controlled for various variables including age, sex, race/ethnicity, previous autologous transplant, CCI, preexisting conditions including body mass index (BMI), nicotine/tobacco use, preexisting diabetes, preexisting hypertension, preexisting cardiovascular conditions, and previous anthracycline use. The goodness of fit was assessed using the method of Hosmer and Lemeshow. Within the treatment group, we also used Cox proportional‐hazards models to examine how the preexisting conditions predicted the newly diagnosed CVAEs. Cox models were also adjusted for the aforementioned patients' characteristics. All statistical tests were two‐sided and statistical significance was defined as p < 0.05. Analyses were conducted using SAS version 9.4 software (SAS Institute).
3 RESULTS
3.1 Patient characteristics
A total of 7330 patients with multiple myeloma were included in the study; 815 (11.1%) carfilzomib users and 6515 (88.9%) carfilzomib nonusers. Figure 1 shows the flowsheet for the study cohort derivation.
FIGURE 1 Flowsheet detailing cohort derivation from the SEER‐Medicare data set. HCPCS, Healthcare Common Procedure Coding System; HMO, Health Maintenance Organization
Baseline characteristics of the entire cohort including carfilzomib users and nonusers are shown in Table 1. Carfilzomib‐user cohort was younger, white race, had lower CCI compare to nonusers. A higher proportion of carfilzomib users had a history of hypertension or pre‐existing cardiovascular diseases. Furthermore, Carfilzomib use was higher in patients with relapsed myeloma and prior history of stem cell transplant (Table S2). No significant differences were observed between the two groups in terms of sex and pre‐existing history of diabetes. The study model was controlled for these different variables.
TABLE 1 Patient demographics and clinical characteristics of carfilzomib users and non‐users
Characteristics Total Carfilzomib use
p‐value
Yes % No %
Year of diagnosis
2001–2012 4459 537 12.0 3922 88.0 0.0001
2013 1088 121 11.1 967 88.9
2014 856 92 10.7 764 89.3
2015 927 65 7.0 862 93.0
Age groups
66–69 1813 286 15.8 1527 84.2 <0.0001
70–74 2015 291 14.4 1724 85.6
75–79 1627 146 9.0 1481 91.0
80+ 1875 92 4.9 1783 95.1
Sex
Male 3846 429 11.2 3417 88.8 0.9185
Female 3484 386 11.1 3098 88.9
Race/ethnicity
Non‐Hispanic white 5332 640 12.0 4692 88.0 <0.0001
Non‐Hispanic black 1076 98 9.1 978 90.9
Other 400 29 7.3 371 92.8
Hispanic 522 48 9.2 474 90.8
Myeloma
New 5621 355 6.3 5266 93.7 <0.0001
Relapsed 1709 460 26.9 1249 73.1
Previous transplant
No 6483 606 9.3 5877 90.7 <0.0001
Yes 847 209 24.7 638 75.3
Charleston comorbidity index
0 4788 613 12.8 4175 87.2 <0.0001
1 1293 129 10.0 1164 90.0
2 631 41 6.5 590 93.5
3+ 618 32 5.2 586 94.8
Body mass index
Other 6775 693 10.2 6082 89.8 <0.0001
Overweight 60 15 25.0 45 75.0
Obesity 495 107 21.6 388 78.4
Nicotine/tobacco use
Never 6565 557 8.5 6008 91.5 <0.0001
Current/former 765 258 33.7 507 66.3
Pre‐existing diabetes
No 4311 465 10.8 3846 89.2 0.2795
Yes 3019 350 11.6 2669 88.4
Pre‐existing hypertension
No 6682 584 8.7 6098 91.3 <0.0001
Yes 648 231 35.6 417 64.4
Pre‐existing cardiovascular conditions
No 3452 302 8.7 3150 91.3 <0.0001
Yes 3878 513 13.2 3365 86.8
Previous anthracycline use
No 7177 755 10.5 6422 89.5 <0.0001
Yes 153 60 39.2 93 60.8
John Wiley & Sons, Ltd3.2 Risk factors associated with CVAEs in the entire study cohort of myeloma patients, including carfilzomib users and nonusers
Based on the multivariate analysis, carfilzomib use was independently associated with an increase in the risk of development of CVAEs in the entire study cohort of MM patients. Compared to carfilzomib nonusers, the HR for CVAEs for carfilzomib users was 1.41 (95% CI 1.26–1.58, p < 0.0001). In addition to exposure to carfilzomib, advancing age, male sex, white race, higher CCI, higher BMI, nicotine/tobacco use, preexisting hypertension, and other cardiovascular diagnosis were associated with an increased risk for CVAEs. Pre‐existing diabetes and previous anthracycline use were not associated with higher CVAEs. Please see Table S3 for results of multivariable analysis of the entire study cohort.
3.3 Risk factors associated with CVAEs in sub‐group of carfilzomib users
Based on the multivariate analysis, age 75–79 years (HR 1.35, p = 0.0394) and above 80 (HR 1.53, p = 0.0118) were associated with a significantly higher risk of CVAEs compared to patients aged 65–69 years. Whereas obesity (HR 1.57, p = 0.0006), pre‐existing hypertension (HR 1.57, p = 0.0006), and preexisting other cardiovascular diagnoses (HR 2.75, p < 0.0001) were also significant risk factors. Patient's sex, race/ethnicity, nicotine/tobacco use, preexisting diabetes, previous anthracycline use, and history of the previous autologous transplant were not associated with higher CVAEs. Please see Figure 2 for details. Among all carfilzomib users, 57.6% (n = 469) were noted to have one or more CVAEs. The median time to onset of these CVAEs was 3.1 months.
FIGURE 2 Adjusted hazard ratios for cardiovascular adverse events in carfilzomib users (n = 815). CI, confidence interval; HR, hazards ratio; NH, non‐Hispanic
3.4 Categories of CVAEs
The study cohort was then analyzed for the hazards of various categories of new‐onset CVAEs. Cardiovascular events were categorized into ischemic heart disease, heart failure, conduction disorders (arrhythmia and heart blocks), and hypertension. Carfilzomib use was significantly associated with increased risk of heart failure (HR 1.47, p = 0.0002), ischemic heart disease (HR 1.45, p = 0.0002), and hypertension (HR 3.33, p < 0.0001), whereas there was no association between carfilzomib use and cardiac conduction disorders (arrhythmia and heart blocks). Please see Figure 3 for details.
FIGURE 3 Adjusted hazard ratios of patient using carfilzomib in cardiovascular adverse effects. CI, confidence interval; HR, hazards ratio
3.5 Symptoms
Hazards of certain new‐onset symptoms were also studied in the entire study cohort. Carfilzomib users were at higher risk of new‐onset edema (HR 5.09, p < 0.0001), syncope (HR 4.27, p < 0.0001), dyspnea (HR 1.33, p < 0.0001), and chest pain (HR 1.18, p < 0.0001) as compared to carfilzomib nonusers (Figure 4).
FIGURE 4 Hazards of new‐onset symptoms in carfilzomib users as compared to nonusers. CI, confidence interval; HR, hazards ratio
3.6 Carfilzomib use pattern
The SEER‐Medicare data set has limited information about drug doses. We analyzed carfilzomib usage information based on reimbursement patterns. Although, not perfect but this does provide some insight into the pattern of carfilzomib use and associated toxicity. The multivariate logistic regression model was used after controlling various variables as described previously.
The overall median duration of carfilzomib therapy was 3.6 months and the median number of carfilzomib doses used was 24. The median interval between the two doses was 4.5 days. Patients receiving twice a week carfilzomib were identified as a treatment interval of fewer than 4 days. Carfilzomib was used once a week in 38% of patients while in rest 62% of patients; carfilzomib was used twice a week. Weekly infusion of carfilzomib was associated with a lower risk of cardiovascular toxicity compare to twice‐weekly infusions (HR 0.76, 95% CI: 0.62–0.92, p = 0.0051).
Carfilzomib was used as a single agent in 61% (n = 496) and in combination with other drugs in 39% (n = 319) of patients. When prescribed in combination, carfilzomib was most commonly used with cyclophosphamide in 27.7% (n = 218) followed by daratumumab in 8.3% (n = 68) and Lenalidomide in 2.7% (n = 22). Combination use with Pomalidomide or Thalidomide was minimal. In comparison to single‐agent carfilzomib, combined use with cyclophosphamide, daratumumab, lenalidomide, pomalidomide, or thalidomide was not associated with increased risk for CVAEs.
4 DISCUSSION
Our study is an extensive review of carfilzomib associated CVAEs using the SEER‐Medicare data set that approximately includes 34% of the U.S. population and represents a commonly encountered patient population as compared to selective patients enrolled through clinical trials. We identified a significantly increased risk of CVAEs with carfilzomib therapy, even after controlling for multiple variables. The incidence of CVAEs (57.6%) was higher as compared to previously reported incidence through pooled analysis but these rates are closer to the prospective study done by Cornell et al to identify the incidence of CVAEs.
14
Similar to previous retrospective studies, we found that pre‐existing hypertension and other cardiovascular diagnoses were associated with a higher risk of CVAEs after carfilzomib use. Elderly patients above age 75 years and obesity were at higher risk for CVAEs from carfilzomib use. The majority of MM patients who received carfilzomib had relapsed disease and were likely to have received previous treatments or underwent an autologous transplant. Our study did not find that patients with either relapsed disease or previous autologous transplant had higher CVAEs after carfilzomib use.
As previously reported in the literature, we also identified highly significant HR for heart failure, ischemic heart disease, and hypertension while there was no association with conduction disorders (arrhythmia and blocks). Conduction disorders have been reported with carfilzomib use, but the literature review was not consistent with this toxicity. Like other studies
6
,
12
our study also identified that carfilzomib users had significant hazards of new‐onset dyspnea, chest pain, edema, and syncope, as compared to nonusers. Although these symptoms are not specific, we recommend careful monitoring of these symptoms as it might help in the early detection of CVAEs.
Our study did not identify any combination regimens to be associated with a higher risk for CVAEs as compared to the use of carfilzomib alone. Once a week use was associated with lower CVAEs as compared to twice a week use of carfilzomib. A study by Moreau et al reported prolonged progression‐free survival and fewer cardiac failure events with the once weekly schedule as compared to a twice‐weekly schedule.
17
Since studies so far have not shown any clear evidence of dose‐dependent cardiovascular toxicity form carfilzomib, this finding suggests that quicker frequency may be related to higher toxicity. Although this finding is significant, we advise caution in clinical interpretation in the absence of exact dosages information, which unfortunately is a known limitation of the SEER‐Medicare data set.
Various preventative and management strategies have been proposed for carfilzomib‐induced cardiotoxicity by single‐center studies.
18
,
19
These include baseline cardiac function evaluation, optimizing underlying hypertension and cardiac conditions, careful fluid management, and symptom directed workup while on carfilzomib therapy. Although faster infusion rates of carfilzomib have been reported to be associated with higher CVAEs the prospective observational study by Cornell et al did not find any such association.
14
,
20
Cautious re‐challenge with a reduced dose of carfilzomib after the resolution of cardiac events has also been recommended. European Myeloma network and the Italian society of arterial hypertension also released a consensus paper with a scoring system based on risk factors and management recommendations for patients using carfilzomib.
21
In summary, with our study results and previous data, we can assertively say that there is enough evidence to strongly associate the significant risk of CVAEs with the use of carfilzomib. As such, there is a need for identifying patients at higher risk, cautious monitoring, prompt identification, and management of carfilzomib associated CVAEs. Patients with pre‐existing cardiovascular conditions should be monitored closely by a multidisciplinary team from cardiology and oncology which is also a recommendation from the International Cardio‐Oncology Society (ICOS).
22
This is absolutely necessary until we have a full understanding of all the risk factors, preventative measures, and long‐term toxicity from carfilzomib use.
5 CONCLUSIONS
This study from a large SEER‐Medicare data set provides further evidence of carfilzomib‐associated CVAEs and identifies potential risk factors.
5.1 Study limitations
This study has an inherent limitation of retrospective design and thus we infer association and not direct causation. Although the SEER database includes data from 19 different geographical areas covering approximately 34% of the U.S. population from diverse demographics and locations it cannot be ascertained that every population group has proper representation. Authors caution that results might be affected by various local risk factors, including access to health care, and should be considered for an individual patient The SEER‐Medicare database does not contain clinical measures of disease severity, information regarding chemotherapy dosage and schedule or management of cardiovascular toxicity. In addition, this study included elderly patients with age ≥ 65 years and prone to reporting bias. Therefore, the results may not be generalizable to younger populations or those not covered by Medicare. We have included nicotine/tobacco use and BMI in analyses based on ICD‐9/10 diagnoses codes from Medicare data. However, the sensitivity of these codes is low. Even considering these limitations, studies from SEER‐Medicare data sets have provided clinically relevant information, which often is not feasible from clinical trials.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The Institution Review Board (IRB) at the University of Florida, Gainesville FL, approved this study and all standard ethical guidelines were followed. A full waiver of informed consent was obtained.
CONSENT TO PUBLICATION
Not applicable. The manuscript does not contain any individual patients' data.
Supporting information
Table S1‐S3
Click here for additional data file.
ACKNOWLEDGEMENTS
None.
DATA AVAILABILITY STATEMENT
The data sets used for the current study are available from SEER‐Medicare. This study used the linked SEER‐Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER‐Medicare database.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal pain'.
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
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BISMUTH, METRONIDAZOLE, OMEPRAZOLE, TETRACYCLINE
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DrugsGivenReaction
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CC BY-NC-ND
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33176617
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2021-02
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'.
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
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BISMUTH SUBCITRATE POTASSIUM\METRONIDAZOLE\TETRACYCLINE HYDROCHLORIDE
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DrugsGivenReaction
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CC BY-NC-ND
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33176617
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2021-02
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypertension'.
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
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BISMUTH SUBCITRATE POTASSIUM\METRONIDAZOLE\TETRACYCLINE HYDROCHLORIDE
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DrugsGivenReaction
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CC BY-NC-ND
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33176617
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2021-02
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypocalcaemia'.
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
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BISMUTH SUBCITRATE POTASSIUM\METRONIDAZOLE\TETRACYCLINE HYDROCHLORIDE
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DrugsGivenReaction
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CC BY-NC-ND
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33176617
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2021-02
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'.
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
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BISMUTH, METRONIDAZOLE, OMEPRAZOLE, TETRACYCLINE
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DrugsGivenReaction
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CC BY-NC-ND
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33176617
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2021-02
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vomiting'.
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
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BISMUTH, METRONIDAZOLE, OMEPRAZOLE, TETRACYCLINE
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DrugsGivenReaction
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CC BY-NC-ND
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33176617
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2021-02
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What was the dosage of drug 'BISMUTH SUBCITRATE POTASSIUM\METRONIDAZOLE\TETRACYCLINE HYDROCHLORIDE'?
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
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What was the dosage of drug 'METRONIDAZOLE'?
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
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What was the dosage of drug 'OMEPRAZOLE'?
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
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What was the dosage of drug 'TETRACYCLINE'?
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
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What was the outcome of reaction 'Hypertension'?
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
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What was the outcome of reaction 'Hypocalcaemia'?
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
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What was the outcome of reaction 'Nausea'?
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
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European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.
There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.
To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.
Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.
Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.
Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.
1 INTRODUCTION
Helicobacter pylori infection is known to be at the root of several of important gastrointestinal diseases, ranging in severity from gastritis, gastroduodenal ulcer disease and preneoplastic lesions, to gastric cancer. 1 In all of these conditions, eradication of this bacterium is considered the best course of action. 2 In addition, H. pylori has been detected in more than half the population worldwide, making it a global health burden. 3 However, we are still in a situation where no therapy is available that achieves a 100% cure rate. Hence, treatment of H. pylori infection remains an important clinical challenge and the current consensus is that suitable therapies should achieve a cure rate of at least 90%. 4 , 5 Nevertheless, the success rate of standard therapies tends to decline due to the increased resistance to antibiotics around the globe. 6 , 7 , 8 Key Summary
The development of a three‐in‐one single‐capsule formulation has led to a resurgence in the use of bismuth quadruple therapy (BQT) to treat Helicobacter pylori infection.
In the largest study carried out to date, the effectiveness of single‐capsule BQT was optimal both as a firstline and as a rescue therapy.
Compliance was the factor most closely associated with treatment effectiveness.
Single‐capsule BQT eradicates H. pylori in approximately 90% of patients in real‐world clinical practice, with a favourable safety profile.
All therapies to treat H. pylori are based on a combination of antibiotics and other adjuvants, ranging from triple therapies involving a proton pump inhibitor (PPI) plus two antibiotics, to quadruple therapies that include bismuth‐free (sequential, concomitant, hybrid regimens) or bismuth‐based therapies. 9 The triple therapy traditionally recommended to eradicate H. pylori, combining the use of a PPI with clarithromycin and amoxicillin or metronidazole, yet appears to fail in over 20% of patients, mainly due to the increasing resistance to these antibiotics worldwide. 7 When considering H. pylori therapies, it is important to differentiate between first‐line therapies and rescue regimens, as the latter are usually compromised by selection or the acquisition of secondary bacterial resistance following previous failed attempts at eradication. 10 , 11 , 12 , 13
Bismuth quadruple therapy (BQT) classically involves a combination of PPI, bismuth, and the antibiotics metronidazole and tetracycline. Randomised clinical trials have shown that BQT eradicates H. pylori better than standard triple therapies and, indeed, the use of BQT may be particularly recommended in areas of high clarithromycin resistance. 9 However, the limited availability of bismuth salts and tetracycline in some countries has restricted the use of BQT. Interest in this therapy resurged with the appearance of the three‐in‐one single‐capsule BQT (marketed as Pylera), containing bismuth, metronidazole and tetracycline, and used as both a first‐line and rescue therapy, as recently reported in a meta‐analysis. 14 Indeed, as a first‐line therapy, 10 days omeprazole and the three‐in‐one single‐capsule BQT was more effective than a 7 days clarithromycin‐based triple therapy in a European phase III trial, 15 confirming the effectiveness of 10 days single‐capsule BQT initially reported. 16
Other factors may also influence the effectiveness of both first‐line and rescue therapies, making it necessary to obtain more information regarding the effectiveness of distinct treatments. For this reason, a European Registry on H. pylori Management (Hp‐EuReg) was set up to collate data regarding the diagnosis, treatment and management of adult patients from over 300 centres in 28 countries. 17 In the current paper, we present an analysis of the data extracted from this registry regarding the patients who were prescribed the three‐in‐one single‐capsule BQT as part of the strategy to manage their H. pylori infection. Accordingly, we analysed the data on the effectiveness and tolerance of this therapy in a real‐world clinical setting as different lines of use. Moreover, we performed a multivariable analysis in an attempt to identify the factors that most strongly influence the success of this therapy with a view to further improving its effectiveness.
2 METHODS
2.1 European Registry on H. pylori management (Hp‐EuReg)
The Hp‐EuReg is an international, multicentre, prospective, noninterventional registry that has been recording information on the management of H. pylori infection since 2013. The Hp‐EuReg scientific committee is currently made up of: Javier P. Gisbert (principal investigator), Francis Megraud, Colm A. O'Morain, Ignasi Puig and Olga P. Nyssen (the two latter are also scientific directors). The Hp‐EuReg protocol 17 establishes national coordinators in the 28 countries selected, where gastroenterologists have been recruited at some 300 centres to provide input to the registry. These specialists introduced a series of variables and outcomes into the registry's database using an electronic case report form. The variables included: the patient's demographic information; any previous attempts at eradication and the treatments employed; the outcomes of any treatment, recording details such as the compliance, the cure rate, the follow‐up, and so on; and any adverse event (AE) reported. The REDCap database 18 is managed and hosted by the Asociación Española de Gastroenterologia (www.aegastro.es), a nonprofit scientific and medical society that focuses on gastroenterology research. The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was prospectively registered at ClinicalTrials.gov (NCT02328131).
2.2 Data analysis
Data were extracted in January 2020, and a quality control check was performed on at least 10% of the records included for each country and centre. The dose of the PPI used for H. pylori eradication treatment was grouped into three categories as reported by Graham et al. 19 and Kirchheiner et al. 20 : low dose, if the potency of acid inhibition was between 4.5 and 27 mg omepra‐zole equivalents when given twice daily; standard dose, between 32 and 40 mg omeprazole equivalents when given twice daily; and high dose, between 54 and 128 mg omeprazole equivalents when given twice daily.
2.3 Effectiveness analysis
The aim of the present analysis was to evaluate the effectiveness and safety of the three‐in‐one single‐capsule BQT when used as any line of treatment (first‐line and any rescue therapy). H. pylori eradication was confirmed with at least one of the following diagnostic methods: urea breath test, stool antigen test and/or histology; at least 1 month after completing eradication treatment.
The main outcome used was the eradication rate achieved with the treatment and it was studied in three subgroups of patients: (a) the intention‐to‐treat (ITT) analysis included all patients that had been registered up to January 2020 and that had at least a 6 month follow‐up, in which lost to follow‐up cases were deemed treatment failures; (b) a per‐protocol (PP) analysis which included all cases that had a complete follow‐up and that had achieved at least 90% compliance with the drug treatment, as defined in the protocol; and (c) a modified ITT (mITT) that aimed to reflect the closest result to that obtained in clinical practice, whereby the mITT included all cases that had completed the follow‐up (i.e., they had undertaken a confirmatory test—success or failure—after the eradication treatment), regardless of compliance but excluding those with an incomplete follow‐up. The effectiveness analyses were performed jointly for patients treated empirically or when treatment was based on the testing of bacterial resistance (as performed in routine clinical practice in each centre). Additional effectiveness analyses were performed separately when the results of an antibiogram were available.
2.4 Statistical analyses
Continuous variables were summarised as the mean and standard deviation, while qualitative variables were presented as the absolute and relative frequencies, displayed as percentages (%). A multivariable analysis was performed to study the relation between the single‐capsule BQT eradication rate in the mITT population and several variables: age, sex (female [ref] vs. male), indication (dyspepsia and others [ref] vs. ulcer disease), compliance (no [ref] vs. yes, as taking >90% of the drug intake), PPI dose (low [ref] vs. standard, and low vs. high); treatment line (first‐line [ref] vs. second‐line vs. all remaining rescue therapies, i.e., third‐line treatment or greater).
3 RESULTS
3.1 Overview and baseline characteristics
From its initiation in May 2013 until January 2020, 34,460 cases from 28 countries were registered in the Hp‐EuReg. Of these, 3439 cases were treated with single‐capsule BQT, and 2100 (6.1%) were prescribed this treatment according to the regimen indicated in the technical sheet (three capsules q.i.d. for 10 days). These latter cases were those considered to be valid for current analysis, excluding the remaining cases. The average age of the cohort analysed was 50.4 (±18.0) years, of whom 64% were women.
The two main medical conditions (81%) for which the single‐capsule BQT was prescribed were dyspepsia (66%) and peptic ulcer (16%). Although 28 countries participated in the Hp‐EuReg, patients only received BQT with the single capsule in 10 of these countries (Table 1). In the five principal countries in which the single‐capsule BQT was used, it was employed as a first‐line treatment in between 46% and 68% of the cases. All the cases studied were treated between 2015 and 2019.
TABLE 1 Patients' basal characteristics
Characteristics at baseline N (%)
Single‐capsule prescriptions (3 capsules q.i.d. for 10 days) 2100 (6.1) a
Female 1337 (63.8)
Age, mean (SD) 50.4 (18.0)
Age 18–30 years 151 (7.3)
Age 31–50 years 745 (36.1)
Age 51‐highest years 1167 (56.6)
Ethnic background (N, %)
Caucasian 1994 (95.0)
Black 13 (0.6)
Asian 28 (1.3)
Other 33 (1.6)
Concurrent medication 944 (45.0)
Proton pump inhibitors (daily or on demand) 675 (71.6)
Acetylsalicylic acid 138 (14.6)
NSAIDs 244 (25.9)
Statins 313 (33.2)
Penicillin allergy 670 (3.1)
Indication (N, %)
Dyspepsia 1367 (65.6)
Ulcer disease 332 (15.8)
No culture performed 2052 (97.7)
Culture (with a result of the antibiotic resistance test) 48 (2.3)
No resistance 3 (6.2)
Clarithromycin resistance 33 (68.7)
Metronidazole resistance 29 (60.4)
Dual clarithromycin + metronidazole resistance 22 (45)
PPI dose
Low 1121 (53.5)
Standard 445 (21.2)
High 529 (25.3)
Compliance
No (<90% drug intake) 66 (3.3)
Yes (≥90% drug intake) 1916 (96.7)
Country
Spain 1677 (79.9)
Italy 274 (13.0)
Portugal 88 (4.2)
Germany 35 (1.7)
Slovenia 17 (0.8)
Russia 3 (0.1)
France 2 (0.1)
Czech Republic 2 (0.1)
Greece 1 (0.0005)
Lithuania 1 (0.0005)
Note: (low dose 4.5–27 mg omeprazole equivalents, b.i.d; standard dose 32–40 mg omeprazole equivalents, b.i.d.; high dose 54–128 mg omeprazole equivalents, b.i.d.).
Abbreviations: N, number of cases; NSAID, nonsteroidal anti‐inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation.
a %, Percentage relative to the total number of patients in the registry (n = 34,460).
3.2 Treatment use
In the cohort analysed, treatment with the single‐capsule BQT was used in different circumstances, mostly in naive patients (64%) or as a second‐line rescue therapy (22%). In the remaining cases (14%), the treatment was used as a rescue treatment after different numbers of precious H. pylori eradication attempts: third‐line (10%); fourth‐line (2.8%); and fifth‐line and beyond (1.4%). Also, the PPI doses used in combination with the single‐capsule BQT varied, with the largest proportion receiving a low PPI dose (54%), the remainder receiving a standard (21%) or a high PPI dose (25%).
3.3 Effectiveness of single‐capsule BQT treatment in different lines of therapy
The effectiveness of the single‐capsule BQT was evaluated using three different measures (ITT, PP and mITT), although we focused on the mITT, as previously mentioned in Section 2. This singlecapsule BQT achieved a 95% eradication rate when used as a first‐line therapy and its success rate as a rescue therapy was also over 90% eradication This success was evident when used both as a second‐line treatment (89% eradication, n = 375) and as a subsequent treatment line, from a third to a sixth line of therapy (92% eradication, n = 236; Table 2). Also, overall mITT eradication significantly improved (p < 0.05) when either standard (recommended) or high PPI doses were used (94% both) as compared to low doses (90%). Finally, a sensitivity analysis was performed excluding patients from Spain: overall mITT effectiveness for non‐Spanish countries was 91%, which did not statistically differ with that of Spain (92.1%).
TABLE 2 Single‐capsule bismuth quadruple therapy effectiveness by line of treatment
ITT PP mITT
N (%) 95% CI N (%) 95% CI N (%) 95% CI
Overall 1724 (85.2) (83.6–86.7) 1761 (92.8) (91.6–94.0) 1777 (91.9) (90.6–93.1)
First‐line 1135 (88.1) (86.3–89.9) 1158 (95.5) (94.2–96.6) 1166 (94.6) (93.2–95.8)
Second‐line 361 (81.5) (77.7–85.2) 370 (90.2) (87.2–93.2) 375 (89.3) (86.2–92.3)
Rescue treatment from third‐line to sixth‐line 228 (85.2) (73.2–82.9) 233 (85.0) (80.6–89.4) 236 (91.9) (79.5–88.4)
Note: The χ 2 test showed statistical significant differences in effectiveness for the different treatment lines as measured by ITT, PP and mITT (p < 0.001).
Abbreviations: CI, confidence interval; ITT, intention‐to‐treat; mITT, modified intention‐to‐treat; PP, per protocol.
3.4 Antibiotic resistance
The influence of bacterial antibiotic resistance on the effectiveness of single‐capsule BQT was evaluated, in particular resistance to clarithromycin, metronidazole or both. The therapy achieved 100% eradication in bacterial antibiotic resistant strains when used as a first or second‐line treatment, both single clarithromycin and metronidazole‐resistant infections, and those resistant to both antibiotics (Table 3). However, this effectiveness decreased when single‐capsule BQT was used as a third‐line treatment for clarithromycin (67% eradication, n = 9) and metronidazole‐resistant (73% eradication, n = 11) infections, and for those infections resistant to both these antibiotics (62%, n = 8; Table 3).
TABLE 3 Effectiveness (by treatment line) of single‐capsule bismuth quadruple therapy in patients with antibiotic bacterial resistance
Overall First‐line Second‐line Third‐line Fourth‐line Fifth‐line
Clarithromycin resistant
E 26 2 7 6 7 4
N 30 2 7 9 7 5
%E 86.7 100 100 66.7 100 80
95% CI (69–96) (16–100) (59–100) (30–92) (59–100) (28–99)
Clarithromycin susceptible
E 14 2 5 4 0 1
N 17 2 5 4 2 1
%E 82.4 100 100 100 0 100
95% CI (56–96) (16–100) (48–100) (40–100) NA (1.2–99)
Metronidazole resistant
E 21 2 4 8 4 3
N 27 2 4 11 6 4
%E 77.8 100 100 72.7 66.6 75
95% CI (58–91) (16–100) (40–100) (39–94) (22–95) (19–99)
Metronidazole susceptible
E 19 2 8 2 3 2
N 20 2 8 2 3 2
%E 95 100 100 100 100 100
95% CI (75–99) (16–100) (63–100) (16–100) (29–100) (16–100)
Dual resistant
E 16 1 3 5 4 3
N 20 1 3 8 4 4
%E 80.0 100 100 62.5 100 75
95% CI (56–94) (1.2–99) (29–100) (24–91) (40–100) (19–99)
Dual susceptible
E 24 3 9 5 3 2
N 27 3 9 5 5 2
%E 88.9 100 100 100 60 100
95% CI (71–97) (29–100) (66–100) (48–100) (14–94) (16–100)
Abbreviations: % E, percentage eradication in the per‐protocol analysis; CI, confidence interval; E, number of patients eradicated; N, total number of patients treated; NA, not applicable.
3.5 Safety
At least one AE was reported by 29% of the patients. The most common AEs reported were nausea (9.5%), diarrhoea (8%), fatigue (6.5%), metallic taste (dysgeu‐sia, 5%), dyspepsia (5%) abdominal pain (5%) and vomiting (3%; see Table 4 for a full list of AEs). These AEs had a mean duration of from 4.8 (±2.9) to 8.4 (±2.3) days. While the AEs were generally mild (99%) and transient, 17% of the patients who experienced fatigue considered it to be severe, as did 14% of those who had anorexia and 10% of those who reported having heartburn (Table 4). Nevertheless, the AEs as a whole had only a limited effect on compliance (3.3% of cases) and provoked a cessation of the treatment in 36 cases (1.7%). Less than 1% of the cases experienced serious AEs that required hospitalisation during the treatment: two patients due to infection by Clostridium difficile; one patient with high blood pressure; one patient due to previous aggravated hypocalcaemia; and one last patient with a range of AEs that included nausea, vomiting and abdominal pain. In this latter patient, the AEs were directly related to the single‐capsule BQT as no other underlying cause could be identified. In all five of these patients the AEs resolved after treatment, leaving no sequelae.
TABLE 4 Frequency, intensity and duration of adverse events
Frequency of AEs Intensity of AEs Length of AEs
N % 95% CI Mild (N) % 95% CI Moderate (N) % 95% CI Severe (N) % 95% CI Mean days (SD)
Nausea 199 9.5 (8.2–10.7) 116 58.3 (51–65) 75 38.0 (31–44) 8 4.0 (1.0–7.0) 6.6 (3.2)
Diarrhoea 174 8.3 (7.1–9.5) 81 46.6 (39–54) 89 51.1 (43–59) 4 2.3 (0.6‐5.7) 6.5 (3.9)
Fatigue 136 6.5 (5.4–7.5) 48 35.3 (27–44) 65 47.8 (39–56) 23 16.9 (10.2–23.6) 8.3 (3.2)
Metallic taste 108 5.1 (4.2–6.1) 62 57.4 (48–67) 45 41.7 (32–51) 1 0.9 (0.02–5.0) 7.7 (3.7)
Dyspepsia 105 5.0 (4.0–5.9) 40 38.1 (28–48) 60 57.1 (47–67) 5 4.8 (1.6–10.8) 7.8 (3.4)
Abdominal pain 103 4.9 (3.9–5.58) 46 44.7 (35–55) 51 49.5 (39–60) 6 5.8 (0.8–10.8) 7.3 (5.0)
Anorexia 79 3.8 (2.9–4.6) 13 16.5 (7.6–25) 55 69.6 (59–80) 11 13.9 (5.6–22.2) 8.4 (2.3)
Vomiting 63 3.0 (2.2–3.7) 30 47.6 (34–61) 29 46.0 (33–59) 4 6.3 (1.7–15.5) 4.8 (2.9)
Heartburn 40 1.9 (1.3–2.5) 8 20.0 (6.3–34) 28 70.0 (54–85) 4 10.0 (2.8–23.6) 6.8 (2.3)
Total 570 28.8 a (27–31) 444 22.0 a (21–24) 497 25.0 a (23–27) 66 3.3 a (2.5–4.2) 7.2 (3.3)
Serious AEs 5 0.9 (0.3–2.0)
Compliance 1916 96.7 (96–97)
Ceased 36 1.7 (1.1–2.4)
Medications
Due to AEs
Abbreviations: AEs, adverse events; CI, confidence interval; N, number of reports; SD, standard deviation.
a Percentage relative to the total of patients reporting information on the intensity of the adverse event (n = 1976).
3.6 Univariate analysis
As shown in Table S1, the following variables were significantly associated with higher mITT eradication rates: compliant as opposed to noncompliant patients (93% vs. 44%); when standard or high (both 94%) PPI doses were used as opposed to low doses (90%); and when the treatment was administered as first‐line (95%), or second‐line (89%) therapy.
3.7 Multivariable analysis
Stepwise multivariable logistic regression analysis was performed in an attempt to define the variables that most strongly influenced the mITT eradication rate. We used a backward modelling strategy, and models were compared using the log‐likelihood ratio. This analysis showed that of all the factors analysed, compliance (odds ratio [OR]: 16.0, 95% confidence interval [CI]: 7.85–32.5) and a high PPI dose (OR: 1.80, 95% CI: 1.14–2.78) were significantly associated with higher therapy success; however, second‐line treatment (OR: 0.50, 95% CI: 0.33–0.75) or third‐line or greater treatment (OR: 0.30, 95% CI: 0.20–0.45) were associated with lesser effectiveness.
4 DISCUSSION
In this study we have taken advantage of the Hp‐EuReg, which has collected comprehensive information from patients diagnosed with H. pylori infection in several countries, to analyse the effectiveness of single‐capsule BQT and the main factors that influence its effectiveness. The use of this registry, containing 2100 patients infected by H. pylori and treated with single‐capsule BQT, makes this the largest study of its kind to date. The information extracted from the registry highlights the effectiveness of single‐capsule BQT in eradicating H. pylori in patients when used as a therapy in different treatment lines and in conjunction with different doses of PPIs. This therapy appears to be safe and successful, both as a first‐line and as a rescue therapy, even against antibiotic‐resistant bacteria.
In terms of effectiveness, a 90% eradication rate has been accepted as the arbitrary threshold for an optimal H. pylori treatment. 4 In the current study, we found that in real‐world use, single‐capsule BQT achieved an eradication rate above 90% when prescribed as a first‐line therapy. Moreover, a similar eradication rate was observed when this therapy was used as a rescue therapy, from a second‐line to sixth‐line treatment, as reported previously. 21 , 22 , 23 , 24 This is higher than the rates of eradication achieved by treatment regimens established previously using triple therapies. 16 In general, the loss of effectiveness of these precious therapies has been associated with bacterial resistance to antibiotics, mainly to clarithromycin or metronizadole. 14
Although information regarding bacterial antibiotic resistance was scarce in this study, the analysis showed that single‐capsule BQT was effective (≥90%) in eradicating infection in those patients with bacteria resistant to either clarithromycin or metronidazole, or both. This was also confirmed when the treatment was used as either a first‐line or second‐line therapy, as reported previously in an earlier meta‐analysis. 14 However, in our study, it did not appear to be as effective against H. pylori infections that were resistant to one of these antibiotics when used as a third‐line therapy. Nevertheless, this response should be confirmed in larger samples, highlighting the utility of performing susceptibility testing on patient samples in order to control better the rates of antibiotic resistance and the potential of specific treatments to overcome this hurdle. 11
In addition, we evaluated further factors that might influence the effectiveness of single‐capsule BQT in eradicating H. pylori infection. While the different PPI doses appeared to have some effect on the effectiveness of the treatment, the overall effectiveness of the therapy was maintained at the threshold consensus value of 90%, even at the lowest PPI dose. As indicated above, the line of treatment influenced the effectiveness in eradicating infection, maintaining the optimal effectiveness in first‐line and rescue therapy. However, the most significant factor influencing the effectiveness of single‐capsule BQT was compliance. There is evidence that bacterial resistance 2 , 7 , 25 and compliance 26 represent the most important factors influencing the success of H. pylori eradication strategies. In our study, data regarding antibiotic bacterial resistance were only available from 6% of the cases, such that resistance was unlikely to have a strong impact on the rate of eradication. Indeed, the high success rates of the single‐capsule BQT when used as a rescue therapy suggest that bacterial resistance may have a weaker negative effect on this treatment than on other alternative regimens.
In contrast to the information on bacterial resistance, compliance data were available from nearly 95% of the cases, offering a better picture of how it might influence the rate of eradication. In the registry, compliance was excellent in 97% of cases and even though three‐in‐one single‐capsule BQT involves taking three capsules four times daily plus a PPI twice daily, it is still less complex than the classic bismuth‐containing quadruple therapy published previously. 16
Finally, it should be noted that the AEs described are consistent with those identified in previous studies 14 and in the drug's technical data sheet. Moreover, the AEs experienced did not have a significant effect on compliance or on the effectiveness of the treatment. The treatment's safety profile was similar to that of an eradication therapy using three antibiotics, as reported in previous systematic reviews. 14 , 27
There are several limitations that should be borne in mind in relation to our study. In terms of the information extracted from the registry, certain features were particularly notable. At the time of sampling, single‐capsule BQT was only used to treat a small percentage of the cases in the registry (6%), derived principally from three main countries (97% in Spain, Italy and Portugal). This geographical bias most likely reflected the commercialisation strategy and implementation of this treatment as well as the year this therapy was launched in these countries, and it might question the generalisability of the results obtained to a pan‐European level. Nevertheless, the size of the cohort analysed (2100 patients), the largest of its type studied to date, suggests that the data obtained for patients with this profile are reliable. While this reflects the situation in Europe, it may perhaps be a limitation when considering extrapolating the data to a more global population. Hence, it will be important to carry out similar studies on other populations around the world.
In summary, we have carried out a comprehensive study on the effectiveness of single‐capsule BQT in real‐world cases of H. pylori infection collected from the Hp‐EuReg, the largest cohort analysed to date. Accordingly, this therapy appears to be an effective and safe treatment to eradicate H. pylori infection, both as a first‐line and rescue therapy overcoming those antibiotic‐resistant strains. The success of this therapy is strongly influenced by the compliance with therapy. While these data seem to support the use of this single‐capsule BQT to combat H. pylori infection, this should be further confirmed in other regions.
CONFLICT OF INTERESTS
Javier P. Gisbert served as a speaker, a consultant and advisory member for, or has received research funding from Mayoly, Allergan and Diasorin. Olga P. Nyssen received research funding from Allergan and Mayoly. Manuel Castro‐Fernandez received retribution from Allergan for training activities. Angeles Perez‐Aisa received retribution from Allergan and Mylan for training activities. The remaining authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Olga P. Nyssen: scientific director, member of the project's scientific committee, coordinated the study, designed and programmed the electronic case report form, reviewed, analysed and interpreted the data, drafted the manuscript and approved the submitted manuscript. Angeles Perez‐Aisa, Manuel Castro‐Fernandez, Rinaldo Pellicano, Jose M. Huguet, Luis Rodrigo, Juan Ortuño, Blas J. Gomez‐Rodriguez, Miguel Areia, Monica Perona, Oscar Nuñez, Marco Romano, Liliana Pozzati, Miguel Fernandez‐Bermejo, Peter Malfertheiner, Luis Fernanadez‐Salazar, Dino Vaira: collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Antonio Gasbarrini, Ricardo M. Pinto, Marino Venerito: acted as national coordinators and as recruiters. They selected national recruiters, collected and helped interpret the data, critically reviewed the manuscript and approved the submitted manuscript. Ignasi Puig: scientific director and member of the project's scientific committee, critically reviewed the manuscript draft and approved the submitted manuscript. Francis Megraud: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Colm O'Morain: member of the project's scientific committee, designed the protocol, planned the study, critically reviewed the manuscript and approved the submitted manuscript. Javier P. Gisbert: directed the project and the project's scientific committee, obtained funding , designed the protocol and planned the study, acted as the national Spanish coordinator, recruited the patients, analysed and interpreted the data, critically reviewed the manuscript and approved the submitted manuscript.
ETHICS APPROVAL
The study was approved by the ethics committee of La Princesa University Hospital (Madrid, Spain) and was pro‐spectively registered at ClinicalTrials.gov (NCT02328131). Written informed consent was obtained from each patient included in the study.
Supporting information
Supplementary Material 1
Click here for additional data file.
Supplementary Material 2
Click here for additional data file.
ACKNOWLEDGMENTS
The author(s) would like to thank the Spanish Association of Gastroenterology (AEG) for providing the electronic case report form service free of charge. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was promoted and funded by the European Helicobacter and Microbiota Study Group, and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomedica en Red de Enfermedades Hepaticas y Digestivas.
|
Recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33176617
| 20,009,914
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Epithelioid mesothelioma'.
|
TFE3 activation in a TSC1-altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms.
Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1-mutated PEComa displaying a TFE3-altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2-mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options.
Introduction
PEComas are a family of mesenchymal tumors that demonstrate immunoreactivity for both melanocytic and smooth muscle markers [1, 2]. They form a biological continuum ranging from benign to overtly malignant aggressive neoplasms. Malignant PEComas are exceedingly rare, with only about 100 cases described in the literature. Radical resection remains the favored treatment option in localized tumors. In locally advanced or metastatic disease, single case studies report short‐lived responses to chemotherapy containing doxorubicin, ifosfamide or gemcitabine [3].
Germline or somatic mutations of the genes TSC1 or TSC2 (TSC1/2) are a driving factor in PEComa development, resulting in activation of the mammalian target of rapamycin (mTOR) pathway [4, 5]. These alterations are the basis for palliative therapy with mTOR inhibitors [3].
A subset of PEComas harboring TFE3 gene fusions has recently been identified, adding them to the group of Xp11 translocation cancers. Here, the introduction of a constitutively active promotor causes oncogenic upregulation of the TFE3 transcription factor [6, 7]. Beside Xp11 translocations, several other causative genomic alterations for TFE3 activation likely exist [8].
Current consensus is that TFE3 and TSC1/2 alterations define distinct biological PEComa subgroups and are mutually exclusive [6, 9, 10]. Here, we report for the first time a malignant PEComa with TFE3 activation and heterozygous loss of TSC1. This case challenges the molecular dichotomy in this tumor entity.
Materials and methods
Studied case
Analyses were performed on tumor samples obtained from a 47‐year‐old woman diagnosed with PEComa in 2017. Written informed consent for the analyses was provided by the patient and posthumously by her husband according to local ethical guidelines.
Immunohistochemical staining and fluorescence in situ hybridization
Samples of the primary tumor and metastases were formalin‐fixed and paraffin‐embedded. H&E stained slides were evaluated by specialized pathologists at Charité‐Universitätsmedizin Berlin and the reference center for urogenital and soft tissue pathology at the Institute of Pathology of the University Erlangen‐Nürnberg in Erlangen, Germany. Immunohistochemistry was performed as described in Supplementary materials and methods using antibodies listed in supplementary material, Table S1.
Molecular analyses
Quantitative PCR, targeted exome sequencing, RNA sequencing (RNA‐Seq) and nanopore long‐read whole‐genome sequencing was performed as described in Supplementary materials and methods.
Results and discussion
Case description
In 2017, a 47‐year‐old woman with known tuberous sclerosis complex (TSC) due to a heterozygous germline TSC1 deletion presented with abdominal pain. A CT scan revealed a mass in the right kidney, leading to the clinical diagnosis of angiomyolipoma. Everolimus was initiated at a low dose of 2.5 mg once daily in accordance with the patient's wishes, resulting in trough levels of 2.5–4 ng/ml.
Four months later, imaging showed rapid growth of the mass. With suspicion of renal cell carcinoma, a radical nephrectomy was performed. Histopathological examination led to the diagnosis of a PEComa, which was 120 × 110 × 110 mm in size and resected to R0. A CT scan of the lungs showed no pulmonary metastases and the tumor board recommended no adjuvant therapy.
Four months later, recurrence was seen in a follow‐up CT scan in the region T12‐L4. The patient reported no symptoms at this time. Everolimus was re‐initiated at 5 mg twice daily. In addition, sorafenib was administered at 200 mg twice daily but had to be discontinued after 2 months due to intolerable gastrointestinal side effects. The patient also received radiation therapy of the painful paravertebral mass (39–45.5 Gy), leading to pronounced tumor regression.
However, hepatic masses appeared after 12 weeks and histopathology confirmed the diagnosis of metastatic malignant PEComa. The patient underwent surgery with R1 resection and did not return to our clinic for 4 months. By then, multiple hepatic, osseous and pulmonary metastases had developed. Chemotherapy with doxorubicin (75 mg/m2) could only be administered once and the patient died of the disease in 2018.
Distinctive TFE3‐rearranged phenotype in a TSC1‐altered PEComa
Histomorphologically, conventional PEComas (so called epithelioid angiomyolipomas) display a monophasic pattern of predominantly epithelioid cells and lack adipose tissue and dysmorphic blood vessels [11]. TFE3‐rearranged PEComas show epithelioid cells arranged into a distinctive nested and pseudoalveolar pattern [6, 10]. The PEComa presented here matched the latter description, displaying a solid, partially nested‐alveolar architecture with extensive tumor necrosis as well as hemorrhage. Adipose tissue and spindle cells were completely absent. The tumor cells contained voluminous, eosinophilic and partially clear cytoplasm with prominent nucleoli and pleomorphic nuclei. Marked nuclear atypia was present (Figure 1A).
Figure 1 PEComa histology and immunohistochemistry (IHC). (A) Representative image of the histomorphological appearance of the presented case (100‐fold total magnification, H&E staining). (B) TFE3 expression in tumor cells (200‐fold total magnification). (C) No MiTF expression in tumor cells from primary tumor (200‐fold total magnification). (D) MiTF expression in tumor cells from hepatic metastasis (200‐fold total magnification).
Immunohistochemical examination of the vital tumor cells revealed partial patchy expression of HMB45, focal expression of Melan A and weak positivity for Cathepsin K, which was mirrored at the RNA level (see supplementary material, Figure S1). There was no immunoreactivity for PAX8, smooth muscle actin and desmin and strong nuclear positivity for TFE3 was observed, again matching the phenotype of TFE3‐altered PEComas (Figure 1B) [6, 10]. As opposed to the primary tumor, MiTF positivity was seen in hepatic metastases (Figure 1C,D), while pulmonary metastases displayed only weak MiTF mRNA expression (see supplementary material, Figure S1). Many TFE3‐rearranged PEComas are MiTF‐nonimmunoreactive and it has been suggested that the TFE3 fusion protein substitutes for MiTF [6]. We consider tumor heterogeneity a possible explanation for the differential MiTF expression, with perhaps only a subset of tumor cells exhibiting TFE3 activation.
Evidence for a dual pathogenic mechanism involving TFE3 and TSC1 in our PEComa case
The known heterozygous germline TSC1 deletion was verified by real‐time PCR (see supplementary material, Figure S2) and only residual TSC1 expression was seen in the transcriptome (see supplementary material, Figure S1). The tumor morphology and TFE3 immunoreactivity, however, were suggestive of a TFE3 fusion. Therefore, fluorescence in situ hybridization (FISH) analysis was performed on the primary tumor. Out of 50 tumor cells, only three showed a translocated break‐apart signal (Figure 2A). The other examined cells did not meet the break‐apart cutoff values, but several cells displayed one co‐localization signal and one small separation of the 5′TFE3 and 3′TFE3 probes (Figure 2B). Similar subtle break‐apart patterns have been described in tumors harboring TFE3 inversions rather than translocations [12, 13, 14]. However, RNA‐Seq analysis performed on a pulmonary PEComa lesion was unable to identify any gene fusions involving TFE3. In order to find aberrations missed by RNA‐Seq, we next performed long‐read whole genome sequencing. Structural variant calling also did not detect TFE3 fusions. However, multiple copy number gains were found, including a large 36 Mbp region encompassing TFE3 on chrX:22015149‐58073962 (Figures 3 and 4). Transcriptome analysis detected an increase in levels of TFE3 mRNA in tumor cells compared to dermal fibroblast controls after normalization for expression of housekeeping genes (see supplementary material, Figure S1). Therefore, similar to Xp11 translocation cancers, TFE3 overexpression is one likely oncogenic driver in this tumor [15].
Figure 2 Interphase FISH with TFE3 break‐apart probe. (A) Break‐apart signal as seen in 6% of cells (arrow). (B) Small separation of the TFE3 probes (arrow).
Figure 3 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosomes 1‐22 finds multiple copy number variations. 2‐Fold genome coverage was achieved; counts averaged over 0.5 MB. Chromosome X is not analyzed or depicted here due to the algorithm used.
Figure 4 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosome X finds copy number gain at chrX:22015149‐58073962. 2‐Fold genome coverage was achieved. Copy number variation for chromosome X (top left panel) and enlarged view of copy number changes for TFE3 (lower right panel).
In addition, targeted exome sequencing revealed a coexistent TP53 mutation. The variant NM_000546.5:c.614A>G (p.Y205C) found was classified as pathogenic. TP53 mutations do occur concurrently with TSC1/2 mutations [10] but have not been described in TFE3‐altered PEComas until now. No additional pathogenic mutations were detected in the other genes tested in our panel (see supplementary material, Table S2).
Conclusion and clinical remarks
In the case presented here, it is clear that the heterozygous loss of TSC1 predisposed to PEComa development, but we believe that the sequential gain of TFE3 contributed to tumorigenesis. Interestingly, the observed TFE3 activation was not due to a TFE3 gene fusion, analogous to reports on TFE3‐expressing/nontranslocated renal cell carcinomas. These tumors are hypothesized to share a biological mechanism with their translocated counterparts based on a similar morphology, immunolabeling and increased expression of a common RNA read‐through molecule [16, 17]. In some of these neoplasms, TFE3 amplification leads to increased gene expression, but other mechanisms resulting in elevated TFE3 levels likely also exist [8, 18]. The same presumably holds true for PEComas like the one presented here. Regarding the TFE3 expression in our case, clonal tumor evolution appears to have played an additional role during the course of disease. At initial diagnosis, FISH analysis was unable to detect a TFE3 amplification in the primary tumor, although genomic profiling of metastases later revealed a copy number gain. Perhaps the additional TP53 mutation, which presumably also contributed to the complex karyotypic changes, promoted the selection of a TFE3‐expressing PEComa subclone in which genomic material on chromosome X was consecutively gained. Indeed, the differential MiTF expression observed here suggests tumor heterogeneity and supports our hypothesis of clonal tumor evolution.
To our knowledge, this is the first case with confirmed heterozygous deletion in a TSC gene and concomitant TFE3 activation with a distinctive malignant epithelioid phenotype. This finding challenges the biological distinction of TFE3‐ and TCS1/2‐altered PEComas. The notion that both the TSC1/2‐mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa is of translational clinical importance. TSC1/2‐mutated PEComas sometimes respond to mTOR‐inhibition therapy [19], but these drugs are mechanistically believed to be inefficient in TFE3‐altered PEComa. MET‐inhibitors, on the other hand, are active in alveolar soft part sarcoma with TFE3 rearrangement [20], a rare subtype of soft‐tissue sarcoma, and could constitute a therapeutic option for TFE3 overexpressing PEComas. Importantly, when there is evidence of dual pathway activation, it appears reasonable to combine both drugs.
Author contributions statement
AF, LB, AD, UK and MS designed the research. AD, DT and AL performed the experiments. LB, AD, UK, BMP, VW, AH, AA and MS analyzed and interpreted the data. MS and JKS wrote the manuscript. AF, LB, AD, UK, DT, MH, BP, VW, AH, AA, SB, RP, RÖ and SM critically commented on and edited the manuscript. All authors have read and approved the manuscript.
Supporting information
Supplementary materials and methods
Figure S1. Expression levels of candidate genes in tumor tissue detected by RNA‐Seq compared to dermal fibroblasts
Figure S2. Results of quantitative PCR for determination of TSC1 copy number compared to the autosomal ALB and the X‐chromosomal F8 gene loci
Table S1. Antibodies used for immunohistochemical staining
Table S2. Genes covered in the NGS panel developed for clinical service at Charité – Universitätsmedizin Berlin
Click here for additional data file.
Acknowledgements
This study was supported by the German Cancer Consortium (DKTK). MS is a participant in the BIH‐Charité Clinician Scientist Program funded by the Charité‐Universitätsmedizin Berlin and Berlin Institute of Health. Open access funding enabled and organized by Projekt DEAL.
|
EVEROLIMUS, SORAFENIB
|
DrugsGivenReaction
|
CC BY
|
33180365
| 19,513,964
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal disorder'.
|
TFE3 activation in a TSC1-altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms.
Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1-mutated PEComa displaying a TFE3-altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2-mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options.
Introduction
PEComas are a family of mesenchymal tumors that demonstrate immunoreactivity for both melanocytic and smooth muscle markers [1, 2]. They form a biological continuum ranging from benign to overtly malignant aggressive neoplasms. Malignant PEComas are exceedingly rare, with only about 100 cases described in the literature. Radical resection remains the favored treatment option in localized tumors. In locally advanced or metastatic disease, single case studies report short‐lived responses to chemotherapy containing doxorubicin, ifosfamide or gemcitabine [3].
Germline or somatic mutations of the genes TSC1 or TSC2 (TSC1/2) are a driving factor in PEComa development, resulting in activation of the mammalian target of rapamycin (mTOR) pathway [4, 5]. These alterations are the basis for palliative therapy with mTOR inhibitors [3].
A subset of PEComas harboring TFE3 gene fusions has recently been identified, adding them to the group of Xp11 translocation cancers. Here, the introduction of a constitutively active promotor causes oncogenic upregulation of the TFE3 transcription factor [6, 7]. Beside Xp11 translocations, several other causative genomic alterations for TFE3 activation likely exist [8].
Current consensus is that TFE3 and TSC1/2 alterations define distinct biological PEComa subgroups and are mutually exclusive [6, 9, 10]. Here, we report for the first time a malignant PEComa with TFE3 activation and heterozygous loss of TSC1. This case challenges the molecular dichotomy in this tumor entity.
Materials and methods
Studied case
Analyses were performed on tumor samples obtained from a 47‐year‐old woman diagnosed with PEComa in 2017. Written informed consent for the analyses was provided by the patient and posthumously by her husband according to local ethical guidelines.
Immunohistochemical staining and fluorescence in situ hybridization
Samples of the primary tumor and metastases were formalin‐fixed and paraffin‐embedded. H&E stained slides were evaluated by specialized pathologists at Charité‐Universitätsmedizin Berlin and the reference center for urogenital and soft tissue pathology at the Institute of Pathology of the University Erlangen‐Nürnberg in Erlangen, Germany. Immunohistochemistry was performed as described in Supplementary materials and methods using antibodies listed in supplementary material, Table S1.
Molecular analyses
Quantitative PCR, targeted exome sequencing, RNA sequencing (RNA‐Seq) and nanopore long‐read whole‐genome sequencing was performed as described in Supplementary materials and methods.
Results and discussion
Case description
In 2017, a 47‐year‐old woman with known tuberous sclerosis complex (TSC) due to a heterozygous germline TSC1 deletion presented with abdominal pain. A CT scan revealed a mass in the right kidney, leading to the clinical diagnosis of angiomyolipoma. Everolimus was initiated at a low dose of 2.5 mg once daily in accordance with the patient's wishes, resulting in trough levels of 2.5–4 ng/ml.
Four months later, imaging showed rapid growth of the mass. With suspicion of renal cell carcinoma, a radical nephrectomy was performed. Histopathological examination led to the diagnosis of a PEComa, which was 120 × 110 × 110 mm in size and resected to R0. A CT scan of the lungs showed no pulmonary metastases and the tumor board recommended no adjuvant therapy.
Four months later, recurrence was seen in a follow‐up CT scan in the region T12‐L4. The patient reported no symptoms at this time. Everolimus was re‐initiated at 5 mg twice daily. In addition, sorafenib was administered at 200 mg twice daily but had to be discontinued after 2 months due to intolerable gastrointestinal side effects. The patient also received radiation therapy of the painful paravertebral mass (39–45.5 Gy), leading to pronounced tumor regression.
However, hepatic masses appeared after 12 weeks and histopathology confirmed the diagnosis of metastatic malignant PEComa. The patient underwent surgery with R1 resection and did not return to our clinic for 4 months. By then, multiple hepatic, osseous and pulmonary metastases had developed. Chemotherapy with doxorubicin (75 mg/m2) could only be administered once and the patient died of the disease in 2018.
Distinctive TFE3‐rearranged phenotype in a TSC1‐altered PEComa
Histomorphologically, conventional PEComas (so called epithelioid angiomyolipomas) display a monophasic pattern of predominantly epithelioid cells and lack adipose tissue and dysmorphic blood vessels [11]. TFE3‐rearranged PEComas show epithelioid cells arranged into a distinctive nested and pseudoalveolar pattern [6, 10]. The PEComa presented here matched the latter description, displaying a solid, partially nested‐alveolar architecture with extensive tumor necrosis as well as hemorrhage. Adipose tissue and spindle cells were completely absent. The tumor cells contained voluminous, eosinophilic and partially clear cytoplasm with prominent nucleoli and pleomorphic nuclei. Marked nuclear atypia was present (Figure 1A).
Figure 1 PEComa histology and immunohistochemistry (IHC). (A) Representative image of the histomorphological appearance of the presented case (100‐fold total magnification, H&E staining). (B) TFE3 expression in tumor cells (200‐fold total magnification). (C) No MiTF expression in tumor cells from primary tumor (200‐fold total magnification). (D) MiTF expression in tumor cells from hepatic metastasis (200‐fold total magnification).
Immunohistochemical examination of the vital tumor cells revealed partial patchy expression of HMB45, focal expression of Melan A and weak positivity for Cathepsin K, which was mirrored at the RNA level (see supplementary material, Figure S1). There was no immunoreactivity for PAX8, smooth muscle actin and desmin and strong nuclear positivity for TFE3 was observed, again matching the phenotype of TFE3‐altered PEComas (Figure 1B) [6, 10]. As opposed to the primary tumor, MiTF positivity was seen in hepatic metastases (Figure 1C,D), while pulmonary metastases displayed only weak MiTF mRNA expression (see supplementary material, Figure S1). Many TFE3‐rearranged PEComas are MiTF‐nonimmunoreactive and it has been suggested that the TFE3 fusion protein substitutes for MiTF [6]. We consider tumor heterogeneity a possible explanation for the differential MiTF expression, with perhaps only a subset of tumor cells exhibiting TFE3 activation.
Evidence for a dual pathogenic mechanism involving TFE3 and TSC1 in our PEComa case
The known heterozygous germline TSC1 deletion was verified by real‐time PCR (see supplementary material, Figure S2) and only residual TSC1 expression was seen in the transcriptome (see supplementary material, Figure S1). The tumor morphology and TFE3 immunoreactivity, however, were suggestive of a TFE3 fusion. Therefore, fluorescence in situ hybridization (FISH) analysis was performed on the primary tumor. Out of 50 tumor cells, only three showed a translocated break‐apart signal (Figure 2A). The other examined cells did not meet the break‐apart cutoff values, but several cells displayed one co‐localization signal and one small separation of the 5′TFE3 and 3′TFE3 probes (Figure 2B). Similar subtle break‐apart patterns have been described in tumors harboring TFE3 inversions rather than translocations [12, 13, 14]. However, RNA‐Seq analysis performed on a pulmonary PEComa lesion was unable to identify any gene fusions involving TFE3. In order to find aberrations missed by RNA‐Seq, we next performed long‐read whole genome sequencing. Structural variant calling also did not detect TFE3 fusions. However, multiple copy number gains were found, including a large 36 Mbp region encompassing TFE3 on chrX:22015149‐58073962 (Figures 3 and 4). Transcriptome analysis detected an increase in levels of TFE3 mRNA in tumor cells compared to dermal fibroblast controls after normalization for expression of housekeeping genes (see supplementary material, Figure S1). Therefore, similar to Xp11 translocation cancers, TFE3 overexpression is one likely oncogenic driver in this tumor [15].
Figure 2 Interphase FISH with TFE3 break‐apart probe. (A) Break‐apart signal as seen in 6% of cells (arrow). (B) Small separation of the TFE3 probes (arrow).
Figure 3 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosomes 1‐22 finds multiple copy number variations. 2‐Fold genome coverage was achieved; counts averaged over 0.5 MB. Chromosome X is not analyzed or depicted here due to the algorithm used.
Figure 4 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosome X finds copy number gain at chrX:22015149‐58073962. 2‐Fold genome coverage was achieved. Copy number variation for chromosome X (top left panel) and enlarged view of copy number changes for TFE3 (lower right panel).
In addition, targeted exome sequencing revealed a coexistent TP53 mutation. The variant NM_000546.5:c.614A>G (p.Y205C) found was classified as pathogenic. TP53 mutations do occur concurrently with TSC1/2 mutations [10] but have not been described in TFE3‐altered PEComas until now. No additional pathogenic mutations were detected in the other genes tested in our panel (see supplementary material, Table S2).
Conclusion and clinical remarks
In the case presented here, it is clear that the heterozygous loss of TSC1 predisposed to PEComa development, but we believe that the sequential gain of TFE3 contributed to tumorigenesis. Interestingly, the observed TFE3 activation was not due to a TFE3 gene fusion, analogous to reports on TFE3‐expressing/nontranslocated renal cell carcinomas. These tumors are hypothesized to share a biological mechanism with their translocated counterparts based on a similar morphology, immunolabeling and increased expression of a common RNA read‐through molecule [16, 17]. In some of these neoplasms, TFE3 amplification leads to increased gene expression, but other mechanisms resulting in elevated TFE3 levels likely also exist [8, 18]. The same presumably holds true for PEComas like the one presented here. Regarding the TFE3 expression in our case, clonal tumor evolution appears to have played an additional role during the course of disease. At initial diagnosis, FISH analysis was unable to detect a TFE3 amplification in the primary tumor, although genomic profiling of metastases later revealed a copy number gain. Perhaps the additional TP53 mutation, which presumably also contributed to the complex karyotypic changes, promoted the selection of a TFE3‐expressing PEComa subclone in which genomic material on chromosome X was consecutively gained. Indeed, the differential MiTF expression observed here suggests tumor heterogeneity and supports our hypothesis of clonal tumor evolution.
To our knowledge, this is the first case with confirmed heterozygous deletion in a TSC gene and concomitant TFE3 activation with a distinctive malignant epithelioid phenotype. This finding challenges the biological distinction of TFE3‐ and TCS1/2‐altered PEComas. The notion that both the TSC1/2‐mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa is of translational clinical importance. TSC1/2‐mutated PEComas sometimes respond to mTOR‐inhibition therapy [19], but these drugs are mechanistically believed to be inefficient in TFE3‐altered PEComa. MET‐inhibitors, on the other hand, are active in alveolar soft part sarcoma with TFE3 rearrangement [20], a rare subtype of soft‐tissue sarcoma, and could constitute a therapeutic option for TFE3 overexpressing PEComas. Importantly, when there is evidence of dual pathway activation, it appears reasonable to combine both drugs.
Author contributions statement
AF, LB, AD, UK and MS designed the research. AD, DT and AL performed the experiments. LB, AD, UK, BMP, VW, AH, AA and MS analyzed and interpreted the data. MS and JKS wrote the manuscript. AF, LB, AD, UK, DT, MH, BP, VW, AH, AA, SB, RP, RÖ and SM critically commented on and edited the manuscript. All authors have read and approved the manuscript.
Supporting information
Supplementary materials and methods
Figure S1. Expression levels of candidate genes in tumor tissue detected by RNA‐Seq compared to dermal fibroblasts
Figure S2. Results of quantitative PCR for determination of TSC1 copy number compared to the autosomal ALB and the X‐chromosomal F8 gene loci
Table S1. Antibodies used for immunohistochemical staining
Table S2. Genes covered in the NGS panel developed for clinical service at Charité – Universitätsmedizin Berlin
Click here for additional data file.
Acknowledgements
This study was supported by the German Cancer Consortium (DKTK). MS is a participant in the BIH‐Charité Clinician Scientist Program funded by the Charité‐Universitätsmedizin Berlin and Berlin Institute of Health. Open access funding enabled and organized by Projekt DEAL.
|
EVEROLIMUS, SORAFENIB
|
DrugsGivenReaction
|
CC BY
|
33180365
| 19,513,964
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastases to bone'.
|
TFE3 activation in a TSC1-altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms.
Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1-mutated PEComa displaying a TFE3-altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2-mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options.
Introduction
PEComas are a family of mesenchymal tumors that demonstrate immunoreactivity for both melanocytic and smooth muscle markers [1, 2]. They form a biological continuum ranging from benign to overtly malignant aggressive neoplasms. Malignant PEComas are exceedingly rare, with only about 100 cases described in the literature. Radical resection remains the favored treatment option in localized tumors. In locally advanced or metastatic disease, single case studies report short‐lived responses to chemotherapy containing doxorubicin, ifosfamide or gemcitabine [3].
Germline or somatic mutations of the genes TSC1 or TSC2 (TSC1/2) are a driving factor in PEComa development, resulting in activation of the mammalian target of rapamycin (mTOR) pathway [4, 5]. These alterations are the basis for palliative therapy with mTOR inhibitors [3].
A subset of PEComas harboring TFE3 gene fusions has recently been identified, adding them to the group of Xp11 translocation cancers. Here, the introduction of a constitutively active promotor causes oncogenic upregulation of the TFE3 transcription factor [6, 7]. Beside Xp11 translocations, several other causative genomic alterations for TFE3 activation likely exist [8].
Current consensus is that TFE3 and TSC1/2 alterations define distinct biological PEComa subgroups and are mutually exclusive [6, 9, 10]. Here, we report for the first time a malignant PEComa with TFE3 activation and heterozygous loss of TSC1. This case challenges the molecular dichotomy in this tumor entity.
Materials and methods
Studied case
Analyses were performed on tumor samples obtained from a 47‐year‐old woman diagnosed with PEComa in 2017. Written informed consent for the analyses was provided by the patient and posthumously by her husband according to local ethical guidelines.
Immunohistochemical staining and fluorescence in situ hybridization
Samples of the primary tumor and metastases were formalin‐fixed and paraffin‐embedded. H&E stained slides were evaluated by specialized pathologists at Charité‐Universitätsmedizin Berlin and the reference center for urogenital and soft tissue pathology at the Institute of Pathology of the University Erlangen‐Nürnberg in Erlangen, Germany. Immunohistochemistry was performed as described in Supplementary materials and methods using antibodies listed in supplementary material, Table S1.
Molecular analyses
Quantitative PCR, targeted exome sequencing, RNA sequencing (RNA‐Seq) and nanopore long‐read whole‐genome sequencing was performed as described in Supplementary materials and methods.
Results and discussion
Case description
In 2017, a 47‐year‐old woman with known tuberous sclerosis complex (TSC) due to a heterozygous germline TSC1 deletion presented with abdominal pain. A CT scan revealed a mass in the right kidney, leading to the clinical diagnosis of angiomyolipoma. Everolimus was initiated at a low dose of 2.5 mg once daily in accordance with the patient's wishes, resulting in trough levels of 2.5–4 ng/ml.
Four months later, imaging showed rapid growth of the mass. With suspicion of renal cell carcinoma, a radical nephrectomy was performed. Histopathological examination led to the diagnosis of a PEComa, which was 120 × 110 × 110 mm in size and resected to R0. A CT scan of the lungs showed no pulmonary metastases and the tumor board recommended no adjuvant therapy.
Four months later, recurrence was seen in a follow‐up CT scan in the region T12‐L4. The patient reported no symptoms at this time. Everolimus was re‐initiated at 5 mg twice daily. In addition, sorafenib was administered at 200 mg twice daily but had to be discontinued after 2 months due to intolerable gastrointestinal side effects. The patient also received radiation therapy of the painful paravertebral mass (39–45.5 Gy), leading to pronounced tumor regression.
However, hepatic masses appeared after 12 weeks and histopathology confirmed the diagnosis of metastatic malignant PEComa. The patient underwent surgery with R1 resection and did not return to our clinic for 4 months. By then, multiple hepatic, osseous and pulmonary metastases had developed. Chemotherapy with doxorubicin (75 mg/m2) could only be administered once and the patient died of the disease in 2018.
Distinctive TFE3‐rearranged phenotype in a TSC1‐altered PEComa
Histomorphologically, conventional PEComas (so called epithelioid angiomyolipomas) display a monophasic pattern of predominantly epithelioid cells and lack adipose tissue and dysmorphic blood vessels [11]. TFE3‐rearranged PEComas show epithelioid cells arranged into a distinctive nested and pseudoalveolar pattern [6, 10]. The PEComa presented here matched the latter description, displaying a solid, partially nested‐alveolar architecture with extensive tumor necrosis as well as hemorrhage. Adipose tissue and spindle cells were completely absent. The tumor cells contained voluminous, eosinophilic and partially clear cytoplasm with prominent nucleoli and pleomorphic nuclei. Marked nuclear atypia was present (Figure 1A).
Figure 1 PEComa histology and immunohistochemistry (IHC). (A) Representative image of the histomorphological appearance of the presented case (100‐fold total magnification, H&E staining). (B) TFE3 expression in tumor cells (200‐fold total magnification). (C) No MiTF expression in tumor cells from primary tumor (200‐fold total magnification). (D) MiTF expression in tumor cells from hepatic metastasis (200‐fold total magnification).
Immunohistochemical examination of the vital tumor cells revealed partial patchy expression of HMB45, focal expression of Melan A and weak positivity for Cathepsin K, which was mirrored at the RNA level (see supplementary material, Figure S1). There was no immunoreactivity for PAX8, smooth muscle actin and desmin and strong nuclear positivity for TFE3 was observed, again matching the phenotype of TFE3‐altered PEComas (Figure 1B) [6, 10]. As opposed to the primary tumor, MiTF positivity was seen in hepatic metastases (Figure 1C,D), while pulmonary metastases displayed only weak MiTF mRNA expression (see supplementary material, Figure S1). Many TFE3‐rearranged PEComas are MiTF‐nonimmunoreactive and it has been suggested that the TFE3 fusion protein substitutes for MiTF [6]. We consider tumor heterogeneity a possible explanation for the differential MiTF expression, with perhaps only a subset of tumor cells exhibiting TFE3 activation.
Evidence for a dual pathogenic mechanism involving TFE3 and TSC1 in our PEComa case
The known heterozygous germline TSC1 deletion was verified by real‐time PCR (see supplementary material, Figure S2) and only residual TSC1 expression was seen in the transcriptome (see supplementary material, Figure S1). The tumor morphology and TFE3 immunoreactivity, however, were suggestive of a TFE3 fusion. Therefore, fluorescence in situ hybridization (FISH) analysis was performed on the primary tumor. Out of 50 tumor cells, only three showed a translocated break‐apart signal (Figure 2A). The other examined cells did not meet the break‐apart cutoff values, but several cells displayed one co‐localization signal and one small separation of the 5′TFE3 and 3′TFE3 probes (Figure 2B). Similar subtle break‐apart patterns have been described in tumors harboring TFE3 inversions rather than translocations [12, 13, 14]. However, RNA‐Seq analysis performed on a pulmonary PEComa lesion was unable to identify any gene fusions involving TFE3. In order to find aberrations missed by RNA‐Seq, we next performed long‐read whole genome sequencing. Structural variant calling also did not detect TFE3 fusions. However, multiple copy number gains were found, including a large 36 Mbp region encompassing TFE3 on chrX:22015149‐58073962 (Figures 3 and 4). Transcriptome analysis detected an increase in levels of TFE3 mRNA in tumor cells compared to dermal fibroblast controls after normalization for expression of housekeeping genes (see supplementary material, Figure S1). Therefore, similar to Xp11 translocation cancers, TFE3 overexpression is one likely oncogenic driver in this tumor [15].
Figure 2 Interphase FISH with TFE3 break‐apart probe. (A) Break‐apart signal as seen in 6% of cells (arrow). (B) Small separation of the TFE3 probes (arrow).
Figure 3 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosomes 1‐22 finds multiple copy number variations. 2‐Fold genome coverage was achieved; counts averaged over 0.5 MB. Chromosome X is not analyzed or depicted here due to the algorithm used.
Figure 4 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosome X finds copy number gain at chrX:22015149‐58073962. 2‐Fold genome coverage was achieved. Copy number variation for chromosome X (top left panel) and enlarged view of copy number changes for TFE3 (lower right panel).
In addition, targeted exome sequencing revealed a coexistent TP53 mutation. The variant NM_000546.5:c.614A>G (p.Y205C) found was classified as pathogenic. TP53 mutations do occur concurrently with TSC1/2 mutations [10] but have not been described in TFE3‐altered PEComas until now. No additional pathogenic mutations were detected in the other genes tested in our panel (see supplementary material, Table S2).
Conclusion and clinical remarks
In the case presented here, it is clear that the heterozygous loss of TSC1 predisposed to PEComa development, but we believe that the sequential gain of TFE3 contributed to tumorigenesis. Interestingly, the observed TFE3 activation was not due to a TFE3 gene fusion, analogous to reports on TFE3‐expressing/nontranslocated renal cell carcinomas. These tumors are hypothesized to share a biological mechanism with their translocated counterparts based on a similar morphology, immunolabeling and increased expression of a common RNA read‐through molecule [16, 17]. In some of these neoplasms, TFE3 amplification leads to increased gene expression, but other mechanisms resulting in elevated TFE3 levels likely also exist [8, 18]. The same presumably holds true for PEComas like the one presented here. Regarding the TFE3 expression in our case, clonal tumor evolution appears to have played an additional role during the course of disease. At initial diagnosis, FISH analysis was unable to detect a TFE3 amplification in the primary tumor, although genomic profiling of metastases later revealed a copy number gain. Perhaps the additional TP53 mutation, which presumably also contributed to the complex karyotypic changes, promoted the selection of a TFE3‐expressing PEComa subclone in which genomic material on chromosome X was consecutively gained. Indeed, the differential MiTF expression observed here suggests tumor heterogeneity and supports our hypothesis of clonal tumor evolution.
To our knowledge, this is the first case with confirmed heterozygous deletion in a TSC gene and concomitant TFE3 activation with a distinctive malignant epithelioid phenotype. This finding challenges the biological distinction of TFE3‐ and TCS1/2‐altered PEComas. The notion that both the TSC1/2‐mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa is of translational clinical importance. TSC1/2‐mutated PEComas sometimes respond to mTOR‐inhibition therapy [19], but these drugs are mechanistically believed to be inefficient in TFE3‐altered PEComa. MET‐inhibitors, on the other hand, are active in alveolar soft part sarcoma with TFE3 rearrangement [20], a rare subtype of soft‐tissue sarcoma, and could constitute a therapeutic option for TFE3 overexpressing PEComas. Importantly, when there is evidence of dual pathway activation, it appears reasonable to combine both drugs.
Author contributions statement
AF, LB, AD, UK and MS designed the research. AD, DT and AL performed the experiments. LB, AD, UK, BMP, VW, AH, AA and MS analyzed and interpreted the data. MS and JKS wrote the manuscript. AF, LB, AD, UK, DT, MH, BP, VW, AH, AA, SB, RP, RÖ and SM critically commented on and edited the manuscript. All authors have read and approved the manuscript.
Supporting information
Supplementary materials and methods
Figure S1. Expression levels of candidate genes in tumor tissue detected by RNA‐Seq compared to dermal fibroblasts
Figure S2. Results of quantitative PCR for determination of TSC1 copy number compared to the autosomal ALB and the X‐chromosomal F8 gene loci
Table S1. Antibodies used for immunohistochemical staining
Table S2. Genes covered in the NGS panel developed for clinical service at Charité – Universitätsmedizin Berlin
Click here for additional data file.
Acknowledgements
This study was supported by the German Cancer Consortium (DKTK). MS is a participant in the BIH‐Charité Clinician Scientist Program funded by the Charité‐Universitätsmedizin Berlin and Berlin Institute of Health. Open access funding enabled and organized by Projekt DEAL.
|
EVEROLIMUS, SORAFENIB
|
DrugsGivenReaction
|
CC BY
|
33180365
| 19,513,964
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastases to liver'.
|
TFE3 activation in a TSC1-altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms.
Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1-mutated PEComa displaying a TFE3-altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2-mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options.
Introduction
PEComas are a family of mesenchymal tumors that demonstrate immunoreactivity for both melanocytic and smooth muscle markers [1, 2]. They form a biological continuum ranging from benign to overtly malignant aggressive neoplasms. Malignant PEComas are exceedingly rare, with only about 100 cases described in the literature. Radical resection remains the favored treatment option in localized tumors. In locally advanced or metastatic disease, single case studies report short‐lived responses to chemotherapy containing doxorubicin, ifosfamide or gemcitabine [3].
Germline or somatic mutations of the genes TSC1 or TSC2 (TSC1/2) are a driving factor in PEComa development, resulting in activation of the mammalian target of rapamycin (mTOR) pathway [4, 5]. These alterations are the basis for palliative therapy with mTOR inhibitors [3].
A subset of PEComas harboring TFE3 gene fusions has recently been identified, adding them to the group of Xp11 translocation cancers. Here, the introduction of a constitutively active promotor causes oncogenic upregulation of the TFE3 transcription factor [6, 7]. Beside Xp11 translocations, several other causative genomic alterations for TFE3 activation likely exist [8].
Current consensus is that TFE3 and TSC1/2 alterations define distinct biological PEComa subgroups and are mutually exclusive [6, 9, 10]. Here, we report for the first time a malignant PEComa with TFE3 activation and heterozygous loss of TSC1. This case challenges the molecular dichotomy in this tumor entity.
Materials and methods
Studied case
Analyses were performed on tumor samples obtained from a 47‐year‐old woman diagnosed with PEComa in 2017. Written informed consent for the analyses was provided by the patient and posthumously by her husband according to local ethical guidelines.
Immunohistochemical staining and fluorescence in situ hybridization
Samples of the primary tumor and metastases were formalin‐fixed and paraffin‐embedded. H&E stained slides were evaluated by specialized pathologists at Charité‐Universitätsmedizin Berlin and the reference center for urogenital and soft tissue pathology at the Institute of Pathology of the University Erlangen‐Nürnberg in Erlangen, Germany. Immunohistochemistry was performed as described in Supplementary materials and methods using antibodies listed in supplementary material, Table S1.
Molecular analyses
Quantitative PCR, targeted exome sequencing, RNA sequencing (RNA‐Seq) and nanopore long‐read whole‐genome sequencing was performed as described in Supplementary materials and methods.
Results and discussion
Case description
In 2017, a 47‐year‐old woman with known tuberous sclerosis complex (TSC) due to a heterozygous germline TSC1 deletion presented with abdominal pain. A CT scan revealed a mass in the right kidney, leading to the clinical diagnosis of angiomyolipoma. Everolimus was initiated at a low dose of 2.5 mg once daily in accordance with the patient's wishes, resulting in trough levels of 2.5–4 ng/ml.
Four months later, imaging showed rapid growth of the mass. With suspicion of renal cell carcinoma, a radical nephrectomy was performed. Histopathological examination led to the diagnosis of a PEComa, which was 120 × 110 × 110 mm in size and resected to R0. A CT scan of the lungs showed no pulmonary metastases and the tumor board recommended no adjuvant therapy.
Four months later, recurrence was seen in a follow‐up CT scan in the region T12‐L4. The patient reported no symptoms at this time. Everolimus was re‐initiated at 5 mg twice daily. In addition, sorafenib was administered at 200 mg twice daily but had to be discontinued after 2 months due to intolerable gastrointestinal side effects. The patient also received radiation therapy of the painful paravertebral mass (39–45.5 Gy), leading to pronounced tumor regression.
However, hepatic masses appeared after 12 weeks and histopathology confirmed the diagnosis of metastatic malignant PEComa. The patient underwent surgery with R1 resection and did not return to our clinic for 4 months. By then, multiple hepatic, osseous and pulmonary metastases had developed. Chemotherapy with doxorubicin (75 mg/m2) could only be administered once and the patient died of the disease in 2018.
Distinctive TFE3‐rearranged phenotype in a TSC1‐altered PEComa
Histomorphologically, conventional PEComas (so called epithelioid angiomyolipomas) display a monophasic pattern of predominantly epithelioid cells and lack adipose tissue and dysmorphic blood vessels [11]. TFE3‐rearranged PEComas show epithelioid cells arranged into a distinctive nested and pseudoalveolar pattern [6, 10]. The PEComa presented here matched the latter description, displaying a solid, partially nested‐alveolar architecture with extensive tumor necrosis as well as hemorrhage. Adipose tissue and spindle cells were completely absent. The tumor cells contained voluminous, eosinophilic and partially clear cytoplasm with prominent nucleoli and pleomorphic nuclei. Marked nuclear atypia was present (Figure 1A).
Figure 1 PEComa histology and immunohistochemistry (IHC). (A) Representative image of the histomorphological appearance of the presented case (100‐fold total magnification, H&E staining). (B) TFE3 expression in tumor cells (200‐fold total magnification). (C) No MiTF expression in tumor cells from primary tumor (200‐fold total magnification). (D) MiTF expression in tumor cells from hepatic metastasis (200‐fold total magnification).
Immunohistochemical examination of the vital tumor cells revealed partial patchy expression of HMB45, focal expression of Melan A and weak positivity for Cathepsin K, which was mirrored at the RNA level (see supplementary material, Figure S1). There was no immunoreactivity for PAX8, smooth muscle actin and desmin and strong nuclear positivity for TFE3 was observed, again matching the phenotype of TFE3‐altered PEComas (Figure 1B) [6, 10]. As opposed to the primary tumor, MiTF positivity was seen in hepatic metastases (Figure 1C,D), while pulmonary metastases displayed only weak MiTF mRNA expression (see supplementary material, Figure S1). Many TFE3‐rearranged PEComas are MiTF‐nonimmunoreactive and it has been suggested that the TFE3 fusion protein substitutes for MiTF [6]. We consider tumor heterogeneity a possible explanation for the differential MiTF expression, with perhaps only a subset of tumor cells exhibiting TFE3 activation.
Evidence for a dual pathogenic mechanism involving TFE3 and TSC1 in our PEComa case
The known heterozygous germline TSC1 deletion was verified by real‐time PCR (see supplementary material, Figure S2) and only residual TSC1 expression was seen in the transcriptome (see supplementary material, Figure S1). The tumor morphology and TFE3 immunoreactivity, however, were suggestive of a TFE3 fusion. Therefore, fluorescence in situ hybridization (FISH) analysis was performed on the primary tumor. Out of 50 tumor cells, only three showed a translocated break‐apart signal (Figure 2A). The other examined cells did not meet the break‐apart cutoff values, but several cells displayed one co‐localization signal and one small separation of the 5′TFE3 and 3′TFE3 probes (Figure 2B). Similar subtle break‐apart patterns have been described in tumors harboring TFE3 inversions rather than translocations [12, 13, 14]. However, RNA‐Seq analysis performed on a pulmonary PEComa lesion was unable to identify any gene fusions involving TFE3. In order to find aberrations missed by RNA‐Seq, we next performed long‐read whole genome sequencing. Structural variant calling also did not detect TFE3 fusions. However, multiple copy number gains were found, including a large 36 Mbp region encompassing TFE3 on chrX:22015149‐58073962 (Figures 3 and 4). Transcriptome analysis detected an increase in levels of TFE3 mRNA in tumor cells compared to dermal fibroblast controls after normalization for expression of housekeeping genes (see supplementary material, Figure S1). Therefore, similar to Xp11 translocation cancers, TFE3 overexpression is one likely oncogenic driver in this tumor [15].
Figure 2 Interphase FISH with TFE3 break‐apart probe. (A) Break‐apart signal as seen in 6% of cells (arrow). (B) Small separation of the TFE3 probes (arrow).
Figure 3 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosomes 1‐22 finds multiple copy number variations. 2‐Fold genome coverage was achieved; counts averaged over 0.5 MB. Chromosome X is not analyzed or depicted here due to the algorithm used.
Figure 4 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosome X finds copy number gain at chrX:22015149‐58073962. 2‐Fold genome coverage was achieved. Copy number variation for chromosome X (top left panel) and enlarged view of copy number changes for TFE3 (lower right panel).
In addition, targeted exome sequencing revealed a coexistent TP53 mutation. The variant NM_000546.5:c.614A>G (p.Y205C) found was classified as pathogenic. TP53 mutations do occur concurrently with TSC1/2 mutations [10] but have not been described in TFE3‐altered PEComas until now. No additional pathogenic mutations were detected in the other genes tested in our panel (see supplementary material, Table S2).
Conclusion and clinical remarks
In the case presented here, it is clear that the heterozygous loss of TSC1 predisposed to PEComa development, but we believe that the sequential gain of TFE3 contributed to tumorigenesis. Interestingly, the observed TFE3 activation was not due to a TFE3 gene fusion, analogous to reports on TFE3‐expressing/nontranslocated renal cell carcinomas. These tumors are hypothesized to share a biological mechanism with their translocated counterparts based on a similar morphology, immunolabeling and increased expression of a common RNA read‐through molecule [16, 17]. In some of these neoplasms, TFE3 amplification leads to increased gene expression, but other mechanisms resulting in elevated TFE3 levels likely also exist [8, 18]. The same presumably holds true for PEComas like the one presented here. Regarding the TFE3 expression in our case, clonal tumor evolution appears to have played an additional role during the course of disease. At initial diagnosis, FISH analysis was unable to detect a TFE3 amplification in the primary tumor, although genomic profiling of metastases later revealed a copy number gain. Perhaps the additional TP53 mutation, which presumably also contributed to the complex karyotypic changes, promoted the selection of a TFE3‐expressing PEComa subclone in which genomic material on chromosome X was consecutively gained. Indeed, the differential MiTF expression observed here suggests tumor heterogeneity and supports our hypothesis of clonal tumor evolution.
To our knowledge, this is the first case with confirmed heterozygous deletion in a TSC gene and concomitant TFE3 activation with a distinctive malignant epithelioid phenotype. This finding challenges the biological distinction of TFE3‐ and TCS1/2‐altered PEComas. The notion that both the TSC1/2‐mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa is of translational clinical importance. TSC1/2‐mutated PEComas sometimes respond to mTOR‐inhibition therapy [19], but these drugs are mechanistically believed to be inefficient in TFE3‐altered PEComa. MET‐inhibitors, on the other hand, are active in alveolar soft part sarcoma with TFE3 rearrangement [20], a rare subtype of soft‐tissue sarcoma, and could constitute a therapeutic option for TFE3 overexpressing PEComas. Importantly, when there is evidence of dual pathway activation, it appears reasonable to combine both drugs.
Author contributions statement
AF, LB, AD, UK and MS designed the research. AD, DT and AL performed the experiments. LB, AD, UK, BMP, VW, AH, AA and MS analyzed and interpreted the data. MS and JKS wrote the manuscript. AF, LB, AD, UK, DT, MH, BP, VW, AH, AA, SB, RP, RÖ and SM critically commented on and edited the manuscript. All authors have read and approved the manuscript.
Supporting information
Supplementary materials and methods
Figure S1. Expression levels of candidate genes in tumor tissue detected by RNA‐Seq compared to dermal fibroblasts
Figure S2. Results of quantitative PCR for determination of TSC1 copy number compared to the autosomal ALB and the X‐chromosomal F8 gene loci
Table S1. Antibodies used for immunohistochemical staining
Table S2. Genes covered in the NGS panel developed for clinical service at Charité – Universitätsmedizin Berlin
Click here for additional data file.
Acknowledgements
This study was supported by the German Cancer Consortium (DKTK). MS is a participant in the BIH‐Charité Clinician Scientist Program funded by the Charité‐Universitätsmedizin Berlin and Berlin Institute of Health. Open access funding enabled and organized by Projekt DEAL.
|
EVEROLIMUS, SORAFENIB
|
DrugsGivenReaction
|
CC BY
|
33180365
| 19,513,964
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastases to lung'.
|
TFE3 activation in a TSC1-altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms.
Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1-mutated PEComa displaying a TFE3-altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2-mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options.
Introduction
PEComas are a family of mesenchymal tumors that demonstrate immunoreactivity for both melanocytic and smooth muscle markers [1, 2]. They form a biological continuum ranging from benign to overtly malignant aggressive neoplasms. Malignant PEComas are exceedingly rare, with only about 100 cases described in the literature. Radical resection remains the favored treatment option in localized tumors. In locally advanced or metastatic disease, single case studies report short‐lived responses to chemotherapy containing doxorubicin, ifosfamide or gemcitabine [3].
Germline or somatic mutations of the genes TSC1 or TSC2 (TSC1/2) are a driving factor in PEComa development, resulting in activation of the mammalian target of rapamycin (mTOR) pathway [4, 5]. These alterations are the basis for palliative therapy with mTOR inhibitors [3].
A subset of PEComas harboring TFE3 gene fusions has recently been identified, adding them to the group of Xp11 translocation cancers. Here, the introduction of a constitutively active promotor causes oncogenic upregulation of the TFE3 transcription factor [6, 7]. Beside Xp11 translocations, several other causative genomic alterations for TFE3 activation likely exist [8].
Current consensus is that TFE3 and TSC1/2 alterations define distinct biological PEComa subgroups and are mutually exclusive [6, 9, 10]. Here, we report for the first time a malignant PEComa with TFE3 activation and heterozygous loss of TSC1. This case challenges the molecular dichotomy in this tumor entity.
Materials and methods
Studied case
Analyses were performed on tumor samples obtained from a 47‐year‐old woman diagnosed with PEComa in 2017. Written informed consent for the analyses was provided by the patient and posthumously by her husband according to local ethical guidelines.
Immunohistochemical staining and fluorescence in situ hybridization
Samples of the primary tumor and metastases were formalin‐fixed and paraffin‐embedded. H&E stained slides were evaluated by specialized pathologists at Charité‐Universitätsmedizin Berlin and the reference center for urogenital and soft tissue pathology at the Institute of Pathology of the University Erlangen‐Nürnberg in Erlangen, Germany. Immunohistochemistry was performed as described in Supplementary materials and methods using antibodies listed in supplementary material, Table S1.
Molecular analyses
Quantitative PCR, targeted exome sequencing, RNA sequencing (RNA‐Seq) and nanopore long‐read whole‐genome sequencing was performed as described in Supplementary materials and methods.
Results and discussion
Case description
In 2017, a 47‐year‐old woman with known tuberous sclerosis complex (TSC) due to a heterozygous germline TSC1 deletion presented with abdominal pain. A CT scan revealed a mass in the right kidney, leading to the clinical diagnosis of angiomyolipoma. Everolimus was initiated at a low dose of 2.5 mg once daily in accordance with the patient's wishes, resulting in trough levels of 2.5–4 ng/ml.
Four months later, imaging showed rapid growth of the mass. With suspicion of renal cell carcinoma, a radical nephrectomy was performed. Histopathological examination led to the diagnosis of a PEComa, which was 120 × 110 × 110 mm in size and resected to R0. A CT scan of the lungs showed no pulmonary metastases and the tumor board recommended no adjuvant therapy.
Four months later, recurrence was seen in a follow‐up CT scan in the region T12‐L4. The patient reported no symptoms at this time. Everolimus was re‐initiated at 5 mg twice daily. In addition, sorafenib was administered at 200 mg twice daily but had to be discontinued after 2 months due to intolerable gastrointestinal side effects. The patient also received radiation therapy of the painful paravertebral mass (39–45.5 Gy), leading to pronounced tumor regression.
However, hepatic masses appeared after 12 weeks and histopathology confirmed the diagnosis of metastatic malignant PEComa. The patient underwent surgery with R1 resection and did not return to our clinic for 4 months. By then, multiple hepatic, osseous and pulmonary metastases had developed. Chemotherapy with doxorubicin (75 mg/m2) could only be administered once and the patient died of the disease in 2018.
Distinctive TFE3‐rearranged phenotype in a TSC1‐altered PEComa
Histomorphologically, conventional PEComas (so called epithelioid angiomyolipomas) display a monophasic pattern of predominantly epithelioid cells and lack adipose tissue and dysmorphic blood vessels [11]. TFE3‐rearranged PEComas show epithelioid cells arranged into a distinctive nested and pseudoalveolar pattern [6, 10]. The PEComa presented here matched the latter description, displaying a solid, partially nested‐alveolar architecture with extensive tumor necrosis as well as hemorrhage. Adipose tissue and spindle cells were completely absent. The tumor cells contained voluminous, eosinophilic and partially clear cytoplasm with prominent nucleoli and pleomorphic nuclei. Marked nuclear atypia was present (Figure 1A).
Figure 1 PEComa histology and immunohistochemistry (IHC). (A) Representative image of the histomorphological appearance of the presented case (100‐fold total magnification, H&E staining). (B) TFE3 expression in tumor cells (200‐fold total magnification). (C) No MiTF expression in tumor cells from primary tumor (200‐fold total magnification). (D) MiTF expression in tumor cells from hepatic metastasis (200‐fold total magnification).
Immunohistochemical examination of the vital tumor cells revealed partial patchy expression of HMB45, focal expression of Melan A and weak positivity for Cathepsin K, which was mirrored at the RNA level (see supplementary material, Figure S1). There was no immunoreactivity for PAX8, smooth muscle actin and desmin and strong nuclear positivity for TFE3 was observed, again matching the phenotype of TFE3‐altered PEComas (Figure 1B) [6, 10]. As opposed to the primary tumor, MiTF positivity was seen in hepatic metastases (Figure 1C,D), while pulmonary metastases displayed only weak MiTF mRNA expression (see supplementary material, Figure S1). Many TFE3‐rearranged PEComas are MiTF‐nonimmunoreactive and it has been suggested that the TFE3 fusion protein substitutes for MiTF [6]. We consider tumor heterogeneity a possible explanation for the differential MiTF expression, with perhaps only a subset of tumor cells exhibiting TFE3 activation.
Evidence for a dual pathogenic mechanism involving TFE3 and TSC1 in our PEComa case
The known heterozygous germline TSC1 deletion was verified by real‐time PCR (see supplementary material, Figure S2) and only residual TSC1 expression was seen in the transcriptome (see supplementary material, Figure S1). The tumor morphology and TFE3 immunoreactivity, however, were suggestive of a TFE3 fusion. Therefore, fluorescence in situ hybridization (FISH) analysis was performed on the primary tumor. Out of 50 tumor cells, only three showed a translocated break‐apart signal (Figure 2A). The other examined cells did not meet the break‐apart cutoff values, but several cells displayed one co‐localization signal and one small separation of the 5′TFE3 and 3′TFE3 probes (Figure 2B). Similar subtle break‐apart patterns have been described in tumors harboring TFE3 inversions rather than translocations [12, 13, 14]. However, RNA‐Seq analysis performed on a pulmonary PEComa lesion was unable to identify any gene fusions involving TFE3. In order to find aberrations missed by RNA‐Seq, we next performed long‐read whole genome sequencing. Structural variant calling also did not detect TFE3 fusions. However, multiple copy number gains were found, including a large 36 Mbp region encompassing TFE3 on chrX:22015149‐58073962 (Figures 3 and 4). Transcriptome analysis detected an increase in levels of TFE3 mRNA in tumor cells compared to dermal fibroblast controls after normalization for expression of housekeeping genes (see supplementary material, Figure S1). Therefore, similar to Xp11 translocation cancers, TFE3 overexpression is one likely oncogenic driver in this tumor [15].
Figure 2 Interphase FISH with TFE3 break‐apart probe. (A) Break‐apart signal as seen in 6% of cells (arrow). (B) Small separation of the TFE3 probes (arrow).
Figure 3 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosomes 1‐22 finds multiple copy number variations. 2‐Fold genome coverage was achieved; counts averaged over 0.5 MB. Chromosome X is not analyzed or depicted here due to the algorithm used.
Figure 4 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosome X finds copy number gain at chrX:22015149‐58073962. 2‐Fold genome coverage was achieved. Copy number variation for chromosome X (top left panel) and enlarged view of copy number changes for TFE3 (lower right panel).
In addition, targeted exome sequencing revealed a coexistent TP53 mutation. The variant NM_000546.5:c.614A>G (p.Y205C) found was classified as pathogenic. TP53 mutations do occur concurrently with TSC1/2 mutations [10] but have not been described in TFE3‐altered PEComas until now. No additional pathogenic mutations were detected in the other genes tested in our panel (see supplementary material, Table S2).
Conclusion and clinical remarks
In the case presented here, it is clear that the heterozygous loss of TSC1 predisposed to PEComa development, but we believe that the sequential gain of TFE3 contributed to tumorigenesis. Interestingly, the observed TFE3 activation was not due to a TFE3 gene fusion, analogous to reports on TFE3‐expressing/nontranslocated renal cell carcinomas. These tumors are hypothesized to share a biological mechanism with their translocated counterparts based on a similar morphology, immunolabeling and increased expression of a common RNA read‐through molecule [16, 17]. In some of these neoplasms, TFE3 amplification leads to increased gene expression, but other mechanisms resulting in elevated TFE3 levels likely also exist [8, 18]. The same presumably holds true for PEComas like the one presented here. Regarding the TFE3 expression in our case, clonal tumor evolution appears to have played an additional role during the course of disease. At initial diagnosis, FISH analysis was unable to detect a TFE3 amplification in the primary tumor, although genomic profiling of metastases later revealed a copy number gain. Perhaps the additional TP53 mutation, which presumably also contributed to the complex karyotypic changes, promoted the selection of a TFE3‐expressing PEComa subclone in which genomic material on chromosome X was consecutively gained. Indeed, the differential MiTF expression observed here suggests tumor heterogeneity and supports our hypothesis of clonal tumor evolution.
To our knowledge, this is the first case with confirmed heterozygous deletion in a TSC gene and concomitant TFE3 activation with a distinctive malignant epithelioid phenotype. This finding challenges the biological distinction of TFE3‐ and TCS1/2‐altered PEComas. The notion that both the TSC1/2‐mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa is of translational clinical importance. TSC1/2‐mutated PEComas sometimes respond to mTOR‐inhibition therapy [19], but these drugs are mechanistically believed to be inefficient in TFE3‐altered PEComa. MET‐inhibitors, on the other hand, are active in alveolar soft part sarcoma with TFE3 rearrangement [20], a rare subtype of soft‐tissue sarcoma, and could constitute a therapeutic option for TFE3 overexpressing PEComas. Importantly, when there is evidence of dual pathway activation, it appears reasonable to combine both drugs.
Author contributions statement
AF, LB, AD, UK and MS designed the research. AD, DT and AL performed the experiments. LB, AD, UK, BMP, VW, AH, AA and MS analyzed and interpreted the data. MS and JKS wrote the manuscript. AF, LB, AD, UK, DT, MH, BP, VW, AH, AA, SB, RP, RÖ and SM critically commented on and edited the manuscript. All authors have read and approved the manuscript.
Supporting information
Supplementary materials and methods
Figure S1. Expression levels of candidate genes in tumor tissue detected by RNA‐Seq compared to dermal fibroblasts
Figure S2. Results of quantitative PCR for determination of TSC1 copy number compared to the autosomal ALB and the X‐chromosomal F8 gene loci
Table S1. Antibodies used for immunohistochemical staining
Table S2. Genes covered in the NGS panel developed for clinical service at Charité – Universitätsmedizin Berlin
Click here for additional data file.
Acknowledgements
This study was supported by the German Cancer Consortium (DKTK). MS is a participant in the BIH‐Charité Clinician Scientist Program funded by the Charité‐Universitätsmedizin Berlin and Berlin Institute of Health. Open access funding enabled and organized by Projekt DEAL.
|
EVEROLIMUS, SORAFENIB
|
DrugsGivenReaction
|
CC BY
|
33180365
| 19,513,964
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastases to spine'.
|
TFE3 activation in a TSC1-altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms.
Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1-mutated PEComa displaying a TFE3-altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2-mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options.
Introduction
PEComas are a family of mesenchymal tumors that demonstrate immunoreactivity for both melanocytic and smooth muscle markers [1, 2]. They form a biological continuum ranging from benign to overtly malignant aggressive neoplasms. Malignant PEComas are exceedingly rare, with only about 100 cases described in the literature. Radical resection remains the favored treatment option in localized tumors. In locally advanced or metastatic disease, single case studies report short‐lived responses to chemotherapy containing doxorubicin, ifosfamide or gemcitabine [3].
Germline or somatic mutations of the genes TSC1 or TSC2 (TSC1/2) are a driving factor in PEComa development, resulting in activation of the mammalian target of rapamycin (mTOR) pathway [4, 5]. These alterations are the basis for palliative therapy with mTOR inhibitors [3].
A subset of PEComas harboring TFE3 gene fusions has recently been identified, adding them to the group of Xp11 translocation cancers. Here, the introduction of a constitutively active promotor causes oncogenic upregulation of the TFE3 transcription factor [6, 7]. Beside Xp11 translocations, several other causative genomic alterations for TFE3 activation likely exist [8].
Current consensus is that TFE3 and TSC1/2 alterations define distinct biological PEComa subgroups and are mutually exclusive [6, 9, 10]. Here, we report for the first time a malignant PEComa with TFE3 activation and heterozygous loss of TSC1. This case challenges the molecular dichotomy in this tumor entity.
Materials and methods
Studied case
Analyses were performed on tumor samples obtained from a 47‐year‐old woman diagnosed with PEComa in 2017. Written informed consent for the analyses was provided by the patient and posthumously by her husband according to local ethical guidelines.
Immunohistochemical staining and fluorescence in situ hybridization
Samples of the primary tumor and metastases were formalin‐fixed and paraffin‐embedded. H&E stained slides were evaluated by specialized pathologists at Charité‐Universitätsmedizin Berlin and the reference center for urogenital and soft tissue pathology at the Institute of Pathology of the University Erlangen‐Nürnberg in Erlangen, Germany. Immunohistochemistry was performed as described in Supplementary materials and methods using antibodies listed in supplementary material, Table S1.
Molecular analyses
Quantitative PCR, targeted exome sequencing, RNA sequencing (RNA‐Seq) and nanopore long‐read whole‐genome sequencing was performed as described in Supplementary materials and methods.
Results and discussion
Case description
In 2017, a 47‐year‐old woman with known tuberous sclerosis complex (TSC) due to a heterozygous germline TSC1 deletion presented with abdominal pain. A CT scan revealed a mass in the right kidney, leading to the clinical diagnosis of angiomyolipoma. Everolimus was initiated at a low dose of 2.5 mg once daily in accordance with the patient's wishes, resulting in trough levels of 2.5–4 ng/ml.
Four months later, imaging showed rapid growth of the mass. With suspicion of renal cell carcinoma, a radical nephrectomy was performed. Histopathological examination led to the diagnosis of a PEComa, which was 120 × 110 × 110 mm in size and resected to R0. A CT scan of the lungs showed no pulmonary metastases and the tumor board recommended no adjuvant therapy.
Four months later, recurrence was seen in a follow‐up CT scan in the region T12‐L4. The patient reported no symptoms at this time. Everolimus was re‐initiated at 5 mg twice daily. In addition, sorafenib was administered at 200 mg twice daily but had to be discontinued after 2 months due to intolerable gastrointestinal side effects. The patient also received radiation therapy of the painful paravertebral mass (39–45.5 Gy), leading to pronounced tumor regression.
However, hepatic masses appeared after 12 weeks and histopathology confirmed the diagnosis of metastatic malignant PEComa. The patient underwent surgery with R1 resection and did not return to our clinic for 4 months. By then, multiple hepatic, osseous and pulmonary metastases had developed. Chemotherapy with doxorubicin (75 mg/m2) could only be administered once and the patient died of the disease in 2018.
Distinctive TFE3‐rearranged phenotype in a TSC1‐altered PEComa
Histomorphologically, conventional PEComas (so called epithelioid angiomyolipomas) display a monophasic pattern of predominantly epithelioid cells and lack adipose tissue and dysmorphic blood vessels [11]. TFE3‐rearranged PEComas show epithelioid cells arranged into a distinctive nested and pseudoalveolar pattern [6, 10]. The PEComa presented here matched the latter description, displaying a solid, partially nested‐alveolar architecture with extensive tumor necrosis as well as hemorrhage. Adipose tissue and spindle cells were completely absent. The tumor cells contained voluminous, eosinophilic and partially clear cytoplasm with prominent nucleoli and pleomorphic nuclei. Marked nuclear atypia was present (Figure 1A).
Figure 1 PEComa histology and immunohistochemistry (IHC). (A) Representative image of the histomorphological appearance of the presented case (100‐fold total magnification, H&E staining). (B) TFE3 expression in tumor cells (200‐fold total magnification). (C) No MiTF expression in tumor cells from primary tumor (200‐fold total magnification). (D) MiTF expression in tumor cells from hepatic metastasis (200‐fold total magnification).
Immunohistochemical examination of the vital tumor cells revealed partial patchy expression of HMB45, focal expression of Melan A and weak positivity for Cathepsin K, which was mirrored at the RNA level (see supplementary material, Figure S1). There was no immunoreactivity for PAX8, smooth muscle actin and desmin and strong nuclear positivity for TFE3 was observed, again matching the phenotype of TFE3‐altered PEComas (Figure 1B) [6, 10]. As opposed to the primary tumor, MiTF positivity was seen in hepatic metastases (Figure 1C,D), while pulmonary metastases displayed only weak MiTF mRNA expression (see supplementary material, Figure S1). Many TFE3‐rearranged PEComas are MiTF‐nonimmunoreactive and it has been suggested that the TFE3 fusion protein substitutes for MiTF [6]. We consider tumor heterogeneity a possible explanation for the differential MiTF expression, with perhaps only a subset of tumor cells exhibiting TFE3 activation.
Evidence for a dual pathogenic mechanism involving TFE3 and TSC1 in our PEComa case
The known heterozygous germline TSC1 deletion was verified by real‐time PCR (see supplementary material, Figure S2) and only residual TSC1 expression was seen in the transcriptome (see supplementary material, Figure S1). The tumor morphology and TFE3 immunoreactivity, however, were suggestive of a TFE3 fusion. Therefore, fluorescence in situ hybridization (FISH) analysis was performed on the primary tumor. Out of 50 tumor cells, only three showed a translocated break‐apart signal (Figure 2A). The other examined cells did not meet the break‐apart cutoff values, but several cells displayed one co‐localization signal and one small separation of the 5′TFE3 and 3′TFE3 probes (Figure 2B). Similar subtle break‐apart patterns have been described in tumors harboring TFE3 inversions rather than translocations [12, 13, 14]. However, RNA‐Seq analysis performed on a pulmonary PEComa lesion was unable to identify any gene fusions involving TFE3. In order to find aberrations missed by RNA‐Seq, we next performed long‐read whole genome sequencing. Structural variant calling also did not detect TFE3 fusions. However, multiple copy number gains were found, including a large 36 Mbp region encompassing TFE3 on chrX:22015149‐58073962 (Figures 3 and 4). Transcriptome analysis detected an increase in levels of TFE3 mRNA in tumor cells compared to dermal fibroblast controls after normalization for expression of housekeeping genes (see supplementary material, Figure S1). Therefore, similar to Xp11 translocation cancers, TFE3 overexpression is one likely oncogenic driver in this tumor [15].
Figure 2 Interphase FISH with TFE3 break‐apart probe. (A) Break‐apart signal as seen in 6% of cells (arrow). (B) Small separation of the TFE3 probes (arrow).
Figure 3 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosomes 1‐22 finds multiple copy number variations. 2‐Fold genome coverage was achieved; counts averaged over 0.5 MB. Chromosome X is not analyzed or depicted here due to the algorithm used.
Figure 4 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosome X finds copy number gain at chrX:22015149‐58073962. 2‐Fold genome coverage was achieved. Copy number variation for chromosome X (top left panel) and enlarged view of copy number changes for TFE3 (lower right panel).
In addition, targeted exome sequencing revealed a coexistent TP53 mutation. The variant NM_000546.5:c.614A>G (p.Y205C) found was classified as pathogenic. TP53 mutations do occur concurrently with TSC1/2 mutations [10] but have not been described in TFE3‐altered PEComas until now. No additional pathogenic mutations were detected in the other genes tested in our panel (see supplementary material, Table S2).
Conclusion and clinical remarks
In the case presented here, it is clear that the heterozygous loss of TSC1 predisposed to PEComa development, but we believe that the sequential gain of TFE3 contributed to tumorigenesis. Interestingly, the observed TFE3 activation was not due to a TFE3 gene fusion, analogous to reports on TFE3‐expressing/nontranslocated renal cell carcinomas. These tumors are hypothesized to share a biological mechanism with their translocated counterparts based on a similar morphology, immunolabeling and increased expression of a common RNA read‐through molecule [16, 17]. In some of these neoplasms, TFE3 amplification leads to increased gene expression, but other mechanisms resulting in elevated TFE3 levels likely also exist [8, 18]. The same presumably holds true for PEComas like the one presented here. Regarding the TFE3 expression in our case, clonal tumor evolution appears to have played an additional role during the course of disease. At initial diagnosis, FISH analysis was unable to detect a TFE3 amplification in the primary tumor, although genomic profiling of metastases later revealed a copy number gain. Perhaps the additional TP53 mutation, which presumably also contributed to the complex karyotypic changes, promoted the selection of a TFE3‐expressing PEComa subclone in which genomic material on chromosome X was consecutively gained. Indeed, the differential MiTF expression observed here suggests tumor heterogeneity and supports our hypothesis of clonal tumor evolution.
To our knowledge, this is the first case with confirmed heterozygous deletion in a TSC gene and concomitant TFE3 activation with a distinctive malignant epithelioid phenotype. This finding challenges the biological distinction of TFE3‐ and TCS1/2‐altered PEComas. The notion that both the TSC1/2‐mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa is of translational clinical importance. TSC1/2‐mutated PEComas sometimes respond to mTOR‐inhibition therapy [19], but these drugs are mechanistically believed to be inefficient in TFE3‐altered PEComa. MET‐inhibitors, on the other hand, are active in alveolar soft part sarcoma with TFE3 rearrangement [20], a rare subtype of soft‐tissue sarcoma, and could constitute a therapeutic option for TFE3 overexpressing PEComas. Importantly, when there is evidence of dual pathway activation, it appears reasonable to combine both drugs.
Author contributions statement
AF, LB, AD, UK and MS designed the research. AD, DT and AL performed the experiments. LB, AD, UK, BMP, VW, AH, AA and MS analyzed and interpreted the data. MS and JKS wrote the manuscript. AF, LB, AD, UK, DT, MH, BP, VW, AH, AA, SB, RP, RÖ and SM critically commented on and edited the manuscript. All authors have read and approved the manuscript.
Supporting information
Supplementary materials and methods
Figure S1. Expression levels of candidate genes in tumor tissue detected by RNA‐Seq compared to dermal fibroblasts
Figure S2. Results of quantitative PCR for determination of TSC1 copy number compared to the autosomal ALB and the X‐chromosomal F8 gene loci
Table S1. Antibodies used for immunohistochemical staining
Table S2. Genes covered in the NGS panel developed for clinical service at Charité – Universitätsmedizin Berlin
Click here for additional data file.
Acknowledgements
This study was supported by the German Cancer Consortium (DKTK). MS is a participant in the BIH‐Charité Clinician Scientist Program funded by the Charité‐Universitätsmedizin Berlin and Berlin Institute of Health. Open access funding enabled and organized by Projekt DEAL.
|
EVEROLIMUS, SORAFENIB
|
DrugsGivenReaction
|
CC BY
|
33180365
| 19,513,964
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'.
|
TFE3 activation in a TSC1-altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms.
Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1-mutated PEComa displaying a TFE3-altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2-mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options.
Introduction
PEComas are a family of mesenchymal tumors that demonstrate immunoreactivity for both melanocytic and smooth muscle markers [1, 2]. They form a biological continuum ranging from benign to overtly malignant aggressive neoplasms. Malignant PEComas are exceedingly rare, with only about 100 cases described in the literature. Radical resection remains the favored treatment option in localized tumors. In locally advanced or metastatic disease, single case studies report short‐lived responses to chemotherapy containing doxorubicin, ifosfamide or gemcitabine [3].
Germline or somatic mutations of the genes TSC1 or TSC2 (TSC1/2) are a driving factor in PEComa development, resulting in activation of the mammalian target of rapamycin (mTOR) pathway [4, 5]. These alterations are the basis for palliative therapy with mTOR inhibitors [3].
A subset of PEComas harboring TFE3 gene fusions has recently been identified, adding them to the group of Xp11 translocation cancers. Here, the introduction of a constitutively active promotor causes oncogenic upregulation of the TFE3 transcription factor [6, 7]. Beside Xp11 translocations, several other causative genomic alterations for TFE3 activation likely exist [8].
Current consensus is that TFE3 and TSC1/2 alterations define distinct biological PEComa subgroups and are mutually exclusive [6, 9, 10]. Here, we report for the first time a malignant PEComa with TFE3 activation and heterozygous loss of TSC1. This case challenges the molecular dichotomy in this tumor entity.
Materials and methods
Studied case
Analyses were performed on tumor samples obtained from a 47‐year‐old woman diagnosed with PEComa in 2017. Written informed consent for the analyses was provided by the patient and posthumously by her husband according to local ethical guidelines.
Immunohistochemical staining and fluorescence in situ hybridization
Samples of the primary tumor and metastases were formalin‐fixed and paraffin‐embedded. H&E stained slides were evaluated by specialized pathologists at Charité‐Universitätsmedizin Berlin and the reference center for urogenital and soft tissue pathology at the Institute of Pathology of the University Erlangen‐Nürnberg in Erlangen, Germany. Immunohistochemistry was performed as described in Supplementary materials and methods using antibodies listed in supplementary material, Table S1.
Molecular analyses
Quantitative PCR, targeted exome sequencing, RNA sequencing (RNA‐Seq) and nanopore long‐read whole‐genome sequencing was performed as described in Supplementary materials and methods.
Results and discussion
Case description
In 2017, a 47‐year‐old woman with known tuberous sclerosis complex (TSC) due to a heterozygous germline TSC1 deletion presented with abdominal pain. A CT scan revealed a mass in the right kidney, leading to the clinical diagnosis of angiomyolipoma. Everolimus was initiated at a low dose of 2.5 mg once daily in accordance with the patient's wishes, resulting in trough levels of 2.5–4 ng/ml.
Four months later, imaging showed rapid growth of the mass. With suspicion of renal cell carcinoma, a radical nephrectomy was performed. Histopathological examination led to the diagnosis of a PEComa, which was 120 × 110 × 110 mm in size and resected to R0. A CT scan of the lungs showed no pulmonary metastases and the tumor board recommended no adjuvant therapy.
Four months later, recurrence was seen in a follow‐up CT scan in the region T12‐L4. The patient reported no symptoms at this time. Everolimus was re‐initiated at 5 mg twice daily. In addition, sorafenib was administered at 200 mg twice daily but had to be discontinued after 2 months due to intolerable gastrointestinal side effects. The patient also received radiation therapy of the painful paravertebral mass (39–45.5 Gy), leading to pronounced tumor regression.
However, hepatic masses appeared after 12 weeks and histopathology confirmed the diagnosis of metastatic malignant PEComa. The patient underwent surgery with R1 resection and did not return to our clinic for 4 months. By then, multiple hepatic, osseous and pulmonary metastases had developed. Chemotherapy with doxorubicin (75 mg/m2) could only be administered once and the patient died of the disease in 2018.
Distinctive TFE3‐rearranged phenotype in a TSC1‐altered PEComa
Histomorphologically, conventional PEComas (so called epithelioid angiomyolipomas) display a monophasic pattern of predominantly epithelioid cells and lack adipose tissue and dysmorphic blood vessels [11]. TFE3‐rearranged PEComas show epithelioid cells arranged into a distinctive nested and pseudoalveolar pattern [6, 10]. The PEComa presented here matched the latter description, displaying a solid, partially nested‐alveolar architecture with extensive tumor necrosis as well as hemorrhage. Adipose tissue and spindle cells were completely absent. The tumor cells contained voluminous, eosinophilic and partially clear cytoplasm with prominent nucleoli and pleomorphic nuclei. Marked nuclear atypia was present (Figure 1A).
Figure 1 PEComa histology and immunohistochemistry (IHC). (A) Representative image of the histomorphological appearance of the presented case (100‐fold total magnification, H&E staining). (B) TFE3 expression in tumor cells (200‐fold total magnification). (C) No MiTF expression in tumor cells from primary tumor (200‐fold total magnification). (D) MiTF expression in tumor cells from hepatic metastasis (200‐fold total magnification).
Immunohistochemical examination of the vital tumor cells revealed partial patchy expression of HMB45, focal expression of Melan A and weak positivity for Cathepsin K, which was mirrored at the RNA level (see supplementary material, Figure S1). There was no immunoreactivity for PAX8, smooth muscle actin and desmin and strong nuclear positivity for TFE3 was observed, again matching the phenotype of TFE3‐altered PEComas (Figure 1B) [6, 10]. As opposed to the primary tumor, MiTF positivity was seen in hepatic metastases (Figure 1C,D), while pulmonary metastases displayed only weak MiTF mRNA expression (see supplementary material, Figure S1). Many TFE3‐rearranged PEComas are MiTF‐nonimmunoreactive and it has been suggested that the TFE3 fusion protein substitutes for MiTF [6]. We consider tumor heterogeneity a possible explanation for the differential MiTF expression, with perhaps only a subset of tumor cells exhibiting TFE3 activation.
Evidence for a dual pathogenic mechanism involving TFE3 and TSC1 in our PEComa case
The known heterozygous germline TSC1 deletion was verified by real‐time PCR (see supplementary material, Figure S2) and only residual TSC1 expression was seen in the transcriptome (see supplementary material, Figure S1). The tumor morphology and TFE3 immunoreactivity, however, were suggestive of a TFE3 fusion. Therefore, fluorescence in situ hybridization (FISH) analysis was performed on the primary tumor. Out of 50 tumor cells, only three showed a translocated break‐apart signal (Figure 2A). The other examined cells did not meet the break‐apart cutoff values, but several cells displayed one co‐localization signal and one small separation of the 5′TFE3 and 3′TFE3 probes (Figure 2B). Similar subtle break‐apart patterns have been described in tumors harboring TFE3 inversions rather than translocations [12, 13, 14]. However, RNA‐Seq analysis performed on a pulmonary PEComa lesion was unable to identify any gene fusions involving TFE3. In order to find aberrations missed by RNA‐Seq, we next performed long‐read whole genome sequencing. Structural variant calling also did not detect TFE3 fusions. However, multiple copy number gains were found, including a large 36 Mbp region encompassing TFE3 on chrX:22015149‐58073962 (Figures 3 and 4). Transcriptome analysis detected an increase in levels of TFE3 mRNA in tumor cells compared to dermal fibroblast controls after normalization for expression of housekeeping genes (see supplementary material, Figure S1). Therefore, similar to Xp11 translocation cancers, TFE3 overexpression is one likely oncogenic driver in this tumor [15].
Figure 2 Interphase FISH with TFE3 break‐apart probe. (A) Break‐apart signal as seen in 6% of cells (arrow). (B) Small separation of the TFE3 probes (arrow).
Figure 3 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosomes 1‐22 finds multiple copy number variations. 2‐Fold genome coverage was achieved; counts averaged over 0.5 MB. Chromosome X is not analyzed or depicted here due to the algorithm used.
Figure 4 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosome X finds copy number gain at chrX:22015149‐58073962. 2‐Fold genome coverage was achieved. Copy number variation for chromosome X (top left panel) and enlarged view of copy number changes for TFE3 (lower right panel).
In addition, targeted exome sequencing revealed a coexistent TP53 mutation. The variant NM_000546.5:c.614A>G (p.Y205C) found was classified as pathogenic. TP53 mutations do occur concurrently with TSC1/2 mutations [10] but have not been described in TFE3‐altered PEComas until now. No additional pathogenic mutations were detected in the other genes tested in our panel (see supplementary material, Table S2).
Conclusion and clinical remarks
In the case presented here, it is clear that the heterozygous loss of TSC1 predisposed to PEComa development, but we believe that the sequential gain of TFE3 contributed to tumorigenesis. Interestingly, the observed TFE3 activation was not due to a TFE3 gene fusion, analogous to reports on TFE3‐expressing/nontranslocated renal cell carcinomas. These tumors are hypothesized to share a biological mechanism with their translocated counterparts based on a similar morphology, immunolabeling and increased expression of a common RNA read‐through molecule [16, 17]. In some of these neoplasms, TFE3 amplification leads to increased gene expression, but other mechanisms resulting in elevated TFE3 levels likely also exist [8, 18]. The same presumably holds true for PEComas like the one presented here. Regarding the TFE3 expression in our case, clonal tumor evolution appears to have played an additional role during the course of disease. At initial diagnosis, FISH analysis was unable to detect a TFE3 amplification in the primary tumor, although genomic profiling of metastases later revealed a copy number gain. Perhaps the additional TP53 mutation, which presumably also contributed to the complex karyotypic changes, promoted the selection of a TFE3‐expressing PEComa subclone in which genomic material on chromosome X was consecutively gained. Indeed, the differential MiTF expression observed here suggests tumor heterogeneity and supports our hypothesis of clonal tumor evolution.
To our knowledge, this is the first case with confirmed heterozygous deletion in a TSC gene and concomitant TFE3 activation with a distinctive malignant epithelioid phenotype. This finding challenges the biological distinction of TFE3‐ and TCS1/2‐altered PEComas. The notion that both the TSC1/2‐mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa is of translational clinical importance. TSC1/2‐mutated PEComas sometimes respond to mTOR‐inhibition therapy [19], but these drugs are mechanistically believed to be inefficient in TFE3‐altered PEComa. MET‐inhibitors, on the other hand, are active in alveolar soft part sarcoma with TFE3 rearrangement [20], a rare subtype of soft‐tissue sarcoma, and could constitute a therapeutic option for TFE3 overexpressing PEComas. Importantly, when there is evidence of dual pathway activation, it appears reasonable to combine both drugs.
Author contributions statement
AF, LB, AD, UK and MS designed the research. AD, DT and AL performed the experiments. LB, AD, UK, BMP, VW, AH, AA and MS analyzed and interpreted the data. MS and JKS wrote the manuscript. AF, LB, AD, UK, DT, MH, BP, VW, AH, AA, SB, RP, RÖ and SM critically commented on and edited the manuscript. All authors have read and approved the manuscript.
Supporting information
Supplementary materials and methods
Figure S1. Expression levels of candidate genes in tumor tissue detected by RNA‐Seq compared to dermal fibroblasts
Figure S2. Results of quantitative PCR for determination of TSC1 copy number compared to the autosomal ALB and the X‐chromosomal F8 gene loci
Table S1. Antibodies used for immunohistochemical staining
Table S2. Genes covered in the NGS panel developed for clinical service at Charité – Universitätsmedizin Berlin
Click here for additional data file.
Acknowledgements
This study was supported by the German Cancer Consortium (DKTK). MS is a participant in the BIH‐Charité Clinician Scientist Program funded by the Charité‐Universitätsmedizin Berlin and Berlin Institute of Health. Open access funding enabled and organized by Projekt DEAL.
|
EVEROLIMUS, SORAFENIB
|
DrugsGivenReaction
|
CC BY
|
33180365
| 19,513,964
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'.
|
TFE3 activation in a TSC1-altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms.
Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1-mutated PEComa displaying a TFE3-altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2-mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options.
Introduction
PEComas are a family of mesenchymal tumors that demonstrate immunoreactivity for both melanocytic and smooth muscle markers [1, 2]. They form a biological continuum ranging from benign to overtly malignant aggressive neoplasms. Malignant PEComas are exceedingly rare, with only about 100 cases described in the literature. Radical resection remains the favored treatment option in localized tumors. In locally advanced or metastatic disease, single case studies report short‐lived responses to chemotherapy containing doxorubicin, ifosfamide or gemcitabine [3].
Germline or somatic mutations of the genes TSC1 or TSC2 (TSC1/2) are a driving factor in PEComa development, resulting in activation of the mammalian target of rapamycin (mTOR) pathway [4, 5]. These alterations are the basis for palliative therapy with mTOR inhibitors [3].
A subset of PEComas harboring TFE3 gene fusions has recently been identified, adding them to the group of Xp11 translocation cancers. Here, the introduction of a constitutively active promotor causes oncogenic upregulation of the TFE3 transcription factor [6, 7]. Beside Xp11 translocations, several other causative genomic alterations for TFE3 activation likely exist [8].
Current consensus is that TFE3 and TSC1/2 alterations define distinct biological PEComa subgroups and are mutually exclusive [6, 9, 10]. Here, we report for the first time a malignant PEComa with TFE3 activation and heterozygous loss of TSC1. This case challenges the molecular dichotomy in this tumor entity.
Materials and methods
Studied case
Analyses were performed on tumor samples obtained from a 47‐year‐old woman diagnosed with PEComa in 2017. Written informed consent for the analyses was provided by the patient and posthumously by her husband according to local ethical guidelines.
Immunohistochemical staining and fluorescence in situ hybridization
Samples of the primary tumor and metastases were formalin‐fixed and paraffin‐embedded. H&E stained slides were evaluated by specialized pathologists at Charité‐Universitätsmedizin Berlin and the reference center for urogenital and soft tissue pathology at the Institute of Pathology of the University Erlangen‐Nürnberg in Erlangen, Germany. Immunohistochemistry was performed as described in Supplementary materials and methods using antibodies listed in supplementary material, Table S1.
Molecular analyses
Quantitative PCR, targeted exome sequencing, RNA sequencing (RNA‐Seq) and nanopore long‐read whole‐genome sequencing was performed as described in Supplementary materials and methods.
Results and discussion
Case description
In 2017, a 47‐year‐old woman with known tuberous sclerosis complex (TSC) due to a heterozygous germline TSC1 deletion presented with abdominal pain. A CT scan revealed a mass in the right kidney, leading to the clinical diagnosis of angiomyolipoma. Everolimus was initiated at a low dose of 2.5 mg once daily in accordance with the patient's wishes, resulting in trough levels of 2.5–4 ng/ml.
Four months later, imaging showed rapid growth of the mass. With suspicion of renal cell carcinoma, a radical nephrectomy was performed. Histopathological examination led to the diagnosis of a PEComa, which was 120 × 110 × 110 mm in size and resected to R0. A CT scan of the lungs showed no pulmonary metastases and the tumor board recommended no adjuvant therapy.
Four months later, recurrence was seen in a follow‐up CT scan in the region T12‐L4. The patient reported no symptoms at this time. Everolimus was re‐initiated at 5 mg twice daily. In addition, sorafenib was administered at 200 mg twice daily but had to be discontinued after 2 months due to intolerable gastrointestinal side effects. The patient also received radiation therapy of the painful paravertebral mass (39–45.5 Gy), leading to pronounced tumor regression.
However, hepatic masses appeared after 12 weeks and histopathology confirmed the diagnosis of metastatic malignant PEComa. The patient underwent surgery with R1 resection and did not return to our clinic for 4 months. By then, multiple hepatic, osseous and pulmonary metastases had developed. Chemotherapy with doxorubicin (75 mg/m2) could only be administered once and the patient died of the disease in 2018.
Distinctive TFE3‐rearranged phenotype in a TSC1‐altered PEComa
Histomorphologically, conventional PEComas (so called epithelioid angiomyolipomas) display a monophasic pattern of predominantly epithelioid cells and lack adipose tissue and dysmorphic blood vessels [11]. TFE3‐rearranged PEComas show epithelioid cells arranged into a distinctive nested and pseudoalveolar pattern [6, 10]. The PEComa presented here matched the latter description, displaying a solid, partially nested‐alveolar architecture with extensive tumor necrosis as well as hemorrhage. Adipose tissue and spindle cells were completely absent. The tumor cells contained voluminous, eosinophilic and partially clear cytoplasm with prominent nucleoli and pleomorphic nuclei. Marked nuclear atypia was present (Figure 1A).
Figure 1 PEComa histology and immunohistochemistry (IHC). (A) Representative image of the histomorphological appearance of the presented case (100‐fold total magnification, H&E staining). (B) TFE3 expression in tumor cells (200‐fold total magnification). (C) No MiTF expression in tumor cells from primary tumor (200‐fold total magnification). (D) MiTF expression in tumor cells from hepatic metastasis (200‐fold total magnification).
Immunohistochemical examination of the vital tumor cells revealed partial patchy expression of HMB45, focal expression of Melan A and weak positivity for Cathepsin K, which was mirrored at the RNA level (see supplementary material, Figure S1). There was no immunoreactivity for PAX8, smooth muscle actin and desmin and strong nuclear positivity for TFE3 was observed, again matching the phenotype of TFE3‐altered PEComas (Figure 1B) [6, 10]. As opposed to the primary tumor, MiTF positivity was seen in hepatic metastases (Figure 1C,D), while pulmonary metastases displayed only weak MiTF mRNA expression (see supplementary material, Figure S1). Many TFE3‐rearranged PEComas are MiTF‐nonimmunoreactive and it has been suggested that the TFE3 fusion protein substitutes for MiTF [6]. We consider tumor heterogeneity a possible explanation for the differential MiTF expression, with perhaps only a subset of tumor cells exhibiting TFE3 activation.
Evidence for a dual pathogenic mechanism involving TFE3 and TSC1 in our PEComa case
The known heterozygous germline TSC1 deletion was verified by real‐time PCR (see supplementary material, Figure S2) and only residual TSC1 expression was seen in the transcriptome (see supplementary material, Figure S1). The tumor morphology and TFE3 immunoreactivity, however, were suggestive of a TFE3 fusion. Therefore, fluorescence in situ hybridization (FISH) analysis was performed on the primary tumor. Out of 50 tumor cells, only three showed a translocated break‐apart signal (Figure 2A). The other examined cells did not meet the break‐apart cutoff values, but several cells displayed one co‐localization signal and one small separation of the 5′TFE3 and 3′TFE3 probes (Figure 2B). Similar subtle break‐apart patterns have been described in tumors harboring TFE3 inversions rather than translocations [12, 13, 14]. However, RNA‐Seq analysis performed on a pulmonary PEComa lesion was unable to identify any gene fusions involving TFE3. In order to find aberrations missed by RNA‐Seq, we next performed long‐read whole genome sequencing. Structural variant calling also did not detect TFE3 fusions. However, multiple copy number gains were found, including a large 36 Mbp region encompassing TFE3 on chrX:22015149‐58073962 (Figures 3 and 4). Transcriptome analysis detected an increase in levels of TFE3 mRNA in tumor cells compared to dermal fibroblast controls after normalization for expression of housekeeping genes (see supplementary material, Figure S1). Therefore, similar to Xp11 translocation cancers, TFE3 overexpression is one likely oncogenic driver in this tumor [15].
Figure 2 Interphase FISH with TFE3 break‐apart probe. (A) Break‐apart signal as seen in 6% of cells (arrow). (B) Small separation of the TFE3 probes (arrow).
Figure 3 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosomes 1‐22 finds multiple copy number variations. 2‐Fold genome coverage was achieved; counts averaged over 0.5 MB. Chromosome X is not analyzed or depicted here due to the algorithm used.
Figure 4 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosome X finds copy number gain at chrX:22015149‐58073962. 2‐Fold genome coverage was achieved. Copy number variation for chromosome X (top left panel) and enlarged view of copy number changes for TFE3 (lower right panel).
In addition, targeted exome sequencing revealed a coexistent TP53 mutation. The variant NM_000546.5:c.614A>G (p.Y205C) found was classified as pathogenic. TP53 mutations do occur concurrently with TSC1/2 mutations [10] but have not been described in TFE3‐altered PEComas until now. No additional pathogenic mutations were detected in the other genes tested in our panel (see supplementary material, Table S2).
Conclusion and clinical remarks
In the case presented here, it is clear that the heterozygous loss of TSC1 predisposed to PEComa development, but we believe that the sequential gain of TFE3 contributed to tumorigenesis. Interestingly, the observed TFE3 activation was not due to a TFE3 gene fusion, analogous to reports on TFE3‐expressing/nontranslocated renal cell carcinomas. These tumors are hypothesized to share a biological mechanism with their translocated counterparts based on a similar morphology, immunolabeling and increased expression of a common RNA read‐through molecule [16, 17]. In some of these neoplasms, TFE3 amplification leads to increased gene expression, but other mechanisms resulting in elevated TFE3 levels likely also exist [8, 18]. The same presumably holds true for PEComas like the one presented here. Regarding the TFE3 expression in our case, clonal tumor evolution appears to have played an additional role during the course of disease. At initial diagnosis, FISH analysis was unable to detect a TFE3 amplification in the primary tumor, although genomic profiling of metastases later revealed a copy number gain. Perhaps the additional TP53 mutation, which presumably also contributed to the complex karyotypic changes, promoted the selection of a TFE3‐expressing PEComa subclone in which genomic material on chromosome X was consecutively gained. Indeed, the differential MiTF expression observed here suggests tumor heterogeneity and supports our hypothesis of clonal tumor evolution.
To our knowledge, this is the first case with confirmed heterozygous deletion in a TSC gene and concomitant TFE3 activation with a distinctive malignant epithelioid phenotype. This finding challenges the biological distinction of TFE3‐ and TCS1/2‐altered PEComas. The notion that both the TSC1/2‐mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa is of translational clinical importance. TSC1/2‐mutated PEComas sometimes respond to mTOR‐inhibition therapy [19], but these drugs are mechanistically believed to be inefficient in TFE3‐altered PEComa. MET‐inhibitors, on the other hand, are active in alveolar soft part sarcoma with TFE3 rearrangement [20], a rare subtype of soft‐tissue sarcoma, and could constitute a therapeutic option for TFE3 overexpressing PEComas. Importantly, when there is evidence of dual pathway activation, it appears reasonable to combine both drugs.
Author contributions statement
AF, LB, AD, UK and MS designed the research. AD, DT and AL performed the experiments. LB, AD, UK, BMP, VW, AH, AA and MS analyzed and interpreted the data. MS and JKS wrote the manuscript. AF, LB, AD, UK, DT, MH, BP, VW, AH, AA, SB, RP, RÖ and SM critically commented on and edited the manuscript. All authors have read and approved the manuscript.
Supporting information
Supplementary materials and methods
Figure S1. Expression levels of candidate genes in tumor tissue detected by RNA‐Seq compared to dermal fibroblasts
Figure S2. Results of quantitative PCR for determination of TSC1 copy number compared to the autosomal ALB and the X‐chromosomal F8 gene loci
Table S1. Antibodies used for immunohistochemical staining
Table S2. Genes covered in the NGS panel developed for clinical service at Charité – Universitätsmedizin Berlin
Click here for additional data file.
Acknowledgements
This study was supported by the German Cancer Consortium (DKTK). MS is a participant in the BIH‐Charité Clinician Scientist Program funded by the Charité‐Universitätsmedizin Berlin and Berlin Institute of Health. Open access funding enabled and organized by Projekt DEAL.
|
EVEROLIMUS, SORAFENIB
|
DrugsGivenReaction
|
CC BY
|
33180365
| 19,513,964
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tumour pain'.
|
TFE3 activation in a TSC1-altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms.
Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1-mutated PEComa displaying a TFE3-altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2-mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options.
Introduction
PEComas are a family of mesenchymal tumors that demonstrate immunoreactivity for both melanocytic and smooth muscle markers [1, 2]. They form a biological continuum ranging from benign to overtly malignant aggressive neoplasms. Malignant PEComas are exceedingly rare, with only about 100 cases described in the literature. Radical resection remains the favored treatment option in localized tumors. In locally advanced or metastatic disease, single case studies report short‐lived responses to chemotherapy containing doxorubicin, ifosfamide or gemcitabine [3].
Germline or somatic mutations of the genes TSC1 or TSC2 (TSC1/2) are a driving factor in PEComa development, resulting in activation of the mammalian target of rapamycin (mTOR) pathway [4, 5]. These alterations are the basis for palliative therapy with mTOR inhibitors [3].
A subset of PEComas harboring TFE3 gene fusions has recently been identified, adding them to the group of Xp11 translocation cancers. Here, the introduction of a constitutively active promotor causes oncogenic upregulation of the TFE3 transcription factor [6, 7]. Beside Xp11 translocations, several other causative genomic alterations for TFE3 activation likely exist [8].
Current consensus is that TFE3 and TSC1/2 alterations define distinct biological PEComa subgroups and are mutually exclusive [6, 9, 10]. Here, we report for the first time a malignant PEComa with TFE3 activation and heterozygous loss of TSC1. This case challenges the molecular dichotomy in this tumor entity.
Materials and methods
Studied case
Analyses were performed on tumor samples obtained from a 47‐year‐old woman diagnosed with PEComa in 2017. Written informed consent for the analyses was provided by the patient and posthumously by her husband according to local ethical guidelines.
Immunohistochemical staining and fluorescence in situ hybridization
Samples of the primary tumor and metastases were formalin‐fixed and paraffin‐embedded. H&E stained slides were evaluated by specialized pathologists at Charité‐Universitätsmedizin Berlin and the reference center for urogenital and soft tissue pathology at the Institute of Pathology of the University Erlangen‐Nürnberg in Erlangen, Germany. Immunohistochemistry was performed as described in Supplementary materials and methods using antibodies listed in supplementary material, Table S1.
Molecular analyses
Quantitative PCR, targeted exome sequencing, RNA sequencing (RNA‐Seq) and nanopore long‐read whole‐genome sequencing was performed as described in Supplementary materials and methods.
Results and discussion
Case description
In 2017, a 47‐year‐old woman with known tuberous sclerosis complex (TSC) due to a heterozygous germline TSC1 deletion presented with abdominal pain. A CT scan revealed a mass in the right kidney, leading to the clinical diagnosis of angiomyolipoma. Everolimus was initiated at a low dose of 2.5 mg once daily in accordance with the patient's wishes, resulting in trough levels of 2.5–4 ng/ml.
Four months later, imaging showed rapid growth of the mass. With suspicion of renal cell carcinoma, a radical nephrectomy was performed. Histopathological examination led to the diagnosis of a PEComa, which was 120 × 110 × 110 mm in size and resected to R0. A CT scan of the lungs showed no pulmonary metastases and the tumor board recommended no adjuvant therapy.
Four months later, recurrence was seen in a follow‐up CT scan in the region T12‐L4. The patient reported no symptoms at this time. Everolimus was re‐initiated at 5 mg twice daily. In addition, sorafenib was administered at 200 mg twice daily but had to be discontinued after 2 months due to intolerable gastrointestinal side effects. The patient also received radiation therapy of the painful paravertebral mass (39–45.5 Gy), leading to pronounced tumor regression.
However, hepatic masses appeared after 12 weeks and histopathology confirmed the diagnosis of metastatic malignant PEComa. The patient underwent surgery with R1 resection and did not return to our clinic for 4 months. By then, multiple hepatic, osseous and pulmonary metastases had developed. Chemotherapy with doxorubicin (75 mg/m2) could only be administered once and the patient died of the disease in 2018.
Distinctive TFE3‐rearranged phenotype in a TSC1‐altered PEComa
Histomorphologically, conventional PEComas (so called epithelioid angiomyolipomas) display a monophasic pattern of predominantly epithelioid cells and lack adipose tissue and dysmorphic blood vessels [11]. TFE3‐rearranged PEComas show epithelioid cells arranged into a distinctive nested and pseudoalveolar pattern [6, 10]. The PEComa presented here matched the latter description, displaying a solid, partially nested‐alveolar architecture with extensive tumor necrosis as well as hemorrhage. Adipose tissue and spindle cells were completely absent. The tumor cells contained voluminous, eosinophilic and partially clear cytoplasm with prominent nucleoli and pleomorphic nuclei. Marked nuclear atypia was present (Figure 1A).
Figure 1 PEComa histology and immunohistochemistry (IHC). (A) Representative image of the histomorphological appearance of the presented case (100‐fold total magnification, H&E staining). (B) TFE3 expression in tumor cells (200‐fold total magnification). (C) No MiTF expression in tumor cells from primary tumor (200‐fold total magnification). (D) MiTF expression in tumor cells from hepatic metastasis (200‐fold total magnification).
Immunohistochemical examination of the vital tumor cells revealed partial patchy expression of HMB45, focal expression of Melan A and weak positivity for Cathepsin K, which was mirrored at the RNA level (see supplementary material, Figure S1). There was no immunoreactivity for PAX8, smooth muscle actin and desmin and strong nuclear positivity for TFE3 was observed, again matching the phenotype of TFE3‐altered PEComas (Figure 1B) [6, 10]. As opposed to the primary tumor, MiTF positivity was seen in hepatic metastases (Figure 1C,D), while pulmonary metastases displayed only weak MiTF mRNA expression (see supplementary material, Figure S1). Many TFE3‐rearranged PEComas are MiTF‐nonimmunoreactive and it has been suggested that the TFE3 fusion protein substitutes for MiTF [6]. We consider tumor heterogeneity a possible explanation for the differential MiTF expression, with perhaps only a subset of tumor cells exhibiting TFE3 activation.
Evidence for a dual pathogenic mechanism involving TFE3 and TSC1 in our PEComa case
The known heterozygous germline TSC1 deletion was verified by real‐time PCR (see supplementary material, Figure S2) and only residual TSC1 expression was seen in the transcriptome (see supplementary material, Figure S1). The tumor morphology and TFE3 immunoreactivity, however, were suggestive of a TFE3 fusion. Therefore, fluorescence in situ hybridization (FISH) analysis was performed on the primary tumor. Out of 50 tumor cells, only three showed a translocated break‐apart signal (Figure 2A). The other examined cells did not meet the break‐apart cutoff values, but several cells displayed one co‐localization signal and one small separation of the 5′TFE3 and 3′TFE3 probes (Figure 2B). Similar subtle break‐apart patterns have been described in tumors harboring TFE3 inversions rather than translocations [12, 13, 14]. However, RNA‐Seq analysis performed on a pulmonary PEComa lesion was unable to identify any gene fusions involving TFE3. In order to find aberrations missed by RNA‐Seq, we next performed long‐read whole genome sequencing. Structural variant calling also did not detect TFE3 fusions. However, multiple copy number gains were found, including a large 36 Mbp region encompassing TFE3 on chrX:22015149‐58073962 (Figures 3 and 4). Transcriptome analysis detected an increase in levels of TFE3 mRNA in tumor cells compared to dermal fibroblast controls after normalization for expression of housekeeping genes (see supplementary material, Figure S1). Therefore, similar to Xp11 translocation cancers, TFE3 overexpression is one likely oncogenic driver in this tumor [15].
Figure 2 Interphase FISH with TFE3 break‐apart probe. (A) Break‐apart signal as seen in 6% of cells (arrow). (B) Small separation of the TFE3 probes (arrow).
Figure 3 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosomes 1‐22 finds multiple copy number variations. 2‐Fold genome coverage was achieved; counts averaged over 0.5 MB. Chromosome X is not analyzed or depicted here due to the algorithm used.
Figure 4 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosome X finds copy number gain at chrX:22015149‐58073962. 2‐Fold genome coverage was achieved. Copy number variation for chromosome X (top left panel) and enlarged view of copy number changes for TFE3 (lower right panel).
In addition, targeted exome sequencing revealed a coexistent TP53 mutation. The variant NM_000546.5:c.614A>G (p.Y205C) found was classified as pathogenic. TP53 mutations do occur concurrently with TSC1/2 mutations [10] but have not been described in TFE3‐altered PEComas until now. No additional pathogenic mutations were detected in the other genes tested in our panel (see supplementary material, Table S2).
Conclusion and clinical remarks
In the case presented here, it is clear that the heterozygous loss of TSC1 predisposed to PEComa development, but we believe that the sequential gain of TFE3 contributed to tumorigenesis. Interestingly, the observed TFE3 activation was not due to a TFE3 gene fusion, analogous to reports on TFE3‐expressing/nontranslocated renal cell carcinomas. These tumors are hypothesized to share a biological mechanism with their translocated counterparts based on a similar morphology, immunolabeling and increased expression of a common RNA read‐through molecule [16, 17]. In some of these neoplasms, TFE3 amplification leads to increased gene expression, but other mechanisms resulting in elevated TFE3 levels likely also exist [8, 18]. The same presumably holds true for PEComas like the one presented here. Regarding the TFE3 expression in our case, clonal tumor evolution appears to have played an additional role during the course of disease. At initial diagnosis, FISH analysis was unable to detect a TFE3 amplification in the primary tumor, although genomic profiling of metastases later revealed a copy number gain. Perhaps the additional TP53 mutation, which presumably also contributed to the complex karyotypic changes, promoted the selection of a TFE3‐expressing PEComa subclone in which genomic material on chromosome X was consecutively gained. Indeed, the differential MiTF expression observed here suggests tumor heterogeneity and supports our hypothesis of clonal tumor evolution.
To our knowledge, this is the first case with confirmed heterozygous deletion in a TSC gene and concomitant TFE3 activation with a distinctive malignant epithelioid phenotype. This finding challenges the biological distinction of TFE3‐ and TCS1/2‐altered PEComas. The notion that both the TSC1/2‐mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa is of translational clinical importance. TSC1/2‐mutated PEComas sometimes respond to mTOR‐inhibition therapy [19], but these drugs are mechanistically believed to be inefficient in TFE3‐altered PEComa. MET‐inhibitors, on the other hand, are active in alveolar soft part sarcoma with TFE3 rearrangement [20], a rare subtype of soft‐tissue sarcoma, and could constitute a therapeutic option for TFE3 overexpressing PEComas. Importantly, when there is evidence of dual pathway activation, it appears reasonable to combine both drugs.
Author contributions statement
AF, LB, AD, UK and MS designed the research. AD, DT and AL performed the experiments. LB, AD, UK, BMP, VW, AH, AA and MS analyzed and interpreted the data. MS and JKS wrote the manuscript. AF, LB, AD, UK, DT, MH, BP, VW, AH, AA, SB, RP, RÖ and SM critically commented on and edited the manuscript. All authors have read and approved the manuscript.
Supporting information
Supplementary materials and methods
Figure S1. Expression levels of candidate genes in tumor tissue detected by RNA‐Seq compared to dermal fibroblasts
Figure S2. Results of quantitative PCR for determination of TSC1 copy number compared to the autosomal ALB and the X‐chromosomal F8 gene loci
Table S1. Antibodies used for immunohistochemical staining
Table S2. Genes covered in the NGS panel developed for clinical service at Charité – Universitätsmedizin Berlin
Click here for additional data file.
Acknowledgements
This study was supported by the German Cancer Consortium (DKTK). MS is a participant in the BIH‐Charité Clinician Scientist Program funded by the Charité‐Universitätsmedizin Berlin and Berlin Institute of Health. Open access funding enabled and organized by Projekt DEAL.
|
EVEROLIMUS, SORAFENIB
|
DrugsGivenReaction
|
CC BY
|
33180365
| 19,513,964
|
2021-01
|
What was the outcome of reaction 'Epithelioid mesothelioma'?
|
TFE3 activation in a TSC1-altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms.
Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1-mutated PEComa displaying a TFE3-altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2-mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options.
Introduction
PEComas are a family of mesenchymal tumors that demonstrate immunoreactivity for both melanocytic and smooth muscle markers [1, 2]. They form a biological continuum ranging from benign to overtly malignant aggressive neoplasms. Malignant PEComas are exceedingly rare, with only about 100 cases described in the literature. Radical resection remains the favored treatment option in localized tumors. In locally advanced or metastatic disease, single case studies report short‐lived responses to chemotherapy containing doxorubicin, ifosfamide or gemcitabine [3].
Germline or somatic mutations of the genes TSC1 or TSC2 (TSC1/2) are a driving factor in PEComa development, resulting in activation of the mammalian target of rapamycin (mTOR) pathway [4, 5]. These alterations are the basis for palliative therapy with mTOR inhibitors [3].
A subset of PEComas harboring TFE3 gene fusions has recently been identified, adding them to the group of Xp11 translocation cancers. Here, the introduction of a constitutively active promotor causes oncogenic upregulation of the TFE3 transcription factor [6, 7]. Beside Xp11 translocations, several other causative genomic alterations for TFE3 activation likely exist [8].
Current consensus is that TFE3 and TSC1/2 alterations define distinct biological PEComa subgroups and are mutually exclusive [6, 9, 10]. Here, we report for the first time a malignant PEComa with TFE3 activation and heterozygous loss of TSC1. This case challenges the molecular dichotomy in this tumor entity.
Materials and methods
Studied case
Analyses were performed on tumor samples obtained from a 47‐year‐old woman diagnosed with PEComa in 2017. Written informed consent for the analyses was provided by the patient and posthumously by her husband according to local ethical guidelines.
Immunohistochemical staining and fluorescence in situ hybridization
Samples of the primary tumor and metastases were formalin‐fixed and paraffin‐embedded. H&E stained slides were evaluated by specialized pathologists at Charité‐Universitätsmedizin Berlin and the reference center for urogenital and soft tissue pathology at the Institute of Pathology of the University Erlangen‐Nürnberg in Erlangen, Germany. Immunohistochemistry was performed as described in Supplementary materials and methods using antibodies listed in supplementary material, Table S1.
Molecular analyses
Quantitative PCR, targeted exome sequencing, RNA sequencing (RNA‐Seq) and nanopore long‐read whole‐genome sequencing was performed as described in Supplementary materials and methods.
Results and discussion
Case description
In 2017, a 47‐year‐old woman with known tuberous sclerosis complex (TSC) due to a heterozygous germline TSC1 deletion presented with abdominal pain. A CT scan revealed a mass in the right kidney, leading to the clinical diagnosis of angiomyolipoma. Everolimus was initiated at a low dose of 2.5 mg once daily in accordance with the patient's wishes, resulting in trough levels of 2.5–4 ng/ml.
Four months later, imaging showed rapid growth of the mass. With suspicion of renal cell carcinoma, a radical nephrectomy was performed. Histopathological examination led to the diagnosis of a PEComa, which was 120 × 110 × 110 mm in size and resected to R0. A CT scan of the lungs showed no pulmonary metastases and the tumor board recommended no adjuvant therapy.
Four months later, recurrence was seen in a follow‐up CT scan in the region T12‐L4. The patient reported no symptoms at this time. Everolimus was re‐initiated at 5 mg twice daily. In addition, sorafenib was administered at 200 mg twice daily but had to be discontinued after 2 months due to intolerable gastrointestinal side effects. The patient also received radiation therapy of the painful paravertebral mass (39–45.5 Gy), leading to pronounced tumor regression.
However, hepatic masses appeared after 12 weeks and histopathology confirmed the diagnosis of metastatic malignant PEComa. The patient underwent surgery with R1 resection and did not return to our clinic for 4 months. By then, multiple hepatic, osseous and pulmonary metastases had developed. Chemotherapy with doxorubicin (75 mg/m2) could only be administered once and the patient died of the disease in 2018.
Distinctive TFE3‐rearranged phenotype in a TSC1‐altered PEComa
Histomorphologically, conventional PEComas (so called epithelioid angiomyolipomas) display a monophasic pattern of predominantly epithelioid cells and lack adipose tissue and dysmorphic blood vessels [11]. TFE3‐rearranged PEComas show epithelioid cells arranged into a distinctive nested and pseudoalveolar pattern [6, 10]. The PEComa presented here matched the latter description, displaying a solid, partially nested‐alveolar architecture with extensive tumor necrosis as well as hemorrhage. Adipose tissue and spindle cells were completely absent. The tumor cells contained voluminous, eosinophilic and partially clear cytoplasm with prominent nucleoli and pleomorphic nuclei. Marked nuclear atypia was present (Figure 1A).
Figure 1 PEComa histology and immunohistochemistry (IHC). (A) Representative image of the histomorphological appearance of the presented case (100‐fold total magnification, H&E staining). (B) TFE3 expression in tumor cells (200‐fold total magnification). (C) No MiTF expression in tumor cells from primary tumor (200‐fold total magnification). (D) MiTF expression in tumor cells from hepatic metastasis (200‐fold total magnification).
Immunohistochemical examination of the vital tumor cells revealed partial patchy expression of HMB45, focal expression of Melan A and weak positivity for Cathepsin K, which was mirrored at the RNA level (see supplementary material, Figure S1). There was no immunoreactivity for PAX8, smooth muscle actin and desmin and strong nuclear positivity for TFE3 was observed, again matching the phenotype of TFE3‐altered PEComas (Figure 1B) [6, 10]. As opposed to the primary tumor, MiTF positivity was seen in hepatic metastases (Figure 1C,D), while pulmonary metastases displayed only weak MiTF mRNA expression (see supplementary material, Figure S1). Many TFE3‐rearranged PEComas are MiTF‐nonimmunoreactive and it has been suggested that the TFE3 fusion protein substitutes for MiTF [6]. We consider tumor heterogeneity a possible explanation for the differential MiTF expression, with perhaps only a subset of tumor cells exhibiting TFE3 activation.
Evidence for a dual pathogenic mechanism involving TFE3 and TSC1 in our PEComa case
The known heterozygous germline TSC1 deletion was verified by real‐time PCR (see supplementary material, Figure S2) and only residual TSC1 expression was seen in the transcriptome (see supplementary material, Figure S1). The tumor morphology and TFE3 immunoreactivity, however, were suggestive of a TFE3 fusion. Therefore, fluorescence in situ hybridization (FISH) analysis was performed on the primary tumor. Out of 50 tumor cells, only three showed a translocated break‐apart signal (Figure 2A). The other examined cells did not meet the break‐apart cutoff values, but several cells displayed one co‐localization signal and one small separation of the 5′TFE3 and 3′TFE3 probes (Figure 2B). Similar subtle break‐apart patterns have been described in tumors harboring TFE3 inversions rather than translocations [12, 13, 14]. However, RNA‐Seq analysis performed on a pulmonary PEComa lesion was unable to identify any gene fusions involving TFE3. In order to find aberrations missed by RNA‐Seq, we next performed long‐read whole genome sequencing. Structural variant calling also did not detect TFE3 fusions. However, multiple copy number gains were found, including a large 36 Mbp region encompassing TFE3 on chrX:22015149‐58073962 (Figures 3 and 4). Transcriptome analysis detected an increase in levels of TFE3 mRNA in tumor cells compared to dermal fibroblast controls after normalization for expression of housekeeping genes (see supplementary material, Figure S1). Therefore, similar to Xp11 translocation cancers, TFE3 overexpression is one likely oncogenic driver in this tumor [15].
Figure 2 Interphase FISH with TFE3 break‐apart probe. (A) Break‐apart signal as seen in 6% of cells (arrow). (B) Small separation of the TFE3 probes (arrow).
Figure 3 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosomes 1‐22 finds multiple copy number variations. 2‐Fold genome coverage was achieved; counts averaged over 0.5 MB. Chromosome X is not analyzed or depicted here due to the algorithm used.
Figure 4 Genomic profiling by an Oxford Nanopore Sequencing‐based assay of PEComa chromosome X finds copy number gain at chrX:22015149‐58073962. 2‐Fold genome coverage was achieved. Copy number variation for chromosome X (top left panel) and enlarged view of copy number changes for TFE3 (lower right panel).
In addition, targeted exome sequencing revealed a coexistent TP53 mutation. The variant NM_000546.5:c.614A>G (p.Y205C) found was classified as pathogenic. TP53 mutations do occur concurrently with TSC1/2 mutations [10] but have not been described in TFE3‐altered PEComas until now. No additional pathogenic mutations were detected in the other genes tested in our panel (see supplementary material, Table S2).
Conclusion and clinical remarks
In the case presented here, it is clear that the heterozygous loss of TSC1 predisposed to PEComa development, but we believe that the sequential gain of TFE3 contributed to tumorigenesis. Interestingly, the observed TFE3 activation was not due to a TFE3 gene fusion, analogous to reports on TFE3‐expressing/nontranslocated renal cell carcinomas. These tumors are hypothesized to share a biological mechanism with their translocated counterparts based on a similar morphology, immunolabeling and increased expression of a common RNA read‐through molecule [16, 17]. In some of these neoplasms, TFE3 amplification leads to increased gene expression, but other mechanisms resulting in elevated TFE3 levels likely also exist [8, 18]. The same presumably holds true for PEComas like the one presented here. Regarding the TFE3 expression in our case, clonal tumor evolution appears to have played an additional role during the course of disease. At initial diagnosis, FISH analysis was unable to detect a TFE3 amplification in the primary tumor, although genomic profiling of metastases later revealed a copy number gain. Perhaps the additional TP53 mutation, which presumably also contributed to the complex karyotypic changes, promoted the selection of a TFE3‐expressing PEComa subclone in which genomic material on chromosome X was consecutively gained. Indeed, the differential MiTF expression observed here suggests tumor heterogeneity and supports our hypothesis of clonal tumor evolution.
To our knowledge, this is the first case with confirmed heterozygous deletion in a TSC gene and concomitant TFE3 activation with a distinctive malignant epithelioid phenotype. This finding challenges the biological distinction of TFE3‐ and TCS1/2‐altered PEComas. The notion that both the TSC1/2‐mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa is of translational clinical importance. TSC1/2‐mutated PEComas sometimes respond to mTOR‐inhibition therapy [19], but these drugs are mechanistically believed to be inefficient in TFE3‐altered PEComa. MET‐inhibitors, on the other hand, are active in alveolar soft part sarcoma with TFE3 rearrangement [20], a rare subtype of soft‐tissue sarcoma, and could constitute a therapeutic option for TFE3 overexpressing PEComas. Importantly, when there is evidence of dual pathway activation, it appears reasonable to combine both drugs.
Author contributions statement
AF, LB, AD, UK and MS designed the research. AD, DT and AL performed the experiments. LB, AD, UK, BMP, VW, AH, AA and MS analyzed and interpreted the data. MS and JKS wrote the manuscript. AF, LB, AD, UK, DT, MH, BP, VW, AH, AA, SB, RP, RÖ and SM critically commented on and edited the manuscript. All authors have read and approved the manuscript.
Supporting information
Supplementary materials and methods
Figure S1. Expression levels of candidate genes in tumor tissue detected by RNA‐Seq compared to dermal fibroblasts
Figure S2. Results of quantitative PCR for determination of TSC1 copy number compared to the autosomal ALB and the X‐chromosomal F8 gene loci
Table S1. Antibodies used for immunohistochemical staining
Table S2. Genes covered in the NGS panel developed for clinical service at Charité – Universitätsmedizin Berlin
Click here for additional data file.
Acknowledgements
This study was supported by the German Cancer Consortium (DKTK). MS is a participant in the BIH‐Charité Clinician Scientist Program funded by the Charité‐Universitätsmedizin Berlin and Berlin Institute of Health. Open access funding enabled and organized by Projekt DEAL.
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Fatal
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ReactionOutcome
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CC BY
|
33180365
| 19,513,964
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anxiety'.
|
Incidence, preventability, and causality of adverse drug reactions at a university hospital emergency department.
OBJECTIVE
To investigate the characteristics of ADRs in patients admitting at the emergency room of a tertiary hospital.
METHODS
We collected the patient records of 1600 emergency room visits of a university hospital in 2018. The patient files were studied retrospectively and all possible ADRs were identified and registered. Patient characteristics, drugs associated with ADRs, causality, severity, preventability, and the role of pharmacogenetics were assessed.
RESULTS
There were 125 cases with ADRs, resulting in a 7.8% overall incidence among emergency visits. The incidence was greatest in visits among elderly patients, reaching 14% (men) to 19% (women) in the 80-89 years age group. The most common causative drugs were warfarin, acetylsalicylic acid (ASA), apixaban, and docetaxel, and the most common ADRs were bleedings and neutropenia and/or severe infections. Only two of the cases might have been prevented by pharmacogenetic testing, as advised in Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines.
CONCLUSIONS
The same ATC classes, antithrombotics and cytostatics, were involved in ADRs causing university clinic hospitalizations as those identified previously in drug-related hospital fatalities. It seems difficult to prevent these events totally, as the treatments are vitally important and their risk-benefit-relationships have been considered thoroughly, and as pharmacogenetic testing could have been useful in only few cases.
Introduction
Successful drug treatment is an obvious goal for healthcare professionals. It improves the prognosis of patient’s life and decreases healthcare costs. Modern medications are very effective, but all of them have adverse effects, too. To avoid adverse drug reactions (ADRs), it is important that drug–drug interactions, contraindications, liver or kidney insufficiency, and other restrictions are considered carefully. For some medications it is, however, particularly complex to balance their benefits and risks for each patient. With effective treatments having narrow therapeutic index, we often have to take risks of causing ADRs.
ADRs are known to cause serious health problems and even deaths in every health care setting [1–3]. Frequencies of ADRs range widely between studies from 3.6 to 61% in hospitalized patients [4, 5]. Reasons for the wide variability are related to the study population, study area, type of hospital, and study methods. For similar reasons, there is also a wide variability in the incidence of ADRs as a cause for hospitalization (0.77 to 9.8%) [2, 6, 7]. Elderly people are found to be especially vulnerable in this respect [8–10].
As these risks are well recognized, information regarding adverse effects in various subgroups or settings is found in many studies [1–3, 11–13]. There is, however, no recent study about ADRs in tertiary care. At a university hospital level, risks causing ADRs are usually well-known and avoidable risks should be quite few. Moreover, there is a lot of enthusiasm and expectations concerning the use of pharmacogenetic testing to help the clinicians to select the right drug and dose for each patient [3].Therefore, we evaluated which drugs were related to ADRs in our hospital at the emergency units covering internal medicine, surgery, neurology, and pulmonology during 6 months and what were the ADRs that they caused. Furthermore, we analyzed whether these risks could have been avoided and whether the use of pharmacogenetics would have helped in avoiding any of these cases.
Material and methods
This was a retrospective, register-based study on emergency room visits in the Helsinki University Hospital (HUCH) during the period July 1 until December 31, 2018. HUCH is a tertiary hospital covering all the specialties in the capital area of Finland. We focused on the emergency room with internal medicine, surgery (excluding orthopedics and plastic surgery), neurology, and pulmonology. There were about 16,500 emergency visits in these specialties during the study period. We randomly selected 10% of the visits (1600) for detailed evaluation.
Two reviewers, one of which was a specialist in internal medicine and clinical pharmacology, first studied the files of these 1600 visits by hand. The potential cases were further analyzed by two other experienced physicians who are also specialists in clinical pharmacology (Suppl). We checked the diagnoses, which were set at the emergency room, medications used by the patients, and symptoms of the patients. Thereafter, we studied the history of that patient both before and after that visit. We analyzed the medication and checked if there was any reexposure during that visit or later. We carefully evaluated whether the symptoms could have been caused by the medication or if there was a nondrug-related explanation. For the ADRs, we used the definition by WHO. The causality of an ADR was assessed with the criteria suggested first by Karch [14] and modified later by Hallas [15]: (1) known ADR or toxic reaction, (2) a reasonable temporal relationship between commencement of drug therapy and onset of adverse reaction, (3) the adverse reaction disappeared upon discontinuation or dose reduction, (4) the symptom or event could not be explained by any other known condition or predisposition of the patient, and (5) the symptoms reappeared upon reexposure, or laboratory tests showed toxic drug levels or drug-induced metabolic disturbances that explained the symptom.
The cases were categorized either “definite causal relationship” (all five criteria must be fulfilled), “probable causal relationship” (criteria 1–4 must be fulfilled), “possible causal relationship” (criteria 1–3 must be fulfilled), or “unlikely/unevaluable causal relationship”. The diagnoses were classified by using the International Classification of Disease 10th Revision (ICD-10, WHO) and drugs were classified by using the Anatomical Therapeutical Chemical (ATC) system. The severity of the ADRs was assessed according to U.S. National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE).
Preventability of the ADRs was assessed by using similar methods as in many previous studies [16–18]. The best practice–based preventability assessment was based on criteria developed by Hallas [15], and it has been modified for use after that [18, 19]. The preventability assessment included a thorough evaluation of whether the drug was prescribed in accordance with treatment protocols and SPCs, whether required therapeutic monitoring or laboratory tests had been performed and whether all patient data (including allergies, other medications etc.) had been checked.
Additionally, we estimated the proportion of the patients that had an ADR, which may be prevented by genotyping in a specific genetic subset, as guided by the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. First, we identified the patients that had an adverse reaction caused by a drug, which is included in any of the CPIC guidelines. Thereafter, we checked if the specific ADR observed is preventable in patients with a certain genetic profile, given the timing of the ADR event in relation to the preceding duration of the causative medication.
The administrative permission for this study was received from Helsinki University Hospital. Ethical review was not needed as the study involved only register data, and there were no contact to the patients. For statistical analysis and for calculating confidence intervals (CI), we used the Wilson method.
Results
In our study, there were 1600 emergency visits, of whom 52.8% were men and 47.2% were women. Of these visits, 125 were identified as ADR cases, resulting in a 7.8% incidence. One patient with adalimumab attended ER two times with different ADRs. There were also two patients who had more than one ADR at the time. Thus, the number of ADRs and patients is not the same. Among the ADR cases, the number of women was 66 (52.8%, 95% CI 44.1–61.3%) which was slightly more than that of men (n = 59, 47.2%, 95% CI 38.7–55.9%). We compared the percentages of ADRs within each age groups and found that patients aged 80–89 had the highest percentage of ADRs per visits (Fig. 1).Fig 1 The gender and age specific percentages of ADRs are shown above the bars. M=men, W=women
The ATC category most often involved with an ADR was B01 (antithrombotic agents) comprising 27.5% of all cases, followed by L01 (antineoplastic agents, 20.6%). They covered almost half (48.1%) of all ADRs. Opioids (N02) was the third group (8.1%), followed by immunosuppressants (L04; 5.6%). Drugs included in the groups B01 and L01 are specified in Fig. 2. Eleven drugs were involved in three or more cases, of which warfarin and ASA were involved in over 10 cases. More specific list can be found in Suppl.Fig. 2 Drugs (n = 160) causing ADRs. The ATC-classes causing more than 4 ADRs are shown in the figure
The most often affected system was gastrointestinal tract (30.0% of ADRs). Blood and lymphatic disorders accounted for 15.0% of the cases, followed by general disorders and administration site disorders (11.3%) and nervous system disorders (10.6%) occurred almost as often. Among ADRs affecting the musculoskeletal system, women were overrepresented. There were four cases with women (100%, 95% CI 51.0–100.0%), whereas men had no musculoskeletal system linked ADRs. Women were overrepresented also with cardiac system disorders (80.0%, 95% CI 37.6–96.4%), infective events (80.0%, 95% CI 49.0–94.3%), and nervous system disorders (70.6%, 95% CI 46.9–86.7%), whereas men were overrepresented in vascular disorders (100%, 95% CI 51.0–100.0%) and metabolic and nutritional disorders (71.4%, 95%CI 35.9–91.8%) (Fig. 3).Fig. 3 System organ classes involved with ADRs
Severe ADRs (n = 77) outnumbered other classes and together with moderate ADRs (n = 56) they comprised 83.1% of the cases. There were only two fatal cases, which were both caused by warfarin, and 15 life-threatening cases. Minority of the cases (n = 10) were mild. The causalities of the case were as follows 20.6% definite, 33.8% probable, and 45.6% possible.
In our study, drugs included in CPIC guidelines were involved in 29 cases [20–26]. Two of these cases had an ADR for which a pharmacogenetic test might reduce the risk of that particular ADR. One of the patients was on codeine and had ileus [20]. The other patient was on capecitabine, and he had severe hypokalemia (ad 2.5 mmol/l) [21]. There was another patient with capecitabine too, but his ADR (constipation) could not have been presented by genotyping the patient beforehand. The rest of the cases did not include ADRs, which could have been prevented by a specific genetic test. These drugs were warfarin (14 cases), clopidogrel (4 cases), tacrolimus (2 cases), allopurinol (2 cases), fluorouracil, oxcarbazepine, escitalopram, and citalopram, e.g. warfarin had been in use in every patient for at least 6 months, and genetic testing for warfarin is evaluated to be useful only in the beginning of the treatment.
There were only two cases with a drug-adverse reaction pair which were considered as potentially preventable in a genetic subset by pharmacogenetic testing, according to CPIC guidelines. There were also 27 other ADR cases with drugs mentioned in CPIC guidelines, but the specific ADRs observed were either unrelated to the recommended genotyping or occurred after prolonged treatment (warfarin associated bleedings).
Discussion
The incidence of ADRs in our university hospital emergency room visits was 7.8%, which was in line with previous studies [2, 27–29]. Comparison to previous studies should be made with caution as study settings, patients, and studied medications differ a lot. The most common drug classes causing ADRs in this study were antithrombotic and antineoplastic agents. They were also most often causing deaths in the same university hospital in earlier studies [6, 30].
In this study, we focused on ADRs in a tertiary hospital emergency ward. ADRs are the most common medication related problem in every health care setting studied [31, 32]. However, most studies focus on primary care setting, while there are only couple of studies from tertiary hospitals [27, 33–36]. There is one recent (2014) study from a university hospital from our country, where the incidence of ADRs was much higher (23.1%) than in our study [37]. Explanation for this difference could be the ages of the patients. They included only patients over 65 years, and the average age was 77. Our patients were 16–94 years, and the average age was 63.4. The characteristics of ADRs depend not only on the studied ward and patient group but also on the country [38, 39]. In a thorough study from India, most ADRs (81.6%) were assessed to be preventable [27]. However, in that study the most common drug classes were antiinfective agents, followed by steroids. Neither of these classes were found in our cases, indicating that there are marked differences in ADR preventability between these two centers. If we exclude these preventable cases from that study, the incidence of the ADRs is close to our study (1.15%).
There are multiple studies evaluating the incidence of ADRs in emergency departments from primary care [13, 28, 40, 41]. Drugs involved in these studies reflect the use of medications in the regional population with its typical age and other patient characteristics. In our Finnish population, children were not included, and the youngest cases were 18–19 years old. While ADRs were observed only infrequently in 20–49 years old people, the majority of ADRs were observed in age groups between 50 and 89 years. In these age groups, more than 8% of the emergency visits were related to ADRs with the highest percentages of 15 to 19% in the 80–89 years age group. There are two likely explanations to this finding: first, many diseases and ADRs are more severe in elderly people, and second, the number of simultaneous medications tends to increase with increasing age [2, 9].
The most important ATC-group in this study was antithrombotic agents (B01) and very close to that was antineoplastic agents (L01). The same two groups were also in the top when we studied ATC-groups involved in fatal cases in the same university hospital area [30]. In that study, cytostatic drugs caused 1.1% of deaths in the hospital and antithrombotic drugs caused 1.0% covering over half of the fatal cases (35/52). In the present study, they covered 48.1% of all ADRs. There were, altogether, 11 drugs causing more than two cases (Table 1), mainly involving either antithrombotics or cytostatics. Antithrombotics (or anticoagulants) and cytostatics have been the most common drugs involved in ADRs also in other studies in every health care setting [2, 3, 9, 10, 16, 28]. Even though the risks connected with these two groups are well known, it is hard to avoid them totally due to their narrow therapeutic window. Both groups are also prescribed to patients with severe diseases, which may also predispose them to ADRs. Deaths caused by cytostatics have diminished year by year in our hospital [30], but at the moment, also fragile patients are treated with them and the medications are more effective meaning that, e.g., leucopenia is inevitable in a subset of patients. There has also been a trend towards an increased intensity of antithrombotic treatments in cardiovascular patients, and overall, the use of antithrombotics has increased, while evaluation of the risk of bleeding has been improved. Perhaps because of improved evaluation and monitoring of patients, there has been even a slight decline in deaths caused by antithrombotic related bleedings during the past decades. In our study, there were six bleeding cases caused by apixaban and 14 by warfarin. Rivaroxaban or edoxaban-related ADRs were not identified in any of the cases. During the same time, the number of users of apixaban and rivaroxaban was about the same in Finland, equaling about 30% of the number of warfarin users. Unfortunately, we were not able to receive the number of the people using these drugs in the specific university hospital area. Nevertheless, it is obvious that the numbers will change in the coming years, after direct anticoagulants have replaced warfarin to a larger extent.Table 1 Drugs involved in three or more cases and the ADRs they caused
Drug Number of ADRs Types of ADRs (n)
warfarin 14 Intestinal bleeding (8), hematuria (2), ICH (2), hemarthrosis (1), bruises (1)
ASA 11 Gastrointestinal bleeding (7), bleeding wound (2), hematuria (1), anemia (1)
docetaxel 6 Febrile neutropenia (3), allergic reaction (1), fever (1), erysipelas (1)
apixaban 6 Gastrointestinal bleeding (4), ICH (1), hematuria (1)
clopidogrel 4 Bleeding wound (2), gastrointestinal bleeding (1), anemia (1)
buprenorphine 4 Cholecystitis (2), spasm of neck muscles and migraine (1), headache and disorientation (1)
bisoprolol 4 Bradycardia (3), hypotension (1)
tramadol 3 Acute cholecystitis (1), tremor in lower and upper extremities and anxiousness (1), nausea, sweating and tremor (1)
prednisolone 3 Sepsis and pneumonia (1), infection NUD (1), hyperglycemia (1)
oxycodone 3 Ileus (2), worsening of cancer pain (1)
methotrexate 3 Respiratory tract infection (1), pulmonary insufficiency (1), hepatic cirrhosis (1)
others 99
Most ADRs were gastrointestinal disorders followed by ADRs involving blood and lymphatic disorders. This is in line with the most often involved ATC classes, antithrombotics, and cytostatics. Furthermore, most ADRs were classified as severe, as many of them were serious bleedings, infections, or other serious toxicities. This finding probably also reflects the university hospital site of the study, as most mild cases are treated in primary care, while more severe cases are usually directed to the university clinic. Clinics involving oncology and hematology patients receiving cytostatics also typically report more severe cases than hospitals without such patients.
There is no universally accepted method for ADR causality grading, although a number of causality assessment scales have been published. Some studies have compared different scales, and they have usually found a poor agreement between the scales [42, 43]. Naranjo criteria have been used in many studies, as well as Hallas criteria. The Hallas criteria include the same general aspects as the Naranjo scale includes, but the Hallas criteria were more suitable for this study [15].
The preventability of ADRs seems to vary a lot between studies, at least from 4.3 to 83% [2, 44, 45]. This variation is not only dependent on different scales but also on different characteristics of patients and drugs. Preventable ADRs include, e.g., those caused by antihypertensives and antibiotics in many studies, while cases assessed as not to be prevented include medications like cytostatics. Most ADRs in our study were caused by antithrombotic agents and antineoplastic agents, which are used only after a precise consideration of the risk-benefit relationship of the treatments that are known to cause ADRs to a small subset of patients. There were, however, nine cases where ADR might have been preventable. Those cases included buprenorphine (2), tramadole (3), oxycodone (2), and bisoprolol (2). In these cases, opioids could have been replaced with other pain medications and bisoprolol could have been used with a lower dose. With these nine cases preventability of ADRs would have been 7.2% of all ADRs.
One aim of this study was to find out if pharmacogenetic testing could have prevented some ADRs. We used the international CPIC guidelines to evaluate if there were recommendations concerning any of the ADR causing drugs. For example, in case of allopurinol, which can be prescribed more safely after testing the HLA-B*5801-allele, the test could only be used to prevent Stevens-Johnson syndrome, not fever or gastrointestinal pain, which were the ADRs of the respective patients [22]. After evaluating every ADR causing drug, we found only two cases for which pharmacogenetic testing might have prevented the ADRs; one patient with hypokalemia related to capecitabine induced diarrhea and one with ileus caused by codeine. For capecitabine, there is evidence that pharmacogenetic testing could prevent severe toxicity [21], and for codeine gastrointestinal opioid adverse effects are shown to be associated with the CYP2D6 metabolizer phenotype [20]. There were also other ADRs caused by drugs included in CPIC guidelines. Warfarin was involved in 14 bleeding cases. Genotype-guided warfarin dosing is thought to be beneficial only when warfarin is started, as it helps to find the first stable international normalized ratio (INR) [23]. However, in all our cases, warfarin had been in use for more than 6 months. Therefore, it was considered unlikely that pharmacogenetic testing could have been used to prevent the ADRs, although carriers of the CYP2C9*3 allele can have a higher risk of bleeding even after prolonged warfarin treatment [46]. Other drugs included in CPIC guidelines were the fluoropyrimidines capecitabine and fluorouracil, whose severe toxicity could be reduced by genotype-guided dosing [21]. However, the cases in this study did not have severe toxicity, but only constipation and fever without neutropenia, and we considered that these ADRs could not have been prevented by pharmacogenetic testing. Further cases included hyponatremia caused by escitalopram or citalopram that we considered not preventable by pharmacogenetic testing [24], as there is no compelling evidence showing that hyponatremia is (es)citalopram concentration-dependent. Yet, there are two cases of escitalopram dose-dependent hyponatremia [47, 48].
Strengths and limitations
The number of emergency visits in our study was quite large. There were 16,535 ER visits during the six study months, and 1600 of them were randomized to our study. The patient files of these 1600 visits were studied carefully by one student and three experienced clinicians and clinical pharmacologists, and all possible ADRs were assessed and only real ADRs were included (case 1 Suppl).
We did not consider lack of drug effect to be an ADR. Therefore, there might have been cases that potentially could have been prevented by a pharmacogenetic testing. For example, clopidogrel is converted to its active metabolite by CYP2C19, and poor metabolizers with two unfunctional copies of CYP2C19 have reduced amount of active clopidogrel metabolites [25], which may result in blood clotting.
Conclusion
The same ATC categories and medications are in top when assessed the ADRs causing hospitalizations and fatal cases caused by medications. It seems difficult to prevent these events totally as the treatments are vitally important and risk-benefit-relationship has been considered thoroughly.
Supplementary Information
ESM 1 (DOCX 157 kb).
Authors’ contributions
M.K, O.L-R, and J.T.B wrote the manuscript; M.K, O.L.-R., J.T.B., and M.N. designed the research; M.K, O.L.-R., J.T.B, and M.N. performed the research and analyzed the data.
Funding
Open access funding provided by University of Helsinki including Helsinki University Central Hospital. State funding for university level health research, Helsinki University Hospital, Helsinki, Finland.
Data availability
Not applicable.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Code availability
Not applicable.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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TRAMADOL HYDROCHLORIDE
|
DrugsGivenReaction
|
CC BY
|
33188450
| 19,623,452
|
2021-04
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cholecystitis acute'.
|
Incidence, preventability, and causality of adverse drug reactions at a university hospital emergency department.
OBJECTIVE
To investigate the characteristics of ADRs in patients admitting at the emergency room of a tertiary hospital.
METHODS
We collected the patient records of 1600 emergency room visits of a university hospital in 2018. The patient files were studied retrospectively and all possible ADRs were identified and registered. Patient characteristics, drugs associated with ADRs, causality, severity, preventability, and the role of pharmacogenetics were assessed.
RESULTS
There were 125 cases with ADRs, resulting in a 7.8% overall incidence among emergency visits. The incidence was greatest in visits among elderly patients, reaching 14% (men) to 19% (women) in the 80-89 years age group. The most common causative drugs were warfarin, acetylsalicylic acid (ASA), apixaban, and docetaxel, and the most common ADRs were bleedings and neutropenia and/or severe infections. Only two of the cases might have been prevented by pharmacogenetic testing, as advised in Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines.
CONCLUSIONS
The same ATC classes, antithrombotics and cytostatics, were involved in ADRs causing university clinic hospitalizations as those identified previously in drug-related hospital fatalities. It seems difficult to prevent these events totally, as the treatments are vitally important and their risk-benefit-relationships have been considered thoroughly, and as pharmacogenetic testing could have been useful in only few cases.
Introduction
Successful drug treatment is an obvious goal for healthcare professionals. It improves the prognosis of patient’s life and decreases healthcare costs. Modern medications are very effective, but all of them have adverse effects, too. To avoid adverse drug reactions (ADRs), it is important that drug–drug interactions, contraindications, liver or kidney insufficiency, and other restrictions are considered carefully. For some medications it is, however, particularly complex to balance their benefits and risks for each patient. With effective treatments having narrow therapeutic index, we often have to take risks of causing ADRs.
ADRs are known to cause serious health problems and even deaths in every health care setting [1–3]. Frequencies of ADRs range widely between studies from 3.6 to 61% in hospitalized patients [4, 5]. Reasons for the wide variability are related to the study population, study area, type of hospital, and study methods. For similar reasons, there is also a wide variability in the incidence of ADRs as a cause for hospitalization (0.77 to 9.8%) [2, 6, 7]. Elderly people are found to be especially vulnerable in this respect [8–10].
As these risks are well recognized, information regarding adverse effects in various subgroups or settings is found in many studies [1–3, 11–13]. There is, however, no recent study about ADRs in tertiary care. At a university hospital level, risks causing ADRs are usually well-known and avoidable risks should be quite few. Moreover, there is a lot of enthusiasm and expectations concerning the use of pharmacogenetic testing to help the clinicians to select the right drug and dose for each patient [3].Therefore, we evaluated which drugs were related to ADRs in our hospital at the emergency units covering internal medicine, surgery, neurology, and pulmonology during 6 months and what were the ADRs that they caused. Furthermore, we analyzed whether these risks could have been avoided and whether the use of pharmacogenetics would have helped in avoiding any of these cases.
Material and methods
This was a retrospective, register-based study on emergency room visits in the Helsinki University Hospital (HUCH) during the period July 1 until December 31, 2018. HUCH is a tertiary hospital covering all the specialties in the capital area of Finland. We focused on the emergency room with internal medicine, surgery (excluding orthopedics and plastic surgery), neurology, and pulmonology. There were about 16,500 emergency visits in these specialties during the study period. We randomly selected 10% of the visits (1600) for detailed evaluation.
Two reviewers, one of which was a specialist in internal medicine and clinical pharmacology, first studied the files of these 1600 visits by hand. The potential cases were further analyzed by two other experienced physicians who are also specialists in clinical pharmacology (Suppl). We checked the diagnoses, which were set at the emergency room, medications used by the patients, and symptoms of the patients. Thereafter, we studied the history of that patient both before and after that visit. We analyzed the medication and checked if there was any reexposure during that visit or later. We carefully evaluated whether the symptoms could have been caused by the medication or if there was a nondrug-related explanation. For the ADRs, we used the definition by WHO. The causality of an ADR was assessed with the criteria suggested first by Karch [14] and modified later by Hallas [15]: (1) known ADR or toxic reaction, (2) a reasonable temporal relationship between commencement of drug therapy and onset of adverse reaction, (3) the adverse reaction disappeared upon discontinuation or dose reduction, (4) the symptom or event could not be explained by any other known condition or predisposition of the patient, and (5) the symptoms reappeared upon reexposure, or laboratory tests showed toxic drug levels or drug-induced metabolic disturbances that explained the symptom.
The cases were categorized either “definite causal relationship” (all five criteria must be fulfilled), “probable causal relationship” (criteria 1–4 must be fulfilled), “possible causal relationship” (criteria 1–3 must be fulfilled), or “unlikely/unevaluable causal relationship”. The diagnoses were classified by using the International Classification of Disease 10th Revision (ICD-10, WHO) and drugs were classified by using the Anatomical Therapeutical Chemical (ATC) system. The severity of the ADRs was assessed according to U.S. National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE).
Preventability of the ADRs was assessed by using similar methods as in many previous studies [16–18]. The best practice–based preventability assessment was based on criteria developed by Hallas [15], and it has been modified for use after that [18, 19]. The preventability assessment included a thorough evaluation of whether the drug was prescribed in accordance with treatment protocols and SPCs, whether required therapeutic monitoring or laboratory tests had been performed and whether all patient data (including allergies, other medications etc.) had been checked.
Additionally, we estimated the proportion of the patients that had an ADR, which may be prevented by genotyping in a specific genetic subset, as guided by the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. First, we identified the patients that had an adverse reaction caused by a drug, which is included in any of the CPIC guidelines. Thereafter, we checked if the specific ADR observed is preventable in patients with a certain genetic profile, given the timing of the ADR event in relation to the preceding duration of the causative medication.
The administrative permission for this study was received from Helsinki University Hospital. Ethical review was not needed as the study involved only register data, and there were no contact to the patients. For statistical analysis and for calculating confidence intervals (CI), we used the Wilson method.
Results
In our study, there were 1600 emergency visits, of whom 52.8% were men and 47.2% were women. Of these visits, 125 were identified as ADR cases, resulting in a 7.8% incidence. One patient with adalimumab attended ER two times with different ADRs. There were also two patients who had more than one ADR at the time. Thus, the number of ADRs and patients is not the same. Among the ADR cases, the number of women was 66 (52.8%, 95% CI 44.1–61.3%) which was slightly more than that of men (n = 59, 47.2%, 95% CI 38.7–55.9%). We compared the percentages of ADRs within each age groups and found that patients aged 80–89 had the highest percentage of ADRs per visits (Fig. 1).Fig 1 The gender and age specific percentages of ADRs are shown above the bars. M=men, W=women
The ATC category most often involved with an ADR was B01 (antithrombotic agents) comprising 27.5% of all cases, followed by L01 (antineoplastic agents, 20.6%). They covered almost half (48.1%) of all ADRs. Opioids (N02) was the third group (8.1%), followed by immunosuppressants (L04; 5.6%). Drugs included in the groups B01 and L01 are specified in Fig. 2. Eleven drugs were involved in three or more cases, of which warfarin and ASA were involved in over 10 cases. More specific list can be found in Suppl.Fig. 2 Drugs (n = 160) causing ADRs. The ATC-classes causing more than 4 ADRs are shown in the figure
The most often affected system was gastrointestinal tract (30.0% of ADRs). Blood and lymphatic disorders accounted for 15.0% of the cases, followed by general disorders and administration site disorders (11.3%) and nervous system disorders (10.6%) occurred almost as often. Among ADRs affecting the musculoskeletal system, women were overrepresented. There were four cases with women (100%, 95% CI 51.0–100.0%), whereas men had no musculoskeletal system linked ADRs. Women were overrepresented also with cardiac system disorders (80.0%, 95% CI 37.6–96.4%), infective events (80.0%, 95% CI 49.0–94.3%), and nervous system disorders (70.6%, 95% CI 46.9–86.7%), whereas men were overrepresented in vascular disorders (100%, 95% CI 51.0–100.0%) and metabolic and nutritional disorders (71.4%, 95%CI 35.9–91.8%) (Fig. 3).Fig. 3 System organ classes involved with ADRs
Severe ADRs (n = 77) outnumbered other classes and together with moderate ADRs (n = 56) they comprised 83.1% of the cases. There were only two fatal cases, which were both caused by warfarin, and 15 life-threatening cases. Minority of the cases (n = 10) were mild. The causalities of the case were as follows 20.6% definite, 33.8% probable, and 45.6% possible.
In our study, drugs included in CPIC guidelines were involved in 29 cases [20–26]. Two of these cases had an ADR for which a pharmacogenetic test might reduce the risk of that particular ADR. One of the patients was on codeine and had ileus [20]. The other patient was on capecitabine, and he had severe hypokalemia (ad 2.5 mmol/l) [21]. There was another patient with capecitabine too, but his ADR (constipation) could not have been presented by genotyping the patient beforehand. The rest of the cases did not include ADRs, which could have been prevented by a specific genetic test. These drugs were warfarin (14 cases), clopidogrel (4 cases), tacrolimus (2 cases), allopurinol (2 cases), fluorouracil, oxcarbazepine, escitalopram, and citalopram, e.g. warfarin had been in use in every patient for at least 6 months, and genetic testing for warfarin is evaluated to be useful only in the beginning of the treatment.
There were only two cases with a drug-adverse reaction pair which were considered as potentially preventable in a genetic subset by pharmacogenetic testing, according to CPIC guidelines. There were also 27 other ADR cases with drugs mentioned in CPIC guidelines, but the specific ADRs observed were either unrelated to the recommended genotyping or occurred after prolonged treatment (warfarin associated bleedings).
Discussion
The incidence of ADRs in our university hospital emergency room visits was 7.8%, which was in line with previous studies [2, 27–29]. Comparison to previous studies should be made with caution as study settings, patients, and studied medications differ a lot. The most common drug classes causing ADRs in this study were antithrombotic and antineoplastic agents. They were also most often causing deaths in the same university hospital in earlier studies [6, 30].
In this study, we focused on ADRs in a tertiary hospital emergency ward. ADRs are the most common medication related problem in every health care setting studied [31, 32]. However, most studies focus on primary care setting, while there are only couple of studies from tertiary hospitals [27, 33–36]. There is one recent (2014) study from a university hospital from our country, where the incidence of ADRs was much higher (23.1%) than in our study [37]. Explanation for this difference could be the ages of the patients. They included only patients over 65 years, and the average age was 77. Our patients were 16–94 years, and the average age was 63.4. The characteristics of ADRs depend not only on the studied ward and patient group but also on the country [38, 39]. In a thorough study from India, most ADRs (81.6%) were assessed to be preventable [27]. However, in that study the most common drug classes were antiinfective agents, followed by steroids. Neither of these classes were found in our cases, indicating that there are marked differences in ADR preventability between these two centers. If we exclude these preventable cases from that study, the incidence of the ADRs is close to our study (1.15%).
There are multiple studies evaluating the incidence of ADRs in emergency departments from primary care [13, 28, 40, 41]. Drugs involved in these studies reflect the use of medications in the regional population with its typical age and other patient characteristics. In our Finnish population, children were not included, and the youngest cases were 18–19 years old. While ADRs were observed only infrequently in 20–49 years old people, the majority of ADRs were observed in age groups between 50 and 89 years. In these age groups, more than 8% of the emergency visits were related to ADRs with the highest percentages of 15 to 19% in the 80–89 years age group. There are two likely explanations to this finding: first, many diseases and ADRs are more severe in elderly people, and second, the number of simultaneous medications tends to increase with increasing age [2, 9].
The most important ATC-group in this study was antithrombotic agents (B01) and very close to that was antineoplastic agents (L01). The same two groups were also in the top when we studied ATC-groups involved in fatal cases in the same university hospital area [30]. In that study, cytostatic drugs caused 1.1% of deaths in the hospital and antithrombotic drugs caused 1.0% covering over half of the fatal cases (35/52). In the present study, they covered 48.1% of all ADRs. There were, altogether, 11 drugs causing more than two cases (Table 1), mainly involving either antithrombotics or cytostatics. Antithrombotics (or anticoagulants) and cytostatics have been the most common drugs involved in ADRs also in other studies in every health care setting [2, 3, 9, 10, 16, 28]. Even though the risks connected with these two groups are well known, it is hard to avoid them totally due to their narrow therapeutic window. Both groups are also prescribed to patients with severe diseases, which may also predispose them to ADRs. Deaths caused by cytostatics have diminished year by year in our hospital [30], but at the moment, also fragile patients are treated with them and the medications are more effective meaning that, e.g., leucopenia is inevitable in a subset of patients. There has also been a trend towards an increased intensity of antithrombotic treatments in cardiovascular patients, and overall, the use of antithrombotics has increased, while evaluation of the risk of bleeding has been improved. Perhaps because of improved evaluation and monitoring of patients, there has been even a slight decline in deaths caused by antithrombotic related bleedings during the past decades. In our study, there were six bleeding cases caused by apixaban and 14 by warfarin. Rivaroxaban or edoxaban-related ADRs were not identified in any of the cases. During the same time, the number of users of apixaban and rivaroxaban was about the same in Finland, equaling about 30% of the number of warfarin users. Unfortunately, we were not able to receive the number of the people using these drugs in the specific university hospital area. Nevertheless, it is obvious that the numbers will change in the coming years, after direct anticoagulants have replaced warfarin to a larger extent.Table 1 Drugs involved in three or more cases and the ADRs they caused
Drug Number of ADRs Types of ADRs (n)
warfarin 14 Intestinal bleeding (8), hematuria (2), ICH (2), hemarthrosis (1), bruises (1)
ASA 11 Gastrointestinal bleeding (7), bleeding wound (2), hematuria (1), anemia (1)
docetaxel 6 Febrile neutropenia (3), allergic reaction (1), fever (1), erysipelas (1)
apixaban 6 Gastrointestinal bleeding (4), ICH (1), hematuria (1)
clopidogrel 4 Bleeding wound (2), gastrointestinal bleeding (1), anemia (1)
buprenorphine 4 Cholecystitis (2), spasm of neck muscles and migraine (1), headache and disorientation (1)
bisoprolol 4 Bradycardia (3), hypotension (1)
tramadol 3 Acute cholecystitis (1), tremor in lower and upper extremities and anxiousness (1), nausea, sweating and tremor (1)
prednisolone 3 Sepsis and pneumonia (1), infection NUD (1), hyperglycemia (1)
oxycodone 3 Ileus (2), worsening of cancer pain (1)
methotrexate 3 Respiratory tract infection (1), pulmonary insufficiency (1), hepatic cirrhosis (1)
others 99
Most ADRs were gastrointestinal disorders followed by ADRs involving blood and lymphatic disorders. This is in line with the most often involved ATC classes, antithrombotics, and cytostatics. Furthermore, most ADRs were classified as severe, as many of them were serious bleedings, infections, or other serious toxicities. This finding probably also reflects the university hospital site of the study, as most mild cases are treated in primary care, while more severe cases are usually directed to the university clinic. Clinics involving oncology and hematology patients receiving cytostatics also typically report more severe cases than hospitals without such patients.
There is no universally accepted method for ADR causality grading, although a number of causality assessment scales have been published. Some studies have compared different scales, and they have usually found a poor agreement between the scales [42, 43]. Naranjo criteria have been used in many studies, as well as Hallas criteria. The Hallas criteria include the same general aspects as the Naranjo scale includes, but the Hallas criteria were more suitable for this study [15].
The preventability of ADRs seems to vary a lot between studies, at least from 4.3 to 83% [2, 44, 45]. This variation is not only dependent on different scales but also on different characteristics of patients and drugs. Preventable ADRs include, e.g., those caused by antihypertensives and antibiotics in many studies, while cases assessed as not to be prevented include medications like cytostatics. Most ADRs in our study were caused by antithrombotic agents and antineoplastic agents, which are used only after a precise consideration of the risk-benefit relationship of the treatments that are known to cause ADRs to a small subset of patients. There were, however, nine cases where ADR might have been preventable. Those cases included buprenorphine (2), tramadole (3), oxycodone (2), and bisoprolol (2). In these cases, opioids could have been replaced with other pain medications and bisoprolol could have been used with a lower dose. With these nine cases preventability of ADRs would have been 7.2% of all ADRs.
One aim of this study was to find out if pharmacogenetic testing could have prevented some ADRs. We used the international CPIC guidelines to evaluate if there were recommendations concerning any of the ADR causing drugs. For example, in case of allopurinol, which can be prescribed more safely after testing the HLA-B*5801-allele, the test could only be used to prevent Stevens-Johnson syndrome, not fever or gastrointestinal pain, which were the ADRs of the respective patients [22]. After evaluating every ADR causing drug, we found only two cases for which pharmacogenetic testing might have prevented the ADRs; one patient with hypokalemia related to capecitabine induced diarrhea and one with ileus caused by codeine. For capecitabine, there is evidence that pharmacogenetic testing could prevent severe toxicity [21], and for codeine gastrointestinal opioid adverse effects are shown to be associated with the CYP2D6 metabolizer phenotype [20]. There were also other ADRs caused by drugs included in CPIC guidelines. Warfarin was involved in 14 bleeding cases. Genotype-guided warfarin dosing is thought to be beneficial only when warfarin is started, as it helps to find the first stable international normalized ratio (INR) [23]. However, in all our cases, warfarin had been in use for more than 6 months. Therefore, it was considered unlikely that pharmacogenetic testing could have been used to prevent the ADRs, although carriers of the CYP2C9*3 allele can have a higher risk of bleeding even after prolonged warfarin treatment [46]. Other drugs included in CPIC guidelines were the fluoropyrimidines capecitabine and fluorouracil, whose severe toxicity could be reduced by genotype-guided dosing [21]. However, the cases in this study did not have severe toxicity, but only constipation and fever without neutropenia, and we considered that these ADRs could not have been prevented by pharmacogenetic testing. Further cases included hyponatremia caused by escitalopram or citalopram that we considered not preventable by pharmacogenetic testing [24], as there is no compelling evidence showing that hyponatremia is (es)citalopram concentration-dependent. Yet, there are two cases of escitalopram dose-dependent hyponatremia [47, 48].
Strengths and limitations
The number of emergency visits in our study was quite large. There were 16,535 ER visits during the six study months, and 1600 of them were randomized to our study. The patient files of these 1600 visits were studied carefully by one student and three experienced clinicians and clinical pharmacologists, and all possible ADRs were assessed and only real ADRs were included (case 1 Suppl).
We did not consider lack of drug effect to be an ADR. Therefore, there might have been cases that potentially could have been prevented by a pharmacogenetic testing. For example, clopidogrel is converted to its active metabolite by CYP2C19, and poor metabolizers with two unfunctional copies of CYP2C19 have reduced amount of active clopidogrel metabolites [25], which may result in blood clotting.
Conclusion
The same ATC categories and medications are in top when assessed the ADRs causing hospitalizations and fatal cases caused by medications. It seems difficult to prevent these events totally as the treatments are vitally important and risk-benefit-relationship has been considered thoroughly.
Supplementary Information
ESM 1 (DOCX 157 kb).
Authors’ contributions
M.K, O.L-R, and J.T.B wrote the manuscript; M.K, O.L.-R., J.T.B., and M.N. designed the research; M.K, O.L.-R., J.T.B, and M.N. performed the research and analyzed the data.
Funding
Open access funding provided by University of Helsinki including Helsinki University Central Hospital. State funding for university level health research, Helsinki University Hospital, Helsinki, Finland.
Data availability
Not applicable.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Code availability
Not applicable.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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TRAMADOL HYDROCHLORIDE
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DrugsGivenReaction
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CC BY
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33188450
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2021-04
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperhidrosis'.
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Incidence, preventability, and causality of adverse drug reactions at a university hospital emergency department.
OBJECTIVE
To investigate the characteristics of ADRs in patients admitting at the emergency room of a tertiary hospital.
METHODS
We collected the patient records of 1600 emergency room visits of a university hospital in 2018. The patient files were studied retrospectively and all possible ADRs were identified and registered. Patient characteristics, drugs associated with ADRs, causality, severity, preventability, and the role of pharmacogenetics were assessed.
RESULTS
There were 125 cases with ADRs, resulting in a 7.8% overall incidence among emergency visits. The incidence was greatest in visits among elderly patients, reaching 14% (men) to 19% (women) in the 80-89 years age group. The most common causative drugs were warfarin, acetylsalicylic acid (ASA), apixaban, and docetaxel, and the most common ADRs were bleedings and neutropenia and/or severe infections. Only two of the cases might have been prevented by pharmacogenetic testing, as advised in Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines.
CONCLUSIONS
The same ATC classes, antithrombotics and cytostatics, were involved in ADRs causing university clinic hospitalizations as those identified previously in drug-related hospital fatalities. It seems difficult to prevent these events totally, as the treatments are vitally important and their risk-benefit-relationships have been considered thoroughly, and as pharmacogenetic testing could have been useful in only few cases.
Introduction
Successful drug treatment is an obvious goal for healthcare professionals. It improves the prognosis of patient’s life and decreases healthcare costs. Modern medications are very effective, but all of them have adverse effects, too. To avoid adverse drug reactions (ADRs), it is important that drug–drug interactions, contraindications, liver or kidney insufficiency, and other restrictions are considered carefully. For some medications it is, however, particularly complex to balance their benefits and risks for each patient. With effective treatments having narrow therapeutic index, we often have to take risks of causing ADRs.
ADRs are known to cause serious health problems and even deaths in every health care setting [1–3]. Frequencies of ADRs range widely between studies from 3.6 to 61% in hospitalized patients [4, 5]. Reasons for the wide variability are related to the study population, study area, type of hospital, and study methods. For similar reasons, there is also a wide variability in the incidence of ADRs as a cause for hospitalization (0.77 to 9.8%) [2, 6, 7]. Elderly people are found to be especially vulnerable in this respect [8–10].
As these risks are well recognized, information regarding adverse effects in various subgroups or settings is found in many studies [1–3, 11–13]. There is, however, no recent study about ADRs in tertiary care. At a university hospital level, risks causing ADRs are usually well-known and avoidable risks should be quite few. Moreover, there is a lot of enthusiasm and expectations concerning the use of pharmacogenetic testing to help the clinicians to select the right drug and dose for each patient [3].Therefore, we evaluated which drugs were related to ADRs in our hospital at the emergency units covering internal medicine, surgery, neurology, and pulmonology during 6 months and what were the ADRs that they caused. Furthermore, we analyzed whether these risks could have been avoided and whether the use of pharmacogenetics would have helped in avoiding any of these cases.
Material and methods
This was a retrospective, register-based study on emergency room visits in the Helsinki University Hospital (HUCH) during the period July 1 until December 31, 2018. HUCH is a tertiary hospital covering all the specialties in the capital area of Finland. We focused on the emergency room with internal medicine, surgery (excluding orthopedics and plastic surgery), neurology, and pulmonology. There were about 16,500 emergency visits in these specialties during the study period. We randomly selected 10% of the visits (1600) for detailed evaluation.
Two reviewers, one of which was a specialist in internal medicine and clinical pharmacology, first studied the files of these 1600 visits by hand. The potential cases were further analyzed by two other experienced physicians who are also specialists in clinical pharmacology (Suppl). We checked the diagnoses, which were set at the emergency room, medications used by the patients, and symptoms of the patients. Thereafter, we studied the history of that patient both before and after that visit. We analyzed the medication and checked if there was any reexposure during that visit or later. We carefully evaluated whether the symptoms could have been caused by the medication or if there was a nondrug-related explanation. For the ADRs, we used the definition by WHO. The causality of an ADR was assessed with the criteria suggested first by Karch [14] and modified later by Hallas [15]: (1) known ADR or toxic reaction, (2) a reasonable temporal relationship between commencement of drug therapy and onset of adverse reaction, (3) the adverse reaction disappeared upon discontinuation or dose reduction, (4) the symptom or event could not be explained by any other known condition or predisposition of the patient, and (5) the symptoms reappeared upon reexposure, or laboratory tests showed toxic drug levels or drug-induced metabolic disturbances that explained the symptom.
The cases were categorized either “definite causal relationship” (all five criteria must be fulfilled), “probable causal relationship” (criteria 1–4 must be fulfilled), “possible causal relationship” (criteria 1–3 must be fulfilled), or “unlikely/unevaluable causal relationship”. The diagnoses were classified by using the International Classification of Disease 10th Revision (ICD-10, WHO) and drugs were classified by using the Anatomical Therapeutical Chemical (ATC) system. The severity of the ADRs was assessed according to U.S. National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE).
Preventability of the ADRs was assessed by using similar methods as in many previous studies [16–18]. The best practice–based preventability assessment was based on criteria developed by Hallas [15], and it has been modified for use after that [18, 19]. The preventability assessment included a thorough evaluation of whether the drug was prescribed in accordance with treatment protocols and SPCs, whether required therapeutic monitoring or laboratory tests had been performed and whether all patient data (including allergies, other medications etc.) had been checked.
Additionally, we estimated the proportion of the patients that had an ADR, which may be prevented by genotyping in a specific genetic subset, as guided by the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. First, we identified the patients that had an adverse reaction caused by a drug, which is included in any of the CPIC guidelines. Thereafter, we checked if the specific ADR observed is preventable in patients with a certain genetic profile, given the timing of the ADR event in relation to the preceding duration of the causative medication.
The administrative permission for this study was received from Helsinki University Hospital. Ethical review was not needed as the study involved only register data, and there were no contact to the patients. For statistical analysis and for calculating confidence intervals (CI), we used the Wilson method.
Results
In our study, there were 1600 emergency visits, of whom 52.8% were men and 47.2% were women. Of these visits, 125 were identified as ADR cases, resulting in a 7.8% incidence. One patient with adalimumab attended ER two times with different ADRs. There were also two patients who had more than one ADR at the time. Thus, the number of ADRs and patients is not the same. Among the ADR cases, the number of women was 66 (52.8%, 95% CI 44.1–61.3%) which was slightly more than that of men (n = 59, 47.2%, 95% CI 38.7–55.9%). We compared the percentages of ADRs within each age groups and found that patients aged 80–89 had the highest percentage of ADRs per visits (Fig. 1).Fig 1 The gender and age specific percentages of ADRs are shown above the bars. M=men, W=women
The ATC category most often involved with an ADR was B01 (antithrombotic agents) comprising 27.5% of all cases, followed by L01 (antineoplastic agents, 20.6%). They covered almost half (48.1%) of all ADRs. Opioids (N02) was the third group (8.1%), followed by immunosuppressants (L04; 5.6%). Drugs included in the groups B01 and L01 are specified in Fig. 2. Eleven drugs were involved in three or more cases, of which warfarin and ASA were involved in over 10 cases. More specific list can be found in Suppl.Fig. 2 Drugs (n = 160) causing ADRs. The ATC-classes causing more than 4 ADRs are shown in the figure
The most often affected system was gastrointestinal tract (30.0% of ADRs). Blood and lymphatic disorders accounted for 15.0% of the cases, followed by general disorders and administration site disorders (11.3%) and nervous system disorders (10.6%) occurred almost as often. Among ADRs affecting the musculoskeletal system, women were overrepresented. There were four cases with women (100%, 95% CI 51.0–100.0%), whereas men had no musculoskeletal system linked ADRs. Women were overrepresented also with cardiac system disorders (80.0%, 95% CI 37.6–96.4%), infective events (80.0%, 95% CI 49.0–94.3%), and nervous system disorders (70.6%, 95% CI 46.9–86.7%), whereas men were overrepresented in vascular disorders (100%, 95% CI 51.0–100.0%) and metabolic and nutritional disorders (71.4%, 95%CI 35.9–91.8%) (Fig. 3).Fig. 3 System organ classes involved with ADRs
Severe ADRs (n = 77) outnumbered other classes and together with moderate ADRs (n = 56) they comprised 83.1% of the cases. There were only two fatal cases, which were both caused by warfarin, and 15 life-threatening cases. Minority of the cases (n = 10) were mild. The causalities of the case were as follows 20.6% definite, 33.8% probable, and 45.6% possible.
In our study, drugs included in CPIC guidelines were involved in 29 cases [20–26]. Two of these cases had an ADR for which a pharmacogenetic test might reduce the risk of that particular ADR. One of the patients was on codeine and had ileus [20]. The other patient was on capecitabine, and he had severe hypokalemia (ad 2.5 mmol/l) [21]. There was another patient with capecitabine too, but his ADR (constipation) could not have been presented by genotyping the patient beforehand. The rest of the cases did not include ADRs, which could have been prevented by a specific genetic test. These drugs were warfarin (14 cases), clopidogrel (4 cases), tacrolimus (2 cases), allopurinol (2 cases), fluorouracil, oxcarbazepine, escitalopram, and citalopram, e.g. warfarin had been in use in every patient for at least 6 months, and genetic testing for warfarin is evaluated to be useful only in the beginning of the treatment.
There were only two cases with a drug-adverse reaction pair which were considered as potentially preventable in a genetic subset by pharmacogenetic testing, according to CPIC guidelines. There were also 27 other ADR cases with drugs mentioned in CPIC guidelines, but the specific ADRs observed were either unrelated to the recommended genotyping or occurred after prolonged treatment (warfarin associated bleedings).
Discussion
The incidence of ADRs in our university hospital emergency room visits was 7.8%, which was in line with previous studies [2, 27–29]. Comparison to previous studies should be made with caution as study settings, patients, and studied medications differ a lot. The most common drug classes causing ADRs in this study were antithrombotic and antineoplastic agents. They were also most often causing deaths in the same university hospital in earlier studies [6, 30].
In this study, we focused on ADRs in a tertiary hospital emergency ward. ADRs are the most common medication related problem in every health care setting studied [31, 32]. However, most studies focus on primary care setting, while there are only couple of studies from tertiary hospitals [27, 33–36]. There is one recent (2014) study from a university hospital from our country, where the incidence of ADRs was much higher (23.1%) than in our study [37]. Explanation for this difference could be the ages of the patients. They included only patients over 65 years, and the average age was 77. Our patients were 16–94 years, and the average age was 63.4. The characteristics of ADRs depend not only on the studied ward and patient group but also on the country [38, 39]. In a thorough study from India, most ADRs (81.6%) were assessed to be preventable [27]. However, in that study the most common drug classes were antiinfective agents, followed by steroids. Neither of these classes were found in our cases, indicating that there are marked differences in ADR preventability between these two centers. If we exclude these preventable cases from that study, the incidence of the ADRs is close to our study (1.15%).
There are multiple studies evaluating the incidence of ADRs in emergency departments from primary care [13, 28, 40, 41]. Drugs involved in these studies reflect the use of medications in the regional population with its typical age and other patient characteristics. In our Finnish population, children were not included, and the youngest cases were 18–19 years old. While ADRs were observed only infrequently in 20–49 years old people, the majority of ADRs were observed in age groups between 50 and 89 years. In these age groups, more than 8% of the emergency visits were related to ADRs with the highest percentages of 15 to 19% in the 80–89 years age group. There are two likely explanations to this finding: first, many diseases and ADRs are more severe in elderly people, and second, the number of simultaneous medications tends to increase with increasing age [2, 9].
The most important ATC-group in this study was antithrombotic agents (B01) and very close to that was antineoplastic agents (L01). The same two groups were also in the top when we studied ATC-groups involved in fatal cases in the same university hospital area [30]. In that study, cytostatic drugs caused 1.1% of deaths in the hospital and antithrombotic drugs caused 1.0% covering over half of the fatal cases (35/52). In the present study, they covered 48.1% of all ADRs. There were, altogether, 11 drugs causing more than two cases (Table 1), mainly involving either antithrombotics or cytostatics. Antithrombotics (or anticoagulants) and cytostatics have been the most common drugs involved in ADRs also in other studies in every health care setting [2, 3, 9, 10, 16, 28]. Even though the risks connected with these two groups are well known, it is hard to avoid them totally due to their narrow therapeutic window. Both groups are also prescribed to patients with severe diseases, which may also predispose them to ADRs. Deaths caused by cytostatics have diminished year by year in our hospital [30], but at the moment, also fragile patients are treated with them and the medications are more effective meaning that, e.g., leucopenia is inevitable in a subset of patients. There has also been a trend towards an increased intensity of antithrombotic treatments in cardiovascular patients, and overall, the use of antithrombotics has increased, while evaluation of the risk of bleeding has been improved. Perhaps because of improved evaluation and monitoring of patients, there has been even a slight decline in deaths caused by antithrombotic related bleedings during the past decades. In our study, there were six bleeding cases caused by apixaban and 14 by warfarin. Rivaroxaban or edoxaban-related ADRs were not identified in any of the cases. During the same time, the number of users of apixaban and rivaroxaban was about the same in Finland, equaling about 30% of the number of warfarin users. Unfortunately, we were not able to receive the number of the people using these drugs in the specific university hospital area. Nevertheless, it is obvious that the numbers will change in the coming years, after direct anticoagulants have replaced warfarin to a larger extent.Table 1 Drugs involved in three or more cases and the ADRs they caused
Drug Number of ADRs Types of ADRs (n)
warfarin 14 Intestinal bleeding (8), hematuria (2), ICH (2), hemarthrosis (1), bruises (1)
ASA 11 Gastrointestinal bleeding (7), bleeding wound (2), hematuria (1), anemia (1)
docetaxel 6 Febrile neutropenia (3), allergic reaction (1), fever (1), erysipelas (1)
apixaban 6 Gastrointestinal bleeding (4), ICH (1), hematuria (1)
clopidogrel 4 Bleeding wound (2), gastrointestinal bleeding (1), anemia (1)
buprenorphine 4 Cholecystitis (2), spasm of neck muscles and migraine (1), headache and disorientation (1)
bisoprolol 4 Bradycardia (3), hypotension (1)
tramadol 3 Acute cholecystitis (1), tremor in lower and upper extremities and anxiousness (1), nausea, sweating and tremor (1)
prednisolone 3 Sepsis and pneumonia (1), infection NUD (1), hyperglycemia (1)
oxycodone 3 Ileus (2), worsening of cancer pain (1)
methotrexate 3 Respiratory tract infection (1), pulmonary insufficiency (1), hepatic cirrhosis (1)
others 99
Most ADRs were gastrointestinal disorders followed by ADRs involving blood and lymphatic disorders. This is in line with the most often involved ATC classes, antithrombotics, and cytostatics. Furthermore, most ADRs were classified as severe, as many of them were serious bleedings, infections, or other serious toxicities. This finding probably also reflects the university hospital site of the study, as most mild cases are treated in primary care, while more severe cases are usually directed to the university clinic. Clinics involving oncology and hematology patients receiving cytostatics also typically report more severe cases than hospitals without such patients.
There is no universally accepted method for ADR causality grading, although a number of causality assessment scales have been published. Some studies have compared different scales, and they have usually found a poor agreement between the scales [42, 43]. Naranjo criteria have been used in many studies, as well as Hallas criteria. The Hallas criteria include the same general aspects as the Naranjo scale includes, but the Hallas criteria were more suitable for this study [15].
The preventability of ADRs seems to vary a lot between studies, at least from 4.3 to 83% [2, 44, 45]. This variation is not only dependent on different scales but also on different characteristics of patients and drugs. Preventable ADRs include, e.g., those caused by antihypertensives and antibiotics in many studies, while cases assessed as not to be prevented include medications like cytostatics. Most ADRs in our study were caused by antithrombotic agents and antineoplastic agents, which are used only after a precise consideration of the risk-benefit relationship of the treatments that are known to cause ADRs to a small subset of patients. There were, however, nine cases where ADR might have been preventable. Those cases included buprenorphine (2), tramadole (3), oxycodone (2), and bisoprolol (2). In these cases, opioids could have been replaced with other pain medications and bisoprolol could have been used with a lower dose. With these nine cases preventability of ADRs would have been 7.2% of all ADRs.
One aim of this study was to find out if pharmacogenetic testing could have prevented some ADRs. We used the international CPIC guidelines to evaluate if there were recommendations concerning any of the ADR causing drugs. For example, in case of allopurinol, which can be prescribed more safely after testing the HLA-B*5801-allele, the test could only be used to prevent Stevens-Johnson syndrome, not fever or gastrointestinal pain, which were the ADRs of the respective patients [22]. After evaluating every ADR causing drug, we found only two cases for which pharmacogenetic testing might have prevented the ADRs; one patient with hypokalemia related to capecitabine induced diarrhea and one with ileus caused by codeine. For capecitabine, there is evidence that pharmacogenetic testing could prevent severe toxicity [21], and for codeine gastrointestinal opioid adverse effects are shown to be associated with the CYP2D6 metabolizer phenotype [20]. There were also other ADRs caused by drugs included in CPIC guidelines. Warfarin was involved in 14 bleeding cases. Genotype-guided warfarin dosing is thought to be beneficial only when warfarin is started, as it helps to find the first stable international normalized ratio (INR) [23]. However, in all our cases, warfarin had been in use for more than 6 months. Therefore, it was considered unlikely that pharmacogenetic testing could have been used to prevent the ADRs, although carriers of the CYP2C9*3 allele can have a higher risk of bleeding even after prolonged warfarin treatment [46]. Other drugs included in CPIC guidelines were the fluoropyrimidines capecitabine and fluorouracil, whose severe toxicity could be reduced by genotype-guided dosing [21]. However, the cases in this study did not have severe toxicity, but only constipation and fever without neutropenia, and we considered that these ADRs could not have been prevented by pharmacogenetic testing. Further cases included hyponatremia caused by escitalopram or citalopram that we considered not preventable by pharmacogenetic testing [24], as there is no compelling evidence showing that hyponatremia is (es)citalopram concentration-dependent. Yet, there are two cases of escitalopram dose-dependent hyponatremia [47, 48].
Strengths and limitations
The number of emergency visits in our study was quite large. There were 16,535 ER visits during the six study months, and 1600 of them were randomized to our study. The patient files of these 1600 visits were studied carefully by one student and three experienced clinicians and clinical pharmacologists, and all possible ADRs were assessed and only real ADRs were included (case 1 Suppl).
We did not consider lack of drug effect to be an ADR. Therefore, there might have been cases that potentially could have been prevented by a pharmacogenetic testing. For example, clopidogrel is converted to its active metabolite by CYP2C19, and poor metabolizers with two unfunctional copies of CYP2C19 have reduced amount of active clopidogrel metabolites [25], which may result in blood clotting.
Conclusion
The same ATC categories and medications are in top when assessed the ADRs causing hospitalizations and fatal cases caused by medications. It seems difficult to prevent these events totally as the treatments are vitally important and risk-benefit-relationship has been considered thoroughly.
Supplementary Information
ESM 1 (DOCX 157 kb).
Authors’ contributions
M.K, O.L-R, and J.T.B wrote the manuscript; M.K, O.L.-R., J.T.B., and M.N. designed the research; M.K, O.L.-R., J.T.B, and M.N. performed the research and analyzed the data.
Funding
Open access funding provided by University of Helsinki including Helsinki University Central Hospital. State funding for university level health research, Helsinki University Hospital, Helsinki, Finland.
Data availability
Not applicable.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Code availability
Not applicable.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
|
TRAMADOL HYDROCHLORIDE
|
DrugsGivenReaction
|
CC BY
|
33188450
| 19,623,452
|
2021-04
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'.
|
Incidence, preventability, and causality of adverse drug reactions at a university hospital emergency department.
OBJECTIVE
To investigate the characteristics of ADRs in patients admitting at the emergency room of a tertiary hospital.
METHODS
We collected the patient records of 1600 emergency room visits of a university hospital in 2018. The patient files were studied retrospectively and all possible ADRs were identified and registered. Patient characteristics, drugs associated with ADRs, causality, severity, preventability, and the role of pharmacogenetics were assessed.
RESULTS
There were 125 cases with ADRs, resulting in a 7.8% overall incidence among emergency visits. The incidence was greatest in visits among elderly patients, reaching 14% (men) to 19% (women) in the 80-89 years age group. The most common causative drugs were warfarin, acetylsalicylic acid (ASA), apixaban, and docetaxel, and the most common ADRs were bleedings and neutropenia and/or severe infections. Only two of the cases might have been prevented by pharmacogenetic testing, as advised in Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines.
CONCLUSIONS
The same ATC classes, antithrombotics and cytostatics, were involved in ADRs causing university clinic hospitalizations as those identified previously in drug-related hospital fatalities. It seems difficult to prevent these events totally, as the treatments are vitally important and their risk-benefit-relationships have been considered thoroughly, and as pharmacogenetic testing could have been useful in only few cases.
Introduction
Successful drug treatment is an obvious goal for healthcare professionals. It improves the prognosis of patient’s life and decreases healthcare costs. Modern medications are very effective, but all of them have adverse effects, too. To avoid adverse drug reactions (ADRs), it is important that drug–drug interactions, contraindications, liver or kidney insufficiency, and other restrictions are considered carefully. For some medications it is, however, particularly complex to balance their benefits and risks for each patient. With effective treatments having narrow therapeutic index, we often have to take risks of causing ADRs.
ADRs are known to cause serious health problems and even deaths in every health care setting [1–3]. Frequencies of ADRs range widely between studies from 3.6 to 61% in hospitalized patients [4, 5]. Reasons for the wide variability are related to the study population, study area, type of hospital, and study methods. For similar reasons, there is also a wide variability in the incidence of ADRs as a cause for hospitalization (0.77 to 9.8%) [2, 6, 7]. Elderly people are found to be especially vulnerable in this respect [8–10].
As these risks are well recognized, information regarding adverse effects in various subgroups or settings is found in many studies [1–3, 11–13]. There is, however, no recent study about ADRs in tertiary care. At a university hospital level, risks causing ADRs are usually well-known and avoidable risks should be quite few. Moreover, there is a lot of enthusiasm and expectations concerning the use of pharmacogenetic testing to help the clinicians to select the right drug and dose for each patient [3].Therefore, we evaluated which drugs were related to ADRs in our hospital at the emergency units covering internal medicine, surgery, neurology, and pulmonology during 6 months and what were the ADRs that they caused. Furthermore, we analyzed whether these risks could have been avoided and whether the use of pharmacogenetics would have helped in avoiding any of these cases.
Material and methods
This was a retrospective, register-based study on emergency room visits in the Helsinki University Hospital (HUCH) during the period July 1 until December 31, 2018. HUCH is a tertiary hospital covering all the specialties in the capital area of Finland. We focused on the emergency room with internal medicine, surgery (excluding orthopedics and plastic surgery), neurology, and pulmonology. There were about 16,500 emergency visits in these specialties during the study period. We randomly selected 10% of the visits (1600) for detailed evaluation.
Two reviewers, one of which was a specialist in internal medicine and clinical pharmacology, first studied the files of these 1600 visits by hand. The potential cases were further analyzed by two other experienced physicians who are also specialists in clinical pharmacology (Suppl). We checked the diagnoses, which were set at the emergency room, medications used by the patients, and symptoms of the patients. Thereafter, we studied the history of that patient both before and after that visit. We analyzed the medication and checked if there was any reexposure during that visit or later. We carefully evaluated whether the symptoms could have been caused by the medication or if there was a nondrug-related explanation. For the ADRs, we used the definition by WHO. The causality of an ADR was assessed with the criteria suggested first by Karch [14] and modified later by Hallas [15]: (1) known ADR or toxic reaction, (2) a reasonable temporal relationship between commencement of drug therapy and onset of adverse reaction, (3) the adverse reaction disappeared upon discontinuation or dose reduction, (4) the symptom or event could not be explained by any other known condition or predisposition of the patient, and (5) the symptoms reappeared upon reexposure, or laboratory tests showed toxic drug levels or drug-induced metabolic disturbances that explained the symptom.
The cases were categorized either “definite causal relationship” (all five criteria must be fulfilled), “probable causal relationship” (criteria 1–4 must be fulfilled), “possible causal relationship” (criteria 1–3 must be fulfilled), or “unlikely/unevaluable causal relationship”. The diagnoses were classified by using the International Classification of Disease 10th Revision (ICD-10, WHO) and drugs were classified by using the Anatomical Therapeutical Chemical (ATC) system. The severity of the ADRs was assessed according to U.S. National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE).
Preventability of the ADRs was assessed by using similar methods as in many previous studies [16–18]. The best practice–based preventability assessment was based on criteria developed by Hallas [15], and it has been modified for use after that [18, 19]. The preventability assessment included a thorough evaluation of whether the drug was prescribed in accordance with treatment protocols and SPCs, whether required therapeutic monitoring or laboratory tests had been performed and whether all patient data (including allergies, other medications etc.) had been checked.
Additionally, we estimated the proportion of the patients that had an ADR, which may be prevented by genotyping in a specific genetic subset, as guided by the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. First, we identified the patients that had an adverse reaction caused by a drug, which is included in any of the CPIC guidelines. Thereafter, we checked if the specific ADR observed is preventable in patients with a certain genetic profile, given the timing of the ADR event in relation to the preceding duration of the causative medication.
The administrative permission for this study was received from Helsinki University Hospital. Ethical review was not needed as the study involved only register data, and there were no contact to the patients. For statistical analysis and for calculating confidence intervals (CI), we used the Wilson method.
Results
In our study, there were 1600 emergency visits, of whom 52.8% were men and 47.2% were women. Of these visits, 125 were identified as ADR cases, resulting in a 7.8% incidence. One patient with adalimumab attended ER two times with different ADRs. There were also two patients who had more than one ADR at the time. Thus, the number of ADRs and patients is not the same. Among the ADR cases, the number of women was 66 (52.8%, 95% CI 44.1–61.3%) which was slightly more than that of men (n = 59, 47.2%, 95% CI 38.7–55.9%). We compared the percentages of ADRs within each age groups and found that patients aged 80–89 had the highest percentage of ADRs per visits (Fig. 1).Fig 1 The gender and age specific percentages of ADRs are shown above the bars. M=men, W=women
The ATC category most often involved with an ADR was B01 (antithrombotic agents) comprising 27.5% of all cases, followed by L01 (antineoplastic agents, 20.6%). They covered almost half (48.1%) of all ADRs. Opioids (N02) was the third group (8.1%), followed by immunosuppressants (L04; 5.6%). Drugs included in the groups B01 and L01 are specified in Fig. 2. Eleven drugs were involved in three or more cases, of which warfarin and ASA were involved in over 10 cases. More specific list can be found in Suppl.Fig. 2 Drugs (n = 160) causing ADRs. The ATC-classes causing more than 4 ADRs are shown in the figure
The most often affected system was gastrointestinal tract (30.0% of ADRs). Blood and lymphatic disorders accounted for 15.0% of the cases, followed by general disorders and administration site disorders (11.3%) and nervous system disorders (10.6%) occurred almost as often. Among ADRs affecting the musculoskeletal system, women were overrepresented. There were four cases with women (100%, 95% CI 51.0–100.0%), whereas men had no musculoskeletal system linked ADRs. Women were overrepresented also with cardiac system disorders (80.0%, 95% CI 37.6–96.4%), infective events (80.0%, 95% CI 49.0–94.3%), and nervous system disorders (70.6%, 95% CI 46.9–86.7%), whereas men were overrepresented in vascular disorders (100%, 95% CI 51.0–100.0%) and metabolic and nutritional disorders (71.4%, 95%CI 35.9–91.8%) (Fig. 3).Fig. 3 System organ classes involved with ADRs
Severe ADRs (n = 77) outnumbered other classes and together with moderate ADRs (n = 56) they comprised 83.1% of the cases. There were only two fatal cases, which were both caused by warfarin, and 15 life-threatening cases. Minority of the cases (n = 10) were mild. The causalities of the case were as follows 20.6% definite, 33.8% probable, and 45.6% possible.
In our study, drugs included in CPIC guidelines were involved in 29 cases [20–26]. Two of these cases had an ADR for which a pharmacogenetic test might reduce the risk of that particular ADR. One of the patients was on codeine and had ileus [20]. The other patient was on capecitabine, and he had severe hypokalemia (ad 2.5 mmol/l) [21]. There was another patient with capecitabine too, but his ADR (constipation) could not have been presented by genotyping the patient beforehand. The rest of the cases did not include ADRs, which could have been prevented by a specific genetic test. These drugs were warfarin (14 cases), clopidogrel (4 cases), tacrolimus (2 cases), allopurinol (2 cases), fluorouracil, oxcarbazepine, escitalopram, and citalopram, e.g. warfarin had been in use in every patient for at least 6 months, and genetic testing for warfarin is evaluated to be useful only in the beginning of the treatment.
There were only two cases with a drug-adverse reaction pair which were considered as potentially preventable in a genetic subset by pharmacogenetic testing, according to CPIC guidelines. There were also 27 other ADR cases with drugs mentioned in CPIC guidelines, but the specific ADRs observed were either unrelated to the recommended genotyping or occurred after prolonged treatment (warfarin associated bleedings).
Discussion
The incidence of ADRs in our university hospital emergency room visits was 7.8%, which was in line with previous studies [2, 27–29]. Comparison to previous studies should be made with caution as study settings, patients, and studied medications differ a lot. The most common drug classes causing ADRs in this study were antithrombotic and antineoplastic agents. They were also most often causing deaths in the same university hospital in earlier studies [6, 30].
In this study, we focused on ADRs in a tertiary hospital emergency ward. ADRs are the most common medication related problem in every health care setting studied [31, 32]. However, most studies focus on primary care setting, while there are only couple of studies from tertiary hospitals [27, 33–36]. There is one recent (2014) study from a university hospital from our country, where the incidence of ADRs was much higher (23.1%) than in our study [37]. Explanation for this difference could be the ages of the patients. They included only patients over 65 years, and the average age was 77. Our patients were 16–94 years, and the average age was 63.4. The characteristics of ADRs depend not only on the studied ward and patient group but also on the country [38, 39]. In a thorough study from India, most ADRs (81.6%) were assessed to be preventable [27]. However, in that study the most common drug classes were antiinfective agents, followed by steroids. Neither of these classes were found in our cases, indicating that there are marked differences in ADR preventability between these two centers. If we exclude these preventable cases from that study, the incidence of the ADRs is close to our study (1.15%).
There are multiple studies evaluating the incidence of ADRs in emergency departments from primary care [13, 28, 40, 41]. Drugs involved in these studies reflect the use of medications in the regional population with its typical age and other patient characteristics. In our Finnish population, children were not included, and the youngest cases were 18–19 years old. While ADRs were observed only infrequently in 20–49 years old people, the majority of ADRs were observed in age groups between 50 and 89 years. In these age groups, more than 8% of the emergency visits were related to ADRs with the highest percentages of 15 to 19% in the 80–89 years age group. There are two likely explanations to this finding: first, many diseases and ADRs are more severe in elderly people, and second, the number of simultaneous medications tends to increase with increasing age [2, 9].
The most important ATC-group in this study was antithrombotic agents (B01) and very close to that was antineoplastic agents (L01). The same two groups were also in the top when we studied ATC-groups involved in fatal cases in the same university hospital area [30]. In that study, cytostatic drugs caused 1.1% of deaths in the hospital and antithrombotic drugs caused 1.0% covering over half of the fatal cases (35/52). In the present study, they covered 48.1% of all ADRs. There were, altogether, 11 drugs causing more than two cases (Table 1), mainly involving either antithrombotics or cytostatics. Antithrombotics (or anticoagulants) and cytostatics have been the most common drugs involved in ADRs also in other studies in every health care setting [2, 3, 9, 10, 16, 28]. Even though the risks connected with these two groups are well known, it is hard to avoid them totally due to their narrow therapeutic window. Both groups are also prescribed to patients with severe diseases, which may also predispose them to ADRs. Deaths caused by cytostatics have diminished year by year in our hospital [30], but at the moment, also fragile patients are treated with them and the medications are more effective meaning that, e.g., leucopenia is inevitable in a subset of patients. There has also been a trend towards an increased intensity of antithrombotic treatments in cardiovascular patients, and overall, the use of antithrombotics has increased, while evaluation of the risk of bleeding has been improved. Perhaps because of improved evaluation and monitoring of patients, there has been even a slight decline in deaths caused by antithrombotic related bleedings during the past decades. In our study, there were six bleeding cases caused by apixaban and 14 by warfarin. Rivaroxaban or edoxaban-related ADRs were not identified in any of the cases. During the same time, the number of users of apixaban and rivaroxaban was about the same in Finland, equaling about 30% of the number of warfarin users. Unfortunately, we were not able to receive the number of the people using these drugs in the specific university hospital area. Nevertheless, it is obvious that the numbers will change in the coming years, after direct anticoagulants have replaced warfarin to a larger extent.Table 1 Drugs involved in three or more cases and the ADRs they caused
Drug Number of ADRs Types of ADRs (n)
warfarin 14 Intestinal bleeding (8), hematuria (2), ICH (2), hemarthrosis (1), bruises (1)
ASA 11 Gastrointestinal bleeding (7), bleeding wound (2), hematuria (1), anemia (1)
docetaxel 6 Febrile neutropenia (3), allergic reaction (1), fever (1), erysipelas (1)
apixaban 6 Gastrointestinal bleeding (4), ICH (1), hematuria (1)
clopidogrel 4 Bleeding wound (2), gastrointestinal bleeding (1), anemia (1)
buprenorphine 4 Cholecystitis (2), spasm of neck muscles and migraine (1), headache and disorientation (1)
bisoprolol 4 Bradycardia (3), hypotension (1)
tramadol 3 Acute cholecystitis (1), tremor in lower and upper extremities and anxiousness (1), nausea, sweating and tremor (1)
prednisolone 3 Sepsis and pneumonia (1), infection NUD (1), hyperglycemia (1)
oxycodone 3 Ileus (2), worsening of cancer pain (1)
methotrexate 3 Respiratory tract infection (1), pulmonary insufficiency (1), hepatic cirrhosis (1)
others 99
Most ADRs were gastrointestinal disorders followed by ADRs involving blood and lymphatic disorders. This is in line with the most often involved ATC classes, antithrombotics, and cytostatics. Furthermore, most ADRs were classified as severe, as many of them were serious bleedings, infections, or other serious toxicities. This finding probably also reflects the university hospital site of the study, as most mild cases are treated in primary care, while more severe cases are usually directed to the university clinic. Clinics involving oncology and hematology patients receiving cytostatics also typically report more severe cases than hospitals without such patients.
There is no universally accepted method for ADR causality grading, although a number of causality assessment scales have been published. Some studies have compared different scales, and they have usually found a poor agreement between the scales [42, 43]. Naranjo criteria have been used in many studies, as well as Hallas criteria. The Hallas criteria include the same general aspects as the Naranjo scale includes, but the Hallas criteria were more suitable for this study [15].
The preventability of ADRs seems to vary a lot between studies, at least from 4.3 to 83% [2, 44, 45]. This variation is not only dependent on different scales but also on different characteristics of patients and drugs. Preventable ADRs include, e.g., those caused by antihypertensives and antibiotics in many studies, while cases assessed as not to be prevented include medications like cytostatics. Most ADRs in our study were caused by antithrombotic agents and antineoplastic agents, which are used only after a precise consideration of the risk-benefit relationship of the treatments that are known to cause ADRs to a small subset of patients. There were, however, nine cases where ADR might have been preventable. Those cases included buprenorphine (2), tramadole (3), oxycodone (2), and bisoprolol (2). In these cases, opioids could have been replaced with other pain medications and bisoprolol could have been used with a lower dose. With these nine cases preventability of ADRs would have been 7.2% of all ADRs.
One aim of this study was to find out if pharmacogenetic testing could have prevented some ADRs. We used the international CPIC guidelines to evaluate if there were recommendations concerning any of the ADR causing drugs. For example, in case of allopurinol, which can be prescribed more safely after testing the HLA-B*5801-allele, the test could only be used to prevent Stevens-Johnson syndrome, not fever or gastrointestinal pain, which were the ADRs of the respective patients [22]. After evaluating every ADR causing drug, we found only two cases for which pharmacogenetic testing might have prevented the ADRs; one patient with hypokalemia related to capecitabine induced diarrhea and one with ileus caused by codeine. For capecitabine, there is evidence that pharmacogenetic testing could prevent severe toxicity [21], and for codeine gastrointestinal opioid adverse effects are shown to be associated with the CYP2D6 metabolizer phenotype [20]. There were also other ADRs caused by drugs included in CPIC guidelines. Warfarin was involved in 14 bleeding cases. Genotype-guided warfarin dosing is thought to be beneficial only when warfarin is started, as it helps to find the first stable international normalized ratio (INR) [23]. However, in all our cases, warfarin had been in use for more than 6 months. Therefore, it was considered unlikely that pharmacogenetic testing could have been used to prevent the ADRs, although carriers of the CYP2C9*3 allele can have a higher risk of bleeding even after prolonged warfarin treatment [46]. Other drugs included in CPIC guidelines were the fluoropyrimidines capecitabine and fluorouracil, whose severe toxicity could be reduced by genotype-guided dosing [21]. However, the cases in this study did not have severe toxicity, but only constipation and fever without neutropenia, and we considered that these ADRs could not have been prevented by pharmacogenetic testing. Further cases included hyponatremia caused by escitalopram or citalopram that we considered not preventable by pharmacogenetic testing [24], as there is no compelling evidence showing that hyponatremia is (es)citalopram concentration-dependent. Yet, there are two cases of escitalopram dose-dependent hyponatremia [47, 48].
Strengths and limitations
The number of emergency visits in our study was quite large. There were 16,535 ER visits during the six study months, and 1600 of them were randomized to our study. The patient files of these 1600 visits were studied carefully by one student and three experienced clinicians and clinical pharmacologists, and all possible ADRs were assessed and only real ADRs were included (case 1 Suppl).
We did not consider lack of drug effect to be an ADR. Therefore, there might have been cases that potentially could have been prevented by a pharmacogenetic testing. For example, clopidogrel is converted to its active metabolite by CYP2C19, and poor metabolizers with two unfunctional copies of CYP2C19 have reduced amount of active clopidogrel metabolites [25], which may result in blood clotting.
Conclusion
The same ATC categories and medications are in top when assessed the ADRs causing hospitalizations and fatal cases caused by medications. It seems difficult to prevent these events totally as the treatments are vitally important and risk-benefit-relationship has been considered thoroughly.
Supplementary Information
ESM 1 (DOCX 157 kb).
Authors’ contributions
M.K, O.L-R, and J.T.B wrote the manuscript; M.K, O.L.-R., J.T.B., and M.N. designed the research; M.K, O.L.-R., J.T.B, and M.N. performed the research and analyzed the data.
Funding
Open access funding provided by University of Helsinki including Helsinki University Central Hospital. State funding for university level health research, Helsinki University Hospital, Helsinki, Finland.
Data availability
Not applicable.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Code availability
Not applicable.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
|
TRAMADOL HYDROCHLORIDE
|
DrugsGivenReaction
|
CC BY
|
33188450
| 19,623,452
|
2021-04
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tremor'.
|
Incidence, preventability, and causality of adverse drug reactions at a university hospital emergency department.
OBJECTIVE
To investigate the characteristics of ADRs in patients admitting at the emergency room of a tertiary hospital.
METHODS
We collected the patient records of 1600 emergency room visits of a university hospital in 2018. The patient files were studied retrospectively and all possible ADRs were identified and registered. Patient characteristics, drugs associated with ADRs, causality, severity, preventability, and the role of pharmacogenetics were assessed.
RESULTS
There were 125 cases with ADRs, resulting in a 7.8% overall incidence among emergency visits. The incidence was greatest in visits among elderly patients, reaching 14% (men) to 19% (women) in the 80-89 years age group. The most common causative drugs were warfarin, acetylsalicylic acid (ASA), apixaban, and docetaxel, and the most common ADRs were bleedings and neutropenia and/or severe infections. Only two of the cases might have been prevented by pharmacogenetic testing, as advised in Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines.
CONCLUSIONS
The same ATC classes, antithrombotics and cytostatics, were involved in ADRs causing university clinic hospitalizations as those identified previously in drug-related hospital fatalities. It seems difficult to prevent these events totally, as the treatments are vitally important and their risk-benefit-relationships have been considered thoroughly, and as pharmacogenetic testing could have been useful in only few cases.
Introduction
Successful drug treatment is an obvious goal for healthcare professionals. It improves the prognosis of patient’s life and decreases healthcare costs. Modern medications are very effective, but all of them have adverse effects, too. To avoid adverse drug reactions (ADRs), it is important that drug–drug interactions, contraindications, liver or kidney insufficiency, and other restrictions are considered carefully. For some medications it is, however, particularly complex to balance their benefits and risks for each patient. With effective treatments having narrow therapeutic index, we often have to take risks of causing ADRs.
ADRs are known to cause serious health problems and even deaths in every health care setting [1–3]. Frequencies of ADRs range widely between studies from 3.6 to 61% in hospitalized patients [4, 5]. Reasons for the wide variability are related to the study population, study area, type of hospital, and study methods. For similar reasons, there is also a wide variability in the incidence of ADRs as a cause for hospitalization (0.77 to 9.8%) [2, 6, 7]. Elderly people are found to be especially vulnerable in this respect [8–10].
As these risks are well recognized, information regarding adverse effects in various subgroups or settings is found in many studies [1–3, 11–13]. There is, however, no recent study about ADRs in tertiary care. At a university hospital level, risks causing ADRs are usually well-known and avoidable risks should be quite few. Moreover, there is a lot of enthusiasm and expectations concerning the use of pharmacogenetic testing to help the clinicians to select the right drug and dose for each patient [3].Therefore, we evaluated which drugs were related to ADRs in our hospital at the emergency units covering internal medicine, surgery, neurology, and pulmonology during 6 months and what were the ADRs that they caused. Furthermore, we analyzed whether these risks could have been avoided and whether the use of pharmacogenetics would have helped in avoiding any of these cases.
Material and methods
This was a retrospective, register-based study on emergency room visits in the Helsinki University Hospital (HUCH) during the period July 1 until December 31, 2018. HUCH is a tertiary hospital covering all the specialties in the capital area of Finland. We focused on the emergency room with internal medicine, surgery (excluding orthopedics and plastic surgery), neurology, and pulmonology. There were about 16,500 emergency visits in these specialties during the study period. We randomly selected 10% of the visits (1600) for detailed evaluation.
Two reviewers, one of which was a specialist in internal medicine and clinical pharmacology, first studied the files of these 1600 visits by hand. The potential cases were further analyzed by two other experienced physicians who are also specialists in clinical pharmacology (Suppl). We checked the diagnoses, which were set at the emergency room, medications used by the patients, and symptoms of the patients. Thereafter, we studied the history of that patient both before and after that visit. We analyzed the medication and checked if there was any reexposure during that visit or later. We carefully evaluated whether the symptoms could have been caused by the medication or if there was a nondrug-related explanation. For the ADRs, we used the definition by WHO. The causality of an ADR was assessed with the criteria suggested first by Karch [14] and modified later by Hallas [15]: (1) known ADR or toxic reaction, (2) a reasonable temporal relationship between commencement of drug therapy and onset of adverse reaction, (3) the adverse reaction disappeared upon discontinuation or dose reduction, (4) the symptom or event could not be explained by any other known condition or predisposition of the patient, and (5) the symptoms reappeared upon reexposure, or laboratory tests showed toxic drug levels or drug-induced metabolic disturbances that explained the symptom.
The cases were categorized either “definite causal relationship” (all five criteria must be fulfilled), “probable causal relationship” (criteria 1–4 must be fulfilled), “possible causal relationship” (criteria 1–3 must be fulfilled), or “unlikely/unevaluable causal relationship”. The diagnoses were classified by using the International Classification of Disease 10th Revision (ICD-10, WHO) and drugs were classified by using the Anatomical Therapeutical Chemical (ATC) system. The severity of the ADRs was assessed according to U.S. National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE).
Preventability of the ADRs was assessed by using similar methods as in many previous studies [16–18]. The best practice–based preventability assessment was based on criteria developed by Hallas [15], and it has been modified for use after that [18, 19]. The preventability assessment included a thorough evaluation of whether the drug was prescribed in accordance with treatment protocols and SPCs, whether required therapeutic monitoring or laboratory tests had been performed and whether all patient data (including allergies, other medications etc.) had been checked.
Additionally, we estimated the proportion of the patients that had an ADR, which may be prevented by genotyping in a specific genetic subset, as guided by the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. First, we identified the patients that had an adverse reaction caused by a drug, which is included in any of the CPIC guidelines. Thereafter, we checked if the specific ADR observed is preventable in patients with a certain genetic profile, given the timing of the ADR event in relation to the preceding duration of the causative medication.
The administrative permission for this study was received from Helsinki University Hospital. Ethical review was not needed as the study involved only register data, and there were no contact to the patients. For statistical analysis and for calculating confidence intervals (CI), we used the Wilson method.
Results
In our study, there were 1600 emergency visits, of whom 52.8% were men and 47.2% were women. Of these visits, 125 were identified as ADR cases, resulting in a 7.8% incidence. One patient with adalimumab attended ER two times with different ADRs. There were also two patients who had more than one ADR at the time. Thus, the number of ADRs and patients is not the same. Among the ADR cases, the number of women was 66 (52.8%, 95% CI 44.1–61.3%) which was slightly more than that of men (n = 59, 47.2%, 95% CI 38.7–55.9%). We compared the percentages of ADRs within each age groups and found that patients aged 80–89 had the highest percentage of ADRs per visits (Fig. 1).Fig 1 The gender and age specific percentages of ADRs are shown above the bars. M=men, W=women
The ATC category most often involved with an ADR was B01 (antithrombotic agents) comprising 27.5% of all cases, followed by L01 (antineoplastic agents, 20.6%). They covered almost half (48.1%) of all ADRs. Opioids (N02) was the third group (8.1%), followed by immunosuppressants (L04; 5.6%). Drugs included in the groups B01 and L01 are specified in Fig. 2. Eleven drugs were involved in three or more cases, of which warfarin and ASA were involved in over 10 cases. More specific list can be found in Suppl.Fig. 2 Drugs (n = 160) causing ADRs. The ATC-classes causing more than 4 ADRs are shown in the figure
The most often affected system was gastrointestinal tract (30.0% of ADRs). Blood and lymphatic disorders accounted for 15.0% of the cases, followed by general disorders and administration site disorders (11.3%) and nervous system disorders (10.6%) occurred almost as often. Among ADRs affecting the musculoskeletal system, women were overrepresented. There were four cases with women (100%, 95% CI 51.0–100.0%), whereas men had no musculoskeletal system linked ADRs. Women were overrepresented also with cardiac system disorders (80.0%, 95% CI 37.6–96.4%), infective events (80.0%, 95% CI 49.0–94.3%), and nervous system disorders (70.6%, 95% CI 46.9–86.7%), whereas men were overrepresented in vascular disorders (100%, 95% CI 51.0–100.0%) and metabolic and nutritional disorders (71.4%, 95%CI 35.9–91.8%) (Fig. 3).Fig. 3 System organ classes involved with ADRs
Severe ADRs (n = 77) outnumbered other classes and together with moderate ADRs (n = 56) they comprised 83.1% of the cases. There were only two fatal cases, which were both caused by warfarin, and 15 life-threatening cases. Minority of the cases (n = 10) were mild. The causalities of the case were as follows 20.6% definite, 33.8% probable, and 45.6% possible.
In our study, drugs included in CPIC guidelines were involved in 29 cases [20–26]. Two of these cases had an ADR for which a pharmacogenetic test might reduce the risk of that particular ADR. One of the patients was on codeine and had ileus [20]. The other patient was on capecitabine, and he had severe hypokalemia (ad 2.5 mmol/l) [21]. There was another patient with capecitabine too, but his ADR (constipation) could not have been presented by genotyping the patient beforehand. The rest of the cases did not include ADRs, which could have been prevented by a specific genetic test. These drugs were warfarin (14 cases), clopidogrel (4 cases), tacrolimus (2 cases), allopurinol (2 cases), fluorouracil, oxcarbazepine, escitalopram, and citalopram, e.g. warfarin had been in use in every patient for at least 6 months, and genetic testing for warfarin is evaluated to be useful only in the beginning of the treatment.
There were only two cases with a drug-adverse reaction pair which were considered as potentially preventable in a genetic subset by pharmacogenetic testing, according to CPIC guidelines. There were also 27 other ADR cases with drugs mentioned in CPIC guidelines, but the specific ADRs observed were either unrelated to the recommended genotyping or occurred after prolonged treatment (warfarin associated bleedings).
Discussion
The incidence of ADRs in our university hospital emergency room visits was 7.8%, which was in line with previous studies [2, 27–29]. Comparison to previous studies should be made with caution as study settings, patients, and studied medications differ a lot. The most common drug classes causing ADRs in this study were antithrombotic and antineoplastic agents. They were also most often causing deaths in the same university hospital in earlier studies [6, 30].
In this study, we focused on ADRs in a tertiary hospital emergency ward. ADRs are the most common medication related problem in every health care setting studied [31, 32]. However, most studies focus on primary care setting, while there are only couple of studies from tertiary hospitals [27, 33–36]. There is one recent (2014) study from a university hospital from our country, where the incidence of ADRs was much higher (23.1%) than in our study [37]. Explanation for this difference could be the ages of the patients. They included only patients over 65 years, and the average age was 77. Our patients were 16–94 years, and the average age was 63.4. The characteristics of ADRs depend not only on the studied ward and patient group but also on the country [38, 39]. In a thorough study from India, most ADRs (81.6%) were assessed to be preventable [27]. However, in that study the most common drug classes were antiinfective agents, followed by steroids. Neither of these classes were found in our cases, indicating that there are marked differences in ADR preventability between these two centers. If we exclude these preventable cases from that study, the incidence of the ADRs is close to our study (1.15%).
There are multiple studies evaluating the incidence of ADRs in emergency departments from primary care [13, 28, 40, 41]. Drugs involved in these studies reflect the use of medications in the regional population with its typical age and other patient characteristics. In our Finnish population, children were not included, and the youngest cases were 18–19 years old. While ADRs were observed only infrequently in 20–49 years old people, the majority of ADRs were observed in age groups between 50 and 89 years. In these age groups, more than 8% of the emergency visits were related to ADRs with the highest percentages of 15 to 19% in the 80–89 years age group. There are two likely explanations to this finding: first, many diseases and ADRs are more severe in elderly people, and second, the number of simultaneous medications tends to increase with increasing age [2, 9].
The most important ATC-group in this study was antithrombotic agents (B01) and very close to that was antineoplastic agents (L01). The same two groups were also in the top when we studied ATC-groups involved in fatal cases in the same university hospital area [30]. In that study, cytostatic drugs caused 1.1% of deaths in the hospital and antithrombotic drugs caused 1.0% covering over half of the fatal cases (35/52). In the present study, they covered 48.1% of all ADRs. There were, altogether, 11 drugs causing more than two cases (Table 1), mainly involving either antithrombotics or cytostatics. Antithrombotics (or anticoagulants) and cytostatics have been the most common drugs involved in ADRs also in other studies in every health care setting [2, 3, 9, 10, 16, 28]. Even though the risks connected with these two groups are well known, it is hard to avoid them totally due to their narrow therapeutic window. Both groups are also prescribed to patients with severe diseases, which may also predispose them to ADRs. Deaths caused by cytostatics have diminished year by year in our hospital [30], but at the moment, also fragile patients are treated with them and the medications are more effective meaning that, e.g., leucopenia is inevitable in a subset of patients. There has also been a trend towards an increased intensity of antithrombotic treatments in cardiovascular patients, and overall, the use of antithrombotics has increased, while evaluation of the risk of bleeding has been improved. Perhaps because of improved evaluation and monitoring of patients, there has been even a slight decline in deaths caused by antithrombotic related bleedings during the past decades. In our study, there were six bleeding cases caused by apixaban and 14 by warfarin. Rivaroxaban or edoxaban-related ADRs were not identified in any of the cases. During the same time, the number of users of apixaban and rivaroxaban was about the same in Finland, equaling about 30% of the number of warfarin users. Unfortunately, we were not able to receive the number of the people using these drugs in the specific university hospital area. Nevertheless, it is obvious that the numbers will change in the coming years, after direct anticoagulants have replaced warfarin to a larger extent.Table 1 Drugs involved in three or more cases and the ADRs they caused
Drug Number of ADRs Types of ADRs (n)
warfarin 14 Intestinal bleeding (8), hematuria (2), ICH (2), hemarthrosis (1), bruises (1)
ASA 11 Gastrointestinal bleeding (7), bleeding wound (2), hematuria (1), anemia (1)
docetaxel 6 Febrile neutropenia (3), allergic reaction (1), fever (1), erysipelas (1)
apixaban 6 Gastrointestinal bleeding (4), ICH (1), hematuria (1)
clopidogrel 4 Bleeding wound (2), gastrointestinal bleeding (1), anemia (1)
buprenorphine 4 Cholecystitis (2), spasm of neck muscles and migraine (1), headache and disorientation (1)
bisoprolol 4 Bradycardia (3), hypotension (1)
tramadol 3 Acute cholecystitis (1), tremor in lower and upper extremities and anxiousness (1), nausea, sweating and tremor (1)
prednisolone 3 Sepsis and pneumonia (1), infection NUD (1), hyperglycemia (1)
oxycodone 3 Ileus (2), worsening of cancer pain (1)
methotrexate 3 Respiratory tract infection (1), pulmonary insufficiency (1), hepatic cirrhosis (1)
others 99
Most ADRs were gastrointestinal disorders followed by ADRs involving blood and lymphatic disorders. This is in line with the most often involved ATC classes, antithrombotics, and cytostatics. Furthermore, most ADRs were classified as severe, as many of them were serious bleedings, infections, or other serious toxicities. This finding probably also reflects the university hospital site of the study, as most mild cases are treated in primary care, while more severe cases are usually directed to the university clinic. Clinics involving oncology and hematology patients receiving cytostatics also typically report more severe cases than hospitals without such patients.
There is no universally accepted method for ADR causality grading, although a number of causality assessment scales have been published. Some studies have compared different scales, and they have usually found a poor agreement between the scales [42, 43]. Naranjo criteria have been used in many studies, as well as Hallas criteria. The Hallas criteria include the same general aspects as the Naranjo scale includes, but the Hallas criteria were more suitable for this study [15].
The preventability of ADRs seems to vary a lot between studies, at least from 4.3 to 83% [2, 44, 45]. This variation is not only dependent on different scales but also on different characteristics of patients and drugs. Preventable ADRs include, e.g., those caused by antihypertensives and antibiotics in many studies, while cases assessed as not to be prevented include medications like cytostatics. Most ADRs in our study were caused by antithrombotic agents and antineoplastic agents, which are used only after a precise consideration of the risk-benefit relationship of the treatments that are known to cause ADRs to a small subset of patients. There were, however, nine cases where ADR might have been preventable. Those cases included buprenorphine (2), tramadole (3), oxycodone (2), and bisoprolol (2). In these cases, opioids could have been replaced with other pain medications and bisoprolol could have been used with a lower dose. With these nine cases preventability of ADRs would have been 7.2% of all ADRs.
One aim of this study was to find out if pharmacogenetic testing could have prevented some ADRs. We used the international CPIC guidelines to evaluate if there were recommendations concerning any of the ADR causing drugs. For example, in case of allopurinol, which can be prescribed more safely after testing the HLA-B*5801-allele, the test could only be used to prevent Stevens-Johnson syndrome, not fever or gastrointestinal pain, which were the ADRs of the respective patients [22]. After evaluating every ADR causing drug, we found only two cases for which pharmacogenetic testing might have prevented the ADRs; one patient with hypokalemia related to capecitabine induced diarrhea and one with ileus caused by codeine. For capecitabine, there is evidence that pharmacogenetic testing could prevent severe toxicity [21], and for codeine gastrointestinal opioid adverse effects are shown to be associated with the CYP2D6 metabolizer phenotype [20]. There were also other ADRs caused by drugs included in CPIC guidelines. Warfarin was involved in 14 bleeding cases. Genotype-guided warfarin dosing is thought to be beneficial only when warfarin is started, as it helps to find the first stable international normalized ratio (INR) [23]. However, in all our cases, warfarin had been in use for more than 6 months. Therefore, it was considered unlikely that pharmacogenetic testing could have been used to prevent the ADRs, although carriers of the CYP2C9*3 allele can have a higher risk of bleeding even after prolonged warfarin treatment [46]. Other drugs included in CPIC guidelines were the fluoropyrimidines capecitabine and fluorouracil, whose severe toxicity could be reduced by genotype-guided dosing [21]. However, the cases in this study did not have severe toxicity, but only constipation and fever without neutropenia, and we considered that these ADRs could not have been prevented by pharmacogenetic testing. Further cases included hyponatremia caused by escitalopram or citalopram that we considered not preventable by pharmacogenetic testing [24], as there is no compelling evidence showing that hyponatremia is (es)citalopram concentration-dependent. Yet, there are two cases of escitalopram dose-dependent hyponatremia [47, 48].
Strengths and limitations
The number of emergency visits in our study was quite large. There were 16,535 ER visits during the six study months, and 1600 of them were randomized to our study. The patient files of these 1600 visits were studied carefully by one student and three experienced clinicians and clinical pharmacologists, and all possible ADRs were assessed and only real ADRs were included (case 1 Suppl).
We did not consider lack of drug effect to be an ADR. Therefore, there might have been cases that potentially could have been prevented by a pharmacogenetic testing. For example, clopidogrel is converted to its active metabolite by CYP2C19, and poor metabolizers with two unfunctional copies of CYP2C19 have reduced amount of active clopidogrel metabolites [25], which may result in blood clotting.
Conclusion
The same ATC categories and medications are in top when assessed the ADRs causing hospitalizations and fatal cases caused by medications. It seems difficult to prevent these events totally as the treatments are vitally important and risk-benefit-relationship has been considered thoroughly.
Supplementary Information
ESM 1 (DOCX 157 kb).
Authors’ contributions
M.K, O.L-R, and J.T.B wrote the manuscript; M.K, O.L.-R., J.T.B., and M.N. designed the research; M.K, O.L.-R., J.T.B, and M.N. performed the research and analyzed the data.
Funding
Open access funding provided by University of Helsinki including Helsinki University Central Hospital. State funding for university level health research, Helsinki University Hospital, Helsinki, Finland.
Data availability
Not applicable.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Code availability
Not applicable.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ascites'.
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Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
|
CYCLOPHOSPHAMIDE, DOXORUBICIN, PREDNISOLONE, RITUXIMAB, VINCRISTINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33191319
| 18,620,249
|
2021-05-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug-induced liver injury'.
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
|
CYCLOPHOSPHAMIDE, DOXORUBICIN HYDROCHLORIDE, PREDNISOLONE, RITUXIMAB, VINCRISTINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33191319
| 18,570,215
|
2021-05-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic fibrosis'.
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
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CYCLOPHOSPHAMIDE, DOXORUBICIN HYDROCHLORIDE, PREDNISOLONE, RITUXIMAB, VINCRISTINE
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DrugsGivenReaction
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CC BY-NC-ND
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33191319
| 18,608,123
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2021-05-15
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic haemorrhage'.
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Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
|
CYCLOPHOSPHAMIDE, DOXORUBICIN HYDROCHLORIDE, PREDNISOLONE, RITUXIMAB, VINCRISTINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33191319
| 18,608,123
|
2021-05-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic lymphocytic infiltration'.
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
|
CYCLOPHOSPHAMIDE, DOXORUBICIN HYDROCHLORIDE, PREDNISOLONE, RITUXIMAB, VINCRISTINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33191319
| 18,608,123
|
2021-05-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic necrosis'.
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
|
CYCLOPHOSPHAMIDE, DOXORUBICIN HYDROCHLORIDE, PREDNISOLONE, RITUXIMAB, VINCRISTINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33191319
| 18,608,123
|
2021-05-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatitis chronic active'.
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
|
CYCLOPHOSPHAMIDE, DOXORUBICIN HYDROCHLORIDE, PREDNISOLONE, RITUXIMAB, VINCRISTINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33191319
| 18,608,123
|
2021-05-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infection reactivation'.
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
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CYCLOPHOSPHAMIDE, DOXORUBICIN, PREDNISOLONE, RITUXIMAB, VINCRISTINE
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DrugsGivenReaction
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CC BY-NC-ND
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33191319
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2021-05-15
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Liver injury'.
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Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
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CYCLOPHOSPHAMIDE, DOXORUBICIN HYDROCHLORIDE, PREDNISOLONE, RITUXIMAB, VINCRISTINE
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DrugsGivenReaction
|
CC BY-NC-ND
|
33191319
| 18,608,123
|
2021-05-15
|
What was the administration route of drug 'CYCLOPHOSPHAMIDE'?
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
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Intravenous (not otherwise specified)
|
DrugAdministrationRoute
|
CC BY-NC-ND
|
33191319
| 18,570,215
|
2021-05-15
|
What was the administration route of drug 'DOXORUBICIN HYDROCHLORIDE'?
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
|
Intravenous (not otherwise specified)
|
DrugAdministrationRoute
|
CC BY-NC-ND
|
33191319
| 18,570,215
|
2021-05-15
|
What was the administration route of drug 'PREDNISOLONE'?
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
|
Oral
|
DrugAdministrationRoute
|
CC BY-NC-ND
|
33191319
| 18,570,215
|
2021-05-15
|
What was the administration route of drug 'RITUXIMAB'?
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
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2021-05-15
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Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
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Intravenous (not otherwise specified)
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DrugAdministrationRoute
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CC BY-NC-ND
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33191319
| 18,570,215
|
2021-05-15
|
What was the dosage of drug 'VINCRISTINE SULFATE'?
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
|
R?CHOP REGIMEN
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DrugDosageText
|
CC BY-NC-ND
|
33191319
| 18,609,070
|
2021-05-15
|
What was the outcome of reaction 'Ascites'?
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
|
Fatal
|
ReactionOutcome
|
CC BY-NC-ND
|
33191319
| 18,620,249
|
2021-05-15
|
What was the outcome of reaction 'Febrile neutropenia'?
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
|
Recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33191319
| 18,687,039
|
2021-05-15
|
What was the outcome of reaction 'Hepatic failure'?
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
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2021-05-15
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What was the outcome of reaction 'Hepatic fibrosis'?
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Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
|
Not recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33191319
| 18,608,123
|
2021-05-15
|
What was the outcome of reaction 'Hepatic haemorrhage'?
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
|
Not recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33191319
| 18,608,123
|
2021-05-15
|
What was the outcome of reaction 'Hepatic lymphocytic infiltration'?
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
|
Not recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33191319
| 18,608,123
|
2021-05-15
|
What was the outcome of reaction 'Hepatic necrosis'?
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
|
Not recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33191319
| 18,608,123
|
2021-05-15
|
What was the outcome of reaction 'Hepatitis chronic active'?
|
Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
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CC BY-NC-ND
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2021-05-15
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What was the outcome of reaction 'Infection reactivation'?
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Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
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Fatal
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ReactionOutcome
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CC BY-NC-ND
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33191319
| 18,620,249
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2021-05-15
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What was the outcome of reaction 'Liver injury'?
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Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy.
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Introduction
Chemotherapy using cytotoxic agents and targeted antibodies has helped prolong the cancer patient survival in recent years (1-4). However, since many chemotherapeutic drugs are metabolised in the liver and directly hepatotoxic (5), chemotherapy can cause liver injury, which sometimes leads to a poor clinical outcome.
The severity of adverse effects on the liver caused by antineoplastic agents depends on the age, gender, genetic susceptibility, concomitant medications, tumour involvement in the liver and preexisting liver diseases, such as fatty liver, chronic hepatitis and liver cirrhosis (6). In particular, cancer patients with hepatitis viruses have to be carefully treated with chemotherapy, as their impaired hepatic function sometimes precludes the administration of anticancer drugs in standard doses or intervals (7).
A major issue that must be considered when treating hepatitis virus-positive cancer patients is the influence of drugs commonly used in cancer treatments on the clinical outcomes of these patients (8). Hepatitis B virus (HBV) reactivation is an established complication occurring among HBV-positive cancer patients treated with chemotherapeutic drugs (9). Reactivation of HBV replication can become severe, resulting in liver failure and death in some cases. In addition, reactivation of hepatitis C virus (HCV) due to immunosuppressive treatment has also been reported in the literature, although data on the clinical outcomes in cancer patients with HCV receiving such treatment have been controversial (10).
Occult HCV infection (OCI), which was first reported by two different research groups approximately at the same time in 2004 (11,12), is a newly recognised mode of HCV infection (13,14). In individuals with OCI, HCV RNA is undetectable in serum using standard polymerase chain reaction (PCR), whereas HCV is latent in the liver, peripheral blood mononuclear cells (PBMCs) and/or ultracentrifuged serum (11,12,15,16).
OCI is now classified into two different subtypes according to the HCV-related virological and immunological status in serum, i.e. seropositive OCI and seronegative OCI (13,14). Specifically, individuals with seropositive OCI test positive for anti-HCV antibody and negative for HCV RNA in serum, while those with seronegative OCI negative for both (13). Recently, based on an acknowledged association between HCV infection and haematological diseases (17), several groups have addressed the prevalence of OCI among patients with these diseases (18-21). However, the significance of OCI in the clinical course of patients with haematological tumours has not yet been verified.
We herein report an anti-HCV antibody-negative lymphoma patient who may have exhibited reactivation of seronegative OCI after chemotherapy.
Case Report
A 79-year-old man with follicular lymphoma (grade 3A) was treated with first-line chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (22). Staging examinations, including a bone marrow biopsy, showed the Ann Arbor stage to be IV. Representative lesions of lymphoma are shown in Fig. 1A. The Follicular Lymphoma International Prognostic Index was judged to be high risk.
Figure 1. Imaging tests performed before (A, B) and after (C, D) R-CHOP therapy. (A) Our patient presented with systemic lymphadenopathy, including swollen abdominal paraaortic and mesenteric lymph nodes as shown by computed tomography (CT), before R-CHOP therapy. (B) CT showed no abnormal morphological results in the liver or spleen before R-CHOP therapy. (C) Massive ascites and atrophy of the liver were revealed by CT 10 months after the commencement of R-CHOP therapy. (D) Oesophageal varices were observed using oesophagogastroduodenoscopy 11 months after the treatment.
Blood and imaging tests found no abnormal results in his liver function, hepatitis virus status and appearance of the liver before chemotherapy (Table 1, Fig. 1B). In particular, the aspartate transaminase (AST) to Platelet Ratio Index (APRI) (23) and Fibrosis-4 (FIB-4) (24) were 0.365 and 2.40, respectively. Computed tomography did not show splenomegaly. No oesophageal varices were observed using oesophagogastroduodenoscopy (data not shown).
Table 1. Results of Blood and Urine Tests Performed before R-CHOP Therapy.
Parameter Value Unit Reference
value Parameter Value Unit Reference
value Parameter Value Unit Reference
value
Blood cell count Biochemistry Immunology
WBC 4.1 ×103/μL 3.3-8.6 TP 7.5 g/dL 6.6-8.1 CRP 0.11 mg/dL 0.00-0.14
St 1 % 0-6 Alb 66.4 % 55.8-66.1 IgG 1,116 mg/dL 861-1,747
Seg 72 % 32-73 α1 2.9 % 2.9-4.9 IgA 166 mg/dL 93-393
Ly 20 % 25-45 α2 8.9 % 7.1-11.8 IgM 96 mg/dL 33-183
Mo 6 % 4-7 β 8.0 % 7.9-13.7 HBs Ag (-) (-)
Eo 1 % 1-5 γ 13.8 % 11.1-18.8 HBs Ab (-) (-)
Ba 0 % 0-2 Alb 4.7 g/dL 4.1-5.1 HBc Ab (-) (-)
RBC 4.47 ×106/μL 4.35-5.55 BUN 21.9 mg/dL 8.0-20.0 HCV Ab (-) (-)
Hb 13.7 g/dL 13.7-16.8 Cr 0.6 mg/dL 0.65-1.07 HIV Ab (-) (-)
Ht 39.9 % 40.7-50.1 UA 4.3 mg/dL 3.7-7.8 HTLV-1 Ab <16 times <16
MCV 89.3 fL 83.6-98.2 Na 139 mEq/L 138-145 Anti-nuclear Ab <40 times <40
MCH 30.6 pg 27.5-33.2 Cl 103 mEq/L 101-108
MCHC 34.3 % 31.7-35.3 K 4.3 mEq/L 3.6-4.8 Tumour marker
Ret 7 ‰ 2-26 Ca 9.3 mg/dL 8.8-10.1 β2-MG 2.3 mg/L 1.0-1.9
Plt 201 ×103/μL 158-348 T-Bil 0.6 mg/dL 0.4-1.5 sIL-2R 956 U/mL 122-496
D-Bil 0.1 mg/dL 0.0-0.3
Coagulation AST 22 IU/L 13-30
PT 12.0 sec 9.8-12.1 ALT 13 IU/L 10-42
92 % 70-130 LDH 209 IU/L 124-222
1.02 ratio 0.85-1.15 ALP 245 IU/L 106-322
APTT 27.1 sec 24.0-39.0 γ-GTP 38 IU/L 13-64
Fib 228 mg/dL 200-400 ChE 335 IU/L 240-486
ATIII 82 % 80-130 Amy 125 IU/L 44-132
FDP 0.2 μg/mL <5.0 CPK 59 IU/L 59-248
D-D dimer 0.6 μg/mL <1.0 Glu 108 mg/dL 73-109
HbA1c 5.5 % 4.3-5.8
T-Chol 245 mg/dL 142-248
Urinanalysis LDL 131 mg/dL 65-163
Protein (-) (-) TG 315 mg/dL 40-234
Glu (-) (-) Fe 107 μg/dL 54-200
OB (-) (-) Ferritin 72 ng/mL 10-250
Bil (-) (-) TIBC 291 μg/dL 253-365
WBC: white blood cell, RBC: red blood cell, Hb: haemoglobin, Ht: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, Ret: reticulocyte, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, Fib: fibrinogen, ATIII: antithrombin III, FDP: fibrin and fibrinogen degradation product, Glu: glucose, OB: occult blood, Bil: bilirubin, TP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, ChE: cholinesterase, Amy: amylase, CPK: creatine phosphokinase, HbAlc: haemoglobin Alc, T-Chol: total cholesterol, LDL: low-density lipoprotein, TG: triglycerides, TIBC: total iron binding capacity, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, HBs Ag: hepatitis B surface antigen, HBs Ab: anti-hepatitis B surface antibody, HBc Ab: anti-hepatitis B core antibody, HCV Ab: anti-hepatitis C virus antibody, HIV Ab: anti-human immunodeficiency virus antibody, HTLV-1 Ab: anti-human T-lymphotropic virus type-1 antibody, Anti-nuclear Ab: anti-nuclear antibody, β2-MG: β2-microglobulin, sIL-2R: soluble interleukin-2 receptor
His disease responded well to the treatment, although mild liver dysfunction occurred after the administration of the second cycle of R-CHOP therapy (Fig. 2). During the fifth cycle of the therapy, a fever, neutropenia and further liver injury developed (Fig. 2). He was diagnosed with febrile neutropenia and treated with antibiotics. Neither bacteraemia nor cytomegalovirus (CMV) viraemia was documented by blood culture tests or other evaluations. He gradually recovered from the fever and neutropenia, but his moderate liver dysfunction remained (Fig. 2).
Figure 2. Clinical course of possible occult hepatitis C virus reactivation and liver failure during treatment. Results representative for the events are shown as follows: red line: serum alanine aminotransferase (ALT), blue line: serum total bilirubin (T-Bil), grey line: plasma prothrombin activity (PT), green line: blood platelet (Plt), grey box: one cycle of R-CHOP therapy, arrow: liver biopsy, HCV Ab: anti-hepatitis C virus (HCV) antibody, HCV RNA: HCV RNA determined using real time PCR (log IU/mL), ND: no data, neg: negative
As there were no apparent causes of liver dysfunction and the possibility of drug-induced liver injury was considered, all drugs used in R-CHOP therapy were discontinued four months after the initiation of R-CHOP therapy. Nevertheless, the moderate liver dysfunction was not ameliorated (Fig. 2). Serum hepatitis-related tests, including HBV DNA, were thus conducted seven months after the treatment and showed no abnormal results (Table 2). Abdominal ultrasonography and magnetic resonance imaging/cholangiopancreatography also exhibited no significant findings except for slight ascites, in which no malignant cells were detected by cytology.
Table 2. Hepatitis-related Virological and Immunological Status in Our Patient’s Serum before and after R-CHOP Therapy.
Parameter Value Unit Reference value
Before treatment
HBs Ag (-) (-)
HBs Ab (-) (-)
HBc Ab (-) (-)
HCV Ab (-) (-)
ANA <40 times <40
IgG 1,116 mg/dL 861-1,747
IgA 166 mg/dL 93-393
IgM 96 mg/dL 33-183
7 months after treatment
HBs Ag (-) (-)
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 975 mg/dL 861-1,747
IgA 144 mg/dL 93-393
IgM 69 mg/dL 33-183
10 months after treatment
HCV Ab (-) (-)
HCV RNA (real time PCR) 7.5 log IU/mL ND
HCV serological group Undetermined
HBs Ag 0.03 IU/mL <0.05
HBV DNA (real time PCR) ND log copies/mL ND
ANA <40 times <40
AMA-M2 <5 U/mL <7
SMA <40 times <40
IgG 1,158 mg/dL 861-1,747
IgA 220 mg/dL 93-393
IgM 97 mg/dL 33-183
CMV pp65 Ag (HRP-C7) ND ND
AMA-M2: anti-mitochondrial M2 antibody, ANA: anti-nuclear antibody, CMV pp65 Ag: cytomegalovirus pp65 antigen, DNA: deoxyribonucleic acid, HBc Ab: anti-hepatitis B core antibody, HBs Ab: anti-hepatitis B surface antibody, HBs Ag: hepatitis B surface antigen, HBV: hepatitis B virus, HCV: hepatitis C virus, HCV Ab: anti-hepatitis C virus antibody, HRP-C7: assay for CMV using a horseradish peroxidase-conjugated monoclonal antibody C7, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, ND: not detected, PCR: polymerase chain reaction, RNA: ribonucleic acid, SMA: anti-smooth muscle antibody
Since moderate liver dysfunction persisted, a liver biopsy was next performed eight months after the therapy (Fig. 2). The tissue specimen revealed acute-on-chronic liver injury (Supplemental material). Hepatocytes widely represented swollen and pale cytoplasm. Moderate to severe mononuclear infiltrates were seen in the portal tract and liver parenchyma. Expansion of the portal tract with mild bridging fibrosis was associated. These histopathological features corresponded to chronic-active hepatitis, i.e. A2F2 according to the new Inuyama Classification. In addition to this, the acidophilic bodies were scattered, and centrilobular necrosis with haemorrhaging was observed, thus suggesting a flare-up of hepatitis. No infiltrated lymphoma cells were observed in the liver specimen using immunohistochemistry for CD20.
Ten months after the commencement of R-CHOP therapy, surprisingly, massive ascites and atrophy of the liver rapidly occurred (Fig. 1C). Therefore, we again examined the hepatitis-related virological and immunological status in serum, including the infectious status for HBV, HCV and CMV. Intriguingly, anti-HCV antibody was again found to be negative by a third-generation chemiluminescent enzyme immunoassay, whereas HCV RNA was detected in his serum using real time PCR (7.5 log IU/mL) (Table 2, Fig. 2). The HCV genotype was untested.
We therefore asked the patient some medical questions relevant to hepatitis in detail. His answers showed that he had no episodes potentially involved with the recent occurrence of acute HCV infection, such as blood transfusion, needle-stick exposure and sexual activity, before and during treatment (25). Furthermore, through our interviews, he finally recollected that he had been diagnosed with liver dysfunction approximately 20 years before. We unfortunately were unable to obtain the details of his medical history concerning liver dysfunction, since his memory was vague.
These findings implied that he may have had seronegative OCI before R-CHOP therapy, with reactivation of HCV, particularly seronegative OCI, possibly occurring consequently due to the treatment. He received best supportive care without antiviral therapy according to his wishes, ultimately succumbing to liver failure 11 months after R-CHOP therapy (Fig. 2).
Discussion
Recently, the two subtypes of OCI have bene considered to be caused by different mechanisms involved with the exposure and clearance of HCV. Seropositive OCI is frequently observed as a result of the resolution of clinically evident chronic hepatitis C by antiviral therapy (12,15,26). Seronegative OCI, by contrast, may be caused by asymptomatic exposure to HCV, at least in some individuals, and may be followed by spontaneous clearance of HCV from the serum and the subsequent disappearance of serum anti-HCV antibody over time (27-29). In our patient, anti-HCV antibody had been undetectable before and during treatment, but serum HCV RNA was finally detected in the final phase (Table 2). Unfortunately, we were unable to confirm whether or not HCV RNA had been present in his serum, liver and/or PBMCs before treatment, since there were no available samples. However, considering the high sensitivity and specificity of the chemiluminescent enzyme immunoassay for serum anti-HCV antibody (30), our patient was very unlikely to have had HCV RNA, at least in his serum, before treatment, unless he had been in an early stage of acute HCV infection. Indeed, our interviews with the patient turned up no opportunities for the patient to have been newly infected with HCV (25) before or during treatment.
Of note, serum anti-HCV antibody can show a false negative in patients with immunocompromised diseases, such as human immunodeficiency virus-1 infection and renal failure (31-34). However, since the present patient had no such diseases before treatment, his anti-HCV antibody was almost certainly a true negative. Taken together, these findings suggest that our patient did not have HCV RNA in his serum before treatment.
In addition, our medical interviews also revealed that our patient had had a history of unspecified liver dysfunction occurring approximately two decades earlier, suggesting that the patient had been infected with HCV long before this presentation, with the virus resolving spontaneously over time and lying latent in his liver and/or PBMCs before undergoing chemotherapy. Indeed, a few individuals have seronegative OCI regardless of underlying diseases (11,18-21,35-41). These findings support the possibility of seronegative OCI in our patient (14).
Reactivation of HCV does occur in HCV-positive cancer patients treated with antineoplastic agents (42). In particular, rituximab, one of the most important chemotherapeutic drugs for lymphoma patients (4), causes HCV reactivation and liver damage (42-44) through immunosuppression after the initiation of rituximab-containing chemotherapy and subsequent immune recovery after the discontinuation of the treatment (10,45). Severe liver dysfunction caused by immunosuppressive treatment such as chemotherapy occurs less frequently in patients with HCV than in those with HBV (10,46). However, once severe hepatitis develops following viral reactivation, the mortality rate seems to be similar between HBV- and HCV-positive patients (47,48). Reactivation and proliferation of HCV generally begins to occur two to four weeks after chemotherapy, damaging the liver and occasionally resulting in a poor patient outcome (10). Indeed, the clinical course of our patient was quite similar to those of patients who developed reactivation of HCV (49) or resolved HBV infection (50) (Fig. 1C, D, 2). Due to chemotherapy, the HCV that was latent in our patient's liver and/or PBMCs may have reactivated and proliferated, injuring the liver and thus eventually causing liver failure.
In conclusion, although the possibility that our patient's event was caused by the recent occurrence of acute hepatitis C still remains, our findings seem to imply the possibility of hitherto unrecognised reactivation of resolved HCV infection, i.e. seronegative OCI, in a clinical course of cancer. At present, there are no useful ways to detect seronegative OCI using commercially available assays. Thus, it is crucial to consider the possibility of reactivation of seronegative OCI if an anti-HCV antibody-negative cancer patient treated with chemotherapy suffers from liver injury of unknown origin.
We should verify this disease in a larger cohort in order to confirm and generalise the results and treatment of this event. The development of useful and convenient assay techniques for OCI is also necessary. These efforts may lead to the establishment of reliable predictive markers and, consequently, to truly personalised approaches for the more effective treatment of cancer patients.
The authors state that they have no Conflict of Interest (COI).
Supplementary Material
Supplemental Figure 1. Pathological imaging of the liver.
Click here for additional data file.
Acknowledgement
We are grateful to Y. Suehiro, R. Sugimoto, K. Taguchi, Y. Aratake, T. Sakoda and K. Mori for their helpful advice. The expert advice on laboratory examinations by M. Yoshinaga is also gratefully acknowledged.
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Not recovered
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ReactionOutcome
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CC BY-NC-ND
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33191319
| 18,608,123
|
2021-05-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Aortitis'.
|
Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.
We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are commonly used to prevent and treat neutropenia caused by cancer chemotherapy. Meta-analyses of randomized controlled trials of G-CSFs as primary prophylaxis against febrile neutropenia have demonstrated significant reductions in the rates of short-term all-cause mortality, as well as rates of infection-related mortality, in patients with solid tumors and malignant lymphoma (1,2). A meta-analysis of 59 randomized controlled trials demonstrated that systemic cancer chemotherapy with primary adjunct G-CSF treatment was associated with a significantly greater intensity of the effect of the delivered chemotherapy doses and with greater relative and absolute risk reductions in all-cause mortality rates than was chemotherapy without adjunct G-CSF treatment over a long period (3). As for drug safety, Teshima et al. reported that according to the results of their post-marketing use survey in Japan, the rate of overall adverse effects was 7.47%; these effects included lumbago (3.84%), fever (1.62%), and bone pain (0.61%), and most were not serious and seemed to be ameliorated by the discontinuation of G-CSF treatment (4).
However, a few cases with serious adverse effects, such as interstitial pneumonia and extramedullary hematopoietic splenic rupture, have been reported after the administration of G-CSF (5,6). Pegfilgrastim, a relatively new G-CSF used to prevent febrile neutropenia, is a modified protein consisting of methoxy polyethylene glycol (PEG) molecular chains attached to a Met1 amino group of genetic recombinant filgrastim whose renal excretion is reduced and whose effects are prolonged (7). In Japan, pegfilgrastim is approved for use only to prevent febrile neutropenia after chemotherapy. To optimize its pharmacological effect and prevent adverse effects, the use of pegfilgrastim is restricted to patients at high risk for febrile neutropenia at least 24 hours after a course of chemotherapy. Over the past two decades, authors have reported cases of aortitis induced by G-CSF preparations such as filgrastim, lenograstim, and pegfilgrastim (8,9). Oshima et al., using the Japanese Adverse Drug Event Report database, reported that G-CSF treatment is associated with an increased risk for aortitis (10).
We herein report a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. This is a rare case of G-CSF induced aortitis occurred in a patient who was being treated for sarcoma and it is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological background.
Case Report
A 56-year-old man who was receiving treatment for the local recurrence of extraosseous mucinous chondrosarcoma on the right lower limb presented to our hospital because of an 8-day history of high fever, general fatigue, and a rash with pain. He did not report either any upper or lower respiratory symptoms, abdominal pain, diarrhea, arthralgias, headache, or visual impairment. He had finished the first 4-day course of chemotherapy with 2-day adriamycin (25 mg/m2 each) and four-day ifosfamide (2.8 g/m2 each), followed 36 hours later by subcutaneous administration of pegylated G-CSF (3.6 mg), and he was discharged immediately. Four days later, the symptoms began.
On presentation, he did not appear ill, and he was alert and oriented. His body weight was 69.4 kg, and his height was 169 cm. His vital signs were as follows: blood pressure, 90/47 mm Hg; pulse rate, 95 beats/min; body temperature, 39.1℃; respiratory rate, 12/min; and oxygen saturation level, 99% on room air. A physical examination revealed palm-sized dark red-to-purplish indurated rashes with tenderness on the right cubital fossa and over the left knee socket (Fig. 1a, b). The surface lymph nodes, liver, and spleen were not palpable. The initial laboratory data revealed the following: a white blood cell count of 15,780/μL (90.0% segmented neutrophils, 7.0% stab neutrophils 1.0% monocytes, 2.0% lymphocytes, and 0% atypical lymphocytes, visually confirmed), hemoglobin level of 11.8 g/dL, platelet count of 109,000/μL, and serum C-reactive protein level of 38.77 mg/dL. Table lists the other laboratory data. The results of antigen tests for influenza virus were negative. Two sets of blood culture were conducted. Computed tomography (CT) without contrast media revealed inflammatory changes in the soft tissue surrounding the aorta, partial reticular change and ground-glass opacities scattered throughout both lungs, and splenomegaly (Fig. 2).
Figure 1. Erythematous skin lesions on the right cubital fossa (a) and over the left knee socket (b), on admission.
Table. Laboratory Data on Admission.
Complete blood count Serological test Urine test
WBC 15,780 ×103/μL CRP 38.77 mg/dL occult blood 2+
N-Stab 7 % IgG 828 mg/dL ketone negative
N-Seg 90 % IgA 327 mg/dL glucose negative
Eosino 0 % IgM 103 mg/dL protein 1+
Baso 0 % IgE 53 mg/dL Urinary sediment
Mono 1 % CH50 >60 CH50/mL RBC <4 /HPF
Lymph 2 % C3 162 mg/dL WBC <4 /HPF
RBC 442 ×104/μL C4 45 mg/dL Squamous cell 0-1 /HPF
Hemoglobin 11.8 g/dL sIL-2R 1,922 U/mL cast positive
Platelet 109 ×104/μL ANA <80 β2 microglobulin 18.7 mg/dL
Biochemistry PR3-ANCA <1.0 U/mL
TP 6.2 g/dL MPO-ANCA <1.0 U/mL
Alb 2.4 g/dL anti ssDNA 2.5 AU/mL
T-bil 0.8 mg/dL anti dsDNA <1.2 IU/mL
D-bil 0.5 mg/dL ASO 38 IU/mL
AST 22 U/L ASK ×320
ALT 99 U/L PCT 0.58 ng/mL
Ch-E 157 U/L IGRA negative
ALP 1,077 U/L RPR <1.0
LAP 149 U/L TPHA 0
γ-GTP 302 U/L HCV Ab 0.03
LD 208 U/L HBs Ag 0 IU/mL
CK 19 U/L CMV IgG 64 UA/mL
UN 33 mg/dL CMV IgM negative
Creatinine 2.29 mg/dL ESR 114 mm/hr
Na 139 mmol/L
K 3.7 mmol/L
Cl 101 mmol/L
Blood Sugar 159 mg/dL
HbA1c 6.4 %
WBC: white blood cell, RBC: red blood cell, AST: asparatate aminotransferase, ALT: alanine aminotransferase, N-stab: stab neutrophil, N-seg: segmented neutrophil, Eosino: eosinophil, Baso: basophil, Mono: monocyte, Lymph; Lymphocyte, TP: total protein, Alb: albumin, T-bil: total bililubin, D-bil: direct bililubin, Ch-E: cholinesterase, ALP: alkaline phosphatase, LAP: leucine aminopeptidase, γ-GTP: γ-glutamyl transpeptidase, LD: lactate dehydrogenase, UN: urea nitrogen, CK: creatine kinase, Na: sodium, K: potassium, Cl: chloride, HbA1c: hemoglobine A1c, CRP: C-reactive protein, IgG: Immunoglobulin G, IgA: Immunoglobulin A, IgM: Immunoglobulin M, IgE: Immunoglobulin E, CH50: 50% hemolytic complement activity, sIL-2 R: soluble Interleukin-2 receptor, ANA: antinuclear antibody, PR3-ANCA: serine proteinase3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-ssDNA: anti-single-stranded DNA antibody, anti-dsDNA: anti-double stranded DNA antibody, ASO: antistreptolysin O, ASK: antistreptokinase, PCT: procalcitonin, IGRA: interferon-gamma releasing assay, RPR: rapid plasma reagin card agglutination test, TPHA: treponema pallidum antibody hemagglutination test, HCV ab: hepatitis C virus antibody, HBs Ag: hepatitis B virus antigen, CMV IgG: cytomegalovirus antibody, immunoglobulin G, CMV IgM: cytomegalovirus antibody, immunoglobulin M, ESR: erythrocyte sedimentation rate
Figure 2. Computed tomography (CT) without contrast media, showing aortitis (a; white arrowheads), patchy interstitial changes scattered throughout both lungs (b; black arrowheads) and a small amount of pleural effusion (b; yellow arrowheads), and splenomegaly (c).
Because he was immunocompromised, we diagnosed systemic inflammatory response syndrome and acute renal failure caused by bacterial infection. We promptly administered 2 L of crystalloid infusion for resuscitation and empirical piperacillin/tazobactam as shown in Fig. 3. His renal function was restored rapidly, but high-grade fever persisted for 4 days, as did the inflammatory markers, despite antibiotic treatment. However, this patient did not appear ill, and his food intake did not decrease during the first 4 days after his admission to this hospital. Furthermore, even with a high-grade fever (>40℃), his pulse rate had stayed in the range of 60/min to 70/min, which represented relative bradycardia, which in turn has been considered a characteristic of drug-related fever (11). A blood culture yielded negative results, as did serological tests (including cytomegalovirus antigen and autoantibodies); thus, we diagnosed aortitis resulting from G-CSF administration.
Figure 3. Clinical course of this case. CRP: C-reactive protein, PIPC/TAZ: piperacillin/tazobactam, PSL: prednisolone, WBC: white blood cell count
Because of concerns about the high-grade fever and the pulmonary findings, we initiated treatment with prednisolone, 60 mg (1 mg/kg) orally on the fourth day of hospitalization. His fever resolved within the day, followed by a rapid improvement in his general condition and laboratory data. The rash had improved simultaneously, although the skin discoloration remained. Six days after initiating prednisolone, we tapered the dosage to 40 mg and discharged the patient on day 18 (Fig. 3). At the 3-month follow-up visit, the patient remained well with the prednisolone dose of 7.5 mg/day, which was discontinued 3 months later.
Discussion
As in other immunocompromised patients after the administration of anticancer drugs, we had to rule out vasculitis secondary to infections before diagnosing the drug-induced aortitis, since infectious disease was strongly associated with systemic vasculitis, including aortitis (12). Hence, it might be important in such patients to evaluate them for common infectious diseases that are often overlooked-not only bacterial bloodstream infections but also tuberculosis, syphilis, viral hepatitis, and human immunodeficiency virus-that are known causes of vasculitis before G-CSF-induced aortitis is diagnosed (13).
In this case, pegfilgrastim was administered 36 hours after the completion of the first cycle of AI (adriamycin, ifosfamide) chemotherapy, and a series of symptoms had begun 4 days later. Most cases of G-CSF-induced aortitis had been reported to occur 1 to 15 days after the administration of G-CSF, and a few cases were reported to develop 1 month to 1 year later (8,14). This variation in the latent period, which could interfere with the clinical diagnosis, might result from pharmacodynamic and pharmacokinetic factors such as the type and amount of G-CSF used, type of the preceding chemotherapy, and individual physiological differences. In fact, pegfilgrastim and lipegfilgrastim, which both have a longer half-life and produce equivalent effects with fewer administrations, have been most often reported as the drug causing aortitis (8-10). It is of interest that this condition has been reported more often in women than in men, although more detailed cases and epidemiological studies are needed to prove that G-CSF-induced aortitis is indeed more common in women.
Searching on web, G-CSF-induced aortitis in a patient being treated for sarcoma was thus found to be extremely rare. One reason why no cases of G-CSF-induced aortitis were previously reported in patients with sarcomas might be due to the low absolute number of such patients. Ogura et al. reported that according to a nationwide organ-specific cancer registry for bone and soft tissue tumors in Japan, the number of patients with sarcomas in 2012 was 1,598, which is an extremely low proportion of the 865,238 cases of all cancers (15,16). We believe that this case report, which concerns an orthopedic cancer, is important because the biological evidence that the administration of G-CSF could provoke aortitis is still lacking.
Although this patient did not exhibit any pulmonary manifestations, the lung interstitial changes found on CT seemed critical and warranted the administration of steroids, since there had been many reports of G-CSF-related pulmonary toxicity, which in some cases progressed to acute respiratory distress syndrome and to death (17-19). In a review of 20 cases of interstitial pneumonia secondary to treatment with G-CSF, Niitsu et al. reported that three patients died of respiratory and multiple organ failure; consequently, they emphasized the importance of starting steroid pulse therapy as early as possible when the diagnosis is made (20).
Although the skin lesions that this patient exhibited were not histologically confirmed, we speculated, from their macroscopic appearance, that they represented neutrophilic eccrine hidradenitis, which is neutrophilic dermatosis characterized by the sudden onset of erythematous papules or plaques with a neutrophilic infiltrate around eccrine glands, together with necrosis of these structures. Rising concentrations of the cytotoxic agents in sweat are thought to be the mechanism of neutrophilic eccrine hidradenitis, and doxorubicin is known to be one of the common causative substances (21). It is of interest that several such cases have been reported to be associated with the administration of G-CSF, and one of them occurred in patients who received pegfilgrastim after AI chemotherapy (22,23).
Without any guidelines available for the treatment of drug-induced aortitis, we set the initial dose of prednisolone as 60 mg, administered it orally, according to the Guideline for Management of Vasculitis Syndrome (Japanese Circulation Society 2008) for the diagnosis of giant cell arteritis (24). However, several cases of G-CSF-induced aortitis that remitted without the administration of prednisolone have been reported. We think that the degree of inflammatory response might vary in individual cases, and so the clinical decision of whether to administer prednisolone must be individualized. In our patient, prednisolone treatment was necessary because of sustained high-grade inflammatory markers and interstitial changes in the lungs.
In summary, we herein described a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. The patient required PSL administration because of the lung injuries and persisting high grade fever. The response to the treatment with PSL was good, and the patient had recovered without any sequelae. It has been almost 30 years since filgrastim was introduced to the market. However, G-CSF induced aortitis has not been well recognized. We speculate that one reason for this might be the lack of algorithm to predict patients at high risk to present this condition. Secondly, there is lack of specific signs and symptoms. In addition, as we described above, the condition sometimes subsides without the administration of steroids or immuno-suppressants which are usually indispensable for the treatment of other types of vasculitis syndrome. Therefore, we speculate that many cases of G-CSF induced may have been overlooked. This case report might be one type of supportive evidence of G-CSF induced aortitis, however, it is necessary to collect and examine future cases regarding what kind of patients: sex, races, age etc., are likely to present with aortitis due to G-CSF.
The authors state that they have no Conflict of Interest (COI).
|
DEXAMETHASONE SODIUM PHOSPHATE, DOXORUBICIN HYDROCHLORIDE, FAMOTIDINE, FUROSEMIDE, GRANISETRON HYDROCHLORIDE, IFOSFAMIDE, MESNA, PEGFILGRASTIM
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33191326
| 17,433,107
|
2021-04-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chemotherapy'.
|
Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.
We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are commonly used to prevent and treat neutropenia caused by cancer chemotherapy. Meta-analyses of randomized controlled trials of G-CSFs as primary prophylaxis against febrile neutropenia have demonstrated significant reductions in the rates of short-term all-cause mortality, as well as rates of infection-related mortality, in patients with solid tumors and malignant lymphoma (1,2). A meta-analysis of 59 randomized controlled trials demonstrated that systemic cancer chemotherapy with primary adjunct G-CSF treatment was associated with a significantly greater intensity of the effect of the delivered chemotherapy doses and with greater relative and absolute risk reductions in all-cause mortality rates than was chemotherapy without adjunct G-CSF treatment over a long period (3). As for drug safety, Teshima et al. reported that according to the results of their post-marketing use survey in Japan, the rate of overall adverse effects was 7.47%; these effects included lumbago (3.84%), fever (1.62%), and bone pain (0.61%), and most were not serious and seemed to be ameliorated by the discontinuation of G-CSF treatment (4).
However, a few cases with serious adverse effects, such as interstitial pneumonia and extramedullary hematopoietic splenic rupture, have been reported after the administration of G-CSF (5,6). Pegfilgrastim, a relatively new G-CSF used to prevent febrile neutropenia, is a modified protein consisting of methoxy polyethylene glycol (PEG) molecular chains attached to a Met1 amino group of genetic recombinant filgrastim whose renal excretion is reduced and whose effects are prolonged (7). In Japan, pegfilgrastim is approved for use only to prevent febrile neutropenia after chemotherapy. To optimize its pharmacological effect and prevent adverse effects, the use of pegfilgrastim is restricted to patients at high risk for febrile neutropenia at least 24 hours after a course of chemotherapy. Over the past two decades, authors have reported cases of aortitis induced by G-CSF preparations such as filgrastim, lenograstim, and pegfilgrastim (8,9). Oshima et al., using the Japanese Adverse Drug Event Report database, reported that G-CSF treatment is associated with an increased risk for aortitis (10).
We herein report a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. This is a rare case of G-CSF induced aortitis occurred in a patient who was being treated for sarcoma and it is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological background.
Case Report
A 56-year-old man who was receiving treatment for the local recurrence of extraosseous mucinous chondrosarcoma on the right lower limb presented to our hospital because of an 8-day history of high fever, general fatigue, and a rash with pain. He did not report either any upper or lower respiratory symptoms, abdominal pain, diarrhea, arthralgias, headache, or visual impairment. He had finished the first 4-day course of chemotherapy with 2-day adriamycin (25 mg/m2 each) and four-day ifosfamide (2.8 g/m2 each), followed 36 hours later by subcutaneous administration of pegylated G-CSF (3.6 mg), and he was discharged immediately. Four days later, the symptoms began.
On presentation, he did not appear ill, and he was alert and oriented. His body weight was 69.4 kg, and his height was 169 cm. His vital signs were as follows: blood pressure, 90/47 mm Hg; pulse rate, 95 beats/min; body temperature, 39.1℃; respiratory rate, 12/min; and oxygen saturation level, 99% on room air. A physical examination revealed palm-sized dark red-to-purplish indurated rashes with tenderness on the right cubital fossa and over the left knee socket (Fig. 1a, b). The surface lymph nodes, liver, and spleen were not palpable. The initial laboratory data revealed the following: a white blood cell count of 15,780/μL (90.0% segmented neutrophils, 7.0% stab neutrophils 1.0% monocytes, 2.0% lymphocytes, and 0% atypical lymphocytes, visually confirmed), hemoglobin level of 11.8 g/dL, platelet count of 109,000/μL, and serum C-reactive protein level of 38.77 mg/dL. Table lists the other laboratory data. The results of antigen tests for influenza virus were negative. Two sets of blood culture were conducted. Computed tomography (CT) without contrast media revealed inflammatory changes in the soft tissue surrounding the aorta, partial reticular change and ground-glass opacities scattered throughout both lungs, and splenomegaly (Fig. 2).
Figure 1. Erythematous skin lesions on the right cubital fossa (a) and over the left knee socket (b), on admission.
Table. Laboratory Data on Admission.
Complete blood count Serological test Urine test
WBC 15,780 ×103/μL CRP 38.77 mg/dL occult blood 2+
N-Stab 7 % IgG 828 mg/dL ketone negative
N-Seg 90 % IgA 327 mg/dL glucose negative
Eosino 0 % IgM 103 mg/dL protein 1+
Baso 0 % IgE 53 mg/dL Urinary sediment
Mono 1 % CH50 >60 CH50/mL RBC <4 /HPF
Lymph 2 % C3 162 mg/dL WBC <4 /HPF
RBC 442 ×104/μL C4 45 mg/dL Squamous cell 0-1 /HPF
Hemoglobin 11.8 g/dL sIL-2R 1,922 U/mL cast positive
Platelet 109 ×104/μL ANA <80 β2 microglobulin 18.7 mg/dL
Biochemistry PR3-ANCA <1.0 U/mL
TP 6.2 g/dL MPO-ANCA <1.0 U/mL
Alb 2.4 g/dL anti ssDNA 2.5 AU/mL
T-bil 0.8 mg/dL anti dsDNA <1.2 IU/mL
D-bil 0.5 mg/dL ASO 38 IU/mL
AST 22 U/L ASK ×320
ALT 99 U/L PCT 0.58 ng/mL
Ch-E 157 U/L IGRA negative
ALP 1,077 U/L RPR <1.0
LAP 149 U/L TPHA 0
γ-GTP 302 U/L HCV Ab 0.03
LD 208 U/L HBs Ag 0 IU/mL
CK 19 U/L CMV IgG 64 UA/mL
UN 33 mg/dL CMV IgM negative
Creatinine 2.29 mg/dL ESR 114 mm/hr
Na 139 mmol/L
K 3.7 mmol/L
Cl 101 mmol/L
Blood Sugar 159 mg/dL
HbA1c 6.4 %
WBC: white blood cell, RBC: red blood cell, AST: asparatate aminotransferase, ALT: alanine aminotransferase, N-stab: stab neutrophil, N-seg: segmented neutrophil, Eosino: eosinophil, Baso: basophil, Mono: monocyte, Lymph; Lymphocyte, TP: total protein, Alb: albumin, T-bil: total bililubin, D-bil: direct bililubin, Ch-E: cholinesterase, ALP: alkaline phosphatase, LAP: leucine aminopeptidase, γ-GTP: γ-glutamyl transpeptidase, LD: lactate dehydrogenase, UN: urea nitrogen, CK: creatine kinase, Na: sodium, K: potassium, Cl: chloride, HbA1c: hemoglobine A1c, CRP: C-reactive protein, IgG: Immunoglobulin G, IgA: Immunoglobulin A, IgM: Immunoglobulin M, IgE: Immunoglobulin E, CH50: 50% hemolytic complement activity, sIL-2 R: soluble Interleukin-2 receptor, ANA: antinuclear antibody, PR3-ANCA: serine proteinase3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-ssDNA: anti-single-stranded DNA antibody, anti-dsDNA: anti-double stranded DNA antibody, ASO: antistreptolysin O, ASK: antistreptokinase, PCT: procalcitonin, IGRA: interferon-gamma releasing assay, RPR: rapid plasma reagin card agglutination test, TPHA: treponema pallidum antibody hemagglutination test, HCV ab: hepatitis C virus antibody, HBs Ag: hepatitis B virus antigen, CMV IgG: cytomegalovirus antibody, immunoglobulin G, CMV IgM: cytomegalovirus antibody, immunoglobulin M, ESR: erythrocyte sedimentation rate
Figure 2. Computed tomography (CT) without contrast media, showing aortitis (a; white arrowheads), patchy interstitial changes scattered throughout both lungs (b; black arrowheads) and a small amount of pleural effusion (b; yellow arrowheads), and splenomegaly (c).
Because he was immunocompromised, we diagnosed systemic inflammatory response syndrome and acute renal failure caused by bacterial infection. We promptly administered 2 L of crystalloid infusion for resuscitation and empirical piperacillin/tazobactam as shown in Fig. 3. His renal function was restored rapidly, but high-grade fever persisted for 4 days, as did the inflammatory markers, despite antibiotic treatment. However, this patient did not appear ill, and his food intake did not decrease during the first 4 days after his admission to this hospital. Furthermore, even with a high-grade fever (>40℃), his pulse rate had stayed in the range of 60/min to 70/min, which represented relative bradycardia, which in turn has been considered a characteristic of drug-related fever (11). A blood culture yielded negative results, as did serological tests (including cytomegalovirus antigen and autoantibodies); thus, we diagnosed aortitis resulting from G-CSF administration.
Figure 3. Clinical course of this case. CRP: C-reactive protein, PIPC/TAZ: piperacillin/tazobactam, PSL: prednisolone, WBC: white blood cell count
Because of concerns about the high-grade fever and the pulmonary findings, we initiated treatment with prednisolone, 60 mg (1 mg/kg) orally on the fourth day of hospitalization. His fever resolved within the day, followed by a rapid improvement in his general condition and laboratory data. The rash had improved simultaneously, although the skin discoloration remained. Six days after initiating prednisolone, we tapered the dosage to 40 mg and discharged the patient on day 18 (Fig. 3). At the 3-month follow-up visit, the patient remained well with the prednisolone dose of 7.5 mg/day, which was discontinued 3 months later.
Discussion
As in other immunocompromised patients after the administration of anticancer drugs, we had to rule out vasculitis secondary to infections before diagnosing the drug-induced aortitis, since infectious disease was strongly associated with systemic vasculitis, including aortitis (12). Hence, it might be important in such patients to evaluate them for common infectious diseases that are often overlooked-not only bacterial bloodstream infections but also tuberculosis, syphilis, viral hepatitis, and human immunodeficiency virus-that are known causes of vasculitis before G-CSF-induced aortitis is diagnosed (13).
In this case, pegfilgrastim was administered 36 hours after the completion of the first cycle of AI (adriamycin, ifosfamide) chemotherapy, and a series of symptoms had begun 4 days later. Most cases of G-CSF-induced aortitis had been reported to occur 1 to 15 days after the administration of G-CSF, and a few cases were reported to develop 1 month to 1 year later (8,14). This variation in the latent period, which could interfere with the clinical diagnosis, might result from pharmacodynamic and pharmacokinetic factors such as the type and amount of G-CSF used, type of the preceding chemotherapy, and individual physiological differences. In fact, pegfilgrastim and lipegfilgrastim, which both have a longer half-life and produce equivalent effects with fewer administrations, have been most often reported as the drug causing aortitis (8-10). It is of interest that this condition has been reported more often in women than in men, although more detailed cases and epidemiological studies are needed to prove that G-CSF-induced aortitis is indeed more common in women.
Searching on web, G-CSF-induced aortitis in a patient being treated for sarcoma was thus found to be extremely rare. One reason why no cases of G-CSF-induced aortitis were previously reported in patients with sarcomas might be due to the low absolute number of such patients. Ogura et al. reported that according to a nationwide organ-specific cancer registry for bone and soft tissue tumors in Japan, the number of patients with sarcomas in 2012 was 1,598, which is an extremely low proportion of the 865,238 cases of all cancers (15,16). We believe that this case report, which concerns an orthopedic cancer, is important because the biological evidence that the administration of G-CSF could provoke aortitis is still lacking.
Although this patient did not exhibit any pulmonary manifestations, the lung interstitial changes found on CT seemed critical and warranted the administration of steroids, since there had been many reports of G-CSF-related pulmonary toxicity, which in some cases progressed to acute respiratory distress syndrome and to death (17-19). In a review of 20 cases of interstitial pneumonia secondary to treatment with G-CSF, Niitsu et al. reported that three patients died of respiratory and multiple organ failure; consequently, they emphasized the importance of starting steroid pulse therapy as early as possible when the diagnosis is made (20).
Although the skin lesions that this patient exhibited were not histologically confirmed, we speculated, from their macroscopic appearance, that they represented neutrophilic eccrine hidradenitis, which is neutrophilic dermatosis characterized by the sudden onset of erythematous papules or plaques with a neutrophilic infiltrate around eccrine glands, together with necrosis of these structures. Rising concentrations of the cytotoxic agents in sweat are thought to be the mechanism of neutrophilic eccrine hidradenitis, and doxorubicin is known to be one of the common causative substances (21). It is of interest that several such cases have been reported to be associated with the administration of G-CSF, and one of them occurred in patients who received pegfilgrastim after AI chemotherapy (22,23).
Without any guidelines available for the treatment of drug-induced aortitis, we set the initial dose of prednisolone as 60 mg, administered it orally, according to the Guideline for Management of Vasculitis Syndrome (Japanese Circulation Society 2008) for the diagnosis of giant cell arteritis (24). However, several cases of G-CSF-induced aortitis that remitted without the administration of prednisolone have been reported. We think that the degree of inflammatory response might vary in individual cases, and so the clinical decision of whether to administer prednisolone must be individualized. In our patient, prednisolone treatment was necessary because of sustained high-grade inflammatory markers and interstitial changes in the lungs.
In summary, we herein described a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. The patient required PSL administration because of the lung injuries and persisting high grade fever. The response to the treatment with PSL was good, and the patient had recovered without any sequelae. It has been almost 30 years since filgrastim was introduced to the market. However, G-CSF induced aortitis has not been well recognized. We speculate that one reason for this might be the lack of algorithm to predict patients at high risk to present this condition. Secondly, there is lack of specific signs and symptoms. In addition, as we described above, the condition sometimes subsides without the administration of steroids or immuno-suppressants which are usually indispensable for the treatment of other types of vasculitis syndrome. Therefore, we speculate that many cases of G-CSF induced may have been overlooked. This case report might be one type of supportive evidence of G-CSF induced aortitis, however, it is necessary to collect and examine future cases regarding what kind of patients: sex, races, age etc., are likely to present with aortitis due to G-CSF.
The authors state that they have no Conflict of Interest (COI).
|
DEXAMETHASONE SODIUM PHOSPHATE, DOXORUBICIN HYDROCHLORIDE, FAMOTIDINE, FUROSEMIDE, GRANISETRON HYDROCHLORIDE, IFOSFAMIDE, MESNA, PEGFILGRASTIM
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33191326
| 17,433,107
|
2021-04-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hidradenitis'.
|
Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.
We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are commonly used to prevent and treat neutropenia caused by cancer chemotherapy. Meta-analyses of randomized controlled trials of G-CSFs as primary prophylaxis against febrile neutropenia have demonstrated significant reductions in the rates of short-term all-cause mortality, as well as rates of infection-related mortality, in patients with solid tumors and malignant lymphoma (1,2). A meta-analysis of 59 randomized controlled trials demonstrated that systemic cancer chemotherapy with primary adjunct G-CSF treatment was associated with a significantly greater intensity of the effect of the delivered chemotherapy doses and with greater relative and absolute risk reductions in all-cause mortality rates than was chemotherapy without adjunct G-CSF treatment over a long period (3). As for drug safety, Teshima et al. reported that according to the results of their post-marketing use survey in Japan, the rate of overall adverse effects was 7.47%; these effects included lumbago (3.84%), fever (1.62%), and bone pain (0.61%), and most were not serious and seemed to be ameliorated by the discontinuation of G-CSF treatment (4).
However, a few cases with serious adverse effects, such as interstitial pneumonia and extramedullary hematopoietic splenic rupture, have been reported after the administration of G-CSF (5,6). Pegfilgrastim, a relatively new G-CSF used to prevent febrile neutropenia, is a modified protein consisting of methoxy polyethylene glycol (PEG) molecular chains attached to a Met1 amino group of genetic recombinant filgrastim whose renal excretion is reduced and whose effects are prolonged (7). In Japan, pegfilgrastim is approved for use only to prevent febrile neutropenia after chemotherapy. To optimize its pharmacological effect and prevent adverse effects, the use of pegfilgrastim is restricted to patients at high risk for febrile neutropenia at least 24 hours after a course of chemotherapy. Over the past two decades, authors have reported cases of aortitis induced by G-CSF preparations such as filgrastim, lenograstim, and pegfilgrastim (8,9). Oshima et al., using the Japanese Adverse Drug Event Report database, reported that G-CSF treatment is associated with an increased risk for aortitis (10).
We herein report a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. This is a rare case of G-CSF induced aortitis occurred in a patient who was being treated for sarcoma and it is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological background.
Case Report
A 56-year-old man who was receiving treatment for the local recurrence of extraosseous mucinous chondrosarcoma on the right lower limb presented to our hospital because of an 8-day history of high fever, general fatigue, and a rash with pain. He did not report either any upper or lower respiratory symptoms, abdominal pain, diarrhea, arthralgias, headache, or visual impairment. He had finished the first 4-day course of chemotherapy with 2-day adriamycin (25 mg/m2 each) and four-day ifosfamide (2.8 g/m2 each), followed 36 hours later by subcutaneous administration of pegylated G-CSF (3.6 mg), and he was discharged immediately. Four days later, the symptoms began.
On presentation, he did not appear ill, and he was alert and oriented. His body weight was 69.4 kg, and his height was 169 cm. His vital signs were as follows: blood pressure, 90/47 mm Hg; pulse rate, 95 beats/min; body temperature, 39.1℃; respiratory rate, 12/min; and oxygen saturation level, 99% on room air. A physical examination revealed palm-sized dark red-to-purplish indurated rashes with tenderness on the right cubital fossa and over the left knee socket (Fig. 1a, b). The surface lymph nodes, liver, and spleen were not palpable. The initial laboratory data revealed the following: a white blood cell count of 15,780/μL (90.0% segmented neutrophils, 7.0% stab neutrophils 1.0% monocytes, 2.0% lymphocytes, and 0% atypical lymphocytes, visually confirmed), hemoglobin level of 11.8 g/dL, platelet count of 109,000/μL, and serum C-reactive protein level of 38.77 mg/dL. Table lists the other laboratory data. The results of antigen tests for influenza virus were negative. Two sets of blood culture were conducted. Computed tomography (CT) without contrast media revealed inflammatory changes in the soft tissue surrounding the aorta, partial reticular change and ground-glass opacities scattered throughout both lungs, and splenomegaly (Fig. 2).
Figure 1. Erythematous skin lesions on the right cubital fossa (a) and over the left knee socket (b), on admission.
Table. Laboratory Data on Admission.
Complete blood count Serological test Urine test
WBC 15,780 ×103/μL CRP 38.77 mg/dL occult blood 2+
N-Stab 7 % IgG 828 mg/dL ketone negative
N-Seg 90 % IgA 327 mg/dL glucose negative
Eosino 0 % IgM 103 mg/dL protein 1+
Baso 0 % IgE 53 mg/dL Urinary sediment
Mono 1 % CH50 >60 CH50/mL RBC <4 /HPF
Lymph 2 % C3 162 mg/dL WBC <4 /HPF
RBC 442 ×104/μL C4 45 mg/dL Squamous cell 0-1 /HPF
Hemoglobin 11.8 g/dL sIL-2R 1,922 U/mL cast positive
Platelet 109 ×104/μL ANA <80 β2 microglobulin 18.7 mg/dL
Biochemistry PR3-ANCA <1.0 U/mL
TP 6.2 g/dL MPO-ANCA <1.0 U/mL
Alb 2.4 g/dL anti ssDNA 2.5 AU/mL
T-bil 0.8 mg/dL anti dsDNA <1.2 IU/mL
D-bil 0.5 mg/dL ASO 38 IU/mL
AST 22 U/L ASK ×320
ALT 99 U/L PCT 0.58 ng/mL
Ch-E 157 U/L IGRA negative
ALP 1,077 U/L RPR <1.0
LAP 149 U/L TPHA 0
γ-GTP 302 U/L HCV Ab 0.03
LD 208 U/L HBs Ag 0 IU/mL
CK 19 U/L CMV IgG 64 UA/mL
UN 33 mg/dL CMV IgM negative
Creatinine 2.29 mg/dL ESR 114 mm/hr
Na 139 mmol/L
K 3.7 mmol/L
Cl 101 mmol/L
Blood Sugar 159 mg/dL
HbA1c 6.4 %
WBC: white blood cell, RBC: red blood cell, AST: asparatate aminotransferase, ALT: alanine aminotransferase, N-stab: stab neutrophil, N-seg: segmented neutrophil, Eosino: eosinophil, Baso: basophil, Mono: monocyte, Lymph; Lymphocyte, TP: total protein, Alb: albumin, T-bil: total bililubin, D-bil: direct bililubin, Ch-E: cholinesterase, ALP: alkaline phosphatase, LAP: leucine aminopeptidase, γ-GTP: γ-glutamyl transpeptidase, LD: lactate dehydrogenase, UN: urea nitrogen, CK: creatine kinase, Na: sodium, K: potassium, Cl: chloride, HbA1c: hemoglobine A1c, CRP: C-reactive protein, IgG: Immunoglobulin G, IgA: Immunoglobulin A, IgM: Immunoglobulin M, IgE: Immunoglobulin E, CH50: 50% hemolytic complement activity, sIL-2 R: soluble Interleukin-2 receptor, ANA: antinuclear antibody, PR3-ANCA: serine proteinase3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-ssDNA: anti-single-stranded DNA antibody, anti-dsDNA: anti-double stranded DNA antibody, ASO: antistreptolysin O, ASK: antistreptokinase, PCT: procalcitonin, IGRA: interferon-gamma releasing assay, RPR: rapid plasma reagin card agglutination test, TPHA: treponema pallidum antibody hemagglutination test, HCV ab: hepatitis C virus antibody, HBs Ag: hepatitis B virus antigen, CMV IgG: cytomegalovirus antibody, immunoglobulin G, CMV IgM: cytomegalovirus antibody, immunoglobulin M, ESR: erythrocyte sedimentation rate
Figure 2. Computed tomography (CT) without contrast media, showing aortitis (a; white arrowheads), patchy interstitial changes scattered throughout both lungs (b; black arrowheads) and a small amount of pleural effusion (b; yellow arrowheads), and splenomegaly (c).
Because he was immunocompromised, we diagnosed systemic inflammatory response syndrome and acute renal failure caused by bacterial infection. We promptly administered 2 L of crystalloid infusion for resuscitation and empirical piperacillin/tazobactam as shown in Fig. 3. His renal function was restored rapidly, but high-grade fever persisted for 4 days, as did the inflammatory markers, despite antibiotic treatment. However, this patient did not appear ill, and his food intake did not decrease during the first 4 days after his admission to this hospital. Furthermore, even with a high-grade fever (>40℃), his pulse rate had stayed in the range of 60/min to 70/min, which represented relative bradycardia, which in turn has been considered a characteristic of drug-related fever (11). A blood culture yielded negative results, as did serological tests (including cytomegalovirus antigen and autoantibodies); thus, we diagnosed aortitis resulting from G-CSF administration.
Figure 3. Clinical course of this case. CRP: C-reactive protein, PIPC/TAZ: piperacillin/tazobactam, PSL: prednisolone, WBC: white blood cell count
Because of concerns about the high-grade fever and the pulmonary findings, we initiated treatment with prednisolone, 60 mg (1 mg/kg) orally on the fourth day of hospitalization. His fever resolved within the day, followed by a rapid improvement in his general condition and laboratory data. The rash had improved simultaneously, although the skin discoloration remained. Six days after initiating prednisolone, we tapered the dosage to 40 mg and discharged the patient on day 18 (Fig. 3). At the 3-month follow-up visit, the patient remained well with the prednisolone dose of 7.5 mg/day, which was discontinued 3 months later.
Discussion
As in other immunocompromised patients after the administration of anticancer drugs, we had to rule out vasculitis secondary to infections before diagnosing the drug-induced aortitis, since infectious disease was strongly associated with systemic vasculitis, including aortitis (12). Hence, it might be important in such patients to evaluate them for common infectious diseases that are often overlooked-not only bacterial bloodstream infections but also tuberculosis, syphilis, viral hepatitis, and human immunodeficiency virus-that are known causes of vasculitis before G-CSF-induced aortitis is diagnosed (13).
In this case, pegfilgrastim was administered 36 hours after the completion of the first cycle of AI (adriamycin, ifosfamide) chemotherapy, and a series of symptoms had begun 4 days later. Most cases of G-CSF-induced aortitis had been reported to occur 1 to 15 days after the administration of G-CSF, and a few cases were reported to develop 1 month to 1 year later (8,14). This variation in the latent period, which could interfere with the clinical diagnosis, might result from pharmacodynamic and pharmacokinetic factors such as the type and amount of G-CSF used, type of the preceding chemotherapy, and individual physiological differences. In fact, pegfilgrastim and lipegfilgrastim, which both have a longer half-life and produce equivalent effects with fewer administrations, have been most often reported as the drug causing aortitis (8-10). It is of interest that this condition has been reported more often in women than in men, although more detailed cases and epidemiological studies are needed to prove that G-CSF-induced aortitis is indeed more common in women.
Searching on web, G-CSF-induced aortitis in a patient being treated for sarcoma was thus found to be extremely rare. One reason why no cases of G-CSF-induced aortitis were previously reported in patients with sarcomas might be due to the low absolute number of such patients. Ogura et al. reported that according to a nationwide organ-specific cancer registry for bone and soft tissue tumors in Japan, the number of patients with sarcomas in 2012 was 1,598, which is an extremely low proportion of the 865,238 cases of all cancers (15,16). We believe that this case report, which concerns an orthopedic cancer, is important because the biological evidence that the administration of G-CSF could provoke aortitis is still lacking.
Although this patient did not exhibit any pulmonary manifestations, the lung interstitial changes found on CT seemed critical and warranted the administration of steroids, since there had been many reports of G-CSF-related pulmonary toxicity, which in some cases progressed to acute respiratory distress syndrome and to death (17-19). In a review of 20 cases of interstitial pneumonia secondary to treatment with G-CSF, Niitsu et al. reported that three patients died of respiratory and multiple organ failure; consequently, they emphasized the importance of starting steroid pulse therapy as early as possible when the diagnosis is made (20).
Although the skin lesions that this patient exhibited were not histologically confirmed, we speculated, from their macroscopic appearance, that they represented neutrophilic eccrine hidradenitis, which is neutrophilic dermatosis characterized by the sudden onset of erythematous papules or plaques with a neutrophilic infiltrate around eccrine glands, together with necrosis of these structures. Rising concentrations of the cytotoxic agents in sweat are thought to be the mechanism of neutrophilic eccrine hidradenitis, and doxorubicin is known to be one of the common causative substances (21). It is of interest that several such cases have been reported to be associated with the administration of G-CSF, and one of them occurred in patients who received pegfilgrastim after AI chemotherapy (22,23).
Without any guidelines available for the treatment of drug-induced aortitis, we set the initial dose of prednisolone as 60 mg, administered it orally, according to the Guideline for Management of Vasculitis Syndrome (Japanese Circulation Society 2008) for the diagnosis of giant cell arteritis (24). However, several cases of G-CSF-induced aortitis that remitted without the administration of prednisolone have been reported. We think that the degree of inflammatory response might vary in individual cases, and so the clinical decision of whether to administer prednisolone must be individualized. In our patient, prednisolone treatment was necessary because of sustained high-grade inflammatory markers and interstitial changes in the lungs.
In summary, we herein described a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. The patient required PSL administration because of the lung injuries and persisting high grade fever. The response to the treatment with PSL was good, and the patient had recovered without any sequelae. It has been almost 30 years since filgrastim was introduced to the market. However, G-CSF induced aortitis has not been well recognized. We speculate that one reason for this might be the lack of algorithm to predict patients at high risk to present this condition. Secondly, there is lack of specific signs and symptoms. In addition, as we described above, the condition sometimes subsides without the administration of steroids or immuno-suppressants which are usually indispensable for the treatment of other types of vasculitis syndrome. Therefore, we speculate that many cases of G-CSF induced may have been overlooked. This case report might be one type of supportive evidence of G-CSF induced aortitis, however, it is necessary to collect and examine future cases regarding what kind of patients: sex, races, age etc., are likely to present with aortitis due to G-CSF.
The authors state that they have no Conflict of Interest (COI).
|
DOXORUBICIN HYDROCHLORIDE, IFOSFAMIDE, PEGFILGRASTIM
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33191326
| 18,682,768
|
2021-04-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'.
|
Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.
We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are commonly used to prevent and treat neutropenia caused by cancer chemotherapy. Meta-analyses of randomized controlled trials of G-CSFs as primary prophylaxis against febrile neutropenia have demonstrated significant reductions in the rates of short-term all-cause mortality, as well as rates of infection-related mortality, in patients with solid tumors and malignant lymphoma (1,2). A meta-analysis of 59 randomized controlled trials demonstrated that systemic cancer chemotherapy with primary adjunct G-CSF treatment was associated with a significantly greater intensity of the effect of the delivered chemotherapy doses and with greater relative and absolute risk reductions in all-cause mortality rates than was chemotherapy without adjunct G-CSF treatment over a long period (3). As for drug safety, Teshima et al. reported that according to the results of their post-marketing use survey in Japan, the rate of overall adverse effects was 7.47%; these effects included lumbago (3.84%), fever (1.62%), and bone pain (0.61%), and most were not serious and seemed to be ameliorated by the discontinuation of G-CSF treatment (4).
However, a few cases with serious adverse effects, such as interstitial pneumonia and extramedullary hematopoietic splenic rupture, have been reported after the administration of G-CSF (5,6). Pegfilgrastim, a relatively new G-CSF used to prevent febrile neutropenia, is a modified protein consisting of methoxy polyethylene glycol (PEG) molecular chains attached to a Met1 amino group of genetic recombinant filgrastim whose renal excretion is reduced and whose effects are prolonged (7). In Japan, pegfilgrastim is approved for use only to prevent febrile neutropenia after chemotherapy. To optimize its pharmacological effect and prevent adverse effects, the use of pegfilgrastim is restricted to patients at high risk for febrile neutropenia at least 24 hours after a course of chemotherapy. Over the past two decades, authors have reported cases of aortitis induced by G-CSF preparations such as filgrastim, lenograstim, and pegfilgrastim (8,9). Oshima et al., using the Japanese Adverse Drug Event Report database, reported that G-CSF treatment is associated with an increased risk for aortitis (10).
We herein report a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. This is a rare case of G-CSF induced aortitis occurred in a patient who was being treated for sarcoma and it is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological background.
Case Report
A 56-year-old man who was receiving treatment for the local recurrence of extraosseous mucinous chondrosarcoma on the right lower limb presented to our hospital because of an 8-day history of high fever, general fatigue, and a rash with pain. He did not report either any upper or lower respiratory symptoms, abdominal pain, diarrhea, arthralgias, headache, or visual impairment. He had finished the first 4-day course of chemotherapy with 2-day adriamycin (25 mg/m2 each) and four-day ifosfamide (2.8 g/m2 each), followed 36 hours later by subcutaneous administration of pegylated G-CSF (3.6 mg), and he was discharged immediately. Four days later, the symptoms began.
On presentation, he did not appear ill, and he was alert and oriented. His body weight was 69.4 kg, and his height was 169 cm. His vital signs were as follows: blood pressure, 90/47 mm Hg; pulse rate, 95 beats/min; body temperature, 39.1℃; respiratory rate, 12/min; and oxygen saturation level, 99% on room air. A physical examination revealed palm-sized dark red-to-purplish indurated rashes with tenderness on the right cubital fossa and over the left knee socket (Fig. 1a, b). The surface lymph nodes, liver, and spleen were not palpable. The initial laboratory data revealed the following: a white blood cell count of 15,780/μL (90.0% segmented neutrophils, 7.0% stab neutrophils 1.0% monocytes, 2.0% lymphocytes, and 0% atypical lymphocytes, visually confirmed), hemoglobin level of 11.8 g/dL, platelet count of 109,000/μL, and serum C-reactive protein level of 38.77 mg/dL. Table lists the other laboratory data. The results of antigen tests for influenza virus were negative. Two sets of blood culture were conducted. Computed tomography (CT) without contrast media revealed inflammatory changes in the soft tissue surrounding the aorta, partial reticular change and ground-glass opacities scattered throughout both lungs, and splenomegaly (Fig. 2).
Figure 1. Erythematous skin lesions on the right cubital fossa (a) and over the left knee socket (b), on admission.
Table. Laboratory Data on Admission.
Complete blood count Serological test Urine test
WBC 15,780 ×103/μL CRP 38.77 mg/dL occult blood 2+
N-Stab 7 % IgG 828 mg/dL ketone negative
N-Seg 90 % IgA 327 mg/dL glucose negative
Eosino 0 % IgM 103 mg/dL protein 1+
Baso 0 % IgE 53 mg/dL Urinary sediment
Mono 1 % CH50 >60 CH50/mL RBC <4 /HPF
Lymph 2 % C3 162 mg/dL WBC <4 /HPF
RBC 442 ×104/μL C4 45 mg/dL Squamous cell 0-1 /HPF
Hemoglobin 11.8 g/dL sIL-2R 1,922 U/mL cast positive
Platelet 109 ×104/μL ANA <80 β2 microglobulin 18.7 mg/dL
Biochemistry PR3-ANCA <1.0 U/mL
TP 6.2 g/dL MPO-ANCA <1.0 U/mL
Alb 2.4 g/dL anti ssDNA 2.5 AU/mL
T-bil 0.8 mg/dL anti dsDNA <1.2 IU/mL
D-bil 0.5 mg/dL ASO 38 IU/mL
AST 22 U/L ASK ×320
ALT 99 U/L PCT 0.58 ng/mL
Ch-E 157 U/L IGRA negative
ALP 1,077 U/L RPR <1.0
LAP 149 U/L TPHA 0
γ-GTP 302 U/L HCV Ab 0.03
LD 208 U/L HBs Ag 0 IU/mL
CK 19 U/L CMV IgG 64 UA/mL
UN 33 mg/dL CMV IgM negative
Creatinine 2.29 mg/dL ESR 114 mm/hr
Na 139 mmol/L
K 3.7 mmol/L
Cl 101 mmol/L
Blood Sugar 159 mg/dL
HbA1c 6.4 %
WBC: white blood cell, RBC: red blood cell, AST: asparatate aminotransferase, ALT: alanine aminotransferase, N-stab: stab neutrophil, N-seg: segmented neutrophil, Eosino: eosinophil, Baso: basophil, Mono: monocyte, Lymph; Lymphocyte, TP: total protein, Alb: albumin, T-bil: total bililubin, D-bil: direct bililubin, Ch-E: cholinesterase, ALP: alkaline phosphatase, LAP: leucine aminopeptidase, γ-GTP: γ-glutamyl transpeptidase, LD: lactate dehydrogenase, UN: urea nitrogen, CK: creatine kinase, Na: sodium, K: potassium, Cl: chloride, HbA1c: hemoglobine A1c, CRP: C-reactive protein, IgG: Immunoglobulin G, IgA: Immunoglobulin A, IgM: Immunoglobulin M, IgE: Immunoglobulin E, CH50: 50% hemolytic complement activity, sIL-2 R: soluble Interleukin-2 receptor, ANA: antinuclear antibody, PR3-ANCA: serine proteinase3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-ssDNA: anti-single-stranded DNA antibody, anti-dsDNA: anti-double stranded DNA antibody, ASO: antistreptolysin O, ASK: antistreptokinase, PCT: procalcitonin, IGRA: interferon-gamma releasing assay, RPR: rapid plasma reagin card agglutination test, TPHA: treponema pallidum antibody hemagglutination test, HCV ab: hepatitis C virus antibody, HBs Ag: hepatitis B virus antigen, CMV IgG: cytomegalovirus antibody, immunoglobulin G, CMV IgM: cytomegalovirus antibody, immunoglobulin M, ESR: erythrocyte sedimentation rate
Figure 2. Computed tomography (CT) without contrast media, showing aortitis (a; white arrowheads), patchy interstitial changes scattered throughout both lungs (b; black arrowheads) and a small amount of pleural effusion (b; yellow arrowheads), and splenomegaly (c).
Because he was immunocompromised, we diagnosed systemic inflammatory response syndrome and acute renal failure caused by bacterial infection. We promptly administered 2 L of crystalloid infusion for resuscitation and empirical piperacillin/tazobactam as shown in Fig. 3. His renal function was restored rapidly, but high-grade fever persisted for 4 days, as did the inflammatory markers, despite antibiotic treatment. However, this patient did not appear ill, and his food intake did not decrease during the first 4 days after his admission to this hospital. Furthermore, even with a high-grade fever (>40℃), his pulse rate had stayed in the range of 60/min to 70/min, which represented relative bradycardia, which in turn has been considered a characteristic of drug-related fever (11). A blood culture yielded negative results, as did serological tests (including cytomegalovirus antigen and autoantibodies); thus, we diagnosed aortitis resulting from G-CSF administration.
Figure 3. Clinical course of this case. CRP: C-reactive protein, PIPC/TAZ: piperacillin/tazobactam, PSL: prednisolone, WBC: white blood cell count
Because of concerns about the high-grade fever and the pulmonary findings, we initiated treatment with prednisolone, 60 mg (1 mg/kg) orally on the fourth day of hospitalization. His fever resolved within the day, followed by a rapid improvement in his general condition and laboratory data. The rash had improved simultaneously, although the skin discoloration remained. Six days after initiating prednisolone, we tapered the dosage to 40 mg and discharged the patient on day 18 (Fig. 3). At the 3-month follow-up visit, the patient remained well with the prednisolone dose of 7.5 mg/day, which was discontinued 3 months later.
Discussion
As in other immunocompromised patients after the administration of anticancer drugs, we had to rule out vasculitis secondary to infections before diagnosing the drug-induced aortitis, since infectious disease was strongly associated with systemic vasculitis, including aortitis (12). Hence, it might be important in such patients to evaluate them for common infectious diseases that are often overlooked-not only bacterial bloodstream infections but also tuberculosis, syphilis, viral hepatitis, and human immunodeficiency virus-that are known causes of vasculitis before G-CSF-induced aortitis is diagnosed (13).
In this case, pegfilgrastim was administered 36 hours after the completion of the first cycle of AI (adriamycin, ifosfamide) chemotherapy, and a series of symptoms had begun 4 days later. Most cases of G-CSF-induced aortitis had been reported to occur 1 to 15 days after the administration of G-CSF, and a few cases were reported to develop 1 month to 1 year later (8,14). This variation in the latent period, which could interfere with the clinical diagnosis, might result from pharmacodynamic and pharmacokinetic factors such as the type and amount of G-CSF used, type of the preceding chemotherapy, and individual physiological differences. In fact, pegfilgrastim and lipegfilgrastim, which both have a longer half-life and produce equivalent effects with fewer administrations, have been most often reported as the drug causing aortitis (8-10). It is of interest that this condition has been reported more often in women than in men, although more detailed cases and epidemiological studies are needed to prove that G-CSF-induced aortitis is indeed more common in women.
Searching on web, G-CSF-induced aortitis in a patient being treated for sarcoma was thus found to be extremely rare. One reason why no cases of G-CSF-induced aortitis were previously reported in patients with sarcomas might be due to the low absolute number of such patients. Ogura et al. reported that according to a nationwide organ-specific cancer registry for bone and soft tissue tumors in Japan, the number of patients with sarcomas in 2012 was 1,598, which is an extremely low proportion of the 865,238 cases of all cancers (15,16). We believe that this case report, which concerns an orthopedic cancer, is important because the biological evidence that the administration of G-CSF could provoke aortitis is still lacking.
Although this patient did not exhibit any pulmonary manifestations, the lung interstitial changes found on CT seemed critical and warranted the administration of steroids, since there had been many reports of G-CSF-related pulmonary toxicity, which in some cases progressed to acute respiratory distress syndrome and to death (17-19). In a review of 20 cases of interstitial pneumonia secondary to treatment with G-CSF, Niitsu et al. reported that three patients died of respiratory and multiple organ failure; consequently, they emphasized the importance of starting steroid pulse therapy as early as possible when the diagnosis is made (20).
Although the skin lesions that this patient exhibited were not histologically confirmed, we speculated, from their macroscopic appearance, that they represented neutrophilic eccrine hidradenitis, which is neutrophilic dermatosis characterized by the sudden onset of erythematous papules or plaques with a neutrophilic infiltrate around eccrine glands, together with necrosis of these structures. Rising concentrations of the cytotoxic agents in sweat are thought to be the mechanism of neutrophilic eccrine hidradenitis, and doxorubicin is known to be one of the common causative substances (21). It is of interest that several such cases have been reported to be associated with the administration of G-CSF, and one of them occurred in patients who received pegfilgrastim after AI chemotherapy (22,23).
Without any guidelines available for the treatment of drug-induced aortitis, we set the initial dose of prednisolone as 60 mg, administered it orally, according to the Guideline for Management of Vasculitis Syndrome (Japanese Circulation Society 2008) for the diagnosis of giant cell arteritis (24). However, several cases of G-CSF-induced aortitis that remitted without the administration of prednisolone have been reported. We think that the degree of inflammatory response might vary in individual cases, and so the clinical decision of whether to administer prednisolone must be individualized. In our patient, prednisolone treatment was necessary because of sustained high-grade inflammatory markers and interstitial changes in the lungs.
In summary, we herein described a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. The patient required PSL administration because of the lung injuries and persisting high grade fever. The response to the treatment with PSL was good, and the patient had recovered without any sequelae. It has been almost 30 years since filgrastim was introduced to the market. However, G-CSF induced aortitis has not been well recognized. We speculate that one reason for this might be the lack of algorithm to predict patients at high risk to present this condition. Secondly, there is lack of specific signs and symptoms. In addition, as we described above, the condition sometimes subsides without the administration of steroids or immuno-suppressants which are usually indispensable for the treatment of other types of vasculitis syndrome. Therefore, we speculate that many cases of G-CSF induced may have been overlooked. This case report might be one type of supportive evidence of G-CSF induced aortitis, however, it is necessary to collect and examine future cases regarding what kind of patients: sex, races, age etc., are likely to present with aortitis due to G-CSF.
The authors state that they have no Conflict of Interest (COI).
|
DEXAMETHASONE SODIUM PHOSPHATE, DOXORUBICIN HYDROCHLORIDE, FAMOTIDINE, FUROSEMIDE, GRANISETRON HYDROCHLORIDE, IFOSFAMIDE, MESNA, PEGFILGRASTIM
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33191326
| 17,433,107
|
2021-04-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash'.
|
Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.
We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are commonly used to prevent and treat neutropenia caused by cancer chemotherapy. Meta-analyses of randomized controlled trials of G-CSFs as primary prophylaxis against febrile neutropenia have demonstrated significant reductions in the rates of short-term all-cause mortality, as well as rates of infection-related mortality, in patients with solid tumors and malignant lymphoma (1,2). A meta-analysis of 59 randomized controlled trials demonstrated that systemic cancer chemotherapy with primary adjunct G-CSF treatment was associated with a significantly greater intensity of the effect of the delivered chemotherapy doses and with greater relative and absolute risk reductions in all-cause mortality rates than was chemotherapy without adjunct G-CSF treatment over a long period (3). As for drug safety, Teshima et al. reported that according to the results of their post-marketing use survey in Japan, the rate of overall adverse effects was 7.47%; these effects included lumbago (3.84%), fever (1.62%), and bone pain (0.61%), and most were not serious and seemed to be ameliorated by the discontinuation of G-CSF treatment (4).
However, a few cases with serious adverse effects, such as interstitial pneumonia and extramedullary hematopoietic splenic rupture, have been reported after the administration of G-CSF (5,6). Pegfilgrastim, a relatively new G-CSF used to prevent febrile neutropenia, is a modified protein consisting of methoxy polyethylene glycol (PEG) molecular chains attached to a Met1 amino group of genetic recombinant filgrastim whose renal excretion is reduced and whose effects are prolonged (7). In Japan, pegfilgrastim is approved for use only to prevent febrile neutropenia after chemotherapy. To optimize its pharmacological effect and prevent adverse effects, the use of pegfilgrastim is restricted to patients at high risk for febrile neutropenia at least 24 hours after a course of chemotherapy. Over the past two decades, authors have reported cases of aortitis induced by G-CSF preparations such as filgrastim, lenograstim, and pegfilgrastim (8,9). Oshima et al., using the Japanese Adverse Drug Event Report database, reported that G-CSF treatment is associated with an increased risk for aortitis (10).
We herein report a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. This is a rare case of G-CSF induced aortitis occurred in a patient who was being treated for sarcoma and it is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological background.
Case Report
A 56-year-old man who was receiving treatment for the local recurrence of extraosseous mucinous chondrosarcoma on the right lower limb presented to our hospital because of an 8-day history of high fever, general fatigue, and a rash with pain. He did not report either any upper or lower respiratory symptoms, abdominal pain, diarrhea, arthralgias, headache, or visual impairment. He had finished the first 4-day course of chemotherapy with 2-day adriamycin (25 mg/m2 each) and four-day ifosfamide (2.8 g/m2 each), followed 36 hours later by subcutaneous administration of pegylated G-CSF (3.6 mg), and he was discharged immediately. Four days later, the symptoms began.
On presentation, he did not appear ill, and he was alert and oriented. His body weight was 69.4 kg, and his height was 169 cm. His vital signs were as follows: blood pressure, 90/47 mm Hg; pulse rate, 95 beats/min; body temperature, 39.1℃; respiratory rate, 12/min; and oxygen saturation level, 99% on room air. A physical examination revealed palm-sized dark red-to-purplish indurated rashes with tenderness on the right cubital fossa and over the left knee socket (Fig. 1a, b). The surface lymph nodes, liver, and spleen were not palpable. The initial laboratory data revealed the following: a white blood cell count of 15,780/μL (90.0% segmented neutrophils, 7.0% stab neutrophils 1.0% monocytes, 2.0% lymphocytes, and 0% atypical lymphocytes, visually confirmed), hemoglobin level of 11.8 g/dL, platelet count of 109,000/μL, and serum C-reactive protein level of 38.77 mg/dL. Table lists the other laboratory data. The results of antigen tests for influenza virus were negative. Two sets of blood culture were conducted. Computed tomography (CT) without contrast media revealed inflammatory changes in the soft tissue surrounding the aorta, partial reticular change and ground-glass opacities scattered throughout both lungs, and splenomegaly (Fig. 2).
Figure 1. Erythematous skin lesions on the right cubital fossa (a) and over the left knee socket (b), on admission.
Table. Laboratory Data on Admission.
Complete blood count Serological test Urine test
WBC 15,780 ×103/μL CRP 38.77 mg/dL occult blood 2+
N-Stab 7 % IgG 828 mg/dL ketone negative
N-Seg 90 % IgA 327 mg/dL glucose negative
Eosino 0 % IgM 103 mg/dL protein 1+
Baso 0 % IgE 53 mg/dL Urinary sediment
Mono 1 % CH50 >60 CH50/mL RBC <4 /HPF
Lymph 2 % C3 162 mg/dL WBC <4 /HPF
RBC 442 ×104/μL C4 45 mg/dL Squamous cell 0-1 /HPF
Hemoglobin 11.8 g/dL sIL-2R 1,922 U/mL cast positive
Platelet 109 ×104/μL ANA <80 β2 microglobulin 18.7 mg/dL
Biochemistry PR3-ANCA <1.0 U/mL
TP 6.2 g/dL MPO-ANCA <1.0 U/mL
Alb 2.4 g/dL anti ssDNA 2.5 AU/mL
T-bil 0.8 mg/dL anti dsDNA <1.2 IU/mL
D-bil 0.5 mg/dL ASO 38 IU/mL
AST 22 U/L ASK ×320
ALT 99 U/L PCT 0.58 ng/mL
Ch-E 157 U/L IGRA negative
ALP 1,077 U/L RPR <1.0
LAP 149 U/L TPHA 0
γ-GTP 302 U/L HCV Ab 0.03
LD 208 U/L HBs Ag 0 IU/mL
CK 19 U/L CMV IgG 64 UA/mL
UN 33 mg/dL CMV IgM negative
Creatinine 2.29 mg/dL ESR 114 mm/hr
Na 139 mmol/L
K 3.7 mmol/L
Cl 101 mmol/L
Blood Sugar 159 mg/dL
HbA1c 6.4 %
WBC: white blood cell, RBC: red blood cell, AST: asparatate aminotransferase, ALT: alanine aminotransferase, N-stab: stab neutrophil, N-seg: segmented neutrophil, Eosino: eosinophil, Baso: basophil, Mono: monocyte, Lymph; Lymphocyte, TP: total protein, Alb: albumin, T-bil: total bililubin, D-bil: direct bililubin, Ch-E: cholinesterase, ALP: alkaline phosphatase, LAP: leucine aminopeptidase, γ-GTP: γ-glutamyl transpeptidase, LD: lactate dehydrogenase, UN: urea nitrogen, CK: creatine kinase, Na: sodium, K: potassium, Cl: chloride, HbA1c: hemoglobine A1c, CRP: C-reactive protein, IgG: Immunoglobulin G, IgA: Immunoglobulin A, IgM: Immunoglobulin M, IgE: Immunoglobulin E, CH50: 50% hemolytic complement activity, sIL-2 R: soluble Interleukin-2 receptor, ANA: antinuclear antibody, PR3-ANCA: serine proteinase3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-ssDNA: anti-single-stranded DNA antibody, anti-dsDNA: anti-double stranded DNA antibody, ASO: antistreptolysin O, ASK: antistreptokinase, PCT: procalcitonin, IGRA: interferon-gamma releasing assay, RPR: rapid plasma reagin card agglutination test, TPHA: treponema pallidum antibody hemagglutination test, HCV ab: hepatitis C virus antibody, HBs Ag: hepatitis B virus antigen, CMV IgG: cytomegalovirus antibody, immunoglobulin G, CMV IgM: cytomegalovirus antibody, immunoglobulin M, ESR: erythrocyte sedimentation rate
Figure 2. Computed tomography (CT) without contrast media, showing aortitis (a; white arrowheads), patchy interstitial changes scattered throughout both lungs (b; black arrowheads) and a small amount of pleural effusion (b; yellow arrowheads), and splenomegaly (c).
Because he was immunocompromised, we diagnosed systemic inflammatory response syndrome and acute renal failure caused by bacterial infection. We promptly administered 2 L of crystalloid infusion for resuscitation and empirical piperacillin/tazobactam as shown in Fig. 3. His renal function was restored rapidly, but high-grade fever persisted for 4 days, as did the inflammatory markers, despite antibiotic treatment. However, this patient did not appear ill, and his food intake did not decrease during the first 4 days after his admission to this hospital. Furthermore, even with a high-grade fever (>40℃), his pulse rate had stayed in the range of 60/min to 70/min, which represented relative bradycardia, which in turn has been considered a characteristic of drug-related fever (11). A blood culture yielded negative results, as did serological tests (including cytomegalovirus antigen and autoantibodies); thus, we diagnosed aortitis resulting from G-CSF administration.
Figure 3. Clinical course of this case. CRP: C-reactive protein, PIPC/TAZ: piperacillin/tazobactam, PSL: prednisolone, WBC: white blood cell count
Because of concerns about the high-grade fever and the pulmonary findings, we initiated treatment with prednisolone, 60 mg (1 mg/kg) orally on the fourth day of hospitalization. His fever resolved within the day, followed by a rapid improvement in his general condition and laboratory data. The rash had improved simultaneously, although the skin discoloration remained. Six days after initiating prednisolone, we tapered the dosage to 40 mg and discharged the patient on day 18 (Fig. 3). At the 3-month follow-up visit, the patient remained well with the prednisolone dose of 7.5 mg/day, which was discontinued 3 months later.
Discussion
As in other immunocompromised patients after the administration of anticancer drugs, we had to rule out vasculitis secondary to infections before diagnosing the drug-induced aortitis, since infectious disease was strongly associated with systemic vasculitis, including aortitis (12). Hence, it might be important in such patients to evaluate them for common infectious diseases that are often overlooked-not only bacterial bloodstream infections but also tuberculosis, syphilis, viral hepatitis, and human immunodeficiency virus-that are known causes of vasculitis before G-CSF-induced aortitis is diagnosed (13).
In this case, pegfilgrastim was administered 36 hours after the completion of the first cycle of AI (adriamycin, ifosfamide) chemotherapy, and a series of symptoms had begun 4 days later. Most cases of G-CSF-induced aortitis had been reported to occur 1 to 15 days after the administration of G-CSF, and a few cases were reported to develop 1 month to 1 year later (8,14). This variation in the latent period, which could interfere with the clinical diagnosis, might result from pharmacodynamic and pharmacokinetic factors such as the type and amount of G-CSF used, type of the preceding chemotherapy, and individual physiological differences. In fact, pegfilgrastim and lipegfilgrastim, which both have a longer half-life and produce equivalent effects with fewer administrations, have been most often reported as the drug causing aortitis (8-10). It is of interest that this condition has been reported more often in women than in men, although more detailed cases and epidemiological studies are needed to prove that G-CSF-induced aortitis is indeed more common in women.
Searching on web, G-CSF-induced aortitis in a patient being treated for sarcoma was thus found to be extremely rare. One reason why no cases of G-CSF-induced aortitis were previously reported in patients with sarcomas might be due to the low absolute number of such patients. Ogura et al. reported that according to a nationwide organ-specific cancer registry for bone and soft tissue tumors in Japan, the number of patients with sarcomas in 2012 was 1,598, which is an extremely low proportion of the 865,238 cases of all cancers (15,16). We believe that this case report, which concerns an orthopedic cancer, is important because the biological evidence that the administration of G-CSF could provoke aortitis is still lacking.
Although this patient did not exhibit any pulmonary manifestations, the lung interstitial changes found on CT seemed critical and warranted the administration of steroids, since there had been many reports of G-CSF-related pulmonary toxicity, which in some cases progressed to acute respiratory distress syndrome and to death (17-19). In a review of 20 cases of interstitial pneumonia secondary to treatment with G-CSF, Niitsu et al. reported that three patients died of respiratory and multiple organ failure; consequently, they emphasized the importance of starting steroid pulse therapy as early as possible when the diagnosis is made (20).
Although the skin lesions that this patient exhibited were not histologically confirmed, we speculated, from their macroscopic appearance, that they represented neutrophilic eccrine hidradenitis, which is neutrophilic dermatosis characterized by the sudden onset of erythematous papules or plaques with a neutrophilic infiltrate around eccrine glands, together with necrosis of these structures. Rising concentrations of the cytotoxic agents in sweat are thought to be the mechanism of neutrophilic eccrine hidradenitis, and doxorubicin is known to be one of the common causative substances (21). It is of interest that several such cases have been reported to be associated with the administration of G-CSF, and one of them occurred in patients who received pegfilgrastim after AI chemotherapy (22,23).
Without any guidelines available for the treatment of drug-induced aortitis, we set the initial dose of prednisolone as 60 mg, administered it orally, according to the Guideline for Management of Vasculitis Syndrome (Japanese Circulation Society 2008) for the diagnosis of giant cell arteritis (24). However, several cases of G-CSF-induced aortitis that remitted without the administration of prednisolone have been reported. We think that the degree of inflammatory response might vary in individual cases, and so the clinical decision of whether to administer prednisolone must be individualized. In our patient, prednisolone treatment was necessary because of sustained high-grade inflammatory markers and interstitial changes in the lungs.
In summary, we herein described a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. The patient required PSL administration because of the lung injuries and persisting high grade fever. The response to the treatment with PSL was good, and the patient had recovered without any sequelae. It has been almost 30 years since filgrastim was introduced to the market. However, G-CSF induced aortitis has not been well recognized. We speculate that one reason for this might be the lack of algorithm to predict patients at high risk to present this condition. Secondly, there is lack of specific signs and symptoms. In addition, as we described above, the condition sometimes subsides without the administration of steroids or immuno-suppressants which are usually indispensable for the treatment of other types of vasculitis syndrome. Therefore, we speculate that many cases of G-CSF induced may have been overlooked. This case report might be one type of supportive evidence of G-CSF induced aortitis, however, it is necessary to collect and examine future cases regarding what kind of patients: sex, races, age etc., are likely to present with aortitis due to G-CSF.
The authors state that they have no Conflict of Interest (COI).
|
DEXAMETHASONE SODIUM PHOSPHATE, DOXORUBICIN HYDROCHLORIDE, FAMOTIDINE, FUROSEMIDE, GRANISETRON HYDROCHLORIDE, IFOSFAMIDE, MESNA, PEGFILGRASTIM
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33191326
| 17,433,107
|
2021-04-15
|
What is the weight of the patient?
|
Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.
We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are commonly used to prevent and treat neutropenia caused by cancer chemotherapy. Meta-analyses of randomized controlled trials of G-CSFs as primary prophylaxis against febrile neutropenia have demonstrated significant reductions in the rates of short-term all-cause mortality, as well as rates of infection-related mortality, in patients with solid tumors and malignant lymphoma (1,2). A meta-analysis of 59 randomized controlled trials demonstrated that systemic cancer chemotherapy with primary adjunct G-CSF treatment was associated with a significantly greater intensity of the effect of the delivered chemotherapy doses and with greater relative and absolute risk reductions in all-cause mortality rates than was chemotherapy without adjunct G-CSF treatment over a long period (3). As for drug safety, Teshima et al. reported that according to the results of their post-marketing use survey in Japan, the rate of overall adverse effects was 7.47%; these effects included lumbago (3.84%), fever (1.62%), and bone pain (0.61%), and most were not serious and seemed to be ameliorated by the discontinuation of G-CSF treatment (4).
However, a few cases with serious adverse effects, such as interstitial pneumonia and extramedullary hematopoietic splenic rupture, have been reported after the administration of G-CSF (5,6). Pegfilgrastim, a relatively new G-CSF used to prevent febrile neutropenia, is a modified protein consisting of methoxy polyethylene glycol (PEG) molecular chains attached to a Met1 amino group of genetic recombinant filgrastim whose renal excretion is reduced and whose effects are prolonged (7). In Japan, pegfilgrastim is approved for use only to prevent febrile neutropenia after chemotherapy. To optimize its pharmacological effect and prevent adverse effects, the use of pegfilgrastim is restricted to patients at high risk for febrile neutropenia at least 24 hours after a course of chemotherapy. Over the past two decades, authors have reported cases of aortitis induced by G-CSF preparations such as filgrastim, lenograstim, and pegfilgrastim (8,9). Oshima et al., using the Japanese Adverse Drug Event Report database, reported that G-CSF treatment is associated with an increased risk for aortitis (10).
We herein report a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. This is a rare case of G-CSF induced aortitis occurred in a patient who was being treated for sarcoma and it is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological background.
Case Report
A 56-year-old man who was receiving treatment for the local recurrence of extraosseous mucinous chondrosarcoma on the right lower limb presented to our hospital because of an 8-day history of high fever, general fatigue, and a rash with pain. He did not report either any upper or lower respiratory symptoms, abdominal pain, diarrhea, arthralgias, headache, or visual impairment. He had finished the first 4-day course of chemotherapy with 2-day adriamycin (25 mg/m2 each) and four-day ifosfamide (2.8 g/m2 each), followed 36 hours later by subcutaneous administration of pegylated G-CSF (3.6 mg), and he was discharged immediately. Four days later, the symptoms began.
On presentation, he did not appear ill, and he was alert and oriented. His body weight was 69.4 kg, and his height was 169 cm. His vital signs were as follows: blood pressure, 90/47 mm Hg; pulse rate, 95 beats/min; body temperature, 39.1℃; respiratory rate, 12/min; and oxygen saturation level, 99% on room air. A physical examination revealed palm-sized dark red-to-purplish indurated rashes with tenderness on the right cubital fossa and over the left knee socket (Fig. 1a, b). The surface lymph nodes, liver, and spleen were not palpable. The initial laboratory data revealed the following: a white blood cell count of 15,780/μL (90.0% segmented neutrophils, 7.0% stab neutrophils 1.0% monocytes, 2.0% lymphocytes, and 0% atypical lymphocytes, visually confirmed), hemoglobin level of 11.8 g/dL, platelet count of 109,000/μL, and serum C-reactive protein level of 38.77 mg/dL. Table lists the other laboratory data. The results of antigen tests for influenza virus were negative. Two sets of blood culture were conducted. Computed tomography (CT) without contrast media revealed inflammatory changes in the soft tissue surrounding the aorta, partial reticular change and ground-glass opacities scattered throughout both lungs, and splenomegaly (Fig. 2).
Figure 1. Erythematous skin lesions on the right cubital fossa (a) and over the left knee socket (b), on admission.
Table. Laboratory Data on Admission.
Complete blood count Serological test Urine test
WBC 15,780 ×103/μL CRP 38.77 mg/dL occult blood 2+
N-Stab 7 % IgG 828 mg/dL ketone negative
N-Seg 90 % IgA 327 mg/dL glucose negative
Eosino 0 % IgM 103 mg/dL protein 1+
Baso 0 % IgE 53 mg/dL Urinary sediment
Mono 1 % CH50 >60 CH50/mL RBC <4 /HPF
Lymph 2 % C3 162 mg/dL WBC <4 /HPF
RBC 442 ×104/μL C4 45 mg/dL Squamous cell 0-1 /HPF
Hemoglobin 11.8 g/dL sIL-2R 1,922 U/mL cast positive
Platelet 109 ×104/μL ANA <80 β2 microglobulin 18.7 mg/dL
Biochemistry PR3-ANCA <1.0 U/mL
TP 6.2 g/dL MPO-ANCA <1.0 U/mL
Alb 2.4 g/dL anti ssDNA 2.5 AU/mL
T-bil 0.8 mg/dL anti dsDNA <1.2 IU/mL
D-bil 0.5 mg/dL ASO 38 IU/mL
AST 22 U/L ASK ×320
ALT 99 U/L PCT 0.58 ng/mL
Ch-E 157 U/L IGRA negative
ALP 1,077 U/L RPR <1.0
LAP 149 U/L TPHA 0
γ-GTP 302 U/L HCV Ab 0.03
LD 208 U/L HBs Ag 0 IU/mL
CK 19 U/L CMV IgG 64 UA/mL
UN 33 mg/dL CMV IgM negative
Creatinine 2.29 mg/dL ESR 114 mm/hr
Na 139 mmol/L
K 3.7 mmol/L
Cl 101 mmol/L
Blood Sugar 159 mg/dL
HbA1c 6.4 %
WBC: white blood cell, RBC: red blood cell, AST: asparatate aminotransferase, ALT: alanine aminotransferase, N-stab: stab neutrophil, N-seg: segmented neutrophil, Eosino: eosinophil, Baso: basophil, Mono: monocyte, Lymph; Lymphocyte, TP: total protein, Alb: albumin, T-bil: total bililubin, D-bil: direct bililubin, Ch-E: cholinesterase, ALP: alkaline phosphatase, LAP: leucine aminopeptidase, γ-GTP: γ-glutamyl transpeptidase, LD: lactate dehydrogenase, UN: urea nitrogen, CK: creatine kinase, Na: sodium, K: potassium, Cl: chloride, HbA1c: hemoglobine A1c, CRP: C-reactive protein, IgG: Immunoglobulin G, IgA: Immunoglobulin A, IgM: Immunoglobulin M, IgE: Immunoglobulin E, CH50: 50% hemolytic complement activity, sIL-2 R: soluble Interleukin-2 receptor, ANA: antinuclear antibody, PR3-ANCA: serine proteinase3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-ssDNA: anti-single-stranded DNA antibody, anti-dsDNA: anti-double stranded DNA antibody, ASO: antistreptolysin O, ASK: antistreptokinase, PCT: procalcitonin, IGRA: interferon-gamma releasing assay, RPR: rapid plasma reagin card agglutination test, TPHA: treponema pallidum antibody hemagglutination test, HCV ab: hepatitis C virus antibody, HBs Ag: hepatitis B virus antigen, CMV IgG: cytomegalovirus antibody, immunoglobulin G, CMV IgM: cytomegalovirus antibody, immunoglobulin M, ESR: erythrocyte sedimentation rate
Figure 2. Computed tomography (CT) without contrast media, showing aortitis (a; white arrowheads), patchy interstitial changes scattered throughout both lungs (b; black arrowheads) and a small amount of pleural effusion (b; yellow arrowheads), and splenomegaly (c).
Because he was immunocompromised, we diagnosed systemic inflammatory response syndrome and acute renal failure caused by bacterial infection. We promptly administered 2 L of crystalloid infusion for resuscitation and empirical piperacillin/tazobactam as shown in Fig. 3. His renal function was restored rapidly, but high-grade fever persisted for 4 days, as did the inflammatory markers, despite antibiotic treatment. However, this patient did not appear ill, and his food intake did not decrease during the first 4 days after his admission to this hospital. Furthermore, even with a high-grade fever (>40℃), his pulse rate had stayed in the range of 60/min to 70/min, which represented relative bradycardia, which in turn has been considered a characteristic of drug-related fever (11). A blood culture yielded negative results, as did serological tests (including cytomegalovirus antigen and autoantibodies); thus, we diagnosed aortitis resulting from G-CSF administration.
Figure 3. Clinical course of this case. CRP: C-reactive protein, PIPC/TAZ: piperacillin/tazobactam, PSL: prednisolone, WBC: white blood cell count
Because of concerns about the high-grade fever and the pulmonary findings, we initiated treatment with prednisolone, 60 mg (1 mg/kg) orally on the fourth day of hospitalization. His fever resolved within the day, followed by a rapid improvement in his general condition and laboratory data. The rash had improved simultaneously, although the skin discoloration remained. Six days after initiating prednisolone, we tapered the dosage to 40 mg and discharged the patient on day 18 (Fig. 3). At the 3-month follow-up visit, the patient remained well with the prednisolone dose of 7.5 mg/day, which was discontinued 3 months later.
Discussion
As in other immunocompromised patients after the administration of anticancer drugs, we had to rule out vasculitis secondary to infections before diagnosing the drug-induced aortitis, since infectious disease was strongly associated with systemic vasculitis, including aortitis (12). Hence, it might be important in such patients to evaluate them for common infectious diseases that are often overlooked-not only bacterial bloodstream infections but also tuberculosis, syphilis, viral hepatitis, and human immunodeficiency virus-that are known causes of vasculitis before G-CSF-induced aortitis is diagnosed (13).
In this case, pegfilgrastim was administered 36 hours after the completion of the first cycle of AI (adriamycin, ifosfamide) chemotherapy, and a series of symptoms had begun 4 days later. Most cases of G-CSF-induced aortitis had been reported to occur 1 to 15 days after the administration of G-CSF, and a few cases were reported to develop 1 month to 1 year later (8,14). This variation in the latent period, which could interfere with the clinical diagnosis, might result from pharmacodynamic and pharmacokinetic factors such as the type and amount of G-CSF used, type of the preceding chemotherapy, and individual physiological differences. In fact, pegfilgrastim and lipegfilgrastim, which both have a longer half-life and produce equivalent effects with fewer administrations, have been most often reported as the drug causing aortitis (8-10). It is of interest that this condition has been reported more often in women than in men, although more detailed cases and epidemiological studies are needed to prove that G-CSF-induced aortitis is indeed more common in women.
Searching on web, G-CSF-induced aortitis in a patient being treated for sarcoma was thus found to be extremely rare. One reason why no cases of G-CSF-induced aortitis were previously reported in patients with sarcomas might be due to the low absolute number of such patients. Ogura et al. reported that according to a nationwide organ-specific cancer registry for bone and soft tissue tumors in Japan, the number of patients with sarcomas in 2012 was 1,598, which is an extremely low proportion of the 865,238 cases of all cancers (15,16). We believe that this case report, which concerns an orthopedic cancer, is important because the biological evidence that the administration of G-CSF could provoke aortitis is still lacking.
Although this patient did not exhibit any pulmonary manifestations, the lung interstitial changes found on CT seemed critical and warranted the administration of steroids, since there had been many reports of G-CSF-related pulmonary toxicity, which in some cases progressed to acute respiratory distress syndrome and to death (17-19). In a review of 20 cases of interstitial pneumonia secondary to treatment with G-CSF, Niitsu et al. reported that three patients died of respiratory and multiple organ failure; consequently, they emphasized the importance of starting steroid pulse therapy as early as possible when the diagnosis is made (20).
Although the skin lesions that this patient exhibited were not histologically confirmed, we speculated, from their macroscopic appearance, that they represented neutrophilic eccrine hidradenitis, which is neutrophilic dermatosis characterized by the sudden onset of erythematous papules or plaques with a neutrophilic infiltrate around eccrine glands, together with necrosis of these structures. Rising concentrations of the cytotoxic agents in sweat are thought to be the mechanism of neutrophilic eccrine hidradenitis, and doxorubicin is known to be one of the common causative substances (21). It is of interest that several such cases have been reported to be associated with the administration of G-CSF, and one of them occurred in patients who received pegfilgrastim after AI chemotherapy (22,23).
Without any guidelines available for the treatment of drug-induced aortitis, we set the initial dose of prednisolone as 60 mg, administered it orally, according to the Guideline for Management of Vasculitis Syndrome (Japanese Circulation Society 2008) for the diagnosis of giant cell arteritis (24). However, several cases of G-CSF-induced aortitis that remitted without the administration of prednisolone have been reported. We think that the degree of inflammatory response might vary in individual cases, and so the clinical decision of whether to administer prednisolone must be individualized. In our patient, prednisolone treatment was necessary because of sustained high-grade inflammatory markers and interstitial changes in the lungs.
In summary, we herein described a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. The patient required PSL administration because of the lung injuries and persisting high grade fever. The response to the treatment with PSL was good, and the patient had recovered without any sequelae. It has been almost 30 years since filgrastim was introduced to the market. However, G-CSF induced aortitis has not been well recognized. We speculate that one reason for this might be the lack of algorithm to predict patients at high risk to present this condition. Secondly, there is lack of specific signs and symptoms. In addition, as we described above, the condition sometimes subsides without the administration of steroids or immuno-suppressants which are usually indispensable for the treatment of other types of vasculitis syndrome. Therefore, we speculate that many cases of G-CSF induced may have been overlooked. This case report might be one type of supportive evidence of G-CSF induced aortitis, however, it is necessary to collect and examine future cases regarding what kind of patients: sex, races, age etc., are likely to present with aortitis due to G-CSF.
The authors state that they have no Conflict of Interest (COI).
|
69.4 kg.
|
Weight
|
CC BY-NC-ND
|
33191326
| 18,682,768
|
2021-04-15
|
What was the administration route of drug 'DOXORUBICIN HYDROCHLORIDE'?
|
Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.
We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are commonly used to prevent and treat neutropenia caused by cancer chemotherapy. Meta-analyses of randomized controlled trials of G-CSFs as primary prophylaxis against febrile neutropenia have demonstrated significant reductions in the rates of short-term all-cause mortality, as well as rates of infection-related mortality, in patients with solid tumors and malignant lymphoma (1,2). A meta-analysis of 59 randomized controlled trials demonstrated that systemic cancer chemotherapy with primary adjunct G-CSF treatment was associated with a significantly greater intensity of the effect of the delivered chemotherapy doses and with greater relative and absolute risk reductions in all-cause mortality rates than was chemotherapy without adjunct G-CSF treatment over a long period (3). As for drug safety, Teshima et al. reported that according to the results of their post-marketing use survey in Japan, the rate of overall adverse effects was 7.47%; these effects included lumbago (3.84%), fever (1.62%), and bone pain (0.61%), and most were not serious and seemed to be ameliorated by the discontinuation of G-CSF treatment (4).
However, a few cases with serious adverse effects, such as interstitial pneumonia and extramedullary hematopoietic splenic rupture, have been reported after the administration of G-CSF (5,6). Pegfilgrastim, a relatively new G-CSF used to prevent febrile neutropenia, is a modified protein consisting of methoxy polyethylene glycol (PEG) molecular chains attached to a Met1 amino group of genetic recombinant filgrastim whose renal excretion is reduced and whose effects are prolonged (7). In Japan, pegfilgrastim is approved for use only to prevent febrile neutropenia after chemotherapy. To optimize its pharmacological effect and prevent adverse effects, the use of pegfilgrastim is restricted to patients at high risk for febrile neutropenia at least 24 hours after a course of chemotherapy. Over the past two decades, authors have reported cases of aortitis induced by G-CSF preparations such as filgrastim, lenograstim, and pegfilgrastim (8,9). Oshima et al., using the Japanese Adverse Drug Event Report database, reported that G-CSF treatment is associated with an increased risk for aortitis (10).
We herein report a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. This is a rare case of G-CSF induced aortitis occurred in a patient who was being treated for sarcoma and it is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological background.
Case Report
A 56-year-old man who was receiving treatment for the local recurrence of extraosseous mucinous chondrosarcoma on the right lower limb presented to our hospital because of an 8-day history of high fever, general fatigue, and a rash with pain. He did not report either any upper or lower respiratory symptoms, abdominal pain, diarrhea, arthralgias, headache, or visual impairment. He had finished the first 4-day course of chemotherapy with 2-day adriamycin (25 mg/m2 each) and four-day ifosfamide (2.8 g/m2 each), followed 36 hours later by subcutaneous administration of pegylated G-CSF (3.6 mg), and he was discharged immediately. Four days later, the symptoms began.
On presentation, he did not appear ill, and he was alert and oriented. His body weight was 69.4 kg, and his height was 169 cm. His vital signs were as follows: blood pressure, 90/47 mm Hg; pulse rate, 95 beats/min; body temperature, 39.1℃; respiratory rate, 12/min; and oxygen saturation level, 99% on room air. A physical examination revealed palm-sized dark red-to-purplish indurated rashes with tenderness on the right cubital fossa and over the left knee socket (Fig. 1a, b). The surface lymph nodes, liver, and spleen were not palpable. The initial laboratory data revealed the following: a white blood cell count of 15,780/μL (90.0% segmented neutrophils, 7.0% stab neutrophils 1.0% monocytes, 2.0% lymphocytes, and 0% atypical lymphocytes, visually confirmed), hemoglobin level of 11.8 g/dL, platelet count of 109,000/μL, and serum C-reactive protein level of 38.77 mg/dL. Table lists the other laboratory data. The results of antigen tests for influenza virus were negative. Two sets of blood culture were conducted. Computed tomography (CT) without contrast media revealed inflammatory changes in the soft tissue surrounding the aorta, partial reticular change and ground-glass opacities scattered throughout both lungs, and splenomegaly (Fig. 2).
Figure 1. Erythematous skin lesions on the right cubital fossa (a) and over the left knee socket (b), on admission.
Table. Laboratory Data on Admission.
Complete blood count Serological test Urine test
WBC 15,780 ×103/μL CRP 38.77 mg/dL occult blood 2+
N-Stab 7 % IgG 828 mg/dL ketone negative
N-Seg 90 % IgA 327 mg/dL glucose negative
Eosino 0 % IgM 103 mg/dL protein 1+
Baso 0 % IgE 53 mg/dL Urinary sediment
Mono 1 % CH50 >60 CH50/mL RBC <4 /HPF
Lymph 2 % C3 162 mg/dL WBC <4 /HPF
RBC 442 ×104/μL C4 45 mg/dL Squamous cell 0-1 /HPF
Hemoglobin 11.8 g/dL sIL-2R 1,922 U/mL cast positive
Platelet 109 ×104/μL ANA <80 β2 microglobulin 18.7 mg/dL
Biochemistry PR3-ANCA <1.0 U/mL
TP 6.2 g/dL MPO-ANCA <1.0 U/mL
Alb 2.4 g/dL anti ssDNA 2.5 AU/mL
T-bil 0.8 mg/dL anti dsDNA <1.2 IU/mL
D-bil 0.5 mg/dL ASO 38 IU/mL
AST 22 U/L ASK ×320
ALT 99 U/L PCT 0.58 ng/mL
Ch-E 157 U/L IGRA negative
ALP 1,077 U/L RPR <1.0
LAP 149 U/L TPHA 0
γ-GTP 302 U/L HCV Ab 0.03
LD 208 U/L HBs Ag 0 IU/mL
CK 19 U/L CMV IgG 64 UA/mL
UN 33 mg/dL CMV IgM negative
Creatinine 2.29 mg/dL ESR 114 mm/hr
Na 139 mmol/L
K 3.7 mmol/L
Cl 101 mmol/L
Blood Sugar 159 mg/dL
HbA1c 6.4 %
WBC: white blood cell, RBC: red blood cell, AST: asparatate aminotransferase, ALT: alanine aminotransferase, N-stab: stab neutrophil, N-seg: segmented neutrophil, Eosino: eosinophil, Baso: basophil, Mono: monocyte, Lymph; Lymphocyte, TP: total protein, Alb: albumin, T-bil: total bililubin, D-bil: direct bililubin, Ch-E: cholinesterase, ALP: alkaline phosphatase, LAP: leucine aminopeptidase, γ-GTP: γ-glutamyl transpeptidase, LD: lactate dehydrogenase, UN: urea nitrogen, CK: creatine kinase, Na: sodium, K: potassium, Cl: chloride, HbA1c: hemoglobine A1c, CRP: C-reactive protein, IgG: Immunoglobulin G, IgA: Immunoglobulin A, IgM: Immunoglobulin M, IgE: Immunoglobulin E, CH50: 50% hemolytic complement activity, sIL-2 R: soluble Interleukin-2 receptor, ANA: antinuclear antibody, PR3-ANCA: serine proteinase3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-ssDNA: anti-single-stranded DNA antibody, anti-dsDNA: anti-double stranded DNA antibody, ASO: antistreptolysin O, ASK: antistreptokinase, PCT: procalcitonin, IGRA: interferon-gamma releasing assay, RPR: rapid plasma reagin card agglutination test, TPHA: treponema pallidum antibody hemagglutination test, HCV ab: hepatitis C virus antibody, HBs Ag: hepatitis B virus antigen, CMV IgG: cytomegalovirus antibody, immunoglobulin G, CMV IgM: cytomegalovirus antibody, immunoglobulin M, ESR: erythrocyte sedimentation rate
Figure 2. Computed tomography (CT) without contrast media, showing aortitis (a; white arrowheads), patchy interstitial changes scattered throughout both lungs (b; black arrowheads) and a small amount of pleural effusion (b; yellow arrowheads), and splenomegaly (c).
Because he was immunocompromised, we diagnosed systemic inflammatory response syndrome and acute renal failure caused by bacterial infection. We promptly administered 2 L of crystalloid infusion for resuscitation and empirical piperacillin/tazobactam as shown in Fig. 3. His renal function was restored rapidly, but high-grade fever persisted for 4 days, as did the inflammatory markers, despite antibiotic treatment. However, this patient did not appear ill, and his food intake did not decrease during the first 4 days after his admission to this hospital. Furthermore, even with a high-grade fever (>40℃), his pulse rate had stayed in the range of 60/min to 70/min, which represented relative bradycardia, which in turn has been considered a characteristic of drug-related fever (11). A blood culture yielded negative results, as did serological tests (including cytomegalovirus antigen and autoantibodies); thus, we diagnosed aortitis resulting from G-CSF administration.
Figure 3. Clinical course of this case. CRP: C-reactive protein, PIPC/TAZ: piperacillin/tazobactam, PSL: prednisolone, WBC: white blood cell count
Because of concerns about the high-grade fever and the pulmonary findings, we initiated treatment with prednisolone, 60 mg (1 mg/kg) orally on the fourth day of hospitalization. His fever resolved within the day, followed by a rapid improvement in his general condition and laboratory data. The rash had improved simultaneously, although the skin discoloration remained. Six days after initiating prednisolone, we tapered the dosage to 40 mg and discharged the patient on day 18 (Fig. 3). At the 3-month follow-up visit, the patient remained well with the prednisolone dose of 7.5 mg/day, which was discontinued 3 months later.
Discussion
As in other immunocompromised patients after the administration of anticancer drugs, we had to rule out vasculitis secondary to infections before diagnosing the drug-induced aortitis, since infectious disease was strongly associated with systemic vasculitis, including aortitis (12). Hence, it might be important in such patients to evaluate them for common infectious diseases that are often overlooked-not only bacterial bloodstream infections but also tuberculosis, syphilis, viral hepatitis, and human immunodeficiency virus-that are known causes of vasculitis before G-CSF-induced aortitis is diagnosed (13).
In this case, pegfilgrastim was administered 36 hours after the completion of the first cycle of AI (adriamycin, ifosfamide) chemotherapy, and a series of symptoms had begun 4 days later. Most cases of G-CSF-induced aortitis had been reported to occur 1 to 15 days after the administration of G-CSF, and a few cases were reported to develop 1 month to 1 year later (8,14). This variation in the latent period, which could interfere with the clinical diagnosis, might result from pharmacodynamic and pharmacokinetic factors such as the type and amount of G-CSF used, type of the preceding chemotherapy, and individual physiological differences. In fact, pegfilgrastim and lipegfilgrastim, which both have a longer half-life and produce equivalent effects with fewer administrations, have been most often reported as the drug causing aortitis (8-10). It is of interest that this condition has been reported more often in women than in men, although more detailed cases and epidemiological studies are needed to prove that G-CSF-induced aortitis is indeed more common in women.
Searching on web, G-CSF-induced aortitis in a patient being treated for sarcoma was thus found to be extremely rare. One reason why no cases of G-CSF-induced aortitis were previously reported in patients with sarcomas might be due to the low absolute number of such patients. Ogura et al. reported that according to a nationwide organ-specific cancer registry for bone and soft tissue tumors in Japan, the number of patients with sarcomas in 2012 was 1,598, which is an extremely low proportion of the 865,238 cases of all cancers (15,16). We believe that this case report, which concerns an orthopedic cancer, is important because the biological evidence that the administration of G-CSF could provoke aortitis is still lacking.
Although this patient did not exhibit any pulmonary manifestations, the lung interstitial changes found on CT seemed critical and warranted the administration of steroids, since there had been many reports of G-CSF-related pulmonary toxicity, which in some cases progressed to acute respiratory distress syndrome and to death (17-19). In a review of 20 cases of interstitial pneumonia secondary to treatment with G-CSF, Niitsu et al. reported that three patients died of respiratory and multiple organ failure; consequently, they emphasized the importance of starting steroid pulse therapy as early as possible when the diagnosis is made (20).
Although the skin lesions that this patient exhibited were not histologically confirmed, we speculated, from their macroscopic appearance, that they represented neutrophilic eccrine hidradenitis, which is neutrophilic dermatosis characterized by the sudden onset of erythematous papules or plaques with a neutrophilic infiltrate around eccrine glands, together with necrosis of these structures. Rising concentrations of the cytotoxic agents in sweat are thought to be the mechanism of neutrophilic eccrine hidradenitis, and doxorubicin is known to be one of the common causative substances (21). It is of interest that several such cases have been reported to be associated with the administration of G-CSF, and one of them occurred in patients who received pegfilgrastim after AI chemotherapy (22,23).
Without any guidelines available for the treatment of drug-induced aortitis, we set the initial dose of prednisolone as 60 mg, administered it orally, according to the Guideline for Management of Vasculitis Syndrome (Japanese Circulation Society 2008) for the diagnosis of giant cell arteritis (24). However, several cases of G-CSF-induced aortitis that remitted without the administration of prednisolone have been reported. We think that the degree of inflammatory response might vary in individual cases, and so the clinical decision of whether to administer prednisolone must be individualized. In our patient, prednisolone treatment was necessary because of sustained high-grade inflammatory markers and interstitial changes in the lungs.
In summary, we herein described a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. The patient required PSL administration because of the lung injuries and persisting high grade fever. The response to the treatment with PSL was good, and the patient had recovered without any sequelae. It has been almost 30 years since filgrastim was introduced to the market. However, G-CSF induced aortitis has not been well recognized. We speculate that one reason for this might be the lack of algorithm to predict patients at high risk to present this condition. Secondly, there is lack of specific signs and symptoms. In addition, as we described above, the condition sometimes subsides without the administration of steroids or immuno-suppressants which are usually indispensable for the treatment of other types of vasculitis syndrome. Therefore, we speculate that many cases of G-CSF induced may have been overlooked. This case report might be one type of supportive evidence of G-CSF induced aortitis, however, it is necessary to collect and examine future cases regarding what kind of patients: sex, races, age etc., are likely to present with aortitis due to G-CSF.
The authors state that they have no Conflict of Interest (COI).
|
Intravenous drip
|
DrugAdministrationRoute
|
CC BY-NC-ND
|
33191326
| 17,433,107
|
2021-04-15
|
What was the administration route of drug 'IFOSFAMIDE'?
|
Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.
We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are commonly used to prevent and treat neutropenia caused by cancer chemotherapy. Meta-analyses of randomized controlled trials of G-CSFs as primary prophylaxis against febrile neutropenia have demonstrated significant reductions in the rates of short-term all-cause mortality, as well as rates of infection-related mortality, in patients with solid tumors and malignant lymphoma (1,2). A meta-analysis of 59 randomized controlled trials demonstrated that systemic cancer chemotherapy with primary adjunct G-CSF treatment was associated with a significantly greater intensity of the effect of the delivered chemotherapy doses and with greater relative and absolute risk reductions in all-cause mortality rates than was chemotherapy without adjunct G-CSF treatment over a long period (3). As for drug safety, Teshima et al. reported that according to the results of their post-marketing use survey in Japan, the rate of overall adverse effects was 7.47%; these effects included lumbago (3.84%), fever (1.62%), and bone pain (0.61%), and most were not serious and seemed to be ameliorated by the discontinuation of G-CSF treatment (4).
However, a few cases with serious adverse effects, such as interstitial pneumonia and extramedullary hematopoietic splenic rupture, have been reported after the administration of G-CSF (5,6). Pegfilgrastim, a relatively new G-CSF used to prevent febrile neutropenia, is a modified protein consisting of methoxy polyethylene glycol (PEG) molecular chains attached to a Met1 amino group of genetic recombinant filgrastim whose renal excretion is reduced and whose effects are prolonged (7). In Japan, pegfilgrastim is approved for use only to prevent febrile neutropenia after chemotherapy. To optimize its pharmacological effect and prevent adverse effects, the use of pegfilgrastim is restricted to patients at high risk for febrile neutropenia at least 24 hours after a course of chemotherapy. Over the past two decades, authors have reported cases of aortitis induced by G-CSF preparations such as filgrastim, lenograstim, and pegfilgrastim (8,9). Oshima et al., using the Japanese Adverse Drug Event Report database, reported that G-CSF treatment is associated with an increased risk for aortitis (10).
We herein report a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. This is a rare case of G-CSF induced aortitis occurred in a patient who was being treated for sarcoma and it is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological background.
Case Report
A 56-year-old man who was receiving treatment for the local recurrence of extraosseous mucinous chondrosarcoma on the right lower limb presented to our hospital because of an 8-day history of high fever, general fatigue, and a rash with pain. He did not report either any upper or lower respiratory symptoms, abdominal pain, diarrhea, arthralgias, headache, or visual impairment. He had finished the first 4-day course of chemotherapy with 2-day adriamycin (25 mg/m2 each) and four-day ifosfamide (2.8 g/m2 each), followed 36 hours later by subcutaneous administration of pegylated G-CSF (3.6 mg), and he was discharged immediately. Four days later, the symptoms began.
On presentation, he did not appear ill, and he was alert and oriented. His body weight was 69.4 kg, and his height was 169 cm. His vital signs were as follows: blood pressure, 90/47 mm Hg; pulse rate, 95 beats/min; body temperature, 39.1℃; respiratory rate, 12/min; and oxygen saturation level, 99% on room air. A physical examination revealed palm-sized dark red-to-purplish indurated rashes with tenderness on the right cubital fossa and over the left knee socket (Fig. 1a, b). The surface lymph nodes, liver, and spleen were not palpable. The initial laboratory data revealed the following: a white blood cell count of 15,780/μL (90.0% segmented neutrophils, 7.0% stab neutrophils 1.0% monocytes, 2.0% lymphocytes, and 0% atypical lymphocytes, visually confirmed), hemoglobin level of 11.8 g/dL, platelet count of 109,000/μL, and serum C-reactive protein level of 38.77 mg/dL. Table lists the other laboratory data. The results of antigen tests for influenza virus were negative. Two sets of blood culture were conducted. Computed tomography (CT) without contrast media revealed inflammatory changes in the soft tissue surrounding the aorta, partial reticular change and ground-glass opacities scattered throughout both lungs, and splenomegaly (Fig. 2).
Figure 1. Erythematous skin lesions on the right cubital fossa (a) and over the left knee socket (b), on admission.
Table. Laboratory Data on Admission.
Complete blood count Serological test Urine test
WBC 15,780 ×103/μL CRP 38.77 mg/dL occult blood 2+
N-Stab 7 % IgG 828 mg/dL ketone negative
N-Seg 90 % IgA 327 mg/dL glucose negative
Eosino 0 % IgM 103 mg/dL protein 1+
Baso 0 % IgE 53 mg/dL Urinary sediment
Mono 1 % CH50 >60 CH50/mL RBC <4 /HPF
Lymph 2 % C3 162 mg/dL WBC <4 /HPF
RBC 442 ×104/μL C4 45 mg/dL Squamous cell 0-1 /HPF
Hemoglobin 11.8 g/dL sIL-2R 1,922 U/mL cast positive
Platelet 109 ×104/μL ANA <80 β2 microglobulin 18.7 mg/dL
Biochemistry PR3-ANCA <1.0 U/mL
TP 6.2 g/dL MPO-ANCA <1.0 U/mL
Alb 2.4 g/dL anti ssDNA 2.5 AU/mL
T-bil 0.8 mg/dL anti dsDNA <1.2 IU/mL
D-bil 0.5 mg/dL ASO 38 IU/mL
AST 22 U/L ASK ×320
ALT 99 U/L PCT 0.58 ng/mL
Ch-E 157 U/L IGRA negative
ALP 1,077 U/L RPR <1.0
LAP 149 U/L TPHA 0
γ-GTP 302 U/L HCV Ab 0.03
LD 208 U/L HBs Ag 0 IU/mL
CK 19 U/L CMV IgG 64 UA/mL
UN 33 mg/dL CMV IgM negative
Creatinine 2.29 mg/dL ESR 114 mm/hr
Na 139 mmol/L
K 3.7 mmol/L
Cl 101 mmol/L
Blood Sugar 159 mg/dL
HbA1c 6.4 %
WBC: white blood cell, RBC: red blood cell, AST: asparatate aminotransferase, ALT: alanine aminotransferase, N-stab: stab neutrophil, N-seg: segmented neutrophil, Eosino: eosinophil, Baso: basophil, Mono: monocyte, Lymph; Lymphocyte, TP: total protein, Alb: albumin, T-bil: total bililubin, D-bil: direct bililubin, Ch-E: cholinesterase, ALP: alkaline phosphatase, LAP: leucine aminopeptidase, γ-GTP: γ-glutamyl transpeptidase, LD: lactate dehydrogenase, UN: urea nitrogen, CK: creatine kinase, Na: sodium, K: potassium, Cl: chloride, HbA1c: hemoglobine A1c, CRP: C-reactive protein, IgG: Immunoglobulin G, IgA: Immunoglobulin A, IgM: Immunoglobulin M, IgE: Immunoglobulin E, CH50: 50% hemolytic complement activity, sIL-2 R: soluble Interleukin-2 receptor, ANA: antinuclear antibody, PR3-ANCA: serine proteinase3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-ssDNA: anti-single-stranded DNA antibody, anti-dsDNA: anti-double stranded DNA antibody, ASO: antistreptolysin O, ASK: antistreptokinase, PCT: procalcitonin, IGRA: interferon-gamma releasing assay, RPR: rapid plasma reagin card agglutination test, TPHA: treponema pallidum antibody hemagglutination test, HCV ab: hepatitis C virus antibody, HBs Ag: hepatitis B virus antigen, CMV IgG: cytomegalovirus antibody, immunoglobulin G, CMV IgM: cytomegalovirus antibody, immunoglobulin M, ESR: erythrocyte sedimentation rate
Figure 2. Computed tomography (CT) without contrast media, showing aortitis (a; white arrowheads), patchy interstitial changes scattered throughout both lungs (b; black arrowheads) and a small amount of pleural effusion (b; yellow arrowheads), and splenomegaly (c).
Because he was immunocompromised, we diagnosed systemic inflammatory response syndrome and acute renal failure caused by bacterial infection. We promptly administered 2 L of crystalloid infusion for resuscitation and empirical piperacillin/tazobactam as shown in Fig. 3. His renal function was restored rapidly, but high-grade fever persisted for 4 days, as did the inflammatory markers, despite antibiotic treatment. However, this patient did not appear ill, and his food intake did not decrease during the first 4 days after his admission to this hospital. Furthermore, even with a high-grade fever (>40℃), his pulse rate had stayed in the range of 60/min to 70/min, which represented relative bradycardia, which in turn has been considered a characteristic of drug-related fever (11). A blood culture yielded negative results, as did serological tests (including cytomegalovirus antigen and autoantibodies); thus, we diagnosed aortitis resulting from G-CSF administration.
Figure 3. Clinical course of this case. CRP: C-reactive protein, PIPC/TAZ: piperacillin/tazobactam, PSL: prednisolone, WBC: white blood cell count
Because of concerns about the high-grade fever and the pulmonary findings, we initiated treatment with prednisolone, 60 mg (1 mg/kg) orally on the fourth day of hospitalization. His fever resolved within the day, followed by a rapid improvement in his general condition and laboratory data. The rash had improved simultaneously, although the skin discoloration remained. Six days after initiating prednisolone, we tapered the dosage to 40 mg and discharged the patient on day 18 (Fig. 3). At the 3-month follow-up visit, the patient remained well with the prednisolone dose of 7.5 mg/day, which was discontinued 3 months later.
Discussion
As in other immunocompromised patients after the administration of anticancer drugs, we had to rule out vasculitis secondary to infections before diagnosing the drug-induced aortitis, since infectious disease was strongly associated with systemic vasculitis, including aortitis (12). Hence, it might be important in such patients to evaluate them for common infectious diseases that are often overlooked-not only bacterial bloodstream infections but also tuberculosis, syphilis, viral hepatitis, and human immunodeficiency virus-that are known causes of vasculitis before G-CSF-induced aortitis is diagnosed (13).
In this case, pegfilgrastim was administered 36 hours after the completion of the first cycle of AI (adriamycin, ifosfamide) chemotherapy, and a series of symptoms had begun 4 days later. Most cases of G-CSF-induced aortitis had been reported to occur 1 to 15 days after the administration of G-CSF, and a few cases were reported to develop 1 month to 1 year later (8,14). This variation in the latent period, which could interfere with the clinical diagnosis, might result from pharmacodynamic and pharmacokinetic factors such as the type and amount of G-CSF used, type of the preceding chemotherapy, and individual physiological differences. In fact, pegfilgrastim and lipegfilgrastim, which both have a longer half-life and produce equivalent effects with fewer administrations, have been most often reported as the drug causing aortitis (8-10). It is of interest that this condition has been reported more often in women than in men, although more detailed cases and epidemiological studies are needed to prove that G-CSF-induced aortitis is indeed more common in women.
Searching on web, G-CSF-induced aortitis in a patient being treated for sarcoma was thus found to be extremely rare. One reason why no cases of G-CSF-induced aortitis were previously reported in patients with sarcomas might be due to the low absolute number of such patients. Ogura et al. reported that according to a nationwide organ-specific cancer registry for bone and soft tissue tumors in Japan, the number of patients with sarcomas in 2012 was 1,598, which is an extremely low proportion of the 865,238 cases of all cancers (15,16). We believe that this case report, which concerns an orthopedic cancer, is important because the biological evidence that the administration of G-CSF could provoke aortitis is still lacking.
Although this patient did not exhibit any pulmonary manifestations, the lung interstitial changes found on CT seemed critical and warranted the administration of steroids, since there had been many reports of G-CSF-related pulmonary toxicity, which in some cases progressed to acute respiratory distress syndrome and to death (17-19). In a review of 20 cases of interstitial pneumonia secondary to treatment with G-CSF, Niitsu et al. reported that three patients died of respiratory and multiple organ failure; consequently, they emphasized the importance of starting steroid pulse therapy as early as possible when the diagnosis is made (20).
Although the skin lesions that this patient exhibited were not histologically confirmed, we speculated, from their macroscopic appearance, that they represented neutrophilic eccrine hidradenitis, which is neutrophilic dermatosis characterized by the sudden onset of erythematous papules or plaques with a neutrophilic infiltrate around eccrine glands, together with necrosis of these structures. Rising concentrations of the cytotoxic agents in sweat are thought to be the mechanism of neutrophilic eccrine hidradenitis, and doxorubicin is known to be one of the common causative substances (21). It is of interest that several such cases have been reported to be associated with the administration of G-CSF, and one of them occurred in patients who received pegfilgrastim after AI chemotherapy (22,23).
Without any guidelines available for the treatment of drug-induced aortitis, we set the initial dose of prednisolone as 60 mg, administered it orally, according to the Guideline for Management of Vasculitis Syndrome (Japanese Circulation Society 2008) for the diagnosis of giant cell arteritis (24). However, several cases of G-CSF-induced aortitis that remitted without the administration of prednisolone have been reported. We think that the degree of inflammatory response might vary in individual cases, and so the clinical decision of whether to administer prednisolone must be individualized. In our patient, prednisolone treatment was necessary because of sustained high-grade inflammatory markers and interstitial changes in the lungs.
In summary, we herein described a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. The patient required PSL administration because of the lung injuries and persisting high grade fever. The response to the treatment with PSL was good, and the patient had recovered without any sequelae. It has been almost 30 years since filgrastim was introduced to the market. However, G-CSF induced aortitis has not been well recognized. We speculate that one reason for this might be the lack of algorithm to predict patients at high risk to present this condition. Secondly, there is lack of specific signs and symptoms. In addition, as we described above, the condition sometimes subsides without the administration of steroids or immuno-suppressants which are usually indispensable for the treatment of other types of vasculitis syndrome. Therefore, we speculate that many cases of G-CSF induced may have been overlooked. This case report might be one type of supportive evidence of G-CSF induced aortitis, however, it is necessary to collect and examine future cases regarding what kind of patients: sex, races, age etc., are likely to present with aortitis due to G-CSF.
The authors state that they have no Conflict of Interest (COI).
|
Intravenous drip
|
DrugAdministrationRoute
|
CC BY-NC-ND
|
33191326
| 17,433,107
|
2021-04-15
|
What was the administration route of drug 'MESNA'?
|
Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.
We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are commonly used to prevent and treat neutropenia caused by cancer chemotherapy. Meta-analyses of randomized controlled trials of G-CSFs as primary prophylaxis against febrile neutropenia have demonstrated significant reductions in the rates of short-term all-cause mortality, as well as rates of infection-related mortality, in patients with solid tumors and malignant lymphoma (1,2). A meta-analysis of 59 randomized controlled trials demonstrated that systemic cancer chemotherapy with primary adjunct G-CSF treatment was associated with a significantly greater intensity of the effect of the delivered chemotherapy doses and with greater relative and absolute risk reductions in all-cause mortality rates than was chemotherapy without adjunct G-CSF treatment over a long period (3). As for drug safety, Teshima et al. reported that according to the results of their post-marketing use survey in Japan, the rate of overall adverse effects was 7.47%; these effects included lumbago (3.84%), fever (1.62%), and bone pain (0.61%), and most were not serious and seemed to be ameliorated by the discontinuation of G-CSF treatment (4).
However, a few cases with serious adverse effects, such as interstitial pneumonia and extramedullary hematopoietic splenic rupture, have been reported after the administration of G-CSF (5,6). Pegfilgrastim, a relatively new G-CSF used to prevent febrile neutropenia, is a modified protein consisting of methoxy polyethylene glycol (PEG) molecular chains attached to a Met1 amino group of genetic recombinant filgrastim whose renal excretion is reduced and whose effects are prolonged (7). In Japan, pegfilgrastim is approved for use only to prevent febrile neutropenia after chemotherapy. To optimize its pharmacological effect and prevent adverse effects, the use of pegfilgrastim is restricted to patients at high risk for febrile neutropenia at least 24 hours after a course of chemotherapy. Over the past two decades, authors have reported cases of aortitis induced by G-CSF preparations such as filgrastim, lenograstim, and pegfilgrastim (8,9). Oshima et al., using the Japanese Adverse Drug Event Report database, reported that G-CSF treatment is associated with an increased risk for aortitis (10).
We herein report a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. This is a rare case of G-CSF induced aortitis occurred in a patient who was being treated for sarcoma and it is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological background.
Case Report
A 56-year-old man who was receiving treatment for the local recurrence of extraosseous mucinous chondrosarcoma on the right lower limb presented to our hospital because of an 8-day history of high fever, general fatigue, and a rash with pain. He did not report either any upper or lower respiratory symptoms, abdominal pain, diarrhea, arthralgias, headache, or visual impairment. He had finished the first 4-day course of chemotherapy with 2-day adriamycin (25 mg/m2 each) and four-day ifosfamide (2.8 g/m2 each), followed 36 hours later by subcutaneous administration of pegylated G-CSF (3.6 mg), and he was discharged immediately. Four days later, the symptoms began.
On presentation, he did not appear ill, and he was alert and oriented. His body weight was 69.4 kg, and his height was 169 cm. His vital signs were as follows: blood pressure, 90/47 mm Hg; pulse rate, 95 beats/min; body temperature, 39.1℃; respiratory rate, 12/min; and oxygen saturation level, 99% on room air. A physical examination revealed palm-sized dark red-to-purplish indurated rashes with tenderness on the right cubital fossa and over the left knee socket (Fig. 1a, b). The surface lymph nodes, liver, and spleen were not palpable. The initial laboratory data revealed the following: a white blood cell count of 15,780/μL (90.0% segmented neutrophils, 7.0% stab neutrophils 1.0% monocytes, 2.0% lymphocytes, and 0% atypical lymphocytes, visually confirmed), hemoglobin level of 11.8 g/dL, platelet count of 109,000/μL, and serum C-reactive protein level of 38.77 mg/dL. Table lists the other laboratory data. The results of antigen tests for influenza virus were negative. Two sets of blood culture were conducted. Computed tomography (CT) without contrast media revealed inflammatory changes in the soft tissue surrounding the aorta, partial reticular change and ground-glass opacities scattered throughout both lungs, and splenomegaly (Fig. 2).
Figure 1. Erythematous skin lesions on the right cubital fossa (a) and over the left knee socket (b), on admission.
Table. Laboratory Data on Admission.
Complete blood count Serological test Urine test
WBC 15,780 ×103/μL CRP 38.77 mg/dL occult blood 2+
N-Stab 7 % IgG 828 mg/dL ketone negative
N-Seg 90 % IgA 327 mg/dL glucose negative
Eosino 0 % IgM 103 mg/dL protein 1+
Baso 0 % IgE 53 mg/dL Urinary sediment
Mono 1 % CH50 >60 CH50/mL RBC <4 /HPF
Lymph 2 % C3 162 mg/dL WBC <4 /HPF
RBC 442 ×104/μL C4 45 mg/dL Squamous cell 0-1 /HPF
Hemoglobin 11.8 g/dL sIL-2R 1,922 U/mL cast positive
Platelet 109 ×104/μL ANA <80 β2 microglobulin 18.7 mg/dL
Biochemistry PR3-ANCA <1.0 U/mL
TP 6.2 g/dL MPO-ANCA <1.0 U/mL
Alb 2.4 g/dL anti ssDNA 2.5 AU/mL
T-bil 0.8 mg/dL anti dsDNA <1.2 IU/mL
D-bil 0.5 mg/dL ASO 38 IU/mL
AST 22 U/L ASK ×320
ALT 99 U/L PCT 0.58 ng/mL
Ch-E 157 U/L IGRA negative
ALP 1,077 U/L RPR <1.0
LAP 149 U/L TPHA 0
γ-GTP 302 U/L HCV Ab 0.03
LD 208 U/L HBs Ag 0 IU/mL
CK 19 U/L CMV IgG 64 UA/mL
UN 33 mg/dL CMV IgM negative
Creatinine 2.29 mg/dL ESR 114 mm/hr
Na 139 mmol/L
K 3.7 mmol/L
Cl 101 mmol/L
Blood Sugar 159 mg/dL
HbA1c 6.4 %
WBC: white blood cell, RBC: red blood cell, AST: asparatate aminotransferase, ALT: alanine aminotransferase, N-stab: stab neutrophil, N-seg: segmented neutrophil, Eosino: eosinophil, Baso: basophil, Mono: monocyte, Lymph; Lymphocyte, TP: total protein, Alb: albumin, T-bil: total bililubin, D-bil: direct bililubin, Ch-E: cholinesterase, ALP: alkaline phosphatase, LAP: leucine aminopeptidase, γ-GTP: γ-glutamyl transpeptidase, LD: lactate dehydrogenase, UN: urea nitrogen, CK: creatine kinase, Na: sodium, K: potassium, Cl: chloride, HbA1c: hemoglobine A1c, CRP: C-reactive protein, IgG: Immunoglobulin G, IgA: Immunoglobulin A, IgM: Immunoglobulin M, IgE: Immunoglobulin E, CH50: 50% hemolytic complement activity, sIL-2 R: soluble Interleukin-2 receptor, ANA: antinuclear antibody, PR3-ANCA: serine proteinase3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-ssDNA: anti-single-stranded DNA antibody, anti-dsDNA: anti-double stranded DNA antibody, ASO: antistreptolysin O, ASK: antistreptokinase, PCT: procalcitonin, IGRA: interferon-gamma releasing assay, RPR: rapid plasma reagin card agglutination test, TPHA: treponema pallidum antibody hemagglutination test, HCV ab: hepatitis C virus antibody, HBs Ag: hepatitis B virus antigen, CMV IgG: cytomegalovirus antibody, immunoglobulin G, CMV IgM: cytomegalovirus antibody, immunoglobulin M, ESR: erythrocyte sedimentation rate
Figure 2. Computed tomography (CT) without contrast media, showing aortitis (a; white arrowheads), patchy interstitial changes scattered throughout both lungs (b; black arrowheads) and a small amount of pleural effusion (b; yellow arrowheads), and splenomegaly (c).
Because he was immunocompromised, we diagnosed systemic inflammatory response syndrome and acute renal failure caused by bacterial infection. We promptly administered 2 L of crystalloid infusion for resuscitation and empirical piperacillin/tazobactam as shown in Fig. 3. His renal function was restored rapidly, but high-grade fever persisted for 4 days, as did the inflammatory markers, despite antibiotic treatment. However, this patient did not appear ill, and his food intake did not decrease during the first 4 days after his admission to this hospital. Furthermore, even with a high-grade fever (>40℃), his pulse rate had stayed in the range of 60/min to 70/min, which represented relative bradycardia, which in turn has been considered a characteristic of drug-related fever (11). A blood culture yielded negative results, as did serological tests (including cytomegalovirus antigen and autoantibodies); thus, we diagnosed aortitis resulting from G-CSF administration.
Figure 3. Clinical course of this case. CRP: C-reactive protein, PIPC/TAZ: piperacillin/tazobactam, PSL: prednisolone, WBC: white blood cell count
Because of concerns about the high-grade fever and the pulmonary findings, we initiated treatment with prednisolone, 60 mg (1 mg/kg) orally on the fourth day of hospitalization. His fever resolved within the day, followed by a rapid improvement in his general condition and laboratory data. The rash had improved simultaneously, although the skin discoloration remained. Six days after initiating prednisolone, we tapered the dosage to 40 mg and discharged the patient on day 18 (Fig. 3). At the 3-month follow-up visit, the patient remained well with the prednisolone dose of 7.5 mg/day, which was discontinued 3 months later.
Discussion
As in other immunocompromised patients after the administration of anticancer drugs, we had to rule out vasculitis secondary to infections before diagnosing the drug-induced aortitis, since infectious disease was strongly associated with systemic vasculitis, including aortitis (12). Hence, it might be important in such patients to evaluate them for common infectious diseases that are often overlooked-not only bacterial bloodstream infections but also tuberculosis, syphilis, viral hepatitis, and human immunodeficiency virus-that are known causes of vasculitis before G-CSF-induced aortitis is diagnosed (13).
In this case, pegfilgrastim was administered 36 hours after the completion of the first cycle of AI (adriamycin, ifosfamide) chemotherapy, and a series of symptoms had begun 4 days later. Most cases of G-CSF-induced aortitis had been reported to occur 1 to 15 days after the administration of G-CSF, and a few cases were reported to develop 1 month to 1 year later (8,14). This variation in the latent period, which could interfere with the clinical diagnosis, might result from pharmacodynamic and pharmacokinetic factors such as the type and amount of G-CSF used, type of the preceding chemotherapy, and individual physiological differences. In fact, pegfilgrastim and lipegfilgrastim, which both have a longer half-life and produce equivalent effects with fewer administrations, have been most often reported as the drug causing aortitis (8-10). It is of interest that this condition has been reported more often in women than in men, although more detailed cases and epidemiological studies are needed to prove that G-CSF-induced aortitis is indeed more common in women.
Searching on web, G-CSF-induced aortitis in a patient being treated for sarcoma was thus found to be extremely rare. One reason why no cases of G-CSF-induced aortitis were previously reported in patients with sarcomas might be due to the low absolute number of such patients. Ogura et al. reported that according to a nationwide organ-specific cancer registry for bone and soft tissue tumors in Japan, the number of patients with sarcomas in 2012 was 1,598, which is an extremely low proportion of the 865,238 cases of all cancers (15,16). We believe that this case report, which concerns an orthopedic cancer, is important because the biological evidence that the administration of G-CSF could provoke aortitis is still lacking.
Although this patient did not exhibit any pulmonary manifestations, the lung interstitial changes found on CT seemed critical and warranted the administration of steroids, since there had been many reports of G-CSF-related pulmonary toxicity, which in some cases progressed to acute respiratory distress syndrome and to death (17-19). In a review of 20 cases of interstitial pneumonia secondary to treatment with G-CSF, Niitsu et al. reported that three patients died of respiratory and multiple organ failure; consequently, they emphasized the importance of starting steroid pulse therapy as early as possible when the diagnosis is made (20).
Although the skin lesions that this patient exhibited were not histologically confirmed, we speculated, from their macroscopic appearance, that they represented neutrophilic eccrine hidradenitis, which is neutrophilic dermatosis characterized by the sudden onset of erythematous papules or plaques with a neutrophilic infiltrate around eccrine glands, together with necrosis of these structures. Rising concentrations of the cytotoxic agents in sweat are thought to be the mechanism of neutrophilic eccrine hidradenitis, and doxorubicin is known to be one of the common causative substances (21). It is of interest that several such cases have been reported to be associated with the administration of G-CSF, and one of them occurred in patients who received pegfilgrastim after AI chemotherapy (22,23).
Without any guidelines available for the treatment of drug-induced aortitis, we set the initial dose of prednisolone as 60 mg, administered it orally, according to the Guideline for Management of Vasculitis Syndrome (Japanese Circulation Society 2008) for the diagnosis of giant cell arteritis (24). However, several cases of G-CSF-induced aortitis that remitted without the administration of prednisolone have been reported. We think that the degree of inflammatory response might vary in individual cases, and so the clinical decision of whether to administer prednisolone must be individualized. In our patient, prednisolone treatment was necessary because of sustained high-grade inflammatory markers and interstitial changes in the lungs.
In summary, we herein described a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. The patient required PSL administration because of the lung injuries and persisting high grade fever. The response to the treatment with PSL was good, and the patient had recovered without any sequelae. It has been almost 30 years since filgrastim was introduced to the market. However, G-CSF induced aortitis has not been well recognized. We speculate that one reason for this might be the lack of algorithm to predict patients at high risk to present this condition. Secondly, there is lack of specific signs and symptoms. In addition, as we described above, the condition sometimes subsides without the administration of steroids or immuno-suppressants which are usually indispensable for the treatment of other types of vasculitis syndrome. Therefore, we speculate that many cases of G-CSF induced may have been overlooked. This case report might be one type of supportive evidence of G-CSF induced aortitis, however, it is necessary to collect and examine future cases regarding what kind of patients: sex, races, age etc., are likely to present with aortitis due to G-CSF.
The authors state that they have no Conflict of Interest (COI).
|
Intravenous drip
|
DrugAdministrationRoute
|
CC BY-NC-ND
|
33191326
| 17,433,107
|
2021-04-15
|
What was the administration route of drug 'PEGFILGRASTIM'?
|
Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.
We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are commonly used to prevent and treat neutropenia caused by cancer chemotherapy. Meta-analyses of randomized controlled trials of G-CSFs as primary prophylaxis against febrile neutropenia have demonstrated significant reductions in the rates of short-term all-cause mortality, as well as rates of infection-related mortality, in patients with solid tumors and malignant lymphoma (1,2). A meta-analysis of 59 randomized controlled trials demonstrated that systemic cancer chemotherapy with primary adjunct G-CSF treatment was associated with a significantly greater intensity of the effect of the delivered chemotherapy doses and with greater relative and absolute risk reductions in all-cause mortality rates than was chemotherapy without adjunct G-CSF treatment over a long period (3). As for drug safety, Teshima et al. reported that according to the results of their post-marketing use survey in Japan, the rate of overall adverse effects was 7.47%; these effects included lumbago (3.84%), fever (1.62%), and bone pain (0.61%), and most were not serious and seemed to be ameliorated by the discontinuation of G-CSF treatment (4).
However, a few cases with serious adverse effects, such as interstitial pneumonia and extramedullary hematopoietic splenic rupture, have been reported after the administration of G-CSF (5,6). Pegfilgrastim, a relatively new G-CSF used to prevent febrile neutropenia, is a modified protein consisting of methoxy polyethylene glycol (PEG) molecular chains attached to a Met1 amino group of genetic recombinant filgrastim whose renal excretion is reduced and whose effects are prolonged (7). In Japan, pegfilgrastim is approved for use only to prevent febrile neutropenia after chemotherapy. To optimize its pharmacological effect and prevent adverse effects, the use of pegfilgrastim is restricted to patients at high risk for febrile neutropenia at least 24 hours after a course of chemotherapy. Over the past two decades, authors have reported cases of aortitis induced by G-CSF preparations such as filgrastim, lenograstim, and pegfilgrastim (8,9). Oshima et al., using the Japanese Adverse Drug Event Report database, reported that G-CSF treatment is associated with an increased risk for aortitis (10).
We herein report a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. This is a rare case of G-CSF induced aortitis occurred in a patient who was being treated for sarcoma and it is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological background.
Case Report
A 56-year-old man who was receiving treatment for the local recurrence of extraosseous mucinous chondrosarcoma on the right lower limb presented to our hospital because of an 8-day history of high fever, general fatigue, and a rash with pain. He did not report either any upper or lower respiratory symptoms, abdominal pain, diarrhea, arthralgias, headache, or visual impairment. He had finished the first 4-day course of chemotherapy with 2-day adriamycin (25 mg/m2 each) and four-day ifosfamide (2.8 g/m2 each), followed 36 hours later by subcutaneous administration of pegylated G-CSF (3.6 mg), and he was discharged immediately. Four days later, the symptoms began.
On presentation, he did not appear ill, and he was alert and oriented. His body weight was 69.4 kg, and his height was 169 cm. His vital signs were as follows: blood pressure, 90/47 mm Hg; pulse rate, 95 beats/min; body temperature, 39.1℃; respiratory rate, 12/min; and oxygen saturation level, 99% on room air. A physical examination revealed palm-sized dark red-to-purplish indurated rashes with tenderness on the right cubital fossa and over the left knee socket (Fig. 1a, b). The surface lymph nodes, liver, and spleen were not palpable. The initial laboratory data revealed the following: a white blood cell count of 15,780/μL (90.0% segmented neutrophils, 7.0% stab neutrophils 1.0% monocytes, 2.0% lymphocytes, and 0% atypical lymphocytes, visually confirmed), hemoglobin level of 11.8 g/dL, platelet count of 109,000/μL, and serum C-reactive protein level of 38.77 mg/dL. Table lists the other laboratory data. The results of antigen tests for influenza virus were negative. Two sets of blood culture were conducted. Computed tomography (CT) without contrast media revealed inflammatory changes in the soft tissue surrounding the aorta, partial reticular change and ground-glass opacities scattered throughout both lungs, and splenomegaly (Fig. 2).
Figure 1. Erythematous skin lesions on the right cubital fossa (a) and over the left knee socket (b), on admission.
Table. Laboratory Data on Admission.
Complete blood count Serological test Urine test
WBC 15,780 ×103/μL CRP 38.77 mg/dL occult blood 2+
N-Stab 7 % IgG 828 mg/dL ketone negative
N-Seg 90 % IgA 327 mg/dL glucose negative
Eosino 0 % IgM 103 mg/dL protein 1+
Baso 0 % IgE 53 mg/dL Urinary sediment
Mono 1 % CH50 >60 CH50/mL RBC <4 /HPF
Lymph 2 % C3 162 mg/dL WBC <4 /HPF
RBC 442 ×104/μL C4 45 mg/dL Squamous cell 0-1 /HPF
Hemoglobin 11.8 g/dL sIL-2R 1,922 U/mL cast positive
Platelet 109 ×104/μL ANA <80 β2 microglobulin 18.7 mg/dL
Biochemistry PR3-ANCA <1.0 U/mL
TP 6.2 g/dL MPO-ANCA <1.0 U/mL
Alb 2.4 g/dL anti ssDNA 2.5 AU/mL
T-bil 0.8 mg/dL anti dsDNA <1.2 IU/mL
D-bil 0.5 mg/dL ASO 38 IU/mL
AST 22 U/L ASK ×320
ALT 99 U/L PCT 0.58 ng/mL
Ch-E 157 U/L IGRA negative
ALP 1,077 U/L RPR <1.0
LAP 149 U/L TPHA 0
γ-GTP 302 U/L HCV Ab 0.03
LD 208 U/L HBs Ag 0 IU/mL
CK 19 U/L CMV IgG 64 UA/mL
UN 33 mg/dL CMV IgM negative
Creatinine 2.29 mg/dL ESR 114 mm/hr
Na 139 mmol/L
K 3.7 mmol/L
Cl 101 mmol/L
Blood Sugar 159 mg/dL
HbA1c 6.4 %
WBC: white blood cell, RBC: red blood cell, AST: asparatate aminotransferase, ALT: alanine aminotransferase, N-stab: stab neutrophil, N-seg: segmented neutrophil, Eosino: eosinophil, Baso: basophil, Mono: monocyte, Lymph; Lymphocyte, TP: total protein, Alb: albumin, T-bil: total bililubin, D-bil: direct bililubin, Ch-E: cholinesterase, ALP: alkaline phosphatase, LAP: leucine aminopeptidase, γ-GTP: γ-glutamyl transpeptidase, LD: lactate dehydrogenase, UN: urea nitrogen, CK: creatine kinase, Na: sodium, K: potassium, Cl: chloride, HbA1c: hemoglobine A1c, CRP: C-reactive protein, IgG: Immunoglobulin G, IgA: Immunoglobulin A, IgM: Immunoglobulin M, IgE: Immunoglobulin E, CH50: 50% hemolytic complement activity, sIL-2 R: soluble Interleukin-2 receptor, ANA: antinuclear antibody, PR3-ANCA: serine proteinase3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-ssDNA: anti-single-stranded DNA antibody, anti-dsDNA: anti-double stranded DNA antibody, ASO: antistreptolysin O, ASK: antistreptokinase, PCT: procalcitonin, IGRA: interferon-gamma releasing assay, RPR: rapid plasma reagin card agglutination test, TPHA: treponema pallidum antibody hemagglutination test, HCV ab: hepatitis C virus antibody, HBs Ag: hepatitis B virus antigen, CMV IgG: cytomegalovirus antibody, immunoglobulin G, CMV IgM: cytomegalovirus antibody, immunoglobulin M, ESR: erythrocyte sedimentation rate
Figure 2. Computed tomography (CT) without contrast media, showing aortitis (a; white arrowheads), patchy interstitial changes scattered throughout both lungs (b; black arrowheads) and a small amount of pleural effusion (b; yellow arrowheads), and splenomegaly (c).
Because he was immunocompromised, we diagnosed systemic inflammatory response syndrome and acute renal failure caused by bacterial infection. We promptly administered 2 L of crystalloid infusion for resuscitation and empirical piperacillin/tazobactam as shown in Fig. 3. His renal function was restored rapidly, but high-grade fever persisted for 4 days, as did the inflammatory markers, despite antibiotic treatment. However, this patient did not appear ill, and his food intake did not decrease during the first 4 days after his admission to this hospital. Furthermore, even with a high-grade fever (>40℃), his pulse rate had stayed in the range of 60/min to 70/min, which represented relative bradycardia, which in turn has been considered a characteristic of drug-related fever (11). A blood culture yielded negative results, as did serological tests (including cytomegalovirus antigen and autoantibodies); thus, we diagnosed aortitis resulting from G-CSF administration.
Figure 3. Clinical course of this case. CRP: C-reactive protein, PIPC/TAZ: piperacillin/tazobactam, PSL: prednisolone, WBC: white blood cell count
Because of concerns about the high-grade fever and the pulmonary findings, we initiated treatment with prednisolone, 60 mg (1 mg/kg) orally on the fourth day of hospitalization. His fever resolved within the day, followed by a rapid improvement in his general condition and laboratory data. The rash had improved simultaneously, although the skin discoloration remained. Six days after initiating prednisolone, we tapered the dosage to 40 mg and discharged the patient on day 18 (Fig. 3). At the 3-month follow-up visit, the patient remained well with the prednisolone dose of 7.5 mg/day, which was discontinued 3 months later.
Discussion
As in other immunocompromised patients after the administration of anticancer drugs, we had to rule out vasculitis secondary to infections before diagnosing the drug-induced aortitis, since infectious disease was strongly associated with systemic vasculitis, including aortitis (12). Hence, it might be important in such patients to evaluate them for common infectious diseases that are often overlooked-not only bacterial bloodstream infections but also tuberculosis, syphilis, viral hepatitis, and human immunodeficiency virus-that are known causes of vasculitis before G-CSF-induced aortitis is diagnosed (13).
In this case, pegfilgrastim was administered 36 hours after the completion of the first cycle of AI (adriamycin, ifosfamide) chemotherapy, and a series of symptoms had begun 4 days later. Most cases of G-CSF-induced aortitis had been reported to occur 1 to 15 days after the administration of G-CSF, and a few cases were reported to develop 1 month to 1 year later (8,14). This variation in the latent period, which could interfere with the clinical diagnosis, might result from pharmacodynamic and pharmacokinetic factors such as the type and amount of G-CSF used, type of the preceding chemotherapy, and individual physiological differences. In fact, pegfilgrastim and lipegfilgrastim, which both have a longer half-life and produce equivalent effects with fewer administrations, have been most often reported as the drug causing aortitis (8-10). It is of interest that this condition has been reported more often in women than in men, although more detailed cases and epidemiological studies are needed to prove that G-CSF-induced aortitis is indeed more common in women.
Searching on web, G-CSF-induced aortitis in a patient being treated for sarcoma was thus found to be extremely rare. One reason why no cases of G-CSF-induced aortitis were previously reported in patients with sarcomas might be due to the low absolute number of such patients. Ogura et al. reported that according to a nationwide organ-specific cancer registry for bone and soft tissue tumors in Japan, the number of patients with sarcomas in 2012 was 1,598, which is an extremely low proportion of the 865,238 cases of all cancers (15,16). We believe that this case report, which concerns an orthopedic cancer, is important because the biological evidence that the administration of G-CSF could provoke aortitis is still lacking.
Although this patient did not exhibit any pulmonary manifestations, the lung interstitial changes found on CT seemed critical and warranted the administration of steroids, since there had been many reports of G-CSF-related pulmonary toxicity, which in some cases progressed to acute respiratory distress syndrome and to death (17-19). In a review of 20 cases of interstitial pneumonia secondary to treatment with G-CSF, Niitsu et al. reported that three patients died of respiratory and multiple organ failure; consequently, they emphasized the importance of starting steroid pulse therapy as early as possible when the diagnosis is made (20).
Although the skin lesions that this patient exhibited were not histologically confirmed, we speculated, from their macroscopic appearance, that they represented neutrophilic eccrine hidradenitis, which is neutrophilic dermatosis characterized by the sudden onset of erythematous papules or plaques with a neutrophilic infiltrate around eccrine glands, together with necrosis of these structures. Rising concentrations of the cytotoxic agents in sweat are thought to be the mechanism of neutrophilic eccrine hidradenitis, and doxorubicin is known to be one of the common causative substances (21). It is of interest that several such cases have been reported to be associated with the administration of G-CSF, and one of them occurred in patients who received pegfilgrastim after AI chemotherapy (22,23).
Without any guidelines available for the treatment of drug-induced aortitis, we set the initial dose of prednisolone as 60 mg, administered it orally, according to the Guideline for Management of Vasculitis Syndrome (Japanese Circulation Society 2008) for the diagnosis of giant cell arteritis (24). However, several cases of G-CSF-induced aortitis that remitted without the administration of prednisolone have been reported. We think that the degree of inflammatory response might vary in individual cases, and so the clinical decision of whether to administer prednisolone must be individualized. In our patient, prednisolone treatment was necessary because of sustained high-grade inflammatory markers and interstitial changes in the lungs.
In summary, we herein described a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. The patient required PSL administration because of the lung injuries and persisting high grade fever. The response to the treatment with PSL was good, and the patient had recovered without any sequelae. It has been almost 30 years since filgrastim was introduced to the market. However, G-CSF induced aortitis has not been well recognized. We speculate that one reason for this might be the lack of algorithm to predict patients at high risk to present this condition. Secondly, there is lack of specific signs and symptoms. In addition, as we described above, the condition sometimes subsides without the administration of steroids or immuno-suppressants which are usually indispensable for the treatment of other types of vasculitis syndrome. Therefore, we speculate that many cases of G-CSF induced may have been overlooked. This case report might be one type of supportive evidence of G-CSF induced aortitis, however, it is necessary to collect and examine future cases regarding what kind of patients: sex, races, age etc., are likely to present with aortitis due to G-CSF.
The authors state that they have no Conflict of Interest (COI).
|
Subcutaneous
|
DrugAdministrationRoute
|
CC BY-NC-ND
|
33191326
| 17,433,107
|
2021-04-15
|
What was the outcome of reaction 'Aortitis'?
|
Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.
We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are commonly used to prevent and treat neutropenia caused by cancer chemotherapy. Meta-analyses of randomized controlled trials of G-CSFs as primary prophylaxis against febrile neutropenia have demonstrated significant reductions in the rates of short-term all-cause mortality, as well as rates of infection-related mortality, in patients with solid tumors and malignant lymphoma (1,2). A meta-analysis of 59 randomized controlled trials demonstrated that systemic cancer chemotherapy with primary adjunct G-CSF treatment was associated with a significantly greater intensity of the effect of the delivered chemotherapy doses and with greater relative and absolute risk reductions in all-cause mortality rates than was chemotherapy without adjunct G-CSF treatment over a long period (3). As for drug safety, Teshima et al. reported that according to the results of their post-marketing use survey in Japan, the rate of overall adverse effects was 7.47%; these effects included lumbago (3.84%), fever (1.62%), and bone pain (0.61%), and most were not serious and seemed to be ameliorated by the discontinuation of G-CSF treatment (4).
However, a few cases with serious adverse effects, such as interstitial pneumonia and extramedullary hematopoietic splenic rupture, have been reported after the administration of G-CSF (5,6). Pegfilgrastim, a relatively new G-CSF used to prevent febrile neutropenia, is a modified protein consisting of methoxy polyethylene glycol (PEG) molecular chains attached to a Met1 amino group of genetic recombinant filgrastim whose renal excretion is reduced and whose effects are prolonged (7). In Japan, pegfilgrastim is approved for use only to prevent febrile neutropenia after chemotherapy. To optimize its pharmacological effect and prevent adverse effects, the use of pegfilgrastim is restricted to patients at high risk for febrile neutropenia at least 24 hours after a course of chemotherapy. Over the past two decades, authors have reported cases of aortitis induced by G-CSF preparations such as filgrastim, lenograstim, and pegfilgrastim (8,9). Oshima et al., using the Japanese Adverse Drug Event Report database, reported that G-CSF treatment is associated with an increased risk for aortitis (10).
We herein report a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. This is a rare case of G-CSF induced aortitis occurred in a patient who was being treated for sarcoma and it is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological background.
Case Report
A 56-year-old man who was receiving treatment for the local recurrence of extraosseous mucinous chondrosarcoma on the right lower limb presented to our hospital because of an 8-day history of high fever, general fatigue, and a rash with pain. He did not report either any upper or lower respiratory symptoms, abdominal pain, diarrhea, arthralgias, headache, or visual impairment. He had finished the first 4-day course of chemotherapy with 2-day adriamycin (25 mg/m2 each) and four-day ifosfamide (2.8 g/m2 each), followed 36 hours later by subcutaneous administration of pegylated G-CSF (3.6 mg), and he was discharged immediately. Four days later, the symptoms began.
On presentation, he did not appear ill, and he was alert and oriented. His body weight was 69.4 kg, and his height was 169 cm. His vital signs were as follows: blood pressure, 90/47 mm Hg; pulse rate, 95 beats/min; body temperature, 39.1℃; respiratory rate, 12/min; and oxygen saturation level, 99% on room air. A physical examination revealed palm-sized dark red-to-purplish indurated rashes with tenderness on the right cubital fossa and over the left knee socket (Fig. 1a, b). The surface lymph nodes, liver, and spleen were not palpable. The initial laboratory data revealed the following: a white blood cell count of 15,780/μL (90.0% segmented neutrophils, 7.0% stab neutrophils 1.0% monocytes, 2.0% lymphocytes, and 0% atypical lymphocytes, visually confirmed), hemoglobin level of 11.8 g/dL, platelet count of 109,000/μL, and serum C-reactive protein level of 38.77 mg/dL. Table lists the other laboratory data. The results of antigen tests for influenza virus were negative. Two sets of blood culture were conducted. Computed tomography (CT) without contrast media revealed inflammatory changes in the soft tissue surrounding the aorta, partial reticular change and ground-glass opacities scattered throughout both lungs, and splenomegaly (Fig. 2).
Figure 1. Erythematous skin lesions on the right cubital fossa (a) and over the left knee socket (b), on admission.
Table. Laboratory Data on Admission.
Complete blood count Serological test Urine test
WBC 15,780 ×103/μL CRP 38.77 mg/dL occult blood 2+
N-Stab 7 % IgG 828 mg/dL ketone negative
N-Seg 90 % IgA 327 mg/dL glucose negative
Eosino 0 % IgM 103 mg/dL protein 1+
Baso 0 % IgE 53 mg/dL Urinary sediment
Mono 1 % CH50 >60 CH50/mL RBC <4 /HPF
Lymph 2 % C3 162 mg/dL WBC <4 /HPF
RBC 442 ×104/μL C4 45 mg/dL Squamous cell 0-1 /HPF
Hemoglobin 11.8 g/dL sIL-2R 1,922 U/mL cast positive
Platelet 109 ×104/μL ANA <80 β2 microglobulin 18.7 mg/dL
Biochemistry PR3-ANCA <1.0 U/mL
TP 6.2 g/dL MPO-ANCA <1.0 U/mL
Alb 2.4 g/dL anti ssDNA 2.5 AU/mL
T-bil 0.8 mg/dL anti dsDNA <1.2 IU/mL
D-bil 0.5 mg/dL ASO 38 IU/mL
AST 22 U/L ASK ×320
ALT 99 U/L PCT 0.58 ng/mL
Ch-E 157 U/L IGRA negative
ALP 1,077 U/L RPR <1.0
LAP 149 U/L TPHA 0
γ-GTP 302 U/L HCV Ab 0.03
LD 208 U/L HBs Ag 0 IU/mL
CK 19 U/L CMV IgG 64 UA/mL
UN 33 mg/dL CMV IgM negative
Creatinine 2.29 mg/dL ESR 114 mm/hr
Na 139 mmol/L
K 3.7 mmol/L
Cl 101 mmol/L
Blood Sugar 159 mg/dL
HbA1c 6.4 %
WBC: white blood cell, RBC: red blood cell, AST: asparatate aminotransferase, ALT: alanine aminotransferase, N-stab: stab neutrophil, N-seg: segmented neutrophil, Eosino: eosinophil, Baso: basophil, Mono: monocyte, Lymph; Lymphocyte, TP: total protein, Alb: albumin, T-bil: total bililubin, D-bil: direct bililubin, Ch-E: cholinesterase, ALP: alkaline phosphatase, LAP: leucine aminopeptidase, γ-GTP: γ-glutamyl transpeptidase, LD: lactate dehydrogenase, UN: urea nitrogen, CK: creatine kinase, Na: sodium, K: potassium, Cl: chloride, HbA1c: hemoglobine A1c, CRP: C-reactive protein, IgG: Immunoglobulin G, IgA: Immunoglobulin A, IgM: Immunoglobulin M, IgE: Immunoglobulin E, CH50: 50% hemolytic complement activity, sIL-2 R: soluble Interleukin-2 receptor, ANA: antinuclear antibody, PR3-ANCA: serine proteinase3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-ssDNA: anti-single-stranded DNA antibody, anti-dsDNA: anti-double stranded DNA antibody, ASO: antistreptolysin O, ASK: antistreptokinase, PCT: procalcitonin, IGRA: interferon-gamma releasing assay, RPR: rapid plasma reagin card agglutination test, TPHA: treponema pallidum antibody hemagglutination test, HCV ab: hepatitis C virus antibody, HBs Ag: hepatitis B virus antigen, CMV IgG: cytomegalovirus antibody, immunoglobulin G, CMV IgM: cytomegalovirus antibody, immunoglobulin M, ESR: erythrocyte sedimentation rate
Figure 2. Computed tomography (CT) without contrast media, showing aortitis (a; white arrowheads), patchy interstitial changes scattered throughout both lungs (b; black arrowheads) and a small amount of pleural effusion (b; yellow arrowheads), and splenomegaly (c).
Because he was immunocompromised, we diagnosed systemic inflammatory response syndrome and acute renal failure caused by bacterial infection. We promptly administered 2 L of crystalloid infusion for resuscitation and empirical piperacillin/tazobactam as shown in Fig. 3. His renal function was restored rapidly, but high-grade fever persisted for 4 days, as did the inflammatory markers, despite antibiotic treatment. However, this patient did not appear ill, and his food intake did not decrease during the first 4 days after his admission to this hospital. Furthermore, even with a high-grade fever (>40℃), his pulse rate had stayed in the range of 60/min to 70/min, which represented relative bradycardia, which in turn has been considered a characteristic of drug-related fever (11). A blood culture yielded negative results, as did serological tests (including cytomegalovirus antigen and autoantibodies); thus, we diagnosed aortitis resulting from G-CSF administration.
Figure 3. Clinical course of this case. CRP: C-reactive protein, PIPC/TAZ: piperacillin/tazobactam, PSL: prednisolone, WBC: white blood cell count
Because of concerns about the high-grade fever and the pulmonary findings, we initiated treatment with prednisolone, 60 mg (1 mg/kg) orally on the fourth day of hospitalization. His fever resolved within the day, followed by a rapid improvement in his general condition and laboratory data. The rash had improved simultaneously, although the skin discoloration remained. Six days after initiating prednisolone, we tapered the dosage to 40 mg and discharged the patient on day 18 (Fig. 3). At the 3-month follow-up visit, the patient remained well with the prednisolone dose of 7.5 mg/day, which was discontinued 3 months later.
Discussion
As in other immunocompromised patients after the administration of anticancer drugs, we had to rule out vasculitis secondary to infections before diagnosing the drug-induced aortitis, since infectious disease was strongly associated with systemic vasculitis, including aortitis (12). Hence, it might be important in such patients to evaluate them for common infectious diseases that are often overlooked-not only bacterial bloodstream infections but also tuberculosis, syphilis, viral hepatitis, and human immunodeficiency virus-that are known causes of vasculitis before G-CSF-induced aortitis is diagnosed (13).
In this case, pegfilgrastim was administered 36 hours after the completion of the first cycle of AI (adriamycin, ifosfamide) chemotherapy, and a series of symptoms had begun 4 days later. Most cases of G-CSF-induced aortitis had been reported to occur 1 to 15 days after the administration of G-CSF, and a few cases were reported to develop 1 month to 1 year later (8,14). This variation in the latent period, which could interfere with the clinical diagnosis, might result from pharmacodynamic and pharmacokinetic factors such as the type and amount of G-CSF used, type of the preceding chemotherapy, and individual physiological differences. In fact, pegfilgrastim and lipegfilgrastim, which both have a longer half-life and produce equivalent effects with fewer administrations, have been most often reported as the drug causing aortitis (8-10). It is of interest that this condition has been reported more often in women than in men, although more detailed cases and epidemiological studies are needed to prove that G-CSF-induced aortitis is indeed more common in women.
Searching on web, G-CSF-induced aortitis in a patient being treated for sarcoma was thus found to be extremely rare. One reason why no cases of G-CSF-induced aortitis were previously reported in patients with sarcomas might be due to the low absolute number of such patients. Ogura et al. reported that according to a nationwide organ-specific cancer registry for bone and soft tissue tumors in Japan, the number of patients with sarcomas in 2012 was 1,598, which is an extremely low proportion of the 865,238 cases of all cancers (15,16). We believe that this case report, which concerns an orthopedic cancer, is important because the biological evidence that the administration of G-CSF could provoke aortitis is still lacking.
Although this patient did not exhibit any pulmonary manifestations, the lung interstitial changes found on CT seemed critical and warranted the administration of steroids, since there had been many reports of G-CSF-related pulmonary toxicity, which in some cases progressed to acute respiratory distress syndrome and to death (17-19). In a review of 20 cases of interstitial pneumonia secondary to treatment with G-CSF, Niitsu et al. reported that three patients died of respiratory and multiple organ failure; consequently, they emphasized the importance of starting steroid pulse therapy as early as possible when the diagnosis is made (20).
Although the skin lesions that this patient exhibited were not histologically confirmed, we speculated, from their macroscopic appearance, that they represented neutrophilic eccrine hidradenitis, which is neutrophilic dermatosis characterized by the sudden onset of erythematous papules or plaques with a neutrophilic infiltrate around eccrine glands, together with necrosis of these structures. Rising concentrations of the cytotoxic agents in sweat are thought to be the mechanism of neutrophilic eccrine hidradenitis, and doxorubicin is known to be one of the common causative substances (21). It is of interest that several such cases have been reported to be associated with the administration of G-CSF, and one of them occurred in patients who received pegfilgrastim after AI chemotherapy (22,23).
Without any guidelines available for the treatment of drug-induced aortitis, we set the initial dose of prednisolone as 60 mg, administered it orally, according to the Guideline for Management of Vasculitis Syndrome (Japanese Circulation Society 2008) for the diagnosis of giant cell arteritis (24). However, several cases of G-CSF-induced aortitis that remitted without the administration of prednisolone have been reported. We think that the degree of inflammatory response might vary in individual cases, and so the clinical decision of whether to administer prednisolone must be individualized. In our patient, prednisolone treatment was necessary because of sustained high-grade inflammatory markers and interstitial changes in the lungs.
In summary, we herein described a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. The patient required PSL administration because of the lung injuries and persisting high grade fever. The response to the treatment with PSL was good, and the patient had recovered without any sequelae. It has been almost 30 years since filgrastim was introduced to the market. However, G-CSF induced aortitis has not been well recognized. We speculate that one reason for this might be the lack of algorithm to predict patients at high risk to present this condition. Secondly, there is lack of specific signs and symptoms. In addition, as we described above, the condition sometimes subsides without the administration of steroids or immuno-suppressants which are usually indispensable for the treatment of other types of vasculitis syndrome. Therefore, we speculate that many cases of G-CSF induced may have been overlooked. This case report might be one type of supportive evidence of G-CSF induced aortitis, however, it is necessary to collect and examine future cases regarding what kind of patients: sex, races, age etc., are likely to present with aortitis due to G-CSF.
The authors state that they have no Conflict of Interest (COI).
|
Recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33191326
| 17,433,107
|
2021-04-15
|
What was the outcome of reaction 'Hidradenitis'?
|
Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.
We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are commonly used to prevent and treat neutropenia caused by cancer chemotherapy. Meta-analyses of randomized controlled trials of G-CSFs as primary prophylaxis against febrile neutropenia have demonstrated significant reductions in the rates of short-term all-cause mortality, as well as rates of infection-related mortality, in patients with solid tumors and malignant lymphoma (1,2). A meta-analysis of 59 randomized controlled trials demonstrated that systemic cancer chemotherapy with primary adjunct G-CSF treatment was associated with a significantly greater intensity of the effect of the delivered chemotherapy doses and with greater relative and absolute risk reductions in all-cause mortality rates than was chemotherapy without adjunct G-CSF treatment over a long period (3). As for drug safety, Teshima et al. reported that according to the results of their post-marketing use survey in Japan, the rate of overall adverse effects was 7.47%; these effects included lumbago (3.84%), fever (1.62%), and bone pain (0.61%), and most were not serious and seemed to be ameliorated by the discontinuation of G-CSF treatment (4).
However, a few cases with serious adverse effects, such as interstitial pneumonia and extramedullary hematopoietic splenic rupture, have been reported after the administration of G-CSF (5,6). Pegfilgrastim, a relatively new G-CSF used to prevent febrile neutropenia, is a modified protein consisting of methoxy polyethylene glycol (PEG) molecular chains attached to a Met1 amino group of genetic recombinant filgrastim whose renal excretion is reduced and whose effects are prolonged (7). In Japan, pegfilgrastim is approved for use only to prevent febrile neutropenia after chemotherapy. To optimize its pharmacological effect and prevent adverse effects, the use of pegfilgrastim is restricted to patients at high risk for febrile neutropenia at least 24 hours after a course of chemotherapy. Over the past two decades, authors have reported cases of aortitis induced by G-CSF preparations such as filgrastim, lenograstim, and pegfilgrastim (8,9). Oshima et al., using the Japanese Adverse Drug Event Report database, reported that G-CSF treatment is associated with an increased risk for aortitis (10).
We herein report a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. This is a rare case of G-CSF induced aortitis occurred in a patient who was being treated for sarcoma and it is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological background.
Case Report
A 56-year-old man who was receiving treatment for the local recurrence of extraosseous mucinous chondrosarcoma on the right lower limb presented to our hospital because of an 8-day history of high fever, general fatigue, and a rash with pain. He did not report either any upper or lower respiratory symptoms, abdominal pain, diarrhea, arthralgias, headache, or visual impairment. He had finished the first 4-day course of chemotherapy with 2-day adriamycin (25 mg/m2 each) and four-day ifosfamide (2.8 g/m2 each), followed 36 hours later by subcutaneous administration of pegylated G-CSF (3.6 mg), and he was discharged immediately. Four days later, the symptoms began.
On presentation, he did not appear ill, and he was alert and oriented. His body weight was 69.4 kg, and his height was 169 cm. His vital signs were as follows: blood pressure, 90/47 mm Hg; pulse rate, 95 beats/min; body temperature, 39.1℃; respiratory rate, 12/min; and oxygen saturation level, 99% on room air. A physical examination revealed palm-sized dark red-to-purplish indurated rashes with tenderness on the right cubital fossa and over the left knee socket (Fig. 1a, b). The surface lymph nodes, liver, and spleen were not palpable. The initial laboratory data revealed the following: a white blood cell count of 15,780/μL (90.0% segmented neutrophils, 7.0% stab neutrophils 1.0% monocytes, 2.0% lymphocytes, and 0% atypical lymphocytes, visually confirmed), hemoglobin level of 11.8 g/dL, platelet count of 109,000/μL, and serum C-reactive protein level of 38.77 mg/dL. Table lists the other laboratory data. The results of antigen tests for influenza virus were negative. Two sets of blood culture were conducted. Computed tomography (CT) without contrast media revealed inflammatory changes in the soft tissue surrounding the aorta, partial reticular change and ground-glass opacities scattered throughout both lungs, and splenomegaly (Fig. 2).
Figure 1. Erythematous skin lesions on the right cubital fossa (a) and over the left knee socket (b), on admission.
Table. Laboratory Data on Admission.
Complete blood count Serological test Urine test
WBC 15,780 ×103/μL CRP 38.77 mg/dL occult blood 2+
N-Stab 7 % IgG 828 mg/dL ketone negative
N-Seg 90 % IgA 327 mg/dL glucose negative
Eosino 0 % IgM 103 mg/dL protein 1+
Baso 0 % IgE 53 mg/dL Urinary sediment
Mono 1 % CH50 >60 CH50/mL RBC <4 /HPF
Lymph 2 % C3 162 mg/dL WBC <4 /HPF
RBC 442 ×104/μL C4 45 mg/dL Squamous cell 0-1 /HPF
Hemoglobin 11.8 g/dL sIL-2R 1,922 U/mL cast positive
Platelet 109 ×104/μL ANA <80 β2 microglobulin 18.7 mg/dL
Biochemistry PR3-ANCA <1.0 U/mL
TP 6.2 g/dL MPO-ANCA <1.0 U/mL
Alb 2.4 g/dL anti ssDNA 2.5 AU/mL
T-bil 0.8 mg/dL anti dsDNA <1.2 IU/mL
D-bil 0.5 mg/dL ASO 38 IU/mL
AST 22 U/L ASK ×320
ALT 99 U/L PCT 0.58 ng/mL
Ch-E 157 U/L IGRA negative
ALP 1,077 U/L RPR <1.0
LAP 149 U/L TPHA 0
γ-GTP 302 U/L HCV Ab 0.03
LD 208 U/L HBs Ag 0 IU/mL
CK 19 U/L CMV IgG 64 UA/mL
UN 33 mg/dL CMV IgM negative
Creatinine 2.29 mg/dL ESR 114 mm/hr
Na 139 mmol/L
K 3.7 mmol/L
Cl 101 mmol/L
Blood Sugar 159 mg/dL
HbA1c 6.4 %
WBC: white blood cell, RBC: red blood cell, AST: asparatate aminotransferase, ALT: alanine aminotransferase, N-stab: stab neutrophil, N-seg: segmented neutrophil, Eosino: eosinophil, Baso: basophil, Mono: monocyte, Lymph; Lymphocyte, TP: total protein, Alb: albumin, T-bil: total bililubin, D-bil: direct bililubin, Ch-E: cholinesterase, ALP: alkaline phosphatase, LAP: leucine aminopeptidase, γ-GTP: γ-glutamyl transpeptidase, LD: lactate dehydrogenase, UN: urea nitrogen, CK: creatine kinase, Na: sodium, K: potassium, Cl: chloride, HbA1c: hemoglobine A1c, CRP: C-reactive protein, IgG: Immunoglobulin G, IgA: Immunoglobulin A, IgM: Immunoglobulin M, IgE: Immunoglobulin E, CH50: 50% hemolytic complement activity, sIL-2 R: soluble Interleukin-2 receptor, ANA: antinuclear antibody, PR3-ANCA: serine proteinase3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-ssDNA: anti-single-stranded DNA antibody, anti-dsDNA: anti-double stranded DNA antibody, ASO: antistreptolysin O, ASK: antistreptokinase, PCT: procalcitonin, IGRA: interferon-gamma releasing assay, RPR: rapid plasma reagin card agglutination test, TPHA: treponema pallidum antibody hemagglutination test, HCV ab: hepatitis C virus antibody, HBs Ag: hepatitis B virus antigen, CMV IgG: cytomegalovirus antibody, immunoglobulin G, CMV IgM: cytomegalovirus antibody, immunoglobulin M, ESR: erythrocyte sedimentation rate
Figure 2. Computed tomography (CT) without contrast media, showing aortitis (a; white arrowheads), patchy interstitial changes scattered throughout both lungs (b; black arrowheads) and a small amount of pleural effusion (b; yellow arrowheads), and splenomegaly (c).
Because he was immunocompromised, we diagnosed systemic inflammatory response syndrome and acute renal failure caused by bacterial infection. We promptly administered 2 L of crystalloid infusion for resuscitation and empirical piperacillin/tazobactam as shown in Fig. 3. His renal function was restored rapidly, but high-grade fever persisted for 4 days, as did the inflammatory markers, despite antibiotic treatment. However, this patient did not appear ill, and his food intake did not decrease during the first 4 days after his admission to this hospital. Furthermore, even with a high-grade fever (>40℃), his pulse rate had stayed in the range of 60/min to 70/min, which represented relative bradycardia, which in turn has been considered a characteristic of drug-related fever (11). A blood culture yielded negative results, as did serological tests (including cytomegalovirus antigen and autoantibodies); thus, we diagnosed aortitis resulting from G-CSF administration.
Figure 3. Clinical course of this case. CRP: C-reactive protein, PIPC/TAZ: piperacillin/tazobactam, PSL: prednisolone, WBC: white blood cell count
Because of concerns about the high-grade fever and the pulmonary findings, we initiated treatment with prednisolone, 60 mg (1 mg/kg) orally on the fourth day of hospitalization. His fever resolved within the day, followed by a rapid improvement in his general condition and laboratory data. The rash had improved simultaneously, although the skin discoloration remained. Six days after initiating prednisolone, we tapered the dosage to 40 mg and discharged the patient on day 18 (Fig. 3). At the 3-month follow-up visit, the patient remained well with the prednisolone dose of 7.5 mg/day, which was discontinued 3 months later.
Discussion
As in other immunocompromised patients after the administration of anticancer drugs, we had to rule out vasculitis secondary to infections before diagnosing the drug-induced aortitis, since infectious disease was strongly associated with systemic vasculitis, including aortitis (12). Hence, it might be important in such patients to evaluate them for common infectious diseases that are often overlooked-not only bacterial bloodstream infections but also tuberculosis, syphilis, viral hepatitis, and human immunodeficiency virus-that are known causes of vasculitis before G-CSF-induced aortitis is diagnosed (13).
In this case, pegfilgrastim was administered 36 hours after the completion of the first cycle of AI (adriamycin, ifosfamide) chemotherapy, and a series of symptoms had begun 4 days later. Most cases of G-CSF-induced aortitis had been reported to occur 1 to 15 days after the administration of G-CSF, and a few cases were reported to develop 1 month to 1 year later (8,14). This variation in the latent period, which could interfere with the clinical diagnosis, might result from pharmacodynamic and pharmacokinetic factors such as the type and amount of G-CSF used, type of the preceding chemotherapy, and individual physiological differences. In fact, pegfilgrastim and lipegfilgrastim, which both have a longer half-life and produce equivalent effects with fewer administrations, have been most often reported as the drug causing aortitis (8-10). It is of interest that this condition has been reported more often in women than in men, although more detailed cases and epidemiological studies are needed to prove that G-CSF-induced aortitis is indeed more common in women.
Searching on web, G-CSF-induced aortitis in a patient being treated for sarcoma was thus found to be extremely rare. One reason why no cases of G-CSF-induced aortitis were previously reported in patients with sarcomas might be due to the low absolute number of such patients. Ogura et al. reported that according to a nationwide organ-specific cancer registry for bone and soft tissue tumors in Japan, the number of patients with sarcomas in 2012 was 1,598, which is an extremely low proportion of the 865,238 cases of all cancers (15,16). We believe that this case report, which concerns an orthopedic cancer, is important because the biological evidence that the administration of G-CSF could provoke aortitis is still lacking.
Although this patient did not exhibit any pulmonary manifestations, the lung interstitial changes found on CT seemed critical and warranted the administration of steroids, since there had been many reports of G-CSF-related pulmonary toxicity, which in some cases progressed to acute respiratory distress syndrome and to death (17-19). In a review of 20 cases of interstitial pneumonia secondary to treatment with G-CSF, Niitsu et al. reported that three patients died of respiratory and multiple organ failure; consequently, they emphasized the importance of starting steroid pulse therapy as early as possible when the diagnosis is made (20).
Although the skin lesions that this patient exhibited were not histologically confirmed, we speculated, from their macroscopic appearance, that they represented neutrophilic eccrine hidradenitis, which is neutrophilic dermatosis characterized by the sudden onset of erythematous papules or plaques with a neutrophilic infiltrate around eccrine glands, together with necrosis of these structures. Rising concentrations of the cytotoxic agents in sweat are thought to be the mechanism of neutrophilic eccrine hidradenitis, and doxorubicin is known to be one of the common causative substances (21). It is of interest that several such cases have been reported to be associated with the administration of G-CSF, and one of them occurred in patients who received pegfilgrastim after AI chemotherapy (22,23).
Without any guidelines available for the treatment of drug-induced aortitis, we set the initial dose of prednisolone as 60 mg, administered it orally, according to the Guideline for Management of Vasculitis Syndrome (Japanese Circulation Society 2008) for the diagnosis of giant cell arteritis (24). However, several cases of G-CSF-induced aortitis that remitted without the administration of prednisolone have been reported. We think that the degree of inflammatory response might vary in individual cases, and so the clinical decision of whether to administer prednisolone must be individualized. In our patient, prednisolone treatment was necessary because of sustained high-grade inflammatory markers and interstitial changes in the lungs.
In summary, we herein described a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. The patient required PSL administration because of the lung injuries and persisting high grade fever. The response to the treatment with PSL was good, and the patient had recovered without any sequelae. It has been almost 30 years since filgrastim was introduced to the market. However, G-CSF induced aortitis has not been well recognized. We speculate that one reason for this might be the lack of algorithm to predict patients at high risk to present this condition. Secondly, there is lack of specific signs and symptoms. In addition, as we described above, the condition sometimes subsides without the administration of steroids or immuno-suppressants which are usually indispensable for the treatment of other types of vasculitis syndrome. Therefore, we speculate that many cases of G-CSF induced may have been overlooked. This case report might be one type of supportive evidence of G-CSF induced aortitis, however, it is necessary to collect and examine future cases regarding what kind of patients: sex, races, age etc., are likely to present with aortitis due to G-CSF.
The authors state that they have no Conflict of Interest (COI).
|
Recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33191326
| 18,682,768
|
2021-04-15
|
What was the outcome of reaction 'Rash'?
|
Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.
We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are commonly used to prevent and treat neutropenia caused by cancer chemotherapy. Meta-analyses of randomized controlled trials of G-CSFs as primary prophylaxis against febrile neutropenia have demonstrated significant reductions in the rates of short-term all-cause mortality, as well as rates of infection-related mortality, in patients with solid tumors and malignant lymphoma (1,2). A meta-analysis of 59 randomized controlled trials demonstrated that systemic cancer chemotherapy with primary adjunct G-CSF treatment was associated with a significantly greater intensity of the effect of the delivered chemotherapy doses and with greater relative and absolute risk reductions in all-cause mortality rates than was chemotherapy without adjunct G-CSF treatment over a long period (3). As for drug safety, Teshima et al. reported that according to the results of their post-marketing use survey in Japan, the rate of overall adverse effects was 7.47%; these effects included lumbago (3.84%), fever (1.62%), and bone pain (0.61%), and most were not serious and seemed to be ameliorated by the discontinuation of G-CSF treatment (4).
However, a few cases with serious adverse effects, such as interstitial pneumonia and extramedullary hematopoietic splenic rupture, have been reported after the administration of G-CSF (5,6). Pegfilgrastim, a relatively new G-CSF used to prevent febrile neutropenia, is a modified protein consisting of methoxy polyethylene glycol (PEG) molecular chains attached to a Met1 amino group of genetic recombinant filgrastim whose renal excretion is reduced and whose effects are prolonged (7). In Japan, pegfilgrastim is approved for use only to prevent febrile neutropenia after chemotherapy. To optimize its pharmacological effect and prevent adverse effects, the use of pegfilgrastim is restricted to patients at high risk for febrile neutropenia at least 24 hours after a course of chemotherapy. Over the past two decades, authors have reported cases of aortitis induced by G-CSF preparations such as filgrastim, lenograstim, and pegfilgrastim (8,9). Oshima et al., using the Japanese Adverse Drug Event Report database, reported that G-CSF treatment is associated with an increased risk for aortitis (10).
We herein report a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. This is a rare case of G-CSF induced aortitis occurred in a patient who was being treated for sarcoma and it is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological background.
Case Report
A 56-year-old man who was receiving treatment for the local recurrence of extraosseous mucinous chondrosarcoma on the right lower limb presented to our hospital because of an 8-day history of high fever, general fatigue, and a rash with pain. He did not report either any upper or lower respiratory symptoms, abdominal pain, diarrhea, arthralgias, headache, or visual impairment. He had finished the first 4-day course of chemotherapy with 2-day adriamycin (25 mg/m2 each) and four-day ifosfamide (2.8 g/m2 each), followed 36 hours later by subcutaneous administration of pegylated G-CSF (3.6 mg), and he was discharged immediately. Four days later, the symptoms began.
On presentation, he did not appear ill, and he was alert and oriented. His body weight was 69.4 kg, and his height was 169 cm. His vital signs were as follows: blood pressure, 90/47 mm Hg; pulse rate, 95 beats/min; body temperature, 39.1℃; respiratory rate, 12/min; and oxygen saturation level, 99% on room air. A physical examination revealed palm-sized dark red-to-purplish indurated rashes with tenderness on the right cubital fossa and over the left knee socket (Fig. 1a, b). The surface lymph nodes, liver, and spleen were not palpable. The initial laboratory data revealed the following: a white blood cell count of 15,780/μL (90.0% segmented neutrophils, 7.0% stab neutrophils 1.0% monocytes, 2.0% lymphocytes, and 0% atypical lymphocytes, visually confirmed), hemoglobin level of 11.8 g/dL, platelet count of 109,000/μL, and serum C-reactive protein level of 38.77 mg/dL. Table lists the other laboratory data. The results of antigen tests for influenza virus were negative. Two sets of blood culture were conducted. Computed tomography (CT) without contrast media revealed inflammatory changes in the soft tissue surrounding the aorta, partial reticular change and ground-glass opacities scattered throughout both lungs, and splenomegaly (Fig. 2).
Figure 1. Erythematous skin lesions on the right cubital fossa (a) and over the left knee socket (b), on admission.
Table. Laboratory Data on Admission.
Complete blood count Serological test Urine test
WBC 15,780 ×103/μL CRP 38.77 mg/dL occult blood 2+
N-Stab 7 % IgG 828 mg/dL ketone negative
N-Seg 90 % IgA 327 mg/dL glucose negative
Eosino 0 % IgM 103 mg/dL protein 1+
Baso 0 % IgE 53 mg/dL Urinary sediment
Mono 1 % CH50 >60 CH50/mL RBC <4 /HPF
Lymph 2 % C3 162 mg/dL WBC <4 /HPF
RBC 442 ×104/μL C4 45 mg/dL Squamous cell 0-1 /HPF
Hemoglobin 11.8 g/dL sIL-2R 1,922 U/mL cast positive
Platelet 109 ×104/μL ANA <80 β2 microglobulin 18.7 mg/dL
Biochemistry PR3-ANCA <1.0 U/mL
TP 6.2 g/dL MPO-ANCA <1.0 U/mL
Alb 2.4 g/dL anti ssDNA 2.5 AU/mL
T-bil 0.8 mg/dL anti dsDNA <1.2 IU/mL
D-bil 0.5 mg/dL ASO 38 IU/mL
AST 22 U/L ASK ×320
ALT 99 U/L PCT 0.58 ng/mL
Ch-E 157 U/L IGRA negative
ALP 1,077 U/L RPR <1.0
LAP 149 U/L TPHA 0
γ-GTP 302 U/L HCV Ab 0.03
LD 208 U/L HBs Ag 0 IU/mL
CK 19 U/L CMV IgG 64 UA/mL
UN 33 mg/dL CMV IgM negative
Creatinine 2.29 mg/dL ESR 114 mm/hr
Na 139 mmol/L
K 3.7 mmol/L
Cl 101 mmol/L
Blood Sugar 159 mg/dL
HbA1c 6.4 %
WBC: white blood cell, RBC: red blood cell, AST: asparatate aminotransferase, ALT: alanine aminotransferase, N-stab: stab neutrophil, N-seg: segmented neutrophil, Eosino: eosinophil, Baso: basophil, Mono: monocyte, Lymph; Lymphocyte, TP: total protein, Alb: albumin, T-bil: total bililubin, D-bil: direct bililubin, Ch-E: cholinesterase, ALP: alkaline phosphatase, LAP: leucine aminopeptidase, γ-GTP: γ-glutamyl transpeptidase, LD: lactate dehydrogenase, UN: urea nitrogen, CK: creatine kinase, Na: sodium, K: potassium, Cl: chloride, HbA1c: hemoglobine A1c, CRP: C-reactive protein, IgG: Immunoglobulin G, IgA: Immunoglobulin A, IgM: Immunoglobulin M, IgE: Immunoglobulin E, CH50: 50% hemolytic complement activity, sIL-2 R: soluble Interleukin-2 receptor, ANA: antinuclear antibody, PR3-ANCA: serine proteinase3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-ssDNA: anti-single-stranded DNA antibody, anti-dsDNA: anti-double stranded DNA antibody, ASO: antistreptolysin O, ASK: antistreptokinase, PCT: procalcitonin, IGRA: interferon-gamma releasing assay, RPR: rapid plasma reagin card agglutination test, TPHA: treponema pallidum antibody hemagglutination test, HCV ab: hepatitis C virus antibody, HBs Ag: hepatitis B virus antigen, CMV IgG: cytomegalovirus antibody, immunoglobulin G, CMV IgM: cytomegalovirus antibody, immunoglobulin M, ESR: erythrocyte sedimentation rate
Figure 2. Computed tomography (CT) without contrast media, showing aortitis (a; white arrowheads), patchy interstitial changes scattered throughout both lungs (b; black arrowheads) and a small amount of pleural effusion (b; yellow arrowheads), and splenomegaly (c).
Because he was immunocompromised, we diagnosed systemic inflammatory response syndrome and acute renal failure caused by bacterial infection. We promptly administered 2 L of crystalloid infusion for resuscitation and empirical piperacillin/tazobactam as shown in Fig. 3. His renal function was restored rapidly, but high-grade fever persisted for 4 days, as did the inflammatory markers, despite antibiotic treatment. However, this patient did not appear ill, and his food intake did not decrease during the first 4 days after his admission to this hospital. Furthermore, even with a high-grade fever (>40℃), his pulse rate had stayed in the range of 60/min to 70/min, which represented relative bradycardia, which in turn has been considered a characteristic of drug-related fever (11). A blood culture yielded negative results, as did serological tests (including cytomegalovirus antigen and autoantibodies); thus, we diagnosed aortitis resulting from G-CSF administration.
Figure 3. Clinical course of this case. CRP: C-reactive protein, PIPC/TAZ: piperacillin/tazobactam, PSL: prednisolone, WBC: white blood cell count
Because of concerns about the high-grade fever and the pulmonary findings, we initiated treatment with prednisolone, 60 mg (1 mg/kg) orally on the fourth day of hospitalization. His fever resolved within the day, followed by a rapid improvement in his general condition and laboratory data. The rash had improved simultaneously, although the skin discoloration remained. Six days after initiating prednisolone, we tapered the dosage to 40 mg and discharged the patient on day 18 (Fig. 3). At the 3-month follow-up visit, the patient remained well with the prednisolone dose of 7.5 mg/day, which was discontinued 3 months later.
Discussion
As in other immunocompromised patients after the administration of anticancer drugs, we had to rule out vasculitis secondary to infections before diagnosing the drug-induced aortitis, since infectious disease was strongly associated with systemic vasculitis, including aortitis (12). Hence, it might be important in such patients to evaluate them for common infectious diseases that are often overlooked-not only bacterial bloodstream infections but also tuberculosis, syphilis, viral hepatitis, and human immunodeficiency virus-that are known causes of vasculitis before G-CSF-induced aortitis is diagnosed (13).
In this case, pegfilgrastim was administered 36 hours after the completion of the first cycle of AI (adriamycin, ifosfamide) chemotherapy, and a series of symptoms had begun 4 days later. Most cases of G-CSF-induced aortitis had been reported to occur 1 to 15 days after the administration of G-CSF, and a few cases were reported to develop 1 month to 1 year later (8,14). This variation in the latent period, which could interfere with the clinical diagnosis, might result from pharmacodynamic and pharmacokinetic factors such as the type and amount of G-CSF used, type of the preceding chemotherapy, and individual physiological differences. In fact, pegfilgrastim and lipegfilgrastim, which both have a longer half-life and produce equivalent effects with fewer administrations, have been most often reported as the drug causing aortitis (8-10). It is of interest that this condition has been reported more often in women than in men, although more detailed cases and epidemiological studies are needed to prove that G-CSF-induced aortitis is indeed more common in women.
Searching on web, G-CSF-induced aortitis in a patient being treated for sarcoma was thus found to be extremely rare. One reason why no cases of G-CSF-induced aortitis were previously reported in patients with sarcomas might be due to the low absolute number of such patients. Ogura et al. reported that according to a nationwide organ-specific cancer registry for bone and soft tissue tumors in Japan, the number of patients with sarcomas in 2012 was 1,598, which is an extremely low proportion of the 865,238 cases of all cancers (15,16). We believe that this case report, which concerns an orthopedic cancer, is important because the biological evidence that the administration of G-CSF could provoke aortitis is still lacking.
Although this patient did not exhibit any pulmonary manifestations, the lung interstitial changes found on CT seemed critical and warranted the administration of steroids, since there had been many reports of G-CSF-related pulmonary toxicity, which in some cases progressed to acute respiratory distress syndrome and to death (17-19). In a review of 20 cases of interstitial pneumonia secondary to treatment with G-CSF, Niitsu et al. reported that three patients died of respiratory and multiple organ failure; consequently, they emphasized the importance of starting steroid pulse therapy as early as possible when the diagnosis is made (20).
Although the skin lesions that this patient exhibited were not histologically confirmed, we speculated, from their macroscopic appearance, that they represented neutrophilic eccrine hidradenitis, which is neutrophilic dermatosis characterized by the sudden onset of erythematous papules or plaques with a neutrophilic infiltrate around eccrine glands, together with necrosis of these structures. Rising concentrations of the cytotoxic agents in sweat are thought to be the mechanism of neutrophilic eccrine hidradenitis, and doxorubicin is known to be one of the common causative substances (21). It is of interest that several such cases have been reported to be associated with the administration of G-CSF, and one of them occurred in patients who received pegfilgrastim after AI chemotherapy (22,23).
Without any guidelines available for the treatment of drug-induced aortitis, we set the initial dose of prednisolone as 60 mg, administered it orally, according to the Guideline for Management of Vasculitis Syndrome (Japanese Circulation Society 2008) for the diagnosis of giant cell arteritis (24). However, several cases of G-CSF-induced aortitis that remitted without the administration of prednisolone have been reported. We think that the degree of inflammatory response might vary in individual cases, and so the clinical decision of whether to administer prednisolone must be individualized. In our patient, prednisolone treatment was necessary because of sustained high-grade inflammatory markers and interstitial changes in the lungs.
In summary, we herein described a case of G-CSF-induced aortitis that coincided with lung injury, splenomegaly, and rash during treatment for extraosseous mucinous chondrosarcoma. The patient required PSL administration because of the lung injuries and persisting high grade fever. The response to the treatment with PSL was good, and the patient had recovered without any sequelae. It has been almost 30 years since filgrastim was introduced to the market. However, G-CSF induced aortitis has not been well recognized. We speculate that one reason for this might be the lack of algorithm to predict patients at high risk to present this condition. Secondly, there is lack of specific signs and symptoms. In addition, as we described above, the condition sometimes subsides without the administration of steroids or immuno-suppressants which are usually indispensable for the treatment of other types of vasculitis syndrome. Therefore, we speculate that many cases of G-CSF induced may have been overlooked. This case report might be one type of supportive evidence of G-CSF induced aortitis, however, it is necessary to collect and examine future cases regarding what kind of patients: sex, races, age etc., are likely to present with aortitis due to G-CSF.
The authors state that they have no Conflict of Interest (COI).
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Recovered
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CC BY-NC-ND
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2021-04-15
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Febrile neutropenia'.
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Extended RAS Analysis of the Phase III EPIC Trial: Irinotecan + Cetuximab Versus Irinotecan as Second-Line Treatment for Patients with Metastatic Colorectal Cancer.
The multicenter, open-label, randomized, phase III EPIC study (EMR 062202-025) investigated cetuximab plus irinotecan versus irinotecan in patients with epidermal growth factor receptor-detectable metastatic colorectal cancer (mCRC) that progressed on first-line fluoropyrimidine- and oxaliplatin-based chemotherapy; we report the outcomes of patients with RAS-wild-type (wt) disease.
Available DNA samples from RAS-unselected patients (n = 1,164 of 1,298 [89.7%]) were reanalyzed for RAS mutations using beads, emulsion, amplification, and magnetics. Baseline characteristics, efficacy, safety, and poststudy therapy were assessed. RAS-wt status was defined as a mutated RAS allele frequency of ≤5%, with all relevant alleles being analyzable.
Baseline characteristics were comparable between the groups (n = 452 patients with RAS-wt mCRC; cetuximab plus irinotecan n = 231, irinotecan n = 221) and between the RAS-wt and RAS-unselected populations. In the cetuximab plus irinotecan versus irinotecan arms, median overall survival was 12.3 versus 12.0 months, median progression-free survival (PFS) was 5.4 versus 2.6 months, and objective response rate (ORR) was 29.4% versus 5.0%, respectively. Quality of life (QoL) was improved in the cetuximab plus irinotecan arm. Serious adverse events occurred in 45.4% (cetuximab plus irinotecan) and 42.4% (irinotecan) of patients. In total, 47.1% of patients in the irinotecan arm received subsequent cetuximab therapy.
PFS, ORR, and QoL were improved with cetuximab plus irinotecan as a second-line treatment in patients with RAS-wt mCRC, confirming that cetuximab-based therapy is suitable in this population. Almost half of patients in the irinotecan arm received poststudy cetuximab, masking a potential overall survival benefit of cetuximab addition.
Cetuximab is approved for the treatment of RAS-wild-type metastatic colorectal cancer (mCRC). In this retrospective analysis of the phase III EPIC study (cetuximab plus irinotecan vs. irinotecan alone as second-line treatment in patients with RAS-unselected mCRC), the subgroup of patients with RAS-wild-type mCRC who received cetuximab plus irinotecan had improved progression-free survival, objective response rate, and quality of life compared with the RAS-unselected population. These findings suggest that cetuximab-based therapy is a suitable second-line treatment for patients with RAS-wild-type mCRC.
Introduction
Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer‐related deaths globally, with approximately 1.8 million new cases and almost 900,000 deaths annually [1].
Cetuximab, an immunoglobulin G subtype 1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) [2], in combination with oxaliplatin‐ or irinotecan‐based doublet chemotherapy, is a first‐line standard‐of‐care treatment for patients with RAS‐wild‐type (wt) metastatic CRC (mCRC) [3, 4, 5]. Later‐line therapies in mCRC tend to include a biological agent in combination with chemotherapy and are selected based on which prior therapies the patient has received [6].
The randomized phase III study EPIC (Erbitux plus Irinotecan for the Treatment of mCRC; EMR 062202‐025), initiated in May 2003, was designed to determine whether the combination of cetuximab and irinotecan as a second‐line therapy would result in longer overall survival (OS) than that with irinotecan alone in irinotecan‐naïve patients with mCRC unselected for RAS mutational status. The original findings of the EPIC trial revealed statistically significantly improved progression‐free survival (PFS) and objective response rate (ORR) with cetuximab plus irinotecan compared with irinotecan, but there was no difference in OS [2]. The observed improvement in PFS and ORR suggests that cetuximab provides tumor control and thus has clinically relevant therapeutic benefit in this patient population. The lack of improvement in OS upon the addition of cetuximab to irinotecan may be attributed to the high crossover rate in the irinotecan arm because cetuximab was already approved in the third‐ and later‐line setting when the EPIC trial was conducted.
At the time this study was initiated, tumor EGFR expression was considered the only potentially relevant biomarker of response for anti‐EGFR inhibitors. This assumption has now been dispelled, and evidence of EGFR expression is no longer an eligibility requirement for anti‐EGFR therapy [3, 4, 5]. Instead, RAS mutations have been established as a much more evidence‐based predictive biomarker [7]. Retrospective analyses of pivotal studies with cetuximab plus chemotherapy, such as CRYSTAL and OPUS, found that ORR, PFS, and OS were significantly improved in patients with RAS‐wt tumors compared with those in patients with RAS‐mutant tumors [8, 9]; thus, extended RAS testing was included in treatment guidelines and product labels [4, 5, 10, 11], and the phase III TAILOR trial became the first to prospectively enroll a RAS‐wt population [12].
Because the EPIC trial was conducted before RAS was identified as a relevant biomarker for selecting patients for cetuximab treatment, a retrospective analysis of the RAS‐wt population was necessary to confirm the increased benefit of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC. We retrospectively analyzed the outcomes of patients with RAS‐wt mCRC in the EPIC study population. An analysis of the KRAS‐mutant population, a small proportion of the total population (n = 108 [8.3%]), has been reported previously [13].
Materials and Methods
EPIC was a multicenter, open‐label, randomized, phase III study that enrolled patients from 221 sites globally. Eligibility criteria have been described previously [2]. Briefly, eligible patients had histologically documented mCRC and immunohistochemical evidence of EGFR expression. Disease progression or discontinuation due to toxicity within 6 months of the last dose of first‐line fluoropyrimidine and oxaliplatin–based treatment for metastatic disease was required. Patients who had previously received irinotecan or anti‐EGFR therapies were not eligible. Patients were randomly assigned 1:1 to receive cetuximab plus irinotecan or irinotecan. The primary endpoint was OS; secondary endpoints included PFS, ORR, and quality of life (QoL). The trial was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the ethics committees of all participating centers, and all patients provided written informed consent.
Treatment
Patients assigned to the cetuximab plus irinotecan arm received an initial cetuximab dose of 400 mg/m2 (2‐hour i.v. infusion) and then 250 mg/m2 (1‐hour i.v. infusion) weekly. Pretreatment with an antihistamine was required prior to the first dose of cetuximab and was administered at the investigator's discretion prior to subsequent doses. Irinotecan was administered at 350 mg/m2 (90‐minute i.v. infusion; 300 mg/m2 for patients aged ≥70 years, those with Eastern Cooperative Oncology Group performance status [ECOG PS] of 2, or those with prior pelvic/abdominal irradiation) every 3 weeks in both treatment arms, starting 1 hour after completing cetuximab infusion for patients in the cetuximab arm. Patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. There were no poststudy treatment limitations (supplemental online Methods).
Extended RAS Analysis
For retrospective biomarker analysis, available DNA samples were reanalyzed for mutations in KRAS and NRAS exons 2, 3, and 4 using BEAMing (beads, emulsion, amplification, magnetics) technology. RAS‐wt status was defined as having all relevant alleles analyzable and a sum of mutated RAS allele frequencies across all tested mutations of ≤5%. The number of DNA samples included in this analysis was higher than the number of tumor samples available for the earlier retrospective analysis of the EPIC trial by KRAS status, which analyzed samples from U.S. sites only (23% of all randomized patients) and was therefore not representative of the overall study population [13]. Baseline characteristics, efficacy, safety, and poststudy therapy were also assessed (additional information for assessments and statistical analysis are provided in the supplemental online Methods).
Results
Baseline Characteristics
From May 2003 to February 2006, 1,298 RAS‐unselected patients with EGFR‐detectable mCRC who had previously progressed on first‐line fluoropyrimidine and oxaliplatin–based chemotherapy were enrolled (Fig. 1). Among the enrolled patients, RAS status could not be determined in 101 patients (7.8%), and 134 patients (10.3%) had no sample available. Of the 452 patients with RAS‐wt mCRC who were randomized, 446 (98.7%) received treatment: 229 of 231 patients (99.1%) in the cetuximab plus irinotecan arm and 217 of 221 patients (98.2%) in the irinotecan arm. Among patients in the cetuximab plus irinotecan and irinotecan arms, only 27 patients (11.7%) and 28 patients (12.7%), respectively, had received previous bevacizumab therapy; bevacizumab had not been approved in many participating countries at the time of this study.
Figure 1 Patient disposition. Abbreviation: wt, wild type.
Baseline characteristics in the randomized population were comparable to those of the unselected population and reasonably balanced between treatment arms within the RAS‐wt subgroup (Table 1). Most patients in the RAS‐wt subgroup were men (62.8%) and had an ECOG PS of 0 or 1 (93.5%). Median age was 61 years, and 38.7% were aged >65 years.
Table 1 Baseline characteristics of the RAS‐wt and RAS‐unselected populations in the EPIC study
Characteristic
RAS‐wt
RAS‐unselected [2]Total (n = 1,298), n (%)
Irinotecan (n = 221), n (%) Cetuximab plus irinotecan (n = 231), n (%) Total (n = 452), n (%)
Sex
Female 74 (33.5) 86 (37.2) 160 (35.4) 482 (37.1)
Male 147 (66.5) 145 (62.8) 292 (64.6) 816 (62.9)
Median age (range), years 60.0 (23–82) 61.0 (33–85) 61.0 (23–85) 62 (21–90)
ECOG PS
0 112 (50.7) 126 (54.5) 238 (52.7) 664 (51.2)
1 101 (45.7) 90 (39.0) 191 (42.3) 555 (42.8)
2 7 (3.2) 15 (6.5) 22 (4.9) 70 (5.4)
Not reported 1 (0.5) 0 1 (0.2) 9 (0.7)
Prior therapy
Radiotherapy 44 (19.9) 46 (19.9) 90 (19.9) 249 (19.2)
Adjuvant 19 (8.6) 15 (6.5) 34 (7.5) 102 (7.9)
Metastatic 8 (3.6) 17 (7.4) 25 (5.5) 70 (5.4)
Neoadjuvant 18 (8.1) 17 (7.4) 35 (7.7) 90 (69.3)
Chemotherapy 221 (100) 231 (100) 452 (100) 1,298 (100)
Adjuvant 55 (24.9) 54 (23.4) 109 (24.1) 646 (49.8)
Metastatic 219 (99.1) 231 (100) 450 (99.6) 1,289 (99.3)
Neoadjuvant 14 (6.3) 17 (7.4) 31 (6.9) 80 (6.2)
First‐line therapy
Fluoropyrimidine 216 (97.7) 225 (97.4) 441 (97.6) 1,266 (97.5)
Oxaliplatin 219 (99.1) 229 (99.1) 448 (99.1) 1,280 (98.6)
Reason for discontinuation
Disease progression 143 (64.7) 144 (62.3) 287 (63.5) 843 (64.9)
Toxicity 29 (13.1) 36 (15.6) 65 (14.4) 207 (15.9)
Other 44 (19.9) 45 (19.5) 89 (19.7) 225 (17.3)
Unknown 3 (1.4) 5 (2.2) 8 (1.8) 11 (0.8)
Tumor type
Colon 160 (72.4) 149 (64.5) 309 (68.4) 902 (69.5)
Rectum 61 (27.6) 82 (35.5) 143 (31.6) 395 (30.4)
Unknown 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.1)
Number of disease sites
1 69 (31.2) 81 (35.1) 150 (33.2) 415 (32.0)
≥ 2 150 (67.9) 149 (64.5) 299 (66.2) 871 (67.1)
Missing 2 (0.9) 1 (0.4) 3 (0.7) 12 (0.9)
EGFR‐positive CRC
Yes 221 (100) 230 (99.6) 451 (99.8) 1,275 (98.2)
No 0 (0.0) 1 (0.4) 1 (0.2) 2 (0.2)
Liver metastases
Yes 170 (76.9) 176 (76.2) 346 (76.5) 989 (76.2)
No 49 (22.2) 54 (23.4) 103 (22.8) 297 (22.9)
Abbreviations: CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; wt, wild type.
Treatment Adherence and Exposure
Patients in the RAS‐wt group received irinotecan for a median duration of 18.0 weeks (range, 0.7–89.1) in the cetuximab plus irinotecan arm and 10.0 weeks (range, 1.1–71.0) in the irinotecan arm; the median cumulative irinotecan doses were 1,798.4 mg/m2 (range, 266.1–7,204.8) and 1,056.8 mg/m2 (range, 173.6–7,150.3), respectively. Median duration of cetuximab treatment was 19.0 weeks (range, 0.7–97.9), and median cumulative dose was 4,524.0 mg/m2 (range, 159.6–22,086.3). In the cetuximab plus irinotecan arm, 79.0% of patients received ≥80% of the planned dose intensity of irinotecan versus 85.7% of patients in the irinotecan arm. For cetuximab treatment, ≥80% of the planned dose intensity was administered in 72.9% of patients.
In the irinotecan arm, 104 patients (47.1%) received cetuximab in a subsequent line of therapy after the EPIC study; 90 (40.7%) received cetuximab plus irinotecan (Fig. 2). In the cetuximab plus irinotecan arm, 26 patients (11.3%) received cetuximab after the study.
Figure 2 Overall survival by subsequent therapy in the RAS–wild‐type population. (A): In the cetuximab plus irinotecan arm of the EPIC study. (B): In the irinotecan arm of the EPIC study. Abbreviation: CI, confidence interval.
Efficacy
Median OS was 12.3 versus 12.0 months (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.71–1.17; p = .4645) in the cetuximab plus irinotecan versus irinotecan arms, respectively (Table 2; Fig. 3A); median PFS was 5.4 versus 2.6 months (HR, 0.57; 95% CI, 0.46–0.69; p < .0001; Table 2; Fig. 3B). ORR was higher in the cetuximab plus irinotecan arm than in the irinotecan arm: 29.4% versus 5.0% (odds ratio [OR], 8.12; 95% CI, 4.04–17.40; p < .0001) (Table 2). An analysis of OS by poststudy treatment within the RAS‐wt population showed improved median OS in patients who received poststudy cetuximab compared with those not receiving cetuximab or any subsequent therapy in both treatment arms (Fig. 2; supplemental online Table 1). In the cetuximab plus irinotecan arm, median OS in patients who had previously received bevacizumab (n = 27) versus those without prior bevacizumab therapy (n = 204) was 10.2 (95% CI, 4.53–14.09) versus 12.8 months (95% CI, 11.47–15.70), respectively. In the irinotecan arm, median OS was not estimable (95% CI, 11.73 months–not estimable) in patients who had received previous bevacizumab (n = 28) versus 11.8 months (95% CI, 9.00–13.31) in patients without prior bevacizumab therapy (n = 193). ORR in patients who had previously received bevacizumab was 18.5% in the cetuximab plus irinotecan arm (n = 27) and 3.6% in the irinotecan arm (n = 28).
Table 2 Summary of efficacy results in the RAS‐wt and RAS‐unselected populations in the EPIC study
RAS‐wt population
RAS‐unselected population [2]
Irinotecan (n = 221) Cetuximab plus irinotecan (n = 231) Irinotecan (n = 650) Cetuximab plus irinotecan (n = 648)
Median duration of therapy (range), weeks
Cetuximab NA 19.0 (0.7–97.9) NA 14.0 (0.7–97.9)
Irinotecan 10.0 (1.1–71.0) 18.0 (0.7–89.1) 9.9 (0.4–71.0) 13.1 (0.7–89.1)
OS
Number of events, n (%) 126 (57.0) 133 (57.6) 429 (66.0) 445 (68.8)
Median (95% CI), months 12.0 (9.36–14.92) 12.3 (11.37–14.09) 9.99 (9.13–11.33) 10.71 (9.59–11.30)
HR (95% CI) 0.91 (0.71–1.17) 0.975 (0.854–1.114)
Log‐rank p value .4645 .7114
PFS
Number of events, n (%) 201 (91.0) 212 (91.8) 598 (92.0) 610 (94.1)
Median (95% CI), months 2.6 (2.30–2.83) 5.4 (4.24–5.75) 2.56 (2.1–2.69) 3.98 (3.15–4.14)
HR (95% CI) 0.57 (0.46–0.69) 0.692 (0.617–0.776)
Log‐rank p value <.0001 <.0001
Response
Primary definition, n (%)
Complete response 0 4 (1.7) 1 (0.2) 9 (1.4)
Partial response 11 (5.0) 64 (27.7) 26 (4.0) 97 (15.0)
Stable disease 100 (45.2) 90 (39.0) 271 (41.7) 292 (45.1)
Progressive disease 71 (32.1) 46 (19.9) 243 (37.4) 174 (26.9)
Not assessable 39 (17.6) 27 (11.7) 109 (16.8) 76 (11.7)
ORR (CR + PR), n (%) [95% CI] 11 (5.0) [2.51–8.73] 68 (29.4) [23.63–35.77] 27 (4.2) [2.75–5.99] 106 (16.4) [13.59–19.44]
Abbreviations: CI, confidence interval; CR, complete response; HR, hazard ratio; NA, not applicable; ORR, overall response rate; OS, overall survival; PFS, progression‐free survival; PR, partial response; wt, wild type.
Figure 3 Survival in the RAS–wild‐type population of the EPIC study. (A): Overall survival. (B): Progression‐free survival. Abbreviations: CI, confidence interval; HR, hazard ratio.
Safety
Adverse events (AEs) in the RAS‐wt population were consistent with the safety profile observed in the overall EPIC safety population and in other cetuximab studies [2, 8, 9], and no new or unexpected safety signals were observed in either treatment arm. In the cetuximab plus irinotecan and irinotecan arms, 76.4% and 61.8% of patients, respectively, experienced a grade ≥ 3 treatment‐emergent AE. Grade ≥ 3 treatment‐related AEs (TRAEs) were observed in 67.7% and 45.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively; the most common grade 3/4 TRAEs (occurring in ≥20 patients in any treatment arm) were diarrhea (32.3% vs. 17.1%) and neutropenia (20.5% vs. 14.3%). In the cetuximab plus irinotecan arm, grade ≥ 3 drug‐related skin reactions were observed in 12.2% of patients, and grade ≥ 3 acne‐like dermatitis occurred in 1.7%. These TRAEs account for the overall higher TRAE rate in the cetuximab plus irinotecan group.
Serious TRAEs occurred in 29.3% and 21.2% of patients in the cetuximab plus irinotecan and irinotecan arms, respectively. Cetuximab‐related serious AEs (SAEs) occurred in 14.4% of patients in the cetuximab plus irinotecan arm. Irinotecan‐related SAEs were observed in 26.6% versus 21.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively. The most common grade ≥ 3 serious TRAEs (occurring in ≥5% of patients) in both treatment arms were febrile neutropenia and diarrhea. Furthermore, serious TRAEs leading to death occurred in eight patients in the cetuximab plus irinotecan arm and were cetuximab‐related in five patients (dyspnea [n = 1], disease progression [n = 1], cardiac failure and renal failure [n = 1], vomiting and sudden death [n = 1], sepsis [n = 1]) and irinotecan‐related in seven patients (diarrhea, cardiac failure and renal failure [n = 1], pneumonia aspiration and respiratory arrest [n = 1], disease progression [n = 1], gastroenteritis [n = 1], neutropenia [n = 1], vomiting and sudden death [n = 1], intestinal perforation, peritonitis and sepsis [n = 1]) versus three patients in the irinotecan arm (febrile neutropenia [n = 1]; intestinal obstruction [n = 1]; neutropenia [n = 1]). AEs resulting in discontinuation of cetuximab occurred in 20.5% of patients in the cetuximab plus irinotecan arm. AEs leading to irinotecan discontinuation were similar in both arms (22.3% vs. 19.4% in the cetuximab plus irinotecan vs. irinotecan arms).
QoL
Compliance rates for the QoL questionnaire in the RAS‐wt population at baseline were 86.1% and 90.0% in the cetuximab plus irinotecan and irinotecan arms, respectively. The on‐study completion rate subsequently decreased over time, stabilizing at approximately 50% at week 21 in each arm and remaining at this level until weeks 51 and 45 in the cetuximab plus irinotecan and irinotecan arms, respectively. Patients who completed the QoL assessment questionnaire answered 96.7% to 100% of the questions. Baseline scores were similar between treatment arms for 13 of 15 QoL scales. For the symptom scale fatigue and the single item insomnia, differences from baseline scores favored cetuximab plus irinotecan over irinotecan (p < .1). A longitudinal model (truncated at week 45) was used to compare change from baseline scores over time between treatment arms. During the course of the study, improved QoL was reported by patients in the cetuximab plus irinotecan arm compared with those in the irinotecan arm for several multi‐item and single‐item scales (supplemental online Table 2). The model also showed advantages for cetuximab treatment for two functioning scales (physical functioning and role functioning), two symptom scales (fatigue and nausea/vomiting), and two single‐item scales (pain and appetite loss), all in favor of the combination treatment (p < .05). A trend for improved cognitive functioning, global health status, and constipation was also observed in the cetuximab plus irinotecan arm (p < .1). The remaining multi‐item and single‐items scales showed no significant differences between the two treatment arms.
Discussion
This retrospective analysis of the RAS‐wt population of the EPIC study reiterates that the addition of cetuximab to irinotecan did not prolong OS—consistent with results of the primary analysis in the non–biomarker‐defined population [2] as well as those of a previous subgroup analysis in the KRAS‐wt population [13]. The lack of change in OS is possibly due to the high rate of poststudy crossover to cetuximab therapy in patients in the irinotecan arm, as suggested by Sobrero et al [2]. Indeed, nearly half of the patients with RAS‐wt tumors in the irinotecan arm received cetuximab in a subsequent line of therapy after the study, potentially masking any OS benefit of the addition of cetuximab to irinotecan. This hypothesis is supported by results from the CO.17 study of cetuximab versus best supportive care (BSC) in pretreated advanced RAS‐ and BRAF‐wt CRC, in which OS was significantly improved with cetuximab compared with BSC (10.1 vs. 4.8 months), with only 7.0% of patients who received BSC subsequently receiving cetuximab [14, 15].
Interestingly, patients in both treatment arms of EPIC who received poststudy cetuximab had improved OS compared with those who received a subsequent therapy without cetuximab or no poststudy therapy, suggesting that the administration of cetuximab at any point in the second or later line may improve survival. Furthermore, these data suggest that cetuximab‐based therapy may be a suitable standard treatment in the rechallenge setting (i.e., retreatment with cetuximab after progression in a subsequent therapy line without cetuximab) as well as beyond progression for patients with RAS‐wt mCRC. Thus, although guidelines recommend the use of cetuximab in the first‐line treatment setting [3, 4, 5], data from this trial support the use of cetuximab in second or subsequent line treatment settings. Of note, limitations of this analysis include a potential bias because of the differences in the proportion of subsequent therapies with and without cetuximab in the two treatment arms. Another possible bias arises from the observation that patients who live longer are more likely to receive cetuximab in any subsequent therapy line.
In contrast to OS, PFS was more than doubled and ORR was approximately sixfold higher in the cetuximab plus irinotecan arm than in the irinotecan arm (p < .0001 each), and this improvement was more prominent than that in the primary analysis [2] and in the analysis of the KRAS‐wt population [13]. These results suggest that second‐line cetuximab may have a clinically meaningful therapeutic benefit in patients with mCRC—considering their survival prognosis of approximately 1 year, which is supported by the improvements observed in the patients’ QoL. Furthermore, patients who received cetuximab continued treatment for longer, likely because of the prolonged PFS. In both this retrospective analysis and the initial results of the EPIC study [2], the longer PFS and higher ORR observed upon the addition of cetuximab to irinotecan may be a better indicator of the additional benefit conferred by cetuximab than OS, because these endpoints are directly related to the study period and are therefore unaffected by subsequent therapies and are clinically relevant in patients with mCRC.
Similar to the results of the primary analysis of the EPIC study, no new or unexpected safety signals in the RAS‐wt population were observed in either treatment arm. Furthermore, the improved QoL, as demonstrated for several single‐ and multi‐item scales in the cetuximab plus irinotecan arm compared with that in the irinotecan arm, is also reflected in the observed treatment duration, which was almost twice as long in the cetuximab plus irinotecan arm than in the irinotecan arm. Although an analysis for efficacy in left‐sided versus right‐sided tumors was not feasible in this retrospective study because of missing data on primary tumor location, the ORR for the RAS‐wt population in this study was among the highest observed to date in the second‐line setting when compared with that reported for other regimens, such as bevacizumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4), as reported for the E3200 study (ORR, 22.7%) [16], and panitumumab plus combination chemotherapy (ORR, 41% for panitumumab plus 5‐fluorouracil, leucovorin, and irinotecan (FOLFIRI) vs. 10% for FOLFIRI in patients with RAS‐wt tumors) [17]. Notably, although ORR and PFS increased from 16.4% to 29.4% and from 4.0 to 5.4 months, respectively, in the RAS‐unselected and the RAS‐wt populations with cetuximab plus irinotecan, the efficacy outcomes for patients receiving irinotecan did not differ between the RAS‐unselected and RAS‐wt populations (PFS, 2.6 months in both populations; ORR: 4.2% and 5.0%, respectively). These findings, as well as the improved QoL observed in the cetuximab plus irinotecan arm, further confirm the increased efficacy of cetuximab in patients with RAS‐wt tumors in second‐line treatment and confirm that RAS testing is predictive of clinical benefit.
Conclusion
This retrospective analysis of RAS‐wt patients enrolled in the EPIC study emphasizes the role of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC.
Author Contributions
Conception/design: Alberto Sobrero, Heinz‐Josef Lenz, Regina Esser, Johannes Nippgen, Howard Burris
Provision of study material or patients: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Collection and/or assembly of data: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Data analysis and interpretation: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Manuscript writing: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Final approval of manuscript: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Werner Scheithauer, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Disclosures
Alberto Sobrero: Amgen, Bayer, Bristol Myers Squibb, Celgene, Eli Lilly & Co., EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany), Roche, Sanofi, Takeda (C/A); Heinz‐Josef Lenz: Bayer, Bristol Myers Squibb, EMD Serono, Roche (C/A), Bayer, Bristol Myers Squibb, EMD Serono, Roche, Takeda (H), Bayer, EMD Serono (other—travel support); Cathy Eng: Bayer, LSK Global PS, Roche, Sirtex, Taiho (C/A); Wenfeng Chen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Regina Esser: Merck KGaA (Darmstadt, Germany) (E, OI); Johannes Nippgen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Howard Burris: AstraZeneca, Celgene, Daiichi Sankyo, FORMA Therapeutics, Incyte, Pfizer (C/A), Agios, AstraZeneca, Arch, Array BioPharma, Arvinas, Bayer, BIND Therapeutics, BioAtla, BioMed Valley, Boehringer‐Ingelheim, Bristol Myers Squibb, CicloMed, CytomX, eFFECTOR, Eli Lilly & Co., Roche/Genentech, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Incyte, Janssen, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck KGaA, Millennium Pharmaceuticals, Mirna Therapeutics, Moderna, Novartis, Pfizer, Revolution Medicine, Seattle Genetics, Tesaro, TG Therapeutics, Verastem, Vertex Pharmaceuticals (RF—institution), HCA/Sarah Cannon (OI). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Appendix S1 Supporting Information.
Click here for additional data file.
Table S1 Median OS by Subsequent Therapy in the RAS wt Population in the EPIC Study
Table S2: Comparison of QoL Between Treatment Arms Using a Longitudinal Analysis
Click here for additional data file.
Acknowledgments
Medical writing assistance was provided by Eleanor Green of ClinicalThinking, Manchester, U.K., and funded by Merck KGaA, Darmstadt, Germany. This assistance consisted of copyediting, editorial and production assistance. This study was sponsored by Bristol Myers Squibb, New York, NY; ImClone Systems, Bridgewater, NJ; Eli Lilly & Co., Indianapolis, IN; and Merck KGaA. Protocol design and funding of medical writing support by ClinicalThinking, Inc., was provided by Merck KGaA. Data interpretation and the final decision to submit for publication was conducted by Merck KGaA and the coordinating investigators.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intestinal obstruction'.
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Extended RAS Analysis of the Phase III EPIC Trial: Irinotecan + Cetuximab Versus Irinotecan as Second-Line Treatment for Patients with Metastatic Colorectal Cancer.
The multicenter, open-label, randomized, phase III EPIC study (EMR 062202-025) investigated cetuximab plus irinotecan versus irinotecan in patients with epidermal growth factor receptor-detectable metastatic colorectal cancer (mCRC) that progressed on first-line fluoropyrimidine- and oxaliplatin-based chemotherapy; we report the outcomes of patients with RAS-wild-type (wt) disease.
Available DNA samples from RAS-unselected patients (n = 1,164 of 1,298 [89.7%]) were reanalyzed for RAS mutations using beads, emulsion, amplification, and magnetics. Baseline characteristics, efficacy, safety, and poststudy therapy were assessed. RAS-wt status was defined as a mutated RAS allele frequency of ≤5%, with all relevant alleles being analyzable.
Baseline characteristics were comparable between the groups (n = 452 patients with RAS-wt mCRC; cetuximab plus irinotecan n = 231, irinotecan n = 221) and between the RAS-wt and RAS-unselected populations. In the cetuximab plus irinotecan versus irinotecan arms, median overall survival was 12.3 versus 12.0 months, median progression-free survival (PFS) was 5.4 versus 2.6 months, and objective response rate (ORR) was 29.4% versus 5.0%, respectively. Quality of life (QoL) was improved in the cetuximab plus irinotecan arm. Serious adverse events occurred in 45.4% (cetuximab plus irinotecan) and 42.4% (irinotecan) of patients. In total, 47.1% of patients in the irinotecan arm received subsequent cetuximab therapy.
PFS, ORR, and QoL were improved with cetuximab plus irinotecan as a second-line treatment in patients with RAS-wt mCRC, confirming that cetuximab-based therapy is suitable in this population. Almost half of patients in the irinotecan arm received poststudy cetuximab, masking a potential overall survival benefit of cetuximab addition.
Cetuximab is approved for the treatment of RAS-wild-type metastatic colorectal cancer (mCRC). In this retrospective analysis of the phase III EPIC study (cetuximab plus irinotecan vs. irinotecan alone as second-line treatment in patients with RAS-unselected mCRC), the subgroup of patients with RAS-wild-type mCRC who received cetuximab plus irinotecan had improved progression-free survival, objective response rate, and quality of life compared with the RAS-unselected population. These findings suggest that cetuximab-based therapy is a suitable second-line treatment for patients with RAS-wild-type mCRC.
Introduction
Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer‐related deaths globally, with approximately 1.8 million new cases and almost 900,000 deaths annually [1].
Cetuximab, an immunoglobulin G subtype 1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) [2], in combination with oxaliplatin‐ or irinotecan‐based doublet chemotherapy, is a first‐line standard‐of‐care treatment for patients with RAS‐wild‐type (wt) metastatic CRC (mCRC) [3, 4, 5]. Later‐line therapies in mCRC tend to include a biological agent in combination with chemotherapy and are selected based on which prior therapies the patient has received [6].
The randomized phase III study EPIC (Erbitux plus Irinotecan for the Treatment of mCRC; EMR 062202‐025), initiated in May 2003, was designed to determine whether the combination of cetuximab and irinotecan as a second‐line therapy would result in longer overall survival (OS) than that with irinotecan alone in irinotecan‐naïve patients with mCRC unselected for RAS mutational status. The original findings of the EPIC trial revealed statistically significantly improved progression‐free survival (PFS) and objective response rate (ORR) with cetuximab plus irinotecan compared with irinotecan, but there was no difference in OS [2]. The observed improvement in PFS and ORR suggests that cetuximab provides tumor control and thus has clinically relevant therapeutic benefit in this patient population. The lack of improvement in OS upon the addition of cetuximab to irinotecan may be attributed to the high crossover rate in the irinotecan arm because cetuximab was already approved in the third‐ and later‐line setting when the EPIC trial was conducted.
At the time this study was initiated, tumor EGFR expression was considered the only potentially relevant biomarker of response for anti‐EGFR inhibitors. This assumption has now been dispelled, and evidence of EGFR expression is no longer an eligibility requirement for anti‐EGFR therapy [3, 4, 5]. Instead, RAS mutations have been established as a much more evidence‐based predictive biomarker [7]. Retrospective analyses of pivotal studies with cetuximab plus chemotherapy, such as CRYSTAL and OPUS, found that ORR, PFS, and OS were significantly improved in patients with RAS‐wt tumors compared with those in patients with RAS‐mutant tumors [8, 9]; thus, extended RAS testing was included in treatment guidelines and product labels [4, 5, 10, 11], and the phase III TAILOR trial became the first to prospectively enroll a RAS‐wt population [12].
Because the EPIC trial was conducted before RAS was identified as a relevant biomarker for selecting patients for cetuximab treatment, a retrospective analysis of the RAS‐wt population was necessary to confirm the increased benefit of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC. We retrospectively analyzed the outcomes of patients with RAS‐wt mCRC in the EPIC study population. An analysis of the KRAS‐mutant population, a small proportion of the total population (n = 108 [8.3%]), has been reported previously [13].
Materials and Methods
EPIC was a multicenter, open‐label, randomized, phase III study that enrolled patients from 221 sites globally. Eligibility criteria have been described previously [2]. Briefly, eligible patients had histologically documented mCRC and immunohistochemical evidence of EGFR expression. Disease progression or discontinuation due to toxicity within 6 months of the last dose of first‐line fluoropyrimidine and oxaliplatin–based treatment for metastatic disease was required. Patients who had previously received irinotecan or anti‐EGFR therapies were not eligible. Patients were randomly assigned 1:1 to receive cetuximab plus irinotecan or irinotecan. The primary endpoint was OS; secondary endpoints included PFS, ORR, and quality of life (QoL). The trial was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the ethics committees of all participating centers, and all patients provided written informed consent.
Treatment
Patients assigned to the cetuximab plus irinotecan arm received an initial cetuximab dose of 400 mg/m2 (2‐hour i.v. infusion) and then 250 mg/m2 (1‐hour i.v. infusion) weekly. Pretreatment with an antihistamine was required prior to the first dose of cetuximab and was administered at the investigator's discretion prior to subsequent doses. Irinotecan was administered at 350 mg/m2 (90‐minute i.v. infusion; 300 mg/m2 for patients aged ≥70 years, those with Eastern Cooperative Oncology Group performance status [ECOG PS] of 2, or those with prior pelvic/abdominal irradiation) every 3 weeks in both treatment arms, starting 1 hour after completing cetuximab infusion for patients in the cetuximab arm. Patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. There were no poststudy treatment limitations (supplemental online Methods).
Extended RAS Analysis
For retrospective biomarker analysis, available DNA samples were reanalyzed for mutations in KRAS and NRAS exons 2, 3, and 4 using BEAMing (beads, emulsion, amplification, magnetics) technology. RAS‐wt status was defined as having all relevant alleles analyzable and a sum of mutated RAS allele frequencies across all tested mutations of ≤5%. The number of DNA samples included in this analysis was higher than the number of tumor samples available for the earlier retrospective analysis of the EPIC trial by KRAS status, which analyzed samples from U.S. sites only (23% of all randomized patients) and was therefore not representative of the overall study population [13]. Baseline characteristics, efficacy, safety, and poststudy therapy were also assessed (additional information for assessments and statistical analysis are provided in the supplemental online Methods).
Results
Baseline Characteristics
From May 2003 to February 2006, 1,298 RAS‐unselected patients with EGFR‐detectable mCRC who had previously progressed on first‐line fluoropyrimidine and oxaliplatin–based chemotherapy were enrolled (Fig. 1). Among the enrolled patients, RAS status could not be determined in 101 patients (7.8%), and 134 patients (10.3%) had no sample available. Of the 452 patients with RAS‐wt mCRC who were randomized, 446 (98.7%) received treatment: 229 of 231 patients (99.1%) in the cetuximab plus irinotecan arm and 217 of 221 patients (98.2%) in the irinotecan arm. Among patients in the cetuximab plus irinotecan and irinotecan arms, only 27 patients (11.7%) and 28 patients (12.7%), respectively, had received previous bevacizumab therapy; bevacizumab had not been approved in many participating countries at the time of this study.
Figure 1 Patient disposition. Abbreviation: wt, wild type.
Baseline characteristics in the randomized population were comparable to those of the unselected population and reasonably balanced between treatment arms within the RAS‐wt subgroup (Table 1). Most patients in the RAS‐wt subgroup were men (62.8%) and had an ECOG PS of 0 or 1 (93.5%). Median age was 61 years, and 38.7% were aged >65 years.
Table 1 Baseline characteristics of the RAS‐wt and RAS‐unselected populations in the EPIC study
Characteristic
RAS‐wt
RAS‐unselected [2]Total (n = 1,298), n (%)
Irinotecan (n = 221), n (%) Cetuximab plus irinotecan (n = 231), n (%) Total (n = 452), n (%)
Sex
Female 74 (33.5) 86 (37.2) 160 (35.4) 482 (37.1)
Male 147 (66.5) 145 (62.8) 292 (64.6) 816 (62.9)
Median age (range), years 60.0 (23–82) 61.0 (33–85) 61.0 (23–85) 62 (21–90)
ECOG PS
0 112 (50.7) 126 (54.5) 238 (52.7) 664 (51.2)
1 101 (45.7) 90 (39.0) 191 (42.3) 555 (42.8)
2 7 (3.2) 15 (6.5) 22 (4.9) 70 (5.4)
Not reported 1 (0.5) 0 1 (0.2) 9 (0.7)
Prior therapy
Radiotherapy 44 (19.9) 46 (19.9) 90 (19.9) 249 (19.2)
Adjuvant 19 (8.6) 15 (6.5) 34 (7.5) 102 (7.9)
Metastatic 8 (3.6) 17 (7.4) 25 (5.5) 70 (5.4)
Neoadjuvant 18 (8.1) 17 (7.4) 35 (7.7) 90 (69.3)
Chemotherapy 221 (100) 231 (100) 452 (100) 1,298 (100)
Adjuvant 55 (24.9) 54 (23.4) 109 (24.1) 646 (49.8)
Metastatic 219 (99.1) 231 (100) 450 (99.6) 1,289 (99.3)
Neoadjuvant 14 (6.3) 17 (7.4) 31 (6.9) 80 (6.2)
First‐line therapy
Fluoropyrimidine 216 (97.7) 225 (97.4) 441 (97.6) 1,266 (97.5)
Oxaliplatin 219 (99.1) 229 (99.1) 448 (99.1) 1,280 (98.6)
Reason for discontinuation
Disease progression 143 (64.7) 144 (62.3) 287 (63.5) 843 (64.9)
Toxicity 29 (13.1) 36 (15.6) 65 (14.4) 207 (15.9)
Other 44 (19.9) 45 (19.5) 89 (19.7) 225 (17.3)
Unknown 3 (1.4) 5 (2.2) 8 (1.8) 11 (0.8)
Tumor type
Colon 160 (72.4) 149 (64.5) 309 (68.4) 902 (69.5)
Rectum 61 (27.6) 82 (35.5) 143 (31.6) 395 (30.4)
Unknown 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.1)
Number of disease sites
1 69 (31.2) 81 (35.1) 150 (33.2) 415 (32.0)
≥ 2 150 (67.9) 149 (64.5) 299 (66.2) 871 (67.1)
Missing 2 (0.9) 1 (0.4) 3 (0.7) 12 (0.9)
EGFR‐positive CRC
Yes 221 (100) 230 (99.6) 451 (99.8) 1,275 (98.2)
No 0 (0.0) 1 (0.4) 1 (0.2) 2 (0.2)
Liver metastases
Yes 170 (76.9) 176 (76.2) 346 (76.5) 989 (76.2)
No 49 (22.2) 54 (23.4) 103 (22.8) 297 (22.9)
Abbreviations: CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; wt, wild type.
Treatment Adherence and Exposure
Patients in the RAS‐wt group received irinotecan for a median duration of 18.0 weeks (range, 0.7–89.1) in the cetuximab plus irinotecan arm and 10.0 weeks (range, 1.1–71.0) in the irinotecan arm; the median cumulative irinotecan doses were 1,798.4 mg/m2 (range, 266.1–7,204.8) and 1,056.8 mg/m2 (range, 173.6–7,150.3), respectively. Median duration of cetuximab treatment was 19.0 weeks (range, 0.7–97.9), and median cumulative dose was 4,524.0 mg/m2 (range, 159.6–22,086.3). In the cetuximab plus irinotecan arm, 79.0% of patients received ≥80% of the planned dose intensity of irinotecan versus 85.7% of patients in the irinotecan arm. For cetuximab treatment, ≥80% of the planned dose intensity was administered in 72.9% of patients.
In the irinotecan arm, 104 patients (47.1%) received cetuximab in a subsequent line of therapy after the EPIC study; 90 (40.7%) received cetuximab plus irinotecan (Fig. 2). In the cetuximab plus irinotecan arm, 26 patients (11.3%) received cetuximab after the study.
Figure 2 Overall survival by subsequent therapy in the RAS–wild‐type population. (A): In the cetuximab plus irinotecan arm of the EPIC study. (B): In the irinotecan arm of the EPIC study. Abbreviation: CI, confidence interval.
Efficacy
Median OS was 12.3 versus 12.0 months (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.71–1.17; p = .4645) in the cetuximab plus irinotecan versus irinotecan arms, respectively (Table 2; Fig. 3A); median PFS was 5.4 versus 2.6 months (HR, 0.57; 95% CI, 0.46–0.69; p < .0001; Table 2; Fig. 3B). ORR was higher in the cetuximab plus irinotecan arm than in the irinotecan arm: 29.4% versus 5.0% (odds ratio [OR], 8.12; 95% CI, 4.04–17.40; p < .0001) (Table 2). An analysis of OS by poststudy treatment within the RAS‐wt population showed improved median OS in patients who received poststudy cetuximab compared with those not receiving cetuximab or any subsequent therapy in both treatment arms (Fig. 2; supplemental online Table 1). In the cetuximab plus irinotecan arm, median OS in patients who had previously received bevacizumab (n = 27) versus those without prior bevacizumab therapy (n = 204) was 10.2 (95% CI, 4.53–14.09) versus 12.8 months (95% CI, 11.47–15.70), respectively. In the irinotecan arm, median OS was not estimable (95% CI, 11.73 months–not estimable) in patients who had received previous bevacizumab (n = 28) versus 11.8 months (95% CI, 9.00–13.31) in patients without prior bevacizumab therapy (n = 193). ORR in patients who had previously received bevacizumab was 18.5% in the cetuximab plus irinotecan arm (n = 27) and 3.6% in the irinotecan arm (n = 28).
Table 2 Summary of efficacy results in the RAS‐wt and RAS‐unselected populations in the EPIC study
RAS‐wt population
RAS‐unselected population [2]
Irinotecan (n = 221) Cetuximab plus irinotecan (n = 231) Irinotecan (n = 650) Cetuximab plus irinotecan (n = 648)
Median duration of therapy (range), weeks
Cetuximab NA 19.0 (0.7–97.9) NA 14.0 (0.7–97.9)
Irinotecan 10.0 (1.1–71.0) 18.0 (0.7–89.1) 9.9 (0.4–71.0) 13.1 (0.7–89.1)
OS
Number of events, n (%) 126 (57.0) 133 (57.6) 429 (66.0) 445 (68.8)
Median (95% CI), months 12.0 (9.36–14.92) 12.3 (11.37–14.09) 9.99 (9.13–11.33) 10.71 (9.59–11.30)
HR (95% CI) 0.91 (0.71–1.17) 0.975 (0.854–1.114)
Log‐rank p value .4645 .7114
PFS
Number of events, n (%) 201 (91.0) 212 (91.8) 598 (92.0) 610 (94.1)
Median (95% CI), months 2.6 (2.30–2.83) 5.4 (4.24–5.75) 2.56 (2.1–2.69) 3.98 (3.15–4.14)
HR (95% CI) 0.57 (0.46–0.69) 0.692 (0.617–0.776)
Log‐rank p value <.0001 <.0001
Response
Primary definition, n (%)
Complete response 0 4 (1.7) 1 (0.2) 9 (1.4)
Partial response 11 (5.0) 64 (27.7) 26 (4.0) 97 (15.0)
Stable disease 100 (45.2) 90 (39.0) 271 (41.7) 292 (45.1)
Progressive disease 71 (32.1) 46 (19.9) 243 (37.4) 174 (26.9)
Not assessable 39 (17.6) 27 (11.7) 109 (16.8) 76 (11.7)
ORR (CR + PR), n (%) [95% CI] 11 (5.0) [2.51–8.73] 68 (29.4) [23.63–35.77] 27 (4.2) [2.75–5.99] 106 (16.4) [13.59–19.44]
Abbreviations: CI, confidence interval; CR, complete response; HR, hazard ratio; NA, not applicable; ORR, overall response rate; OS, overall survival; PFS, progression‐free survival; PR, partial response; wt, wild type.
Figure 3 Survival in the RAS–wild‐type population of the EPIC study. (A): Overall survival. (B): Progression‐free survival. Abbreviations: CI, confidence interval; HR, hazard ratio.
Safety
Adverse events (AEs) in the RAS‐wt population were consistent with the safety profile observed in the overall EPIC safety population and in other cetuximab studies [2, 8, 9], and no new or unexpected safety signals were observed in either treatment arm. In the cetuximab plus irinotecan and irinotecan arms, 76.4% and 61.8% of patients, respectively, experienced a grade ≥ 3 treatment‐emergent AE. Grade ≥ 3 treatment‐related AEs (TRAEs) were observed in 67.7% and 45.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively; the most common grade 3/4 TRAEs (occurring in ≥20 patients in any treatment arm) were diarrhea (32.3% vs. 17.1%) and neutropenia (20.5% vs. 14.3%). In the cetuximab plus irinotecan arm, grade ≥ 3 drug‐related skin reactions were observed in 12.2% of patients, and grade ≥ 3 acne‐like dermatitis occurred in 1.7%. These TRAEs account for the overall higher TRAE rate in the cetuximab plus irinotecan group.
Serious TRAEs occurred in 29.3% and 21.2% of patients in the cetuximab plus irinotecan and irinotecan arms, respectively. Cetuximab‐related serious AEs (SAEs) occurred in 14.4% of patients in the cetuximab plus irinotecan arm. Irinotecan‐related SAEs were observed in 26.6% versus 21.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively. The most common grade ≥ 3 serious TRAEs (occurring in ≥5% of patients) in both treatment arms were febrile neutropenia and diarrhea. Furthermore, serious TRAEs leading to death occurred in eight patients in the cetuximab plus irinotecan arm and were cetuximab‐related in five patients (dyspnea [n = 1], disease progression [n = 1], cardiac failure and renal failure [n = 1], vomiting and sudden death [n = 1], sepsis [n = 1]) and irinotecan‐related in seven patients (diarrhea, cardiac failure and renal failure [n = 1], pneumonia aspiration and respiratory arrest [n = 1], disease progression [n = 1], gastroenteritis [n = 1], neutropenia [n = 1], vomiting and sudden death [n = 1], intestinal perforation, peritonitis and sepsis [n = 1]) versus three patients in the irinotecan arm (febrile neutropenia [n = 1]; intestinal obstruction [n = 1]; neutropenia [n = 1]). AEs resulting in discontinuation of cetuximab occurred in 20.5% of patients in the cetuximab plus irinotecan arm. AEs leading to irinotecan discontinuation were similar in both arms (22.3% vs. 19.4% in the cetuximab plus irinotecan vs. irinotecan arms).
QoL
Compliance rates for the QoL questionnaire in the RAS‐wt population at baseline were 86.1% and 90.0% in the cetuximab plus irinotecan and irinotecan arms, respectively. The on‐study completion rate subsequently decreased over time, stabilizing at approximately 50% at week 21 in each arm and remaining at this level until weeks 51 and 45 in the cetuximab plus irinotecan and irinotecan arms, respectively. Patients who completed the QoL assessment questionnaire answered 96.7% to 100% of the questions. Baseline scores were similar between treatment arms for 13 of 15 QoL scales. For the symptom scale fatigue and the single item insomnia, differences from baseline scores favored cetuximab plus irinotecan over irinotecan (p < .1). A longitudinal model (truncated at week 45) was used to compare change from baseline scores over time between treatment arms. During the course of the study, improved QoL was reported by patients in the cetuximab plus irinotecan arm compared with those in the irinotecan arm for several multi‐item and single‐item scales (supplemental online Table 2). The model also showed advantages for cetuximab treatment for two functioning scales (physical functioning and role functioning), two symptom scales (fatigue and nausea/vomiting), and two single‐item scales (pain and appetite loss), all in favor of the combination treatment (p < .05). A trend for improved cognitive functioning, global health status, and constipation was also observed in the cetuximab plus irinotecan arm (p < .1). The remaining multi‐item and single‐items scales showed no significant differences between the two treatment arms.
Discussion
This retrospective analysis of the RAS‐wt population of the EPIC study reiterates that the addition of cetuximab to irinotecan did not prolong OS—consistent with results of the primary analysis in the non–biomarker‐defined population [2] as well as those of a previous subgroup analysis in the KRAS‐wt population [13]. The lack of change in OS is possibly due to the high rate of poststudy crossover to cetuximab therapy in patients in the irinotecan arm, as suggested by Sobrero et al [2]. Indeed, nearly half of the patients with RAS‐wt tumors in the irinotecan arm received cetuximab in a subsequent line of therapy after the study, potentially masking any OS benefit of the addition of cetuximab to irinotecan. This hypothesis is supported by results from the CO.17 study of cetuximab versus best supportive care (BSC) in pretreated advanced RAS‐ and BRAF‐wt CRC, in which OS was significantly improved with cetuximab compared with BSC (10.1 vs. 4.8 months), with only 7.0% of patients who received BSC subsequently receiving cetuximab [14, 15].
Interestingly, patients in both treatment arms of EPIC who received poststudy cetuximab had improved OS compared with those who received a subsequent therapy without cetuximab or no poststudy therapy, suggesting that the administration of cetuximab at any point in the second or later line may improve survival. Furthermore, these data suggest that cetuximab‐based therapy may be a suitable standard treatment in the rechallenge setting (i.e., retreatment with cetuximab after progression in a subsequent therapy line without cetuximab) as well as beyond progression for patients with RAS‐wt mCRC. Thus, although guidelines recommend the use of cetuximab in the first‐line treatment setting [3, 4, 5], data from this trial support the use of cetuximab in second or subsequent line treatment settings. Of note, limitations of this analysis include a potential bias because of the differences in the proportion of subsequent therapies with and without cetuximab in the two treatment arms. Another possible bias arises from the observation that patients who live longer are more likely to receive cetuximab in any subsequent therapy line.
In contrast to OS, PFS was more than doubled and ORR was approximately sixfold higher in the cetuximab plus irinotecan arm than in the irinotecan arm (p < .0001 each), and this improvement was more prominent than that in the primary analysis [2] and in the analysis of the KRAS‐wt population [13]. These results suggest that second‐line cetuximab may have a clinically meaningful therapeutic benefit in patients with mCRC—considering their survival prognosis of approximately 1 year, which is supported by the improvements observed in the patients’ QoL. Furthermore, patients who received cetuximab continued treatment for longer, likely because of the prolonged PFS. In both this retrospective analysis and the initial results of the EPIC study [2], the longer PFS and higher ORR observed upon the addition of cetuximab to irinotecan may be a better indicator of the additional benefit conferred by cetuximab than OS, because these endpoints are directly related to the study period and are therefore unaffected by subsequent therapies and are clinically relevant in patients with mCRC.
Similar to the results of the primary analysis of the EPIC study, no new or unexpected safety signals in the RAS‐wt population were observed in either treatment arm. Furthermore, the improved QoL, as demonstrated for several single‐ and multi‐item scales in the cetuximab plus irinotecan arm compared with that in the irinotecan arm, is also reflected in the observed treatment duration, which was almost twice as long in the cetuximab plus irinotecan arm than in the irinotecan arm. Although an analysis for efficacy in left‐sided versus right‐sided tumors was not feasible in this retrospective study because of missing data on primary tumor location, the ORR for the RAS‐wt population in this study was among the highest observed to date in the second‐line setting when compared with that reported for other regimens, such as bevacizumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4), as reported for the E3200 study (ORR, 22.7%) [16], and panitumumab plus combination chemotherapy (ORR, 41% for panitumumab plus 5‐fluorouracil, leucovorin, and irinotecan (FOLFIRI) vs. 10% for FOLFIRI in patients with RAS‐wt tumors) [17]. Notably, although ORR and PFS increased from 16.4% to 29.4% and from 4.0 to 5.4 months, respectively, in the RAS‐unselected and the RAS‐wt populations with cetuximab plus irinotecan, the efficacy outcomes for patients receiving irinotecan did not differ between the RAS‐unselected and RAS‐wt populations (PFS, 2.6 months in both populations; ORR: 4.2% and 5.0%, respectively). These findings, as well as the improved QoL observed in the cetuximab plus irinotecan arm, further confirm the increased efficacy of cetuximab in patients with RAS‐wt tumors in second‐line treatment and confirm that RAS testing is predictive of clinical benefit.
Conclusion
This retrospective analysis of RAS‐wt patients enrolled in the EPIC study emphasizes the role of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC.
Author Contributions
Conception/design: Alberto Sobrero, Heinz‐Josef Lenz, Regina Esser, Johannes Nippgen, Howard Burris
Provision of study material or patients: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Collection and/or assembly of data: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Data analysis and interpretation: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Manuscript writing: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Final approval of manuscript: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Werner Scheithauer, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Disclosures
Alberto Sobrero: Amgen, Bayer, Bristol Myers Squibb, Celgene, Eli Lilly & Co., EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany), Roche, Sanofi, Takeda (C/A); Heinz‐Josef Lenz: Bayer, Bristol Myers Squibb, EMD Serono, Roche (C/A), Bayer, Bristol Myers Squibb, EMD Serono, Roche, Takeda (H), Bayer, EMD Serono (other—travel support); Cathy Eng: Bayer, LSK Global PS, Roche, Sirtex, Taiho (C/A); Wenfeng Chen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Regina Esser: Merck KGaA (Darmstadt, Germany) (E, OI); Johannes Nippgen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Howard Burris: AstraZeneca, Celgene, Daiichi Sankyo, FORMA Therapeutics, Incyte, Pfizer (C/A), Agios, AstraZeneca, Arch, Array BioPharma, Arvinas, Bayer, BIND Therapeutics, BioAtla, BioMed Valley, Boehringer‐Ingelheim, Bristol Myers Squibb, CicloMed, CytomX, eFFECTOR, Eli Lilly & Co., Roche/Genentech, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Incyte, Janssen, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck KGaA, Millennium Pharmaceuticals, Mirna Therapeutics, Moderna, Novartis, Pfizer, Revolution Medicine, Seattle Genetics, Tesaro, TG Therapeutics, Verastem, Vertex Pharmaceuticals (RF—institution), HCA/Sarah Cannon (OI). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Appendix S1 Supporting Information.
Click here for additional data file.
Table S1 Median OS by Subsequent Therapy in the RAS wt Population in the EPIC Study
Table S2: Comparison of QoL Between Treatment Arms Using a Longitudinal Analysis
Click here for additional data file.
Acknowledgments
Medical writing assistance was provided by Eleanor Green of ClinicalThinking, Manchester, U.K., and funded by Merck KGaA, Darmstadt, Germany. This assistance consisted of copyediting, editorial and production assistance. This study was sponsored by Bristol Myers Squibb, New York, NY; ImClone Systems, Bridgewater, NJ; Eli Lilly & Co., Indianapolis, IN; and Merck KGaA. Protocol design and funding of medical writing support by ClinicalThinking, Inc., was provided by Merck KGaA. Data interpretation and the final decision to submit for publication was conducted by Merck KGaA and the coordinating investigators.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'.
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Extended RAS Analysis of the Phase III EPIC Trial: Irinotecan + Cetuximab Versus Irinotecan as Second-Line Treatment for Patients with Metastatic Colorectal Cancer.
The multicenter, open-label, randomized, phase III EPIC study (EMR 062202-025) investigated cetuximab plus irinotecan versus irinotecan in patients with epidermal growth factor receptor-detectable metastatic colorectal cancer (mCRC) that progressed on first-line fluoropyrimidine- and oxaliplatin-based chemotherapy; we report the outcomes of patients with RAS-wild-type (wt) disease.
Available DNA samples from RAS-unselected patients (n = 1,164 of 1,298 [89.7%]) were reanalyzed for RAS mutations using beads, emulsion, amplification, and magnetics. Baseline characteristics, efficacy, safety, and poststudy therapy were assessed. RAS-wt status was defined as a mutated RAS allele frequency of ≤5%, with all relevant alleles being analyzable.
Baseline characteristics were comparable between the groups (n = 452 patients with RAS-wt mCRC; cetuximab plus irinotecan n = 231, irinotecan n = 221) and between the RAS-wt and RAS-unselected populations. In the cetuximab plus irinotecan versus irinotecan arms, median overall survival was 12.3 versus 12.0 months, median progression-free survival (PFS) was 5.4 versus 2.6 months, and objective response rate (ORR) was 29.4% versus 5.0%, respectively. Quality of life (QoL) was improved in the cetuximab plus irinotecan arm. Serious adverse events occurred in 45.4% (cetuximab plus irinotecan) and 42.4% (irinotecan) of patients. In total, 47.1% of patients in the irinotecan arm received subsequent cetuximab therapy.
PFS, ORR, and QoL were improved with cetuximab plus irinotecan as a second-line treatment in patients with RAS-wt mCRC, confirming that cetuximab-based therapy is suitable in this population. Almost half of patients in the irinotecan arm received poststudy cetuximab, masking a potential overall survival benefit of cetuximab addition.
Cetuximab is approved for the treatment of RAS-wild-type metastatic colorectal cancer (mCRC). In this retrospective analysis of the phase III EPIC study (cetuximab plus irinotecan vs. irinotecan alone as second-line treatment in patients with RAS-unselected mCRC), the subgroup of patients with RAS-wild-type mCRC who received cetuximab plus irinotecan had improved progression-free survival, objective response rate, and quality of life compared with the RAS-unselected population. These findings suggest that cetuximab-based therapy is a suitable second-line treatment for patients with RAS-wild-type mCRC.
Introduction
Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer‐related deaths globally, with approximately 1.8 million new cases and almost 900,000 deaths annually [1].
Cetuximab, an immunoglobulin G subtype 1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) [2], in combination with oxaliplatin‐ or irinotecan‐based doublet chemotherapy, is a first‐line standard‐of‐care treatment for patients with RAS‐wild‐type (wt) metastatic CRC (mCRC) [3, 4, 5]. Later‐line therapies in mCRC tend to include a biological agent in combination with chemotherapy and are selected based on which prior therapies the patient has received [6].
The randomized phase III study EPIC (Erbitux plus Irinotecan for the Treatment of mCRC; EMR 062202‐025), initiated in May 2003, was designed to determine whether the combination of cetuximab and irinotecan as a second‐line therapy would result in longer overall survival (OS) than that with irinotecan alone in irinotecan‐naïve patients with mCRC unselected for RAS mutational status. The original findings of the EPIC trial revealed statistically significantly improved progression‐free survival (PFS) and objective response rate (ORR) with cetuximab plus irinotecan compared with irinotecan, but there was no difference in OS [2]. The observed improvement in PFS and ORR suggests that cetuximab provides tumor control and thus has clinically relevant therapeutic benefit in this patient population. The lack of improvement in OS upon the addition of cetuximab to irinotecan may be attributed to the high crossover rate in the irinotecan arm because cetuximab was already approved in the third‐ and later‐line setting when the EPIC trial was conducted.
At the time this study was initiated, tumor EGFR expression was considered the only potentially relevant biomarker of response for anti‐EGFR inhibitors. This assumption has now been dispelled, and evidence of EGFR expression is no longer an eligibility requirement for anti‐EGFR therapy [3, 4, 5]. Instead, RAS mutations have been established as a much more evidence‐based predictive biomarker [7]. Retrospective analyses of pivotal studies with cetuximab plus chemotherapy, such as CRYSTAL and OPUS, found that ORR, PFS, and OS were significantly improved in patients with RAS‐wt tumors compared with those in patients with RAS‐mutant tumors [8, 9]; thus, extended RAS testing was included in treatment guidelines and product labels [4, 5, 10, 11], and the phase III TAILOR trial became the first to prospectively enroll a RAS‐wt population [12].
Because the EPIC trial was conducted before RAS was identified as a relevant biomarker for selecting patients for cetuximab treatment, a retrospective analysis of the RAS‐wt population was necessary to confirm the increased benefit of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC. We retrospectively analyzed the outcomes of patients with RAS‐wt mCRC in the EPIC study population. An analysis of the KRAS‐mutant population, a small proportion of the total population (n = 108 [8.3%]), has been reported previously [13].
Materials and Methods
EPIC was a multicenter, open‐label, randomized, phase III study that enrolled patients from 221 sites globally. Eligibility criteria have been described previously [2]. Briefly, eligible patients had histologically documented mCRC and immunohistochemical evidence of EGFR expression. Disease progression or discontinuation due to toxicity within 6 months of the last dose of first‐line fluoropyrimidine and oxaliplatin–based treatment for metastatic disease was required. Patients who had previously received irinotecan or anti‐EGFR therapies were not eligible. Patients were randomly assigned 1:1 to receive cetuximab plus irinotecan or irinotecan. The primary endpoint was OS; secondary endpoints included PFS, ORR, and quality of life (QoL). The trial was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the ethics committees of all participating centers, and all patients provided written informed consent.
Treatment
Patients assigned to the cetuximab plus irinotecan arm received an initial cetuximab dose of 400 mg/m2 (2‐hour i.v. infusion) and then 250 mg/m2 (1‐hour i.v. infusion) weekly. Pretreatment with an antihistamine was required prior to the first dose of cetuximab and was administered at the investigator's discretion prior to subsequent doses. Irinotecan was administered at 350 mg/m2 (90‐minute i.v. infusion; 300 mg/m2 for patients aged ≥70 years, those with Eastern Cooperative Oncology Group performance status [ECOG PS] of 2, or those with prior pelvic/abdominal irradiation) every 3 weeks in both treatment arms, starting 1 hour after completing cetuximab infusion for patients in the cetuximab arm. Patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. There were no poststudy treatment limitations (supplemental online Methods).
Extended RAS Analysis
For retrospective biomarker analysis, available DNA samples were reanalyzed for mutations in KRAS and NRAS exons 2, 3, and 4 using BEAMing (beads, emulsion, amplification, magnetics) technology. RAS‐wt status was defined as having all relevant alleles analyzable and a sum of mutated RAS allele frequencies across all tested mutations of ≤5%. The number of DNA samples included in this analysis was higher than the number of tumor samples available for the earlier retrospective analysis of the EPIC trial by KRAS status, which analyzed samples from U.S. sites only (23% of all randomized patients) and was therefore not representative of the overall study population [13]. Baseline characteristics, efficacy, safety, and poststudy therapy were also assessed (additional information for assessments and statistical analysis are provided in the supplemental online Methods).
Results
Baseline Characteristics
From May 2003 to February 2006, 1,298 RAS‐unselected patients with EGFR‐detectable mCRC who had previously progressed on first‐line fluoropyrimidine and oxaliplatin–based chemotherapy were enrolled (Fig. 1). Among the enrolled patients, RAS status could not be determined in 101 patients (7.8%), and 134 patients (10.3%) had no sample available. Of the 452 patients with RAS‐wt mCRC who were randomized, 446 (98.7%) received treatment: 229 of 231 patients (99.1%) in the cetuximab plus irinotecan arm and 217 of 221 patients (98.2%) in the irinotecan arm. Among patients in the cetuximab plus irinotecan and irinotecan arms, only 27 patients (11.7%) and 28 patients (12.7%), respectively, had received previous bevacizumab therapy; bevacizumab had not been approved in many participating countries at the time of this study.
Figure 1 Patient disposition. Abbreviation: wt, wild type.
Baseline characteristics in the randomized population were comparable to those of the unselected population and reasonably balanced between treatment arms within the RAS‐wt subgroup (Table 1). Most patients in the RAS‐wt subgroup were men (62.8%) and had an ECOG PS of 0 or 1 (93.5%). Median age was 61 years, and 38.7% were aged >65 years.
Table 1 Baseline characteristics of the RAS‐wt and RAS‐unselected populations in the EPIC study
Characteristic
RAS‐wt
RAS‐unselected [2]Total (n = 1,298), n (%)
Irinotecan (n = 221), n (%) Cetuximab plus irinotecan (n = 231), n (%) Total (n = 452), n (%)
Sex
Female 74 (33.5) 86 (37.2) 160 (35.4) 482 (37.1)
Male 147 (66.5) 145 (62.8) 292 (64.6) 816 (62.9)
Median age (range), years 60.0 (23–82) 61.0 (33–85) 61.0 (23–85) 62 (21–90)
ECOG PS
0 112 (50.7) 126 (54.5) 238 (52.7) 664 (51.2)
1 101 (45.7) 90 (39.0) 191 (42.3) 555 (42.8)
2 7 (3.2) 15 (6.5) 22 (4.9) 70 (5.4)
Not reported 1 (0.5) 0 1 (0.2) 9 (0.7)
Prior therapy
Radiotherapy 44 (19.9) 46 (19.9) 90 (19.9) 249 (19.2)
Adjuvant 19 (8.6) 15 (6.5) 34 (7.5) 102 (7.9)
Metastatic 8 (3.6) 17 (7.4) 25 (5.5) 70 (5.4)
Neoadjuvant 18 (8.1) 17 (7.4) 35 (7.7) 90 (69.3)
Chemotherapy 221 (100) 231 (100) 452 (100) 1,298 (100)
Adjuvant 55 (24.9) 54 (23.4) 109 (24.1) 646 (49.8)
Metastatic 219 (99.1) 231 (100) 450 (99.6) 1,289 (99.3)
Neoadjuvant 14 (6.3) 17 (7.4) 31 (6.9) 80 (6.2)
First‐line therapy
Fluoropyrimidine 216 (97.7) 225 (97.4) 441 (97.6) 1,266 (97.5)
Oxaliplatin 219 (99.1) 229 (99.1) 448 (99.1) 1,280 (98.6)
Reason for discontinuation
Disease progression 143 (64.7) 144 (62.3) 287 (63.5) 843 (64.9)
Toxicity 29 (13.1) 36 (15.6) 65 (14.4) 207 (15.9)
Other 44 (19.9) 45 (19.5) 89 (19.7) 225 (17.3)
Unknown 3 (1.4) 5 (2.2) 8 (1.8) 11 (0.8)
Tumor type
Colon 160 (72.4) 149 (64.5) 309 (68.4) 902 (69.5)
Rectum 61 (27.6) 82 (35.5) 143 (31.6) 395 (30.4)
Unknown 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.1)
Number of disease sites
1 69 (31.2) 81 (35.1) 150 (33.2) 415 (32.0)
≥ 2 150 (67.9) 149 (64.5) 299 (66.2) 871 (67.1)
Missing 2 (0.9) 1 (0.4) 3 (0.7) 12 (0.9)
EGFR‐positive CRC
Yes 221 (100) 230 (99.6) 451 (99.8) 1,275 (98.2)
No 0 (0.0) 1 (0.4) 1 (0.2) 2 (0.2)
Liver metastases
Yes 170 (76.9) 176 (76.2) 346 (76.5) 989 (76.2)
No 49 (22.2) 54 (23.4) 103 (22.8) 297 (22.9)
Abbreviations: CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; wt, wild type.
Treatment Adherence and Exposure
Patients in the RAS‐wt group received irinotecan for a median duration of 18.0 weeks (range, 0.7–89.1) in the cetuximab plus irinotecan arm and 10.0 weeks (range, 1.1–71.0) in the irinotecan arm; the median cumulative irinotecan doses were 1,798.4 mg/m2 (range, 266.1–7,204.8) and 1,056.8 mg/m2 (range, 173.6–7,150.3), respectively. Median duration of cetuximab treatment was 19.0 weeks (range, 0.7–97.9), and median cumulative dose was 4,524.0 mg/m2 (range, 159.6–22,086.3). In the cetuximab plus irinotecan arm, 79.0% of patients received ≥80% of the planned dose intensity of irinotecan versus 85.7% of patients in the irinotecan arm. For cetuximab treatment, ≥80% of the planned dose intensity was administered in 72.9% of patients.
In the irinotecan arm, 104 patients (47.1%) received cetuximab in a subsequent line of therapy after the EPIC study; 90 (40.7%) received cetuximab plus irinotecan (Fig. 2). In the cetuximab plus irinotecan arm, 26 patients (11.3%) received cetuximab after the study.
Figure 2 Overall survival by subsequent therapy in the RAS–wild‐type population. (A): In the cetuximab plus irinotecan arm of the EPIC study. (B): In the irinotecan arm of the EPIC study. Abbreviation: CI, confidence interval.
Efficacy
Median OS was 12.3 versus 12.0 months (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.71–1.17; p = .4645) in the cetuximab plus irinotecan versus irinotecan arms, respectively (Table 2; Fig. 3A); median PFS was 5.4 versus 2.6 months (HR, 0.57; 95% CI, 0.46–0.69; p < .0001; Table 2; Fig. 3B). ORR was higher in the cetuximab plus irinotecan arm than in the irinotecan arm: 29.4% versus 5.0% (odds ratio [OR], 8.12; 95% CI, 4.04–17.40; p < .0001) (Table 2). An analysis of OS by poststudy treatment within the RAS‐wt population showed improved median OS in patients who received poststudy cetuximab compared with those not receiving cetuximab or any subsequent therapy in both treatment arms (Fig. 2; supplemental online Table 1). In the cetuximab plus irinotecan arm, median OS in patients who had previously received bevacizumab (n = 27) versus those without prior bevacizumab therapy (n = 204) was 10.2 (95% CI, 4.53–14.09) versus 12.8 months (95% CI, 11.47–15.70), respectively. In the irinotecan arm, median OS was not estimable (95% CI, 11.73 months–not estimable) in patients who had received previous bevacizumab (n = 28) versus 11.8 months (95% CI, 9.00–13.31) in patients without prior bevacizumab therapy (n = 193). ORR in patients who had previously received bevacizumab was 18.5% in the cetuximab plus irinotecan arm (n = 27) and 3.6% in the irinotecan arm (n = 28).
Table 2 Summary of efficacy results in the RAS‐wt and RAS‐unselected populations in the EPIC study
RAS‐wt population
RAS‐unselected population [2]
Irinotecan (n = 221) Cetuximab plus irinotecan (n = 231) Irinotecan (n = 650) Cetuximab plus irinotecan (n = 648)
Median duration of therapy (range), weeks
Cetuximab NA 19.0 (0.7–97.9) NA 14.0 (0.7–97.9)
Irinotecan 10.0 (1.1–71.0) 18.0 (0.7–89.1) 9.9 (0.4–71.0) 13.1 (0.7–89.1)
OS
Number of events, n (%) 126 (57.0) 133 (57.6) 429 (66.0) 445 (68.8)
Median (95% CI), months 12.0 (9.36–14.92) 12.3 (11.37–14.09) 9.99 (9.13–11.33) 10.71 (9.59–11.30)
HR (95% CI) 0.91 (0.71–1.17) 0.975 (0.854–1.114)
Log‐rank p value .4645 .7114
PFS
Number of events, n (%) 201 (91.0) 212 (91.8) 598 (92.0) 610 (94.1)
Median (95% CI), months 2.6 (2.30–2.83) 5.4 (4.24–5.75) 2.56 (2.1–2.69) 3.98 (3.15–4.14)
HR (95% CI) 0.57 (0.46–0.69) 0.692 (0.617–0.776)
Log‐rank p value <.0001 <.0001
Response
Primary definition, n (%)
Complete response 0 4 (1.7) 1 (0.2) 9 (1.4)
Partial response 11 (5.0) 64 (27.7) 26 (4.0) 97 (15.0)
Stable disease 100 (45.2) 90 (39.0) 271 (41.7) 292 (45.1)
Progressive disease 71 (32.1) 46 (19.9) 243 (37.4) 174 (26.9)
Not assessable 39 (17.6) 27 (11.7) 109 (16.8) 76 (11.7)
ORR (CR + PR), n (%) [95% CI] 11 (5.0) [2.51–8.73] 68 (29.4) [23.63–35.77] 27 (4.2) [2.75–5.99] 106 (16.4) [13.59–19.44]
Abbreviations: CI, confidence interval; CR, complete response; HR, hazard ratio; NA, not applicable; ORR, overall response rate; OS, overall survival; PFS, progression‐free survival; PR, partial response; wt, wild type.
Figure 3 Survival in the RAS–wild‐type population of the EPIC study. (A): Overall survival. (B): Progression‐free survival. Abbreviations: CI, confidence interval; HR, hazard ratio.
Safety
Adverse events (AEs) in the RAS‐wt population were consistent with the safety profile observed in the overall EPIC safety population and in other cetuximab studies [2, 8, 9], and no new or unexpected safety signals were observed in either treatment arm. In the cetuximab plus irinotecan and irinotecan arms, 76.4% and 61.8% of patients, respectively, experienced a grade ≥ 3 treatment‐emergent AE. Grade ≥ 3 treatment‐related AEs (TRAEs) were observed in 67.7% and 45.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively; the most common grade 3/4 TRAEs (occurring in ≥20 patients in any treatment arm) were diarrhea (32.3% vs. 17.1%) and neutropenia (20.5% vs. 14.3%). In the cetuximab plus irinotecan arm, grade ≥ 3 drug‐related skin reactions were observed in 12.2% of patients, and grade ≥ 3 acne‐like dermatitis occurred in 1.7%. These TRAEs account for the overall higher TRAE rate in the cetuximab plus irinotecan group.
Serious TRAEs occurred in 29.3% and 21.2% of patients in the cetuximab plus irinotecan and irinotecan arms, respectively. Cetuximab‐related serious AEs (SAEs) occurred in 14.4% of patients in the cetuximab plus irinotecan arm. Irinotecan‐related SAEs were observed in 26.6% versus 21.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively. The most common grade ≥ 3 serious TRAEs (occurring in ≥5% of patients) in both treatment arms were febrile neutropenia and diarrhea. Furthermore, serious TRAEs leading to death occurred in eight patients in the cetuximab plus irinotecan arm and were cetuximab‐related in five patients (dyspnea [n = 1], disease progression [n = 1], cardiac failure and renal failure [n = 1], vomiting and sudden death [n = 1], sepsis [n = 1]) and irinotecan‐related in seven patients (diarrhea, cardiac failure and renal failure [n = 1], pneumonia aspiration and respiratory arrest [n = 1], disease progression [n = 1], gastroenteritis [n = 1], neutropenia [n = 1], vomiting and sudden death [n = 1], intestinal perforation, peritonitis and sepsis [n = 1]) versus three patients in the irinotecan arm (febrile neutropenia [n = 1]; intestinal obstruction [n = 1]; neutropenia [n = 1]). AEs resulting in discontinuation of cetuximab occurred in 20.5% of patients in the cetuximab plus irinotecan arm. AEs leading to irinotecan discontinuation were similar in both arms (22.3% vs. 19.4% in the cetuximab plus irinotecan vs. irinotecan arms).
QoL
Compliance rates for the QoL questionnaire in the RAS‐wt population at baseline were 86.1% and 90.0% in the cetuximab plus irinotecan and irinotecan arms, respectively. The on‐study completion rate subsequently decreased over time, stabilizing at approximately 50% at week 21 in each arm and remaining at this level until weeks 51 and 45 in the cetuximab plus irinotecan and irinotecan arms, respectively. Patients who completed the QoL assessment questionnaire answered 96.7% to 100% of the questions. Baseline scores were similar between treatment arms for 13 of 15 QoL scales. For the symptom scale fatigue and the single item insomnia, differences from baseline scores favored cetuximab plus irinotecan over irinotecan (p < .1). A longitudinal model (truncated at week 45) was used to compare change from baseline scores over time between treatment arms. During the course of the study, improved QoL was reported by patients in the cetuximab plus irinotecan arm compared with those in the irinotecan arm for several multi‐item and single‐item scales (supplemental online Table 2). The model also showed advantages for cetuximab treatment for two functioning scales (physical functioning and role functioning), two symptom scales (fatigue and nausea/vomiting), and two single‐item scales (pain and appetite loss), all in favor of the combination treatment (p < .05). A trend for improved cognitive functioning, global health status, and constipation was also observed in the cetuximab plus irinotecan arm (p < .1). The remaining multi‐item and single‐items scales showed no significant differences between the two treatment arms.
Discussion
This retrospective analysis of the RAS‐wt population of the EPIC study reiterates that the addition of cetuximab to irinotecan did not prolong OS—consistent with results of the primary analysis in the non–biomarker‐defined population [2] as well as those of a previous subgroup analysis in the KRAS‐wt population [13]. The lack of change in OS is possibly due to the high rate of poststudy crossover to cetuximab therapy in patients in the irinotecan arm, as suggested by Sobrero et al [2]. Indeed, nearly half of the patients with RAS‐wt tumors in the irinotecan arm received cetuximab in a subsequent line of therapy after the study, potentially masking any OS benefit of the addition of cetuximab to irinotecan. This hypothesis is supported by results from the CO.17 study of cetuximab versus best supportive care (BSC) in pretreated advanced RAS‐ and BRAF‐wt CRC, in which OS was significantly improved with cetuximab compared with BSC (10.1 vs. 4.8 months), with only 7.0% of patients who received BSC subsequently receiving cetuximab [14, 15].
Interestingly, patients in both treatment arms of EPIC who received poststudy cetuximab had improved OS compared with those who received a subsequent therapy without cetuximab or no poststudy therapy, suggesting that the administration of cetuximab at any point in the second or later line may improve survival. Furthermore, these data suggest that cetuximab‐based therapy may be a suitable standard treatment in the rechallenge setting (i.e., retreatment with cetuximab after progression in a subsequent therapy line without cetuximab) as well as beyond progression for patients with RAS‐wt mCRC. Thus, although guidelines recommend the use of cetuximab in the first‐line treatment setting [3, 4, 5], data from this trial support the use of cetuximab in second or subsequent line treatment settings. Of note, limitations of this analysis include a potential bias because of the differences in the proportion of subsequent therapies with and without cetuximab in the two treatment arms. Another possible bias arises from the observation that patients who live longer are more likely to receive cetuximab in any subsequent therapy line.
In contrast to OS, PFS was more than doubled and ORR was approximately sixfold higher in the cetuximab plus irinotecan arm than in the irinotecan arm (p < .0001 each), and this improvement was more prominent than that in the primary analysis [2] and in the analysis of the KRAS‐wt population [13]. These results suggest that second‐line cetuximab may have a clinically meaningful therapeutic benefit in patients with mCRC—considering their survival prognosis of approximately 1 year, which is supported by the improvements observed in the patients’ QoL. Furthermore, patients who received cetuximab continued treatment for longer, likely because of the prolonged PFS. In both this retrospective analysis and the initial results of the EPIC study [2], the longer PFS and higher ORR observed upon the addition of cetuximab to irinotecan may be a better indicator of the additional benefit conferred by cetuximab than OS, because these endpoints are directly related to the study period and are therefore unaffected by subsequent therapies and are clinically relevant in patients with mCRC.
Similar to the results of the primary analysis of the EPIC study, no new or unexpected safety signals in the RAS‐wt population were observed in either treatment arm. Furthermore, the improved QoL, as demonstrated for several single‐ and multi‐item scales in the cetuximab plus irinotecan arm compared with that in the irinotecan arm, is also reflected in the observed treatment duration, which was almost twice as long in the cetuximab plus irinotecan arm than in the irinotecan arm. Although an analysis for efficacy in left‐sided versus right‐sided tumors was not feasible in this retrospective study because of missing data on primary tumor location, the ORR for the RAS‐wt population in this study was among the highest observed to date in the second‐line setting when compared with that reported for other regimens, such as bevacizumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4), as reported for the E3200 study (ORR, 22.7%) [16], and panitumumab plus combination chemotherapy (ORR, 41% for panitumumab plus 5‐fluorouracil, leucovorin, and irinotecan (FOLFIRI) vs. 10% for FOLFIRI in patients with RAS‐wt tumors) [17]. Notably, although ORR and PFS increased from 16.4% to 29.4% and from 4.0 to 5.4 months, respectively, in the RAS‐unselected and the RAS‐wt populations with cetuximab plus irinotecan, the efficacy outcomes for patients receiving irinotecan did not differ between the RAS‐unselected and RAS‐wt populations (PFS, 2.6 months in both populations; ORR: 4.2% and 5.0%, respectively). These findings, as well as the improved QoL observed in the cetuximab plus irinotecan arm, further confirm the increased efficacy of cetuximab in patients with RAS‐wt tumors in second‐line treatment and confirm that RAS testing is predictive of clinical benefit.
Conclusion
This retrospective analysis of RAS‐wt patients enrolled in the EPIC study emphasizes the role of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC.
Author Contributions
Conception/design: Alberto Sobrero, Heinz‐Josef Lenz, Regina Esser, Johannes Nippgen, Howard Burris
Provision of study material or patients: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Collection and/or assembly of data: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Data analysis and interpretation: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Manuscript writing: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Final approval of manuscript: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Werner Scheithauer, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Disclosures
Alberto Sobrero: Amgen, Bayer, Bristol Myers Squibb, Celgene, Eli Lilly & Co., EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany), Roche, Sanofi, Takeda (C/A); Heinz‐Josef Lenz: Bayer, Bristol Myers Squibb, EMD Serono, Roche (C/A), Bayer, Bristol Myers Squibb, EMD Serono, Roche, Takeda (H), Bayer, EMD Serono (other—travel support); Cathy Eng: Bayer, LSK Global PS, Roche, Sirtex, Taiho (C/A); Wenfeng Chen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Regina Esser: Merck KGaA (Darmstadt, Germany) (E, OI); Johannes Nippgen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Howard Burris: AstraZeneca, Celgene, Daiichi Sankyo, FORMA Therapeutics, Incyte, Pfizer (C/A), Agios, AstraZeneca, Arch, Array BioPharma, Arvinas, Bayer, BIND Therapeutics, BioAtla, BioMed Valley, Boehringer‐Ingelheim, Bristol Myers Squibb, CicloMed, CytomX, eFFECTOR, Eli Lilly & Co., Roche/Genentech, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Incyte, Janssen, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck KGaA, Millennium Pharmaceuticals, Mirna Therapeutics, Moderna, Novartis, Pfizer, Revolution Medicine, Seattle Genetics, Tesaro, TG Therapeutics, Verastem, Vertex Pharmaceuticals (RF—institution), HCA/Sarah Cannon (OI). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Appendix S1 Supporting Information.
Click here for additional data file.
Table S1 Median OS by Subsequent Therapy in the RAS wt Population in the EPIC Study
Table S2: Comparison of QoL Between Treatment Arms Using a Longitudinal Analysis
Click here for additional data file.
Acknowledgments
Medical writing assistance was provided by Eleanor Green of ClinicalThinking, Manchester, U.K., and funded by Merck KGaA, Darmstadt, Germany. This assistance consisted of copyediting, editorial and production assistance. This study was sponsored by Bristol Myers Squibb, New York, NY; ImClone Systems, Bridgewater, NJ; Eli Lilly & Co., Indianapolis, IN; and Merck KGaA. Protocol design and funding of medical writing support by ClinicalThinking, Inc., was provided by Merck KGaA. Data interpretation and the final decision to submit for publication was conducted by Merck KGaA and the coordinating investigators.
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IRINOTECAN HYDROCHLORIDE
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DrugsGivenReaction
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CC BY-NC-ND
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33191588
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2021-02
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What was the administration route of drug 'IRINOTECAN HYDROCHLORIDE'?
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Extended RAS Analysis of the Phase III EPIC Trial: Irinotecan + Cetuximab Versus Irinotecan as Second-Line Treatment for Patients with Metastatic Colorectal Cancer.
The multicenter, open-label, randomized, phase III EPIC study (EMR 062202-025) investigated cetuximab plus irinotecan versus irinotecan in patients with epidermal growth factor receptor-detectable metastatic colorectal cancer (mCRC) that progressed on first-line fluoropyrimidine- and oxaliplatin-based chemotherapy; we report the outcomes of patients with RAS-wild-type (wt) disease.
Available DNA samples from RAS-unselected patients (n = 1,164 of 1,298 [89.7%]) were reanalyzed for RAS mutations using beads, emulsion, amplification, and magnetics. Baseline characteristics, efficacy, safety, and poststudy therapy were assessed. RAS-wt status was defined as a mutated RAS allele frequency of ≤5%, with all relevant alleles being analyzable.
Baseline characteristics were comparable between the groups (n = 452 patients with RAS-wt mCRC; cetuximab plus irinotecan n = 231, irinotecan n = 221) and between the RAS-wt and RAS-unselected populations. In the cetuximab plus irinotecan versus irinotecan arms, median overall survival was 12.3 versus 12.0 months, median progression-free survival (PFS) was 5.4 versus 2.6 months, and objective response rate (ORR) was 29.4% versus 5.0%, respectively. Quality of life (QoL) was improved in the cetuximab plus irinotecan arm. Serious adverse events occurred in 45.4% (cetuximab plus irinotecan) and 42.4% (irinotecan) of patients. In total, 47.1% of patients in the irinotecan arm received subsequent cetuximab therapy.
PFS, ORR, and QoL were improved with cetuximab plus irinotecan as a second-line treatment in patients with RAS-wt mCRC, confirming that cetuximab-based therapy is suitable in this population. Almost half of patients in the irinotecan arm received poststudy cetuximab, masking a potential overall survival benefit of cetuximab addition.
Cetuximab is approved for the treatment of RAS-wild-type metastatic colorectal cancer (mCRC). In this retrospective analysis of the phase III EPIC study (cetuximab plus irinotecan vs. irinotecan alone as second-line treatment in patients with RAS-unselected mCRC), the subgroup of patients with RAS-wild-type mCRC who received cetuximab plus irinotecan had improved progression-free survival, objective response rate, and quality of life compared with the RAS-unselected population. These findings suggest that cetuximab-based therapy is a suitable second-line treatment for patients with RAS-wild-type mCRC.
Introduction
Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer‐related deaths globally, with approximately 1.8 million new cases and almost 900,000 deaths annually [1].
Cetuximab, an immunoglobulin G subtype 1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) [2], in combination with oxaliplatin‐ or irinotecan‐based doublet chemotherapy, is a first‐line standard‐of‐care treatment for patients with RAS‐wild‐type (wt) metastatic CRC (mCRC) [3, 4, 5]. Later‐line therapies in mCRC tend to include a biological agent in combination with chemotherapy and are selected based on which prior therapies the patient has received [6].
The randomized phase III study EPIC (Erbitux plus Irinotecan for the Treatment of mCRC; EMR 062202‐025), initiated in May 2003, was designed to determine whether the combination of cetuximab and irinotecan as a second‐line therapy would result in longer overall survival (OS) than that with irinotecan alone in irinotecan‐naïve patients with mCRC unselected for RAS mutational status. The original findings of the EPIC trial revealed statistically significantly improved progression‐free survival (PFS) and objective response rate (ORR) with cetuximab plus irinotecan compared with irinotecan, but there was no difference in OS [2]. The observed improvement in PFS and ORR suggests that cetuximab provides tumor control and thus has clinically relevant therapeutic benefit in this patient population. The lack of improvement in OS upon the addition of cetuximab to irinotecan may be attributed to the high crossover rate in the irinotecan arm because cetuximab was already approved in the third‐ and later‐line setting when the EPIC trial was conducted.
At the time this study was initiated, tumor EGFR expression was considered the only potentially relevant biomarker of response for anti‐EGFR inhibitors. This assumption has now been dispelled, and evidence of EGFR expression is no longer an eligibility requirement for anti‐EGFR therapy [3, 4, 5]. Instead, RAS mutations have been established as a much more evidence‐based predictive biomarker [7]. Retrospective analyses of pivotal studies with cetuximab plus chemotherapy, such as CRYSTAL and OPUS, found that ORR, PFS, and OS were significantly improved in patients with RAS‐wt tumors compared with those in patients with RAS‐mutant tumors [8, 9]; thus, extended RAS testing was included in treatment guidelines and product labels [4, 5, 10, 11], and the phase III TAILOR trial became the first to prospectively enroll a RAS‐wt population [12].
Because the EPIC trial was conducted before RAS was identified as a relevant biomarker for selecting patients for cetuximab treatment, a retrospective analysis of the RAS‐wt population was necessary to confirm the increased benefit of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC. We retrospectively analyzed the outcomes of patients with RAS‐wt mCRC in the EPIC study population. An analysis of the KRAS‐mutant population, a small proportion of the total population (n = 108 [8.3%]), has been reported previously [13].
Materials and Methods
EPIC was a multicenter, open‐label, randomized, phase III study that enrolled patients from 221 sites globally. Eligibility criteria have been described previously [2]. Briefly, eligible patients had histologically documented mCRC and immunohistochemical evidence of EGFR expression. Disease progression or discontinuation due to toxicity within 6 months of the last dose of first‐line fluoropyrimidine and oxaliplatin–based treatment for metastatic disease was required. Patients who had previously received irinotecan or anti‐EGFR therapies were not eligible. Patients were randomly assigned 1:1 to receive cetuximab plus irinotecan or irinotecan. The primary endpoint was OS; secondary endpoints included PFS, ORR, and quality of life (QoL). The trial was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the ethics committees of all participating centers, and all patients provided written informed consent.
Treatment
Patients assigned to the cetuximab plus irinotecan arm received an initial cetuximab dose of 400 mg/m2 (2‐hour i.v. infusion) and then 250 mg/m2 (1‐hour i.v. infusion) weekly. Pretreatment with an antihistamine was required prior to the first dose of cetuximab and was administered at the investigator's discretion prior to subsequent doses. Irinotecan was administered at 350 mg/m2 (90‐minute i.v. infusion; 300 mg/m2 for patients aged ≥70 years, those with Eastern Cooperative Oncology Group performance status [ECOG PS] of 2, or those with prior pelvic/abdominal irradiation) every 3 weeks in both treatment arms, starting 1 hour after completing cetuximab infusion for patients in the cetuximab arm. Patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. There were no poststudy treatment limitations (supplemental online Methods).
Extended RAS Analysis
For retrospective biomarker analysis, available DNA samples were reanalyzed for mutations in KRAS and NRAS exons 2, 3, and 4 using BEAMing (beads, emulsion, amplification, magnetics) technology. RAS‐wt status was defined as having all relevant alleles analyzable and a sum of mutated RAS allele frequencies across all tested mutations of ≤5%. The number of DNA samples included in this analysis was higher than the number of tumor samples available for the earlier retrospective analysis of the EPIC trial by KRAS status, which analyzed samples from U.S. sites only (23% of all randomized patients) and was therefore not representative of the overall study population [13]. Baseline characteristics, efficacy, safety, and poststudy therapy were also assessed (additional information for assessments and statistical analysis are provided in the supplemental online Methods).
Results
Baseline Characteristics
From May 2003 to February 2006, 1,298 RAS‐unselected patients with EGFR‐detectable mCRC who had previously progressed on first‐line fluoropyrimidine and oxaliplatin–based chemotherapy were enrolled (Fig. 1). Among the enrolled patients, RAS status could not be determined in 101 patients (7.8%), and 134 patients (10.3%) had no sample available. Of the 452 patients with RAS‐wt mCRC who were randomized, 446 (98.7%) received treatment: 229 of 231 patients (99.1%) in the cetuximab plus irinotecan arm and 217 of 221 patients (98.2%) in the irinotecan arm. Among patients in the cetuximab plus irinotecan and irinotecan arms, only 27 patients (11.7%) and 28 patients (12.7%), respectively, had received previous bevacizumab therapy; bevacizumab had not been approved in many participating countries at the time of this study.
Figure 1 Patient disposition. Abbreviation: wt, wild type.
Baseline characteristics in the randomized population were comparable to those of the unselected population and reasonably balanced between treatment arms within the RAS‐wt subgroup (Table 1). Most patients in the RAS‐wt subgroup were men (62.8%) and had an ECOG PS of 0 or 1 (93.5%). Median age was 61 years, and 38.7% were aged >65 years.
Table 1 Baseline characteristics of the RAS‐wt and RAS‐unselected populations in the EPIC study
Characteristic
RAS‐wt
RAS‐unselected [2]Total (n = 1,298), n (%)
Irinotecan (n = 221), n (%) Cetuximab plus irinotecan (n = 231), n (%) Total (n = 452), n (%)
Sex
Female 74 (33.5) 86 (37.2) 160 (35.4) 482 (37.1)
Male 147 (66.5) 145 (62.8) 292 (64.6) 816 (62.9)
Median age (range), years 60.0 (23–82) 61.0 (33–85) 61.0 (23–85) 62 (21–90)
ECOG PS
0 112 (50.7) 126 (54.5) 238 (52.7) 664 (51.2)
1 101 (45.7) 90 (39.0) 191 (42.3) 555 (42.8)
2 7 (3.2) 15 (6.5) 22 (4.9) 70 (5.4)
Not reported 1 (0.5) 0 1 (0.2) 9 (0.7)
Prior therapy
Radiotherapy 44 (19.9) 46 (19.9) 90 (19.9) 249 (19.2)
Adjuvant 19 (8.6) 15 (6.5) 34 (7.5) 102 (7.9)
Metastatic 8 (3.6) 17 (7.4) 25 (5.5) 70 (5.4)
Neoadjuvant 18 (8.1) 17 (7.4) 35 (7.7) 90 (69.3)
Chemotherapy 221 (100) 231 (100) 452 (100) 1,298 (100)
Adjuvant 55 (24.9) 54 (23.4) 109 (24.1) 646 (49.8)
Metastatic 219 (99.1) 231 (100) 450 (99.6) 1,289 (99.3)
Neoadjuvant 14 (6.3) 17 (7.4) 31 (6.9) 80 (6.2)
First‐line therapy
Fluoropyrimidine 216 (97.7) 225 (97.4) 441 (97.6) 1,266 (97.5)
Oxaliplatin 219 (99.1) 229 (99.1) 448 (99.1) 1,280 (98.6)
Reason for discontinuation
Disease progression 143 (64.7) 144 (62.3) 287 (63.5) 843 (64.9)
Toxicity 29 (13.1) 36 (15.6) 65 (14.4) 207 (15.9)
Other 44 (19.9) 45 (19.5) 89 (19.7) 225 (17.3)
Unknown 3 (1.4) 5 (2.2) 8 (1.8) 11 (0.8)
Tumor type
Colon 160 (72.4) 149 (64.5) 309 (68.4) 902 (69.5)
Rectum 61 (27.6) 82 (35.5) 143 (31.6) 395 (30.4)
Unknown 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.1)
Number of disease sites
1 69 (31.2) 81 (35.1) 150 (33.2) 415 (32.0)
≥ 2 150 (67.9) 149 (64.5) 299 (66.2) 871 (67.1)
Missing 2 (0.9) 1 (0.4) 3 (0.7) 12 (0.9)
EGFR‐positive CRC
Yes 221 (100) 230 (99.6) 451 (99.8) 1,275 (98.2)
No 0 (0.0) 1 (0.4) 1 (0.2) 2 (0.2)
Liver metastases
Yes 170 (76.9) 176 (76.2) 346 (76.5) 989 (76.2)
No 49 (22.2) 54 (23.4) 103 (22.8) 297 (22.9)
Abbreviations: CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; wt, wild type.
Treatment Adherence and Exposure
Patients in the RAS‐wt group received irinotecan for a median duration of 18.0 weeks (range, 0.7–89.1) in the cetuximab plus irinotecan arm and 10.0 weeks (range, 1.1–71.0) in the irinotecan arm; the median cumulative irinotecan doses were 1,798.4 mg/m2 (range, 266.1–7,204.8) and 1,056.8 mg/m2 (range, 173.6–7,150.3), respectively. Median duration of cetuximab treatment was 19.0 weeks (range, 0.7–97.9), and median cumulative dose was 4,524.0 mg/m2 (range, 159.6–22,086.3). In the cetuximab plus irinotecan arm, 79.0% of patients received ≥80% of the planned dose intensity of irinotecan versus 85.7% of patients in the irinotecan arm. For cetuximab treatment, ≥80% of the planned dose intensity was administered in 72.9% of patients.
In the irinotecan arm, 104 patients (47.1%) received cetuximab in a subsequent line of therapy after the EPIC study; 90 (40.7%) received cetuximab plus irinotecan (Fig. 2). In the cetuximab plus irinotecan arm, 26 patients (11.3%) received cetuximab after the study.
Figure 2 Overall survival by subsequent therapy in the RAS–wild‐type population. (A): In the cetuximab plus irinotecan arm of the EPIC study. (B): In the irinotecan arm of the EPIC study. Abbreviation: CI, confidence interval.
Efficacy
Median OS was 12.3 versus 12.0 months (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.71–1.17; p = .4645) in the cetuximab plus irinotecan versus irinotecan arms, respectively (Table 2; Fig. 3A); median PFS was 5.4 versus 2.6 months (HR, 0.57; 95% CI, 0.46–0.69; p < .0001; Table 2; Fig. 3B). ORR was higher in the cetuximab plus irinotecan arm than in the irinotecan arm: 29.4% versus 5.0% (odds ratio [OR], 8.12; 95% CI, 4.04–17.40; p < .0001) (Table 2). An analysis of OS by poststudy treatment within the RAS‐wt population showed improved median OS in patients who received poststudy cetuximab compared with those not receiving cetuximab or any subsequent therapy in both treatment arms (Fig. 2; supplemental online Table 1). In the cetuximab plus irinotecan arm, median OS in patients who had previously received bevacizumab (n = 27) versus those without prior bevacizumab therapy (n = 204) was 10.2 (95% CI, 4.53–14.09) versus 12.8 months (95% CI, 11.47–15.70), respectively. In the irinotecan arm, median OS was not estimable (95% CI, 11.73 months–not estimable) in patients who had received previous bevacizumab (n = 28) versus 11.8 months (95% CI, 9.00–13.31) in patients without prior bevacizumab therapy (n = 193). ORR in patients who had previously received bevacizumab was 18.5% in the cetuximab plus irinotecan arm (n = 27) and 3.6% in the irinotecan arm (n = 28).
Table 2 Summary of efficacy results in the RAS‐wt and RAS‐unselected populations in the EPIC study
RAS‐wt population
RAS‐unselected population [2]
Irinotecan (n = 221) Cetuximab plus irinotecan (n = 231) Irinotecan (n = 650) Cetuximab plus irinotecan (n = 648)
Median duration of therapy (range), weeks
Cetuximab NA 19.0 (0.7–97.9) NA 14.0 (0.7–97.9)
Irinotecan 10.0 (1.1–71.0) 18.0 (0.7–89.1) 9.9 (0.4–71.0) 13.1 (0.7–89.1)
OS
Number of events, n (%) 126 (57.0) 133 (57.6) 429 (66.0) 445 (68.8)
Median (95% CI), months 12.0 (9.36–14.92) 12.3 (11.37–14.09) 9.99 (9.13–11.33) 10.71 (9.59–11.30)
HR (95% CI) 0.91 (0.71–1.17) 0.975 (0.854–1.114)
Log‐rank p value .4645 .7114
PFS
Number of events, n (%) 201 (91.0) 212 (91.8) 598 (92.0) 610 (94.1)
Median (95% CI), months 2.6 (2.30–2.83) 5.4 (4.24–5.75) 2.56 (2.1–2.69) 3.98 (3.15–4.14)
HR (95% CI) 0.57 (0.46–0.69) 0.692 (0.617–0.776)
Log‐rank p value <.0001 <.0001
Response
Primary definition, n (%)
Complete response 0 4 (1.7) 1 (0.2) 9 (1.4)
Partial response 11 (5.0) 64 (27.7) 26 (4.0) 97 (15.0)
Stable disease 100 (45.2) 90 (39.0) 271 (41.7) 292 (45.1)
Progressive disease 71 (32.1) 46 (19.9) 243 (37.4) 174 (26.9)
Not assessable 39 (17.6) 27 (11.7) 109 (16.8) 76 (11.7)
ORR (CR + PR), n (%) [95% CI] 11 (5.0) [2.51–8.73] 68 (29.4) [23.63–35.77] 27 (4.2) [2.75–5.99] 106 (16.4) [13.59–19.44]
Abbreviations: CI, confidence interval; CR, complete response; HR, hazard ratio; NA, not applicable; ORR, overall response rate; OS, overall survival; PFS, progression‐free survival; PR, partial response; wt, wild type.
Figure 3 Survival in the RAS–wild‐type population of the EPIC study. (A): Overall survival. (B): Progression‐free survival. Abbreviations: CI, confidence interval; HR, hazard ratio.
Safety
Adverse events (AEs) in the RAS‐wt population were consistent with the safety profile observed in the overall EPIC safety population and in other cetuximab studies [2, 8, 9], and no new or unexpected safety signals were observed in either treatment arm. In the cetuximab plus irinotecan and irinotecan arms, 76.4% and 61.8% of patients, respectively, experienced a grade ≥ 3 treatment‐emergent AE. Grade ≥ 3 treatment‐related AEs (TRAEs) were observed in 67.7% and 45.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively; the most common grade 3/4 TRAEs (occurring in ≥20 patients in any treatment arm) were diarrhea (32.3% vs. 17.1%) and neutropenia (20.5% vs. 14.3%). In the cetuximab plus irinotecan arm, grade ≥ 3 drug‐related skin reactions were observed in 12.2% of patients, and grade ≥ 3 acne‐like dermatitis occurred in 1.7%. These TRAEs account for the overall higher TRAE rate in the cetuximab plus irinotecan group.
Serious TRAEs occurred in 29.3% and 21.2% of patients in the cetuximab plus irinotecan and irinotecan arms, respectively. Cetuximab‐related serious AEs (SAEs) occurred in 14.4% of patients in the cetuximab plus irinotecan arm. Irinotecan‐related SAEs were observed in 26.6% versus 21.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively. The most common grade ≥ 3 serious TRAEs (occurring in ≥5% of patients) in both treatment arms were febrile neutropenia and diarrhea. Furthermore, serious TRAEs leading to death occurred in eight patients in the cetuximab plus irinotecan arm and were cetuximab‐related in five patients (dyspnea [n = 1], disease progression [n = 1], cardiac failure and renal failure [n = 1], vomiting and sudden death [n = 1], sepsis [n = 1]) and irinotecan‐related in seven patients (diarrhea, cardiac failure and renal failure [n = 1], pneumonia aspiration and respiratory arrest [n = 1], disease progression [n = 1], gastroenteritis [n = 1], neutropenia [n = 1], vomiting and sudden death [n = 1], intestinal perforation, peritonitis and sepsis [n = 1]) versus three patients in the irinotecan arm (febrile neutropenia [n = 1]; intestinal obstruction [n = 1]; neutropenia [n = 1]). AEs resulting in discontinuation of cetuximab occurred in 20.5% of patients in the cetuximab plus irinotecan arm. AEs leading to irinotecan discontinuation were similar in both arms (22.3% vs. 19.4% in the cetuximab plus irinotecan vs. irinotecan arms).
QoL
Compliance rates for the QoL questionnaire in the RAS‐wt population at baseline were 86.1% and 90.0% in the cetuximab plus irinotecan and irinotecan arms, respectively. The on‐study completion rate subsequently decreased over time, stabilizing at approximately 50% at week 21 in each arm and remaining at this level until weeks 51 and 45 in the cetuximab plus irinotecan and irinotecan arms, respectively. Patients who completed the QoL assessment questionnaire answered 96.7% to 100% of the questions. Baseline scores were similar between treatment arms for 13 of 15 QoL scales. For the symptom scale fatigue and the single item insomnia, differences from baseline scores favored cetuximab plus irinotecan over irinotecan (p < .1). A longitudinal model (truncated at week 45) was used to compare change from baseline scores over time between treatment arms. During the course of the study, improved QoL was reported by patients in the cetuximab plus irinotecan arm compared with those in the irinotecan arm for several multi‐item and single‐item scales (supplemental online Table 2). The model also showed advantages for cetuximab treatment for two functioning scales (physical functioning and role functioning), two symptom scales (fatigue and nausea/vomiting), and two single‐item scales (pain and appetite loss), all in favor of the combination treatment (p < .05). A trend for improved cognitive functioning, global health status, and constipation was also observed in the cetuximab plus irinotecan arm (p < .1). The remaining multi‐item and single‐items scales showed no significant differences between the two treatment arms.
Discussion
This retrospective analysis of the RAS‐wt population of the EPIC study reiterates that the addition of cetuximab to irinotecan did not prolong OS—consistent with results of the primary analysis in the non–biomarker‐defined population [2] as well as those of a previous subgroup analysis in the KRAS‐wt population [13]. The lack of change in OS is possibly due to the high rate of poststudy crossover to cetuximab therapy in patients in the irinotecan arm, as suggested by Sobrero et al [2]. Indeed, nearly half of the patients with RAS‐wt tumors in the irinotecan arm received cetuximab in a subsequent line of therapy after the study, potentially masking any OS benefit of the addition of cetuximab to irinotecan. This hypothesis is supported by results from the CO.17 study of cetuximab versus best supportive care (BSC) in pretreated advanced RAS‐ and BRAF‐wt CRC, in which OS was significantly improved with cetuximab compared with BSC (10.1 vs. 4.8 months), with only 7.0% of patients who received BSC subsequently receiving cetuximab [14, 15].
Interestingly, patients in both treatment arms of EPIC who received poststudy cetuximab had improved OS compared with those who received a subsequent therapy without cetuximab or no poststudy therapy, suggesting that the administration of cetuximab at any point in the second or later line may improve survival. Furthermore, these data suggest that cetuximab‐based therapy may be a suitable standard treatment in the rechallenge setting (i.e., retreatment with cetuximab after progression in a subsequent therapy line without cetuximab) as well as beyond progression for patients with RAS‐wt mCRC. Thus, although guidelines recommend the use of cetuximab in the first‐line treatment setting [3, 4, 5], data from this trial support the use of cetuximab in second or subsequent line treatment settings. Of note, limitations of this analysis include a potential bias because of the differences in the proportion of subsequent therapies with and without cetuximab in the two treatment arms. Another possible bias arises from the observation that patients who live longer are more likely to receive cetuximab in any subsequent therapy line.
In contrast to OS, PFS was more than doubled and ORR was approximately sixfold higher in the cetuximab plus irinotecan arm than in the irinotecan arm (p < .0001 each), and this improvement was more prominent than that in the primary analysis [2] and in the analysis of the KRAS‐wt population [13]. These results suggest that second‐line cetuximab may have a clinically meaningful therapeutic benefit in patients with mCRC—considering their survival prognosis of approximately 1 year, which is supported by the improvements observed in the patients’ QoL. Furthermore, patients who received cetuximab continued treatment for longer, likely because of the prolonged PFS. In both this retrospective analysis and the initial results of the EPIC study [2], the longer PFS and higher ORR observed upon the addition of cetuximab to irinotecan may be a better indicator of the additional benefit conferred by cetuximab than OS, because these endpoints are directly related to the study period and are therefore unaffected by subsequent therapies and are clinically relevant in patients with mCRC.
Similar to the results of the primary analysis of the EPIC study, no new or unexpected safety signals in the RAS‐wt population were observed in either treatment arm. Furthermore, the improved QoL, as demonstrated for several single‐ and multi‐item scales in the cetuximab plus irinotecan arm compared with that in the irinotecan arm, is also reflected in the observed treatment duration, which was almost twice as long in the cetuximab plus irinotecan arm than in the irinotecan arm. Although an analysis for efficacy in left‐sided versus right‐sided tumors was not feasible in this retrospective study because of missing data on primary tumor location, the ORR for the RAS‐wt population in this study was among the highest observed to date in the second‐line setting when compared with that reported for other regimens, such as bevacizumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4), as reported for the E3200 study (ORR, 22.7%) [16], and panitumumab plus combination chemotherapy (ORR, 41% for panitumumab plus 5‐fluorouracil, leucovorin, and irinotecan (FOLFIRI) vs. 10% for FOLFIRI in patients with RAS‐wt tumors) [17]. Notably, although ORR and PFS increased from 16.4% to 29.4% and from 4.0 to 5.4 months, respectively, in the RAS‐unselected and the RAS‐wt populations with cetuximab plus irinotecan, the efficacy outcomes for patients receiving irinotecan did not differ between the RAS‐unselected and RAS‐wt populations (PFS, 2.6 months in both populations; ORR: 4.2% and 5.0%, respectively). These findings, as well as the improved QoL observed in the cetuximab plus irinotecan arm, further confirm the increased efficacy of cetuximab in patients with RAS‐wt tumors in second‐line treatment and confirm that RAS testing is predictive of clinical benefit.
Conclusion
This retrospective analysis of RAS‐wt patients enrolled in the EPIC study emphasizes the role of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC.
Author Contributions
Conception/design: Alberto Sobrero, Heinz‐Josef Lenz, Regina Esser, Johannes Nippgen, Howard Burris
Provision of study material or patients: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Collection and/or assembly of data: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Data analysis and interpretation: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Manuscript writing: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Final approval of manuscript: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Werner Scheithauer, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Disclosures
Alberto Sobrero: Amgen, Bayer, Bristol Myers Squibb, Celgene, Eli Lilly & Co., EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany), Roche, Sanofi, Takeda (C/A); Heinz‐Josef Lenz: Bayer, Bristol Myers Squibb, EMD Serono, Roche (C/A), Bayer, Bristol Myers Squibb, EMD Serono, Roche, Takeda (H), Bayer, EMD Serono (other—travel support); Cathy Eng: Bayer, LSK Global PS, Roche, Sirtex, Taiho (C/A); Wenfeng Chen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Regina Esser: Merck KGaA (Darmstadt, Germany) (E, OI); Johannes Nippgen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Howard Burris: AstraZeneca, Celgene, Daiichi Sankyo, FORMA Therapeutics, Incyte, Pfizer (C/A), Agios, AstraZeneca, Arch, Array BioPharma, Arvinas, Bayer, BIND Therapeutics, BioAtla, BioMed Valley, Boehringer‐Ingelheim, Bristol Myers Squibb, CicloMed, CytomX, eFFECTOR, Eli Lilly & Co., Roche/Genentech, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Incyte, Janssen, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck KGaA, Millennium Pharmaceuticals, Mirna Therapeutics, Moderna, Novartis, Pfizer, Revolution Medicine, Seattle Genetics, Tesaro, TG Therapeutics, Verastem, Vertex Pharmaceuticals (RF—institution), HCA/Sarah Cannon (OI). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Appendix S1 Supporting Information.
Click here for additional data file.
Table S1 Median OS by Subsequent Therapy in the RAS wt Population in the EPIC Study
Table S2: Comparison of QoL Between Treatment Arms Using a Longitudinal Analysis
Click here for additional data file.
Acknowledgments
Medical writing assistance was provided by Eleanor Green of ClinicalThinking, Manchester, U.K., and funded by Merck KGaA, Darmstadt, Germany. This assistance consisted of copyediting, editorial and production assistance. This study was sponsored by Bristol Myers Squibb, New York, NY; ImClone Systems, Bridgewater, NJ; Eli Lilly & Co., Indianapolis, IN; and Merck KGaA. Protocol design and funding of medical writing support by ClinicalThinking, Inc., was provided by Merck KGaA. Data interpretation and the final decision to submit for publication was conducted by Merck KGaA and the coordinating investigators.
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What was the dosage of drug 'IRINOTECAN HYDROCHLORIDE'?
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Extended RAS Analysis of the Phase III EPIC Trial: Irinotecan + Cetuximab Versus Irinotecan as Second-Line Treatment for Patients with Metastatic Colorectal Cancer.
The multicenter, open-label, randomized, phase III EPIC study (EMR 062202-025) investigated cetuximab plus irinotecan versus irinotecan in patients with epidermal growth factor receptor-detectable metastatic colorectal cancer (mCRC) that progressed on first-line fluoropyrimidine- and oxaliplatin-based chemotherapy; we report the outcomes of patients with RAS-wild-type (wt) disease.
Available DNA samples from RAS-unselected patients (n = 1,164 of 1,298 [89.7%]) were reanalyzed for RAS mutations using beads, emulsion, amplification, and magnetics. Baseline characteristics, efficacy, safety, and poststudy therapy were assessed. RAS-wt status was defined as a mutated RAS allele frequency of ≤5%, with all relevant alleles being analyzable.
Baseline characteristics were comparable between the groups (n = 452 patients with RAS-wt mCRC; cetuximab plus irinotecan n = 231, irinotecan n = 221) and between the RAS-wt and RAS-unselected populations. In the cetuximab plus irinotecan versus irinotecan arms, median overall survival was 12.3 versus 12.0 months, median progression-free survival (PFS) was 5.4 versus 2.6 months, and objective response rate (ORR) was 29.4% versus 5.0%, respectively. Quality of life (QoL) was improved in the cetuximab plus irinotecan arm. Serious adverse events occurred in 45.4% (cetuximab plus irinotecan) and 42.4% (irinotecan) of patients. In total, 47.1% of patients in the irinotecan arm received subsequent cetuximab therapy.
PFS, ORR, and QoL were improved with cetuximab plus irinotecan as a second-line treatment in patients with RAS-wt mCRC, confirming that cetuximab-based therapy is suitable in this population. Almost half of patients in the irinotecan arm received poststudy cetuximab, masking a potential overall survival benefit of cetuximab addition.
Cetuximab is approved for the treatment of RAS-wild-type metastatic colorectal cancer (mCRC). In this retrospective analysis of the phase III EPIC study (cetuximab plus irinotecan vs. irinotecan alone as second-line treatment in patients with RAS-unselected mCRC), the subgroup of patients with RAS-wild-type mCRC who received cetuximab plus irinotecan had improved progression-free survival, objective response rate, and quality of life compared with the RAS-unselected population. These findings suggest that cetuximab-based therapy is a suitable second-line treatment for patients with RAS-wild-type mCRC.
Introduction
Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer‐related deaths globally, with approximately 1.8 million new cases and almost 900,000 deaths annually [1].
Cetuximab, an immunoglobulin G subtype 1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) [2], in combination with oxaliplatin‐ or irinotecan‐based doublet chemotherapy, is a first‐line standard‐of‐care treatment for patients with RAS‐wild‐type (wt) metastatic CRC (mCRC) [3, 4, 5]. Later‐line therapies in mCRC tend to include a biological agent in combination with chemotherapy and are selected based on which prior therapies the patient has received [6].
The randomized phase III study EPIC (Erbitux plus Irinotecan for the Treatment of mCRC; EMR 062202‐025), initiated in May 2003, was designed to determine whether the combination of cetuximab and irinotecan as a second‐line therapy would result in longer overall survival (OS) than that with irinotecan alone in irinotecan‐naïve patients with mCRC unselected for RAS mutational status. The original findings of the EPIC trial revealed statistically significantly improved progression‐free survival (PFS) and objective response rate (ORR) with cetuximab plus irinotecan compared with irinotecan, but there was no difference in OS [2]. The observed improvement in PFS and ORR suggests that cetuximab provides tumor control and thus has clinically relevant therapeutic benefit in this patient population. The lack of improvement in OS upon the addition of cetuximab to irinotecan may be attributed to the high crossover rate in the irinotecan arm because cetuximab was already approved in the third‐ and later‐line setting when the EPIC trial was conducted.
At the time this study was initiated, tumor EGFR expression was considered the only potentially relevant biomarker of response for anti‐EGFR inhibitors. This assumption has now been dispelled, and evidence of EGFR expression is no longer an eligibility requirement for anti‐EGFR therapy [3, 4, 5]. Instead, RAS mutations have been established as a much more evidence‐based predictive biomarker [7]. Retrospective analyses of pivotal studies with cetuximab plus chemotherapy, such as CRYSTAL and OPUS, found that ORR, PFS, and OS were significantly improved in patients with RAS‐wt tumors compared with those in patients with RAS‐mutant tumors [8, 9]; thus, extended RAS testing was included in treatment guidelines and product labels [4, 5, 10, 11], and the phase III TAILOR trial became the first to prospectively enroll a RAS‐wt population [12].
Because the EPIC trial was conducted before RAS was identified as a relevant biomarker for selecting patients for cetuximab treatment, a retrospective analysis of the RAS‐wt population was necessary to confirm the increased benefit of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC. We retrospectively analyzed the outcomes of patients with RAS‐wt mCRC in the EPIC study population. An analysis of the KRAS‐mutant population, a small proportion of the total population (n = 108 [8.3%]), has been reported previously [13].
Materials and Methods
EPIC was a multicenter, open‐label, randomized, phase III study that enrolled patients from 221 sites globally. Eligibility criteria have been described previously [2]. Briefly, eligible patients had histologically documented mCRC and immunohistochemical evidence of EGFR expression. Disease progression or discontinuation due to toxicity within 6 months of the last dose of first‐line fluoropyrimidine and oxaliplatin–based treatment for metastatic disease was required. Patients who had previously received irinotecan or anti‐EGFR therapies were not eligible. Patients were randomly assigned 1:1 to receive cetuximab plus irinotecan or irinotecan. The primary endpoint was OS; secondary endpoints included PFS, ORR, and quality of life (QoL). The trial was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the ethics committees of all participating centers, and all patients provided written informed consent.
Treatment
Patients assigned to the cetuximab plus irinotecan arm received an initial cetuximab dose of 400 mg/m2 (2‐hour i.v. infusion) and then 250 mg/m2 (1‐hour i.v. infusion) weekly. Pretreatment with an antihistamine was required prior to the first dose of cetuximab and was administered at the investigator's discretion prior to subsequent doses. Irinotecan was administered at 350 mg/m2 (90‐minute i.v. infusion; 300 mg/m2 for patients aged ≥70 years, those with Eastern Cooperative Oncology Group performance status [ECOG PS] of 2, or those with prior pelvic/abdominal irradiation) every 3 weeks in both treatment arms, starting 1 hour after completing cetuximab infusion for patients in the cetuximab arm. Patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. There were no poststudy treatment limitations (supplemental online Methods).
Extended RAS Analysis
For retrospective biomarker analysis, available DNA samples were reanalyzed for mutations in KRAS and NRAS exons 2, 3, and 4 using BEAMing (beads, emulsion, amplification, magnetics) technology. RAS‐wt status was defined as having all relevant alleles analyzable and a sum of mutated RAS allele frequencies across all tested mutations of ≤5%. The number of DNA samples included in this analysis was higher than the number of tumor samples available for the earlier retrospective analysis of the EPIC trial by KRAS status, which analyzed samples from U.S. sites only (23% of all randomized patients) and was therefore not representative of the overall study population [13]. Baseline characteristics, efficacy, safety, and poststudy therapy were also assessed (additional information for assessments and statistical analysis are provided in the supplemental online Methods).
Results
Baseline Characteristics
From May 2003 to February 2006, 1,298 RAS‐unselected patients with EGFR‐detectable mCRC who had previously progressed on first‐line fluoropyrimidine and oxaliplatin–based chemotherapy were enrolled (Fig. 1). Among the enrolled patients, RAS status could not be determined in 101 patients (7.8%), and 134 patients (10.3%) had no sample available. Of the 452 patients with RAS‐wt mCRC who were randomized, 446 (98.7%) received treatment: 229 of 231 patients (99.1%) in the cetuximab plus irinotecan arm and 217 of 221 patients (98.2%) in the irinotecan arm. Among patients in the cetuximab plus irinotecan and irinotecan arms, only 27 patients (11.7%) and 28 patients (12.7%), respectively, had received previous bevacizumab therapy; bevacizumab had not been approved in many participating countries at the time of this study.
Figure 1 Patient disposition. Abbreviation: wt, wild type.
Baseline characteristics in the randomized population were comparable to those of the unselected population and reasonably balanced between treatment arms within the RAS‐wt subgroup (Table 1). Most patients in the RAS‐wt subgroup were men (62.8%) and had an ECOG PS of 0 or 1 (93.5%). Median age was 61 years, and 38.7% were aged >65 years.
Table 1 Baseline characteristics of the RAS‐wt and RAS‐unselected populations in the EPIC study
Characteristic
RAS‐wt
RAS‐unselected [2]Total (n = 1,298), n (%)
Irinotecan (n = 221), n (%) Cetuximab plus irinotecan (n = 231), n (%) Total (n = 452), n (%)
Sex
Female 74 (33.5) 86 (37.2) 160 (35.4) 482 (37.1)
Male 147 (66.5) 145 (62.8) 292 (64.6) 816 (62.9)
Median age (range), years 60.0 (23–82) 61.0 (33–85) 61.0 (23–85) 62 (21–90)
ECOG PS
0 112 (50.7) 126 (54.5) 238 (52.7) 664 (51.2)
1 101 (45.7) 90 (39.0) 191 (42.3) 555 (42.8)
2 7 (3.2) 15 (6.5) 22 (4.9) 70 (5.4)
Not reported 1 (0.5) 0 1 (0.2) 9 (0.7)
Prior therapy
Radiotherapy 44 (19.9) 46 (19.9) 90 (19.9) 249 (19.2)
Adjuvant 19 (8.6) 15 (6.5) 34 (7.5) 102 (7.9)
Metastatic 8 (3.6) 17 (7.4) 25 (5.5) 70 (5.4)
Neoadjuvant 18 (8.1) 17 (7.4) 35 (7.7) 90 (69.3)
Chemotherapy 221 (100) 231 (100) 452 (100) 1,298 (100)
Adjuvant 55 (24.9) 54 (23.4) 109 (24.1) 646 (49.8)
Metastatic 219 (99.1) 231 (100) 450 (99.6) 1,289 (99.3)
Neoadjuvant 14 (6.3) 17 (7.4) 31 (6.9) 80 (6.2)
First‐line therapy
Fluoropyrimidine 216 (97.7) 225 (97.4) 441 (97.6) 1,266 (97.5)
Oxaliplatin 219 (99.1) 229 (99.1) 448 (99.1) 1,280 (98.6)
Reason for discontinuation
Disease progression 143 (64.7) 144 (62.3) 287 (63.5) 843 (64.9)
Toxicity 29 (13.1) 36 (15.6) 65 (14.4) 207 (15.9)
Other 44 (19.9) 45 (19.5) 89 (19.7) 225 (17.3)
Unknown 3 (1.4) 5 (2.2) 8 (1.8) 11 (0.8)
Tumor type
Colon 160 (72.4) 149 (64.5) 309 (68.4) 902 (69.5)
Rectum 61 (27.6) 82 (35.5) 143 (31.6) 395 (30.4)
Unknown 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.1)
Number of disease sites
1 69 (31.2) 81 (35.1) 150 (33.2) 415 (32.0)
≥ 2 150 (67.9) 149 (64.5) 299 (66.2) 871 (67.1)
Missing 2 (0.9) 1 (0.4) 3 (0.7) 12 (0.9)
EGFR‐positive CRC
Yes 221 (100) 230 (99.6) 451 (99.8) 1,275 (98.2)
No 0 (0.0) 1 (0.4) 1 (0.2) 2 (0.2)
Liver metastases
Yes 170 (76.9) 176 (76.2) 346 (76.5) 989 (76.2)
No 49 (22.2) 54 (23.4) 103 (22.8) 297 (22.9)
Abbreviations: CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; wt, wild type.
Treatment Adherence and Exposure
Patients in the RAS‐wt group received irinotecan for a median duration of 18.0 weeks (range, 0.7–89.1) in the cetuximab plus irinotecan arm and 10.0 weeks (range, 1.1–71.0) in the irinotecan arm; the median cumulative irinotecan doses were 1,798.4 mg/m2 (range, 266.1–7,204.8) and 1,056.8 mg/m2 (range, 173.6–7,150.3), respectively. Median duration of cetuximab treatment was 19.0 weeks (range, 0.7–97.9), and median cumulative dose was 4,524.0 mg/m2 (range, 159.6–22,086.3). In the cetuximab plus irinotecan arm, 79.0% of patients received ≥80% of the planned dose intensity of irinotecan versus 85.7% of patients in the irinotecan arm. For cetuximab treatment, ≥80% of the planned dose intensity was administered in 72.9% of patients.
In the irinotecan arm, 104 patients (47.1%) received cetuximab in a subsequent line of therapy after the EPIC study; 90 (40.7%) received cetuximab plus irinotecan (Fig. 2). In the cetuximab plus irinotecan arm, 26 patients (11.3%) received cetuximab after the study.
Figure 2 Overall survival by subsequent therapy in the RAS–wild‐type population. (A): In the cetuximab plus irinotecan arm of the EPIC study. (B): In the irinotecan arm of the EPIC study. Abbreviation: CI, confidence interval.
Efficacy
Median OS was 12.3 versus 12.0 months (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.71–1.17; p = .4645) in the cetuximab plus irinotecan versus irinotecan arms, respectively (Table 2; Fig. 3A); median PFS was 5.4 versus 2.6 months (HR, 0.57; 95% CI, 0.46–0.69; p < .0001; Table 2; Fig. 3B). ORR was higher in the cetuximab plus irinotecan arm than in the irinotecan arm: 29.4% versus 5.0% (odds ratio [OR], 8.12; 95% CI, 4.04–17.40; p < .0001) (Table 2). An analysis of OS by poststudy treatment within the RAS‐wt population showed improved median OS in patients who received poststudy cetuximab compared with those not receiving cetuximab or any subsequent therapy in both treatment arms (Fig. 2; supplemental online Table 1). In the cetuximab plus irinotecan arm, median OS in patients who had previously received bevacizumab (n = 27) versus those without prior bevacizumab therapy (n = 204) was 10.2 (95% CI, 4.53–14.09) versus 12.8 months (95% CI, 11.47–15.70), respectively. In the irinotecan arm, median OS was not estimable (95% CI, 11.73 months–not estimable) in patients who had received previous bevacizumab (n = 28) versus 11.8 months (95% CI, 9.00–13.31) in patients without prior bevacizumab therapy (n = 193). ORR in patients who had previously received bevacizumab was 18.5% in the cetuximab plus irinotecan arm (n = 27) and 3.6% in the irinotecan arm (n = 28).
Table 2 Summary of efficacy results in the RAS‐wt and RAS‐unselected populations in the EPIC study
RAS‐wt population
RAS‐unselected population [2]
Irinotecan (n = 221) Cetuximab plus irinotecan (n = 231) Irinotecan (n = 650) Cetuximab plus irinotecan (n = 648)
Median duration of therapy (range), weeks
Cetuximab NA 19.0 (0.7–97.9) NA 14.0 (0.7–97.9)
Irinotecan 10.0 (1.1–71.0) 18.0 (0.7–89.1) 9.9 (0.4–71.0) 13.1 (0.7–89.1)
OS
Number of events, n (%) 126 (57.0) 133 (57.6) 429 (66.0) 445 (68.8)
Median (95% CI), months 12.0 (9.36–14.92) 12.3 (11.37–14.09) 9.99 (9.13–11.33) 10.71 (9.59–11.30)
HR (95% CI) 0.91 (0.71–1.17) 0.975 (0.854–1.114)
Log‐rank p value .4645 .7114
PFS
Number of events, n (%) 201 (91.0) 212 (91.8) 598 (92.0) 610 (94.1)
Median (95% CI), months 2.6 (2.30–2.83) 5.4 (4.24–5.75) 2.56 (2.1–2.69) 3.98 (3.15–4.14)
HR (95% CI) 0.57 (0.46–0.69) 0.692 (0.617–0.776)
Log‐rank p value <.0001 <.0001
Response
Primary definition, n (%)
Complete response 0 4 (1.7) 1 (0.2) 9 (1.4)
Partial response 11 (5.0) 64 (27.7) 26 (4.0) 97 (15.0)
Stable disease 100 (45.2) 90 (39.0) 271 (41.7) 292 (45.1)
Progressive disease 71 (32.1) 46 (19.9) 243 (37.4) 174 (26.9)
Not assessable 39 (17.6) 27 (11.7) 109 (16.8) 76 (11.7)
ORR (CR + PR), n (%) [95% CI] 11 (5.0) [2.51–8.73] 68 (29.4) [23.63–35.77] 27 (4.2) [2.75–5.99] 106 (16.4) [13.59–19.44]
Abbreviations: CI, confidence interval; CR, complete response; HR, hazard ratio; NA, not applicable; ORR, overall response rate; OS, overall survival; PFS, progression‐free survival; PR, partial response; wt, wild type.
Figure 3 Survival in the RAS–wild‐type population of the EPIC study. (A): Overall survival. (B): Progression‐free survival. Abbreviations: CI, confidence interval; HR, hazard ratio.
Safety
Adverse events (AEs) in the RAS‐wt population were consistent with the safety profile observed in the overall EPIC safety population and in other cetuximab studies [2, 8, 9], and no new or unexpected safety signals were observed in either treatment arm. In the cetuximab plus irinotecan and irinotecan arms, 76.4% and 61.8% of patients, respectively, experienced a grade ≥ 3 treatment‐emergent AE. Grade ≥ 3 treatment‐related AEs (TRAEs) were observed in 67.7% and 45.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively; the most common grade 3/4 TRAEs (occurring in ≥20 patients in any treatment arm) were diarrhea (32.3% vs. 17.1%) and neutropenia (20.5% vs. 14.3%). In the cetuximab plus irinotecan arm, grade ≥ 3 drug‐related skin reactions were observed in 12.2% of patients, and grade ≥ 3 acne‐like dermatitis occurred in 1.7%. These TRAEs account for the overall higher TRAE rate in the cetuximab plus irinotecan group.
Serious TRAEs occurred in 29.3% and 21.2% of patients in the cetuximab plus irinotecan and irinotecan arms, respectively. Cetuximab‐related serious AEs (SAEs) occurred in 14.4% of patients in the cetuximab plus irinotecan arm. Irinotecan‐related SAEs were observed in 26.6% versus 21.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively. The most common grade ≥ 3 serious TRAEs (occurring in ≥5% of patients) in both treatment arms were febrile neutropenia and diarrhea. Furthermore, serious TRAEs leading to death occurred in eight patients in the cetuximab plus irinotecan arm and were cetuximab‐related in five patients (dyspnea [n = 1], disease progression [n = 1], cardiac failure and renal failure [n = 1], vomiting and sudden death [n = 1], sepsis [n = 1]) and irinotecan‐related in seven patients (diarrhea, cardiac failure and renal failure [n = 1], pneumonia aspiration and respiratory arrest [n = 1], disease progression [n = 1], gastroenteritis [n = 1], neutropenia [n = 1], vomiting and sudden death [n = 1], intestinal perforation, peritonitis and sepsis [n = 1]) versus three patients in the irinotecan arm (febrile neutropenia [n = 1]; intestinal obstruction [n = 1]; neutropenia [n = 1]). AEs resulting in discontinuation of cetuximab occurred in 20.5% of patients in the cetuximab plus irinotecan arm. AEs leading to irinotecan discontinuation were similar in both arms (22.3% vs. 19.4% in the cetuximab plus irinotecan vs. irinotecan arms).
QoL
Compliance rates for the QoL questionnaire in the RAS‐wt population at baseline were 86.1% and 90.0% in the cetuximab plus irinotecan and irinotecan arms, respectively. The on‐study completion rate subsequently decreased over time, stabilizing at approximately 50% at week 21 in each arm and remaining at this level until weeks 51 and 45 in the cetuximab plus irinotecan and irinotecan arms, respectively. Patients who completed the QoL assessment questionnaire answered 96.7% to 100% of the questions. Baseline scores were similar between treatment arms for 13 of 15 QoL scales. For the symptom scale fatigue and the single item insomnia, differences from baseline scores favored cetuximab plus irinotecan over irinotecan (p < .1). A longitudinal model (truncated at week 45) was used to compare change from baseline scores over time between treatment arms. During the course of the study, improved QoL was reported by patients in the cetuximab plus irinotecan arm compared with those in the irinotecan arm for several multi‐item and single‐item scales (supplemental online Table 2). The model also showed advantages for cetuximab treatment for two functioning scales (physical functioning and role functioning), two symptom scales (fatigue and nausea/vomiting), and two single‐item scales (pain and appetite loss), all in favor of the combination treatment (p < .05). A trend for improved cognitive functioning, global health status, and constipation was also observed in the cetuximab plus irinotecan arm (p < .1). The remaining multi‐item and single‐items scales showed no significant differences between the two treatment arms.
Discussion
This retrospective analysis of the RAS‐wt population of the EPIC study reiterates that the addition of cetuximab to irinotecan did not prolong OS—consistent with results of the primary analysis in the non–biomarker‐defined population [2] as well as those of a previous subgroup analysis in the KRAS‐wt population [13]. The lack of change in OS is possibly due to the high rate of poststudy crossover to cetuximab therapy in patients in the irinotecan arm, as suggested by Sobrero et al [2]. Indeed, nearly half of the patients with RAS‐wt tumors in the irinotecan arm received cetuximab in a subsequent line of therapy after the study, potentially masking any OS benefit of the addition of cetuximab to irinotecan. This hypothesis is supported by results from the CO.17 study of cetuximab versus best supportive care (BSC) in pretreated advanced RAS‐ and BRAF‐wt CRC, in which OS was significantly improved with cetuximab compared with BSC (10.1 vs. 4.8 months), with only 7.0% of patients who received BSC subsequently receiving cetuximab [14, 15].
Interestingly, patients in both treatment arms of EPIC who received poststudy cetuximab had improved OS compared with those who received a subsequent therapy without cetuximab or no poststudy therapy, suggesting that the administration of cetuximab at any point in the second or later line may improve survival. Furthermore, these data suggest that cetuximab‐based therapy may be a suitable standard treatment in the rechallenge setting (i.e., retreatment with cetuximab after progression in a subsequent therapy line without cetuximab) as well as beyond progression for patients with RAS‐wt mCRC. Thus, although guidelines recommend the use of cetuximab in the first‐line treatment setting [3, 4, 5], data from this trial support the use of cetuximab in second or subsequent line treatment settings. Of note, limitations of this analysis include a potential bias because of the differences in the proportion of subsequent therapies with and without cetuximab in the two treatment arms. Another possible bias arises from the observation that patients who live longer are more likely to receive cetuximab in any subsequent therapy line.
In contrast to OS, PFS was more than doubled and ORR was approximately sixfold higher in the cetuximab plus irinotecan arm than in the irinotecan arm (p < .0001 each), and this improvement was more prominent than that in the primary analysis [2] and in the analysis of the KRAS‐wt population [13]. These results suggest that second‐line cetuximab may have a clinically meaningful therapeutic benefit in patients with mCRC—considering their survival prognosis of approximately 1 year, which is supported by the improvements observed in the patients’ QoL. Furthermore, patients who received cetuximab continued treatment for longer, likely because of the prolonged PFS. In both this retrospective analysis and the initial results of the EPIC study [2], the longer PFS and higher ORR observed upon the addition of cetuximab to irinotecan may be a better indicator of the additional benefit conferred by cetuximab than OS, because these endpoints are directly related to the study period and are therefore unaffected by subsequent therapies and are clinically relevant in patients with mCRC.
Similar to the results of the primary analysis of the EPIC study, no new or unexpected safety signals in the RAS‐wt population were observed in either treatment arm. Furthermore, the improved QoL, as demonstrated for several single‐ and multi‐item scales in the cetuximab plus irinotecan arm compared with that in the irinotecan arm, is also reflected in the observed treatment duration, which was almost twice as long in the cetuximab plus irinotecan arm than in the irinotecan arm. Although an analysis for efficacy in left‐sided versus right‐sided tumors was not feasible in this retrospective study because of missing data on primary tumor location, the ORR for the RAS‐wt population in this study was among the highest observed to date in the second‐line setting when compared with that reported for other regimens, such as bevacizumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4), as reported for the E3200 study (ORR, 22.7%) [16], and panitumumab plus combination chemotherapy (ORR, 41% for panitumumab plus 5‐fluorouracil, leucovorin, and irinotecan (FOLFIRI) vs. 10% for FOLFIRI in patients with RAS‐wt tumors) [17]. Notably, although ORR and PFS increased from 16.4% to 29.4% and from 4.0 to 5.4 months, respectively, in the RAS‐unselected and the RAS‐wt populations with cetuximab plus irinotecan, the efficacy outcomes for patients receiving irinotecan did not differ between the RAS‐unselected and RAS‐wt populations (PFS, 2.6 months in both populations; ORR: 4.2% and 5.0%, respectively). These findings, as well as the improved QoL observed in the cetuximab plus irinotecan arm, further confirm the increased efficacy of cetuximab in patients with RAS‐wt tumors in second‐line treatment and confirm that RAS testing is predictive of clinical benefit.
Conclusion
This retrospective analysis of RAS‐wt patients enrolled in the EPIC study emphasizes the role of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC.
Author Contributions
Conception/design: Alberto Sobrero, Heinz‐Josef Lenz, Regina Esser, Johannes Nippgen, Howard Burris
Provision of study material or patients: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Collection and/or assembly of data: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Data analysis and interpretation: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Manuscript writing: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Final approval of manuscript: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Werner Scheithauer, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Disclosures
Alberto Sobrero: Amgen, Bayer, Bristol Myers Squibb, Celgene, Eli Lilly & Co., EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany), Roche, Sanofi, Takeda (C/A); Heinz‐Josef Lenz: Bayer, Bristol Myers Squibb, EMD Serono, Roche (C/A), Bayer, Bristol Myers Squibb, EMD Serono, Roche, Takeda (H), Bayer, EMD Serono (other—travel support); Cathy Eng: Bayer, LSK Global PS, Roche, Sirtex, Taiho (C/A); Wenfeng Chen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Regina Esser: Merck KGaA (Darmstadt, Germany) (E, OI); Johannes Nippgen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Howard Burris: AstraZeneca, Celgene, Daiichi Sankyo, FORMA Therapeutics, Incyte, Pfizer (C/A), Agios, AstraZeneca, Arch, Array BioPharma, Arvinas, Bayer, BIND Therapeutics, BioAtla, BioMed Valley, Boehringer‐Ingelheim, Bristol Myers Squibb, CicloMed, CytomX, eFFECTOR, Eli Lilly & Co., Roche/Genentech, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Incyte, Janssen, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck KGaA, Millennium Pharmaceuticals, Mirna Therapeutics, Moderna, Novartis, Pfizer, Revolution Medicine, Seattle Genetics, Tesaro, TG Therapeutics, Verastem, Vertex Pharmaceuticals (RF—institution), HCA/Sarah Cannon (OI). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Appendix S1 Supporting Information.
Click here for additional data file.
Table S1 Median OS by Subsequent Therapy in the RAS wt Population in the EPIC Study
Table S2: Comparison of QoL Between Treatment Arms Using a Longitudinal Analysis
Click here for additional data file.
Acknowledgments
Medical writing assistance was provided by Eleanor Green of ClinicalThinking, Manchester, U.K., and funded by Merck KGaA, Darmstadt, Germany. This assistance consisted of copyediting, editorial and production assistance. This study was sponsored by Bristol Myers Squibb, New York, NY; ImClone Systems, Bridgewater, NJ; Eli Lilly & Co., Indianapolis, IN; and Merck KGaA. Protocol design and funding of medical writing support by ClinicalThinking, Inc., was provided by Merck KGaA. Data interpretation and the final decision to submit for publication was conducted by Merck KGaA and the coordinating investigators.
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Extended RAS Analysis of the Phase III EPIC Trial: Irinotecan + Cetuximab Versus Irinotecan as Second-Line Treatment for Patients with Metastatic Colorectal Cancer.
The multicenter, open-label, randomized, phase III EPIC study (EMR 062202-025) investigated cetuximab plus irinotecan versus irinotecan in patients with epidermal growth factor receptor-detectable metastatic colorectal cancer (mCRC) that progressed on first-line fluoropyrimidine- and oxaliplatin-based chemotherapy; we report the outcomes of patients with RAS-wild-type (wt) disease.
Available DNA samples from RAS-unselected patients (n = 1,164 of 1,298 [89.7%]) were reanalyzed for RAS mutations using beads, emulsion, amplification, and magnetics. Baseline characteristics, efficacy, safety, and poststudy therapy were assessed. RAS-wt status was defined as a mutated RAS allele frequency of ≤5%, with all relevant alleles being analyzable.
Baseline characteristics were comparable between the groups (n = 452 patients with RAS-wt mCRC; cetuximab plus irinotecan n = 231, irinotecan n = 221) and between the RAS-wt and RAS-unselected populations. In the cetuximab plus irinotecan versus irinotecan arms, median overall survival was 12.3 versus 12.0 months, median progression-free survival (PFS) was 5.4 versus 2.6 months, and objective response rate (ORR) was 29.4% versus 5.0%, respectively. Quality of life (QoL) was improved in the cetuximab plus irinotecan arm. Serious adverse events occurred in 45.4% (cetuximab plus irinotecan) and 42.4% (irinotecan) of patients. In total, 47.1% of patients in the irinotecan arm received subsequent cetuximab therapy.
PFS, ORR, and QoL were improved with cetuximab plus irinotecan as a second-line treatment in patients with RAS-wt mCRC, confirming that cetuximab-based therapy is suitable in this population. Almost half of patients in the irinotecan arm received poststudy cetuximab, masking a potential overall survival benefit of cetuximab addition.
Cetuximab is approved for the treatment of RAS-wild-type metastatic colorectal cancer (mCRC). In this retrospective analysis of the phase III EPIC study (cetuximab plus irinotecan vs. irinotecan alone as second-line treatment in patients with RAS-unselected mCRC), the subgroup of patients with RAS-wild-type mCRC who received cetuximab plus irinotecan had improved progression-free survival, objective response rate, and quality of life compared with the RAS-unselected population. These findings suggest that cetuximab-based therapy is a suitable second-line treatment for patients with RAS-wild-type mCRC.
Introduction
Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer‐related deaths globally, with approximately 1.8 million new cases and almost 900,000 deaths annually [1].
Cetuximab, an immunoglobulin G subtype 1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) [2], in combination with oxaliplatin‐ or irinotecan‐based doublet chemotherapy, is a first‐line standard‐of‐care treatment for patients with RAS‐wild‐type (wt) metastatic CRC (mCRC) [3, 4, 5]. Later‐line therapies in mCRC tend to include a biological agent in combination with chemotherapy and are selected based on which prior therapies the patient has received [6].
The randomized phase III study EPIC (Erbitux plus Irinotecan for the Treatment of mCRC; EMR 062202‐025), initiated in May 2003, was designed to determine whether the combination of cetuximab and irinotecan as a second‐line therapy would result in longer overall survival (OS) than that with irinotecan alone in irinotecan‐naïve patients with mCRC unselected for RAS mutational status. The original findings of the EPIC trial revealed statistically significantly improved progression‐free survival (PFS) and objective response rate (ORR) with cetuximab plus irinotecan compared with irinotecan, but there was no difference in OS [2]. The observed improvement in PFS and ORR suggests that cetuximab provides tumor control and thus has clinically relevant therapeutic benefit in this patient population. The lack of improvement in OS upon the addition of cetuximab to irinotecan may be attributed to the high crossover rate in the irinotecan arm because cetuximab was already approved in the third‐ and later‐line setting when the EPIC trial was conducted.
At the time this study was initiated, tumor EGFR expression was considered the only potentially relevant biomarker of response for anti‐EGFR inhibitors. This assumption has now been dispelled, and evidence of EGFR expression is no longer an eligibility requirement for anti‐EGFR therapy [3, 4, 5]. Instead, RAS mutations have been established as a much more evidence‐based predictive biomarker [7]. Retrospective analyses of pivotal studies with cetuximab plus chemotherapy, such as CRYSTAL and OPUS, found that ORR, PFS, and OS were significantly improved in patients with RAS‐wt tumors compared with those in patients with RAS‐mutant tumors [8, 9]; thus, extended RAS testing was included in treatment guidelines and product labels [4, 5, 10, 11], and the phase III TAILOR trial became the first to prospectively enroll a RAS‐wt population [12].
Because the EPIC trial was conducted before RAS was identified as a relevant biomarker for selecting patients for cetuximab treatment, a retrospective analysis of the RAS‐wt population was necessary to confirm the increased benefit of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC. We retrospectively analyzed the outcomes of patients with RAS‐wt mCRC in the EPIC study population. An analysis of the KRAS‐mutant population, a small proportion of the total population (n = 108 [8.3%]), has been reported previously [13].
Materials and Methods
EPIC was a multicenter, open‐label, randomized, phase III study that enrolled patients from 221 sites globally. Eligibility criteria have been described previously [2]. Briefly, eligible patients had histologically documented mCRC and immunohistochemical evidence of EGFR expression. Disease progression or discontinuation due to toxicity within 6 months of the last dose of first‐line fluoropyrimidine and oxaliplatin–based treatment for metastatic disease was required. Patients who had previously received irinotecan or anti‐EGFR therapies were not eligible. Patients were randomly assigned 1:1 to receive cetuximab plus irinotecan or irinotecan. The primary endpoint was OS; secondary endpoints included PFS, ORR, and quality of life (QoL). The trial was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the ethics committees of all participating centers, and all patients provided written informed consent.
Treatment
Patients assigned to the cetuximab plus irinotecan arm received an initial cetuximab dose of 400 mg/m2 (2‐hour i.v. infusion) and then 250 mg/m2 (1‐hour i.v. infusion) weekly. Pretreatment with an antihistamine was required prior to the first dose of cetuximab and was administered at the investigator's discretion prior to subsequent doses. Irinotecan was administered at 350 mg/m2 (90‐minute i.v. infusion; 300 mg/m2 for patients aged ≥70 years, those with Eastern Cooperative Oncology Group performance status [ECOG PS] of 2, or those with prior pelvic/abdominal irradiation) every 3 weeks in both treatment arms, starting 1 hour after completing cetuximab infusion for patients in the cetuximab arm. Patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. There were no poststudy treatment limitations (supplemental online Methods).
Extended RAS Analysis
For retrospective biomarker analysis, available DNA samples were reanalyzed for mutations in KRAS and NRAS exons 2, 3, and 4 using BEAMing (beads, emulsion, amplification, magnetics) technology. RAS‐wt status was defined as having all relevant alleles analyzable and a sum of mutated RAS allele frequencies across all tested mutations of ≤5%. The number of DNA samples included in this analysis was higher than the number of tumor samples available for the earlier retrospective analysis of the EPIC trial by KRAS status, which analyzed samples from U.S. sites only (23% of all randomized patients) and was therefore not representative of the overall study population [13]. Baseline characteristics, efficacy, safety, and poststudy therapy were also assessed (additional information for assessments and statistical analysis are provided in the supplemental online Methods).
Results
Baseline Characteristics
From May 2003 to February 2006, 1,298 RAS‐unselected patients with EGFR‐detectable mCRC who had previously progressed on first‐line fluoropyrimidine and oxaliplatin–based chemotherapy were enrolled (Fig. 1). Among the enrolled patients, RAS status could not be determined in 101 patients (7.8%), and 134 patients (10.3%) had no sample available. Of the 452 patients with RAS‐wt mCRC who were randomized, 446 (98.7%) received treatment: 229 of 231 patients (99.1%) in the cetuximab plus irinotecan arm and 217 of 221 patients (98.2%) in the irinotecan arm. Among patients in the cetuximab plus irinotecan and irinotecan arms, only 27 patients (11.7%) and 28 patients (12.7%), respectively, had received previous bevacizumab therapy; bevacizumab had not been approved in many participating countries at the time of this study.
Figure 1 Patient disposition. Abbreviation: wt, wild type.
Baseline characteristics in the randomized population were comparable to those of the unselected population and reasonably balanced between treatment arms within the RAS‐wt subgroup (Table 1). Most patients in the RAS‐wt subgroup were men (62.8%) and had an ECOG PS of 0 or 1 (93.5%). Median age was 61 years, and 38.7% were aged >65 years.
Table 1 Baseline characteristics of the RAS‐wt and RAS‐unselected populations in the EPIC study
Characteristic
RAS‐wt
RAS‐unselected [2]Total (n = 1,298), n (%)
Irinotecan (n = 221), n (%) Cetuximab plus irinotecan (n = 231), n (%) Total (n = 452), n (%)
Sex
Female 74 (33.5) 86 (37.2) 160 (35.4) 482 (37.1)
Male 147 (66.5) 145 (62.8) 292 (64.6) 816 (62.9)
Median age (range), years 60.0 (23–82) 61.0 (33–85) 61.0 (23–85) 62 (21–90)
ECOG PS
0 112 (50.7) 126 (54.5) 238 (52.7) 664 (51.2)
1 101 (45.7) 90 (39.0) 191 (42.3) 555 (42.8)
2 7 (3.2) 15 (6.5) 22 (4.9) 70 (5.4)
Not reported 1 (0.5) 0 1 (0.2) 9 (0.7)
Prior therapy
Radiotherapy 44 (19.9) 46 (19.9) 90 (19.9) 249 (19.2)
Adjuvant 19 (8.6) 15 (6.5) 34 (7.5) 102 (7.9)
Metastatic 8 (3.6) 17 (7.4) 25 (5.5) 70 (5.4)
Neoadjuvant 18 (8.1) 17 (7.4) 35 (7.7) 90 (69.3)
Chemotherapy 221 (100) 231 (100) 452 (100) 1,298 (100)
Adjuvant 55 (24.9) 54 (23.4) 109 (24.1) 646 (49.8)
Metastatic 219 (99.1) 231 (100) 450 (99.6) 1,289 (99.3)
Neoadjuvant 14 (6.3) 17 (7.4) 31 (6.9) 80 (6.2)
First‐line therapy
Fluoropyrimidine 216 (97.7) 225 (97.4) 441 (97.6) 1,266 (97.5)
Oxaliplatin 219 (99.1) 229 (99.1) 448 (99.1) 1,280 (98.6)
Reason for discontinuation
Disease progression 143 (64.7) 144 (62.3) 287 (63.5) 843 (64.9)
Toxicity 29 (13.1) 36 (15.6) 65 (14.4) 207 (15.9)
Other 44 (19.9) 45 (19.5) 89 (19.7) 225 (17.3)
Unknown 3 (1.4) 5 (2.2) 8 (1.8) 11 (0.8)
Tumor type
Colon 160 (72.4) 149 (64.5) 309 (68.4) 902 (69.5)
Rectum 61 (27.6) 82 (35.5) 143 (31.6) 395 (30.4)
Unknown 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.1)
Number of disease sites
1 69 (31.2) 81 (35.1) 150 (33.2) 415 (32.0)
≥ 2 150 (67.9) 149 (64.5) 299 (66.2) 871 (67.1)
Missing 2 (0.9) 1 (0.4) 3 (0.7) 12 (0.9)
EGFR‐positive CRC
Yes 221 (100) 230 (99.6) 451 (99.8) 1,275 (98.2)
No 0 (0.0) 1 (0.4) 1 (0.2) 2 (0.2)
Liver metastases
Yes 170 (76.9) 176 (76.2) 346 (76.5) 989 (76.2)
No 49 (22.2) 54 (23.4) 103 (22.8) 297 (22.9)
Abbreviations: CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; wt, wild type.
Treatment Adherence and Exposure
Patients in the RAS‐wt group received irinotecan for a median duration of 18.0 weeks (range, 0.7–89.1) in the cetuximab plus irinotecan arm and 10.0 weeks (range, 1.1–71.0) in the irinotecan arm; the median cumulative irinotecan doses were 1,798.4 mg/m2 (range, 266.1–7,204.8) and 1,056.8 mg/m2 (range, 173.6–7,150.3), respectively. Median duration of cetuximab treatment was 19.0 weeks (range, 0.7–97.9), and median cumulative dose was 4,524.0 mg/m2 (range, 159.6–22,086.3). In the cetuximab plus irinotecan arm, 79.0% of patients received ≥80% of the planned dose intensity of irinotecan versus 85.7% of patients in the irinotecan arm. For cetuximab treatment, ≥80% of the planned dose intensity was administered in 72.9% of patients.
In the irinotecan arm, 104 patients (47.1%) received cetuximab in a subsequent line of therapy after the EPIC study; 90 (40.7%) received cetuximab plus irinotecan (Fig. 2). In the cetuximab plus irinotecan arm, 26 patients (11.3%) received cetuximab after the study.
Figure 2 Overall survival by subsequent therapy in the RAS–wild‐type population. (A): In the cetuximab plus irinotecan arm of the EPIC study. (B): In the irinotecan arm of the EPIC study. Abbreviation: CI, confidence interval.
Efficacy
Median OS was 12.3 versus 12.0 months (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.71–1.17; p = .4645) in the cetuximab plus irinotecan versus irinotecan arms, respectively (Table 2; Fig. 3A); median PFS was 5.4 versus 2.6 months (HR, 0.57; 95% CI, 0.46–0.69; p < .0001; Table 2; Fig. 3B). ORR was higher in the cetuximab plus irinotecan arm than in the irinotecan arm: 29.4% versus 5.0% (odds ratio [OR], 8.12; 95% CI, 4.04–17.40; p < .0001) (Table 2). An analysis of OS by poststudy treatment within the RAS‐wt population showed improved median OS in patients who received poststudy cetuximab compared with those not receiving cetuximab or any subsequent therapy in both treatment arms (Fig. 2; supplemental online Table 1). In the cetuximab plus irinotecan arm, median OS in patients who had previously received bevacizumab (n = 27) versus those without prior bevacizumab therapy (n = 204) was 10.2 (95% CI, 4.53–14.09) versus 12.8 months (95% CI, 11.47–15.70), respectively. In the irinotecan arm, median OS was not estimable (95% CI, 11.73 months–not estimable) in patients who had received previous bevacizumab (n = 28) versus 11.8 months (95% CI, 9.00–13.31) in patients without prior bevacizumab therapy (n = 193). ORR in patients who had previously received bevacizumab was 18.5% in the cetuximab plus irinotecan arm (n = 27) and 3.6% in the irinotecan arm (n = 28).
Table 2 Summary of efficacy results in the RAS‐wt and RAS‐unselected populations in the EPIC study
RAS‐wt population
RAS‐unselected population [2]
Irinotecan (n = 221) Cetuximab plus irinotecan (n = 231) Irinotecan (n = 650) Cetuximab plus irinotecan (n = 648)
Median duration of therapy (range), weeks
Cetuximab NA 19.0 (0.7–97.9) NA 14.0 (0.7–97.9)
Irinotecan 10.0 (1.1–71.0) 18.0 (0.7–89.1) 9.9 (0.4–71.0) 13.1 (0.7–89.1)
OS
Number of events, n (%) 126 (57.0) 133 (57.6) 429 (66.0) 445 (68.8)
Median (95% CI), months 12.0 (9.36–14.92) 12.3 (11.37–14.09) 9.99 (9.13–11.33) 10.71 (9.59–11.30)
HR (95% CI) 0.91 (0.71–1.17) 0.975 (0.854–1.114)
Log‐rank p value .4645 .7114
PFS
Number of events, n (%) 201 (91.0) 212 (91.8) 598 (92.0) 610 (94.1)
Median (95% CI), months 2.6 (2.30–2.83) 5.4 (4.24–5.75) 2.56 (2.1–2.69) 3.98 (3.15–4.14)
HR (95% CI) 0.57 (0.46–0.69) 0.692 (0.617–0.776)
Log‐rank p value <.0001 <.0001
Response
Primary definition, n (%)
Complete response 0 4 (1.7) 1 (0.2) 9 (1.4)
Partial response 11 (5.0) 64 (27.7) 26 (4.0) 97 (15.0)
Stable disease 100 (45.2) 90 (39.0) 271 (41.7) 292 (45.1)
Progressive disease 71 (32.1) 46 (19.9) 243 (37.4) 174 (26.9)
Not assessable 39 (17.6) 27 (11.7) 109 (16.8) 76 (11.7)
ORR (CR + PR), n (%) [95% CI] 11 (5.0) [2.51–8.73] 68 (29.4) [23.63–35.77] 27 (4.2) [2.75–5.99] 106 (16.4) [13.59–19.44]
Abbreviations: CI, confidence interval; CR, complete response; HR, hazard ratio; NA, not applicable; ORR, overall response rate; OS, overall survival; PFS, progression‐free survival; PR, partial response; wt, wild type.
Figure 3 Survival in the RAS–wild‐type population of the EPIC study. (A): Overall survival. (B): Progression‐free survival. Abbreviations: CI, confidence interval; HR, hazard ratio.
Safety
Adverse events (AEs) in the RAS‐wt population were consistent with the safety profile observed in the overall EPIC safety population and in other cetuximab studies [2, 8, 9], and no new or unexpected safety signals were observed in either treatment arm. In the cetuximab plus irinotecan and irinotecan arms, 76.4% and 61.8% of patients, respectively, experienced a grade ≥ 3 treatment‐emergent AE. Grade ≥ 3 treatment‐related AEs (TRAEs) were observed in 67.7% and 45.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively; the most common grade 3/4 TRAEs (occurring in ≥20 patients in any treatment arm) were diarrhea (32.3% vs. 17.1%) and neutropenia (20.5% vs. 14.3%). In the cetuximab plus irinotecan arm, grade ≥ 3 drug‐related skin reactions were observed in 12.2% of patients, and grade ≥ 3 acne‐like dermatitis occurred in 1.7%. These TRAEs account for the overall higher TRAE rate in the cetuximab plus irinotecan group.
Serious TRAEs occurred in 29.3% and 21.2% of patients in the cetuximab plus irinotecan and irinotecan arms, respectively. Cetuximab‐related serious AEs (SAEs) occurred in 14.4% of patients in the cetuximab plus irinotecan arm. Irinotecan‐related SAEs were observed in 26.6% versus 21.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively. The most common grade ≥ 3 serious TRAEs (occurring in ≥5% of patients) in both treatment arms were febrile neutropenia and diarrhea. Furthermore, serious TRAEs leading to death occurred in eight patients in the cetuximab plus irinotecan arm and were cetuximab‐related in five patients (dyspnea [n = 1], disease progression [n = 1], cardiac failure and renal failure [n = 1], vomiting and sudden death [n = 1], sepsis [n = 1]) and irinotecan‐related in seven patients (diarrhea, cardiac failure and renal failure [n = 1], pneumonia aspiration and respiratory arrest [n = 1], disease progression [n = 1], gastroenteritis [n = 1], neutropenia [n = 1], vomiting and sudden death [n = 1], intestinal perforation, peritonitis and sepsis [n = 1]) versus three patients in the irinotecan arm (febrile neutropenia [n = 1]; intestinal obstruction [n = 1]; neutropenia [n = 1]). AEs resulting in discontinuation of cetuximab occurred in 20.5% of patients in the cetuximab plus irinotecan arm. AEs leading to irinotecan discontinuation were similar in both arms (22.3% vs. 19.4% in the cetuximab plus irinotecan vs. irinotecan arms).
QoL
Compliance rates for the QoL questionnaire in the RAS‐wt population at baseline were 86.1% and 90.0% in the cetuximab plus irinotecan and irinotecan arms, respectively. The on‐study completion rate subsequently decreased over time, stabilizing at approximately 50% at week 21 in each arm and remaining at this level until weeks 51 and 45 in the cetuximab plus irinotecan and irinotecan arms, respectively. Patients who completed the QoL assessment questionnaire answered 96.7% to 100% of the questions. Baseline scores were similar between treatment arms for 13 of 15 QoL scales. For the symptom scale fatigue and the single item insomnia, differences from baseline scores favored cetuximab plus irinotecan over irinotecan (p < .1). A longitudinal model (truncated at week 45) was used to compare change from baseline scores over time between treatment arms. During the course of the study, improved QoL was reported by patients in the cetuximab plus irinotecan arm compared with those in the irinotecan arm for several multi‐item and single‐item scales (supplemental online Table 2). The model also showed advantages for cetuximab treatment for two functioning scales (physical functioning and role functioning), two symptom scales (fatigue and nausea/vomiting), and two single‐item scales (pain and appetite loss), all in favor of the combination treatment (p < .05). A trend for improved cognitive functioning, global health status, and constipation was also observed in the cetuximab plus irinotecan arm (p < .1). The remaining multi‐item and single‐items scales showed no significant differences between the two treatment arms.
Discussion
This retrospective analysis of the RAS‐wt population of the EPIC study reiterates that the addition of cetuximab to irinotecan did not prolong OS—consistent with results of the primary analysis in the non–biomarker‐defined population [2] as well as those of a previous subgroup analysis in the KRAS‐wt population [13]. The lack of change in OS is possibly due to the high rate of poststudy crossover to cetuximab therapy in patients in the irinotecan arm, as suggested by Sobrero et al [2]. Indeed, nearly half of the patients with RAS‐wt tumors in the irinotecan arm received cetuximab in a subsequent line of therapy after the study, potentially masking any OS benefit of the addition of cetuximab to irinotecan. This hypothesis is supported by results from the CO.17 study of cetuximab versus best supportive care (BSC) in pretreated advanced RAS‐ and BRAF‐wt CRC, in which OS was significantly improved with cetuximab compared with BSC (10.1 vs. 4.8 months), with only 7.0% of patients who received BSC subsequently receiving cetuximab [14, 15].
Interestingly, patients in both treatment arms of EPIC who received poststudy cetuximab had improved OS compared with those who received a subsequent therapy without cetuximab or no poststudy therapy, suggesting that the administration of cetuximab at any point in the second or later line may improve survival. Furthermore, these data suggest that cetuximab‐based therapy may be a suitable standard treatment in the rechallenge setting (i.e., retreatment with cetuximab after progression in a subsequent therapy line without cetuximab) as well as beyond progression for patients with RAS‐wt mCRC. Thus, although guidelines recommend the use of cetuximab in the first‐line treatment setting [3, 4, 5], data from this trial support the use of cetuximab in second or subsequent line treatment settings. Of note, limitations of this analysis include a potential bias because of the differences in the proportion of subsequent therapies with and without cetuximab in the two treatment arms. Another possible bias arises from the observation that patients who live longer are more likely to receive cetuximab in any subsequent therapy line.
In contrast to OS, PFS was more than doubled and ORR was approximately sixfold higher in the cetuximab plus irinotecan arm than in the irinotecan arm (p < .0001 each), and this improvement was more prominent than that in the primary analysis [2] and in the analysis of the KRAS‐wt population [13]. These results suggest that second‐line cetuximab may have a clinically meaningful therapeutic benefit in patients with mCRC—considering their survival prognosis of approximately 1 year, which is supported by the improvements observed in the patients’ QoL. Furthermore, patients who received cetuximab continued treatment for longer, likely because of the prolonged PFS. In both this retrospective analysis and the initial results of the EPIC study [2], the longer PFS and higher ORR observed upon the addition of cetuximab to irinotecan may be a better indicator of the additional benefit conferred by cetuximab than OS, because these endpoints are directly related to the study period and are therefore unaffected by subsequent therapies and are clinically relevant in patients with mCRC.
Similar to the results of the primary analysis of the EPIC study, no new or unexpected safety signals in the RAS‐wt population were observed in either treatment arm. Furthermore, the improved QoL, as demonstrated for several single‐ and multi‐item scales in the cetuximab plus irinotecan arm compared with that in the irinotecan arm, is also reflected in the observed treatment duration, which was almost twice as long in the cetuximab plus irinotecan arm than in the irinotecan arm. Although an analysis for efficacy in left‐sided versus right‐sided tumors was not feasible in this retrospective study because of missing data on primary tumor location, the ORR for the RAS‐wt population in this study was among the highest observed to date in the second‐line setting when compared with that reported for other regimens, such as bevacizumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4), as reported for the E3200 study (ORR, 22.7%) [16], and panitumumab plus combination chemotherapy (ORR, 41% for panitumumab plus 5‐fluorouracil, leucovorin, and irinotecan (FOLFIRI) vs. 10% for FOLFIRI in patients with RAS‐wt tumors) [17]. Notably, although ORR and PFS increased from 16.4% to 29.4% and from 4.0 to 5.4 months, respectively, in the RAS‐unselected and the RAS‐wt populations with cetuximab plus irinotecan, the efficacy outcomes for patients receiving irinotecan did not differ between the RAS‐unselected and RAS‐wt populations (PFS, 2.6 months in both populations; ORR: 4.2% and 5.0%, respectively). These findings, as well as the improved QoL observed in the cetuximab plus irinotecan arm, further confirm the increased efficacy of cetuximab in patients with RAS‐wt tumors in second‐line treatment and confirm that RAS testing is predictive of clinical benefit.
Conclusion
This retrospective analysis of RAS‐wt patients enrolled in the EPIC study emphasizes the role of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC.
Author Contributions
Conception/design: Alberto Sobrero, Heinz‐Josef Lenz, Regina Esser, Johannes Nippgen, Howard Burris
Provision of study material or patients: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Collection and/or assembly of data: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Data analysis and interpretation: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Manuscript writing: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Final approval of manuscript: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Werner Scheithauer, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Disclosures
Alberto Sobrero: Amgen, Bayer, Bristol Myers Squibb, Celgene, Eli Lilly & Co., EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany), Roche, Sanofi, Takeda (C/A); Heinz‐Josef Lenz: Bayer, Bristol Myers Squibb, EMD Serono, Roche (C/A), Bayer, Bristol Myers Squibb, EMD Serono, Roche, Takeda (H), Bayer, EMD Serono (other—travel support); Cathy Eng: Bayer, LSK Global PS, Roche, Sirtex, Taiho (C/A); Wenfeng Chen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Regina Esser: Merck KGaA (Darmstadt, Germany) (E, OI); Johannes Nippgen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Howard Burris: AstraZeneca, Celgene, Daiichi Sankyo, FORMA Therapeutics, Incyte, Pfizer (C/A), Agios, AstraZeneca, Arch, Array BioPharma, Arvinas, Bayer, BIND Therapeutics, BioAtla, BioMed Valley, Boehringer‐Ingelheim, Bristol Myers Squibb, CicloMed, CytomX, eFFECTOR, Eli Lilly & Co., Roche/Genentech, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Incyte, Janssen, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck KGaA, Millennium Pharmaceuticals, Mirna Therapeutics, Moderna, Novartis, Pfizer, Revolution Medicine, Seattle Genetics, Tesaro, TG Therapeutics, Verastem, Vertex Pharmaceuticals (RF—institution), HCA/Sarah Cannon (OI). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Appendix S1 Supporting Information.
Click here for additional data file.
Table S1 Median OS by Subsequent Therapy in the RAS wt Population in the EPIC Study
Table S2: Comparison of QoL Between Treatment Arms Using a Longitudinal Analysis
Click here for additional data file.
Acknowledgments
Medical writing assistance was provided by Eleanor Green of ClinicalThinking, Manchester, U.K., and funded by Merck KGaA, Darmstadt, Germany. This assistance consisted of copyediting, editorial and production assistance. This study was sponsored by Bristol Myers Squibb, New York, NY; ImClone Systems, Bridgewater, NJ; Eli Lilly & Co., Indianapolis, IN; and Merck KGaA. Protocol design and funding of medical writing support by ClinicalThinking, Inc., was provided by Merck KGaA. Data interpretation and the final decision to submit for publication was conducted by Merck KGaA and the coordinating investigators.
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Extended RAS Analysis of the Phase III EPIC Trial: Irinotecan + Cetuximab Versus Irinotecan as Second-Line Treatment for Patients with Metastatic Colorectal Cancer.
The multicenter, open-label, randomized, phase III EPIC study (EMR 062202-025) investigated cetuximab plus irinotecan versus irinotecan in patients with epidermal growth factor receptor-detectable metastatic colorectal cancer (mCRC) that progressed on first-line fluoropyrimidine- and oxaliplatin-based chemotherapy; we report the outcomes of patients with RAS-wild-type (wt) disease.
Available DNA samples from RAS-unselected patients (n = 1,164 of 1,298 [89.7%]) were reanalyzed for RAS mutations using beads, emulsion, amplification, and magnetics. Baseline characteristics, efficacy, safety, and poststudy therapy were assessed. RAS-wt status was defined as a mutated RAS allele frequency of ≤5%, with all relevant alleles being analyzable.
Baseline characteristics were comparable between the groups (n = 452 patients with RAS-wt mCRC; cetuximab plus irinotecan n = 231, irinotecan n = 221) and between the RAS-wt and RAS-unselected populations. In the cetuximab plus irinotecan versus irinotecan arms, median overall survival was 12.3 versus 12.0 months, median progression-free survival (PFS) was 5.4 versus 2.6 months, and objective response rate (ORR) was 29.4% versus 5.0%, respectively. Quality of life (QoL) was improved in the cetuximab plus irinotecan arm. Serious adverse events occurred in 45.4% (cetuximab plus irinotecan) and 42.4% (irinotecan) of patients. In total, 47.1% of patients in the irinotecan arm received subsequent cetuximab therapy.
PFS, ORR, and QoL were improved with cetuximab plus irinotecan as a second-line treatment in patients with RAS-wt mCRC, confirming that cetuximab-based therapy is suitable in this population. Almost half of patients in the irinotecan arm received poststudy cetuximab, masking a potential overall survival benefit of cetuximab addition.
Cetuximab is approved for the treatment of RAS-wild-type metastatic colorectal cancer (mCRC). In this retrospective analysis of the phase III EPIC study (cetuximab plus irinotecan vs. irinotecan alone as second-line treatment in patients with RAS-unselected mCRC), the subgroup of patients with RAS-wild-type mCRC who received cetuximab plus irinotecan had improved progression-free survival, objective response rate, and quality of life compared with the RAS-unselected population. These findings suggest that cetuximab-based therapy is a suitable second-line treatment for patients with RAS-wild-type mCRC.
Introduction
Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer‐related deaths globally, with approximately 1.8 million new cases and almost 900,000 deaths annually [1].
Cetuximab, an immunoglobulin G subtype 1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) [2], in combination with oxaliplatin‐ or irinotecan‐based doublet chemotherapy, is a first‐line standard‐of‐care treatment for patients with RAS‐wild‐type (wt) metastatic CRC (mCRC) [3, 4, 5]. Later‐line therapies in mCRC tend to include a biological agent in combination with chemotherapy and are selected based on which prior therapies the patient has received [6].
The randomized phase III study EPIC (Erbitux plus Irinotecan for the Treatment of mCRC; EMR 062202‐025), initiated in May 2003, was designed to determine whether the combination of cetuximab and irinotecan as a second‐line therapy would result in longer overall survival (OS) than that with irinotecan alone in irinotecan‐naïve patients with mCRC unselected for RAS mutational status. The original findings of the EPIC trial revealed statistically significantly improved progression‐free survival (PFS) and objective response rate (ORR) with cetuximab plus irinotecan compared with irinotecan, but there was no difference in OS [2]. The observed improvement in PFS and ORR suggests that cetuximab provides tumor control and thus has clinically relevant therapeutic benefit in this patient population. The lack of improvement in OS upon the addition of cetuximab to irinotecan may be attributed to the high crossover rate in the irinotecan arm because cetuximab was already approved in the third‐ and later‐line setting when the EPIC trial was conducted.
At the time this study was initiated, tumor EGFR expression was considered the only potentially relevant biomarker of response for anti‐EGFR inhibitors. This assumption has now been dispelled, and evidence of EGFR expression is no longer an eligibility requirement for anti‐EGFR therapy [3, 4, 5]. Instead, RAS mutations have been established as a much more evidence‐based predictive biomarker [7]. Retrospective analyses of pivotal studies with cetuximab plus chemotherapy, such as CRYSTAL and OPUS, found that ORR, PFS, and OS were significantly improved in patients with RAS‐wt tumors compared with those in patients with RAS‐mutant tumors [8, 9]; thus, extended RAS testing was included in treatment guidelines and product labels [4, 5, 10, 11], and the phase III TAILOR trial became the first to prospectively enroll a RAS‐wt population [12].
Because the EPIC trial was conducted before RAS was identified as a relevant biomarker for selecting patients for cetuximab treatment, a retrospective analysis of the RAS‐wt population was necessary to confirm the increased benefit of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC. We retrospectively analyzed the outcomes of patients with RAS‐wt mCRC in the EPIC study population. An analysis of the KRAS‐mutant population, a small proportion of the total population (n = 108 [8.3%]), has been reported previously [13].
Materials and Methods
EPIC was a multicenter, open‐label, randomized, phase III study that enrolled patients from 221 sites globally. Eligibility criteria have been described previously [2]. Briefly, eligible patients had histologically documented mCRC and immunohistochemical evidence of EGFR expression. Disease progression or discontinuation due to toxicity within 6 months of the last dose of first‐line fluoropyrimidine and oxaliplatin–based treatment for metastatic disease was required. Patients who had previously received irinotecan or anti‐EGFR therapies were not eligible. Patients were randomly assigned 1:1 to receive cetuximab plus irinotecan or irinotecan. The primary endpoint was OS; secondary endpoints included PFS, ORR, and quality of life (QoL). The trial was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the ethics committees of all participating centers, and all patients provided written informed consent.
Treatment
Patients assigned to the cetuximab plus irinotecan arm received an initial cetuximab dose of 400 mg/m2 (2‐hour i.v. infusion) and then 250 mg/m2 (1‐hour i.v. infusion) weekly. Pretreatment with an antihistamine was required prior to the first dose of cetuximab and was administered at the investigator's discretion prior to subsequent doses. Irinotecan was administered at 350 mg/m2 (90‐minute i.v. infusion; 300 mg/m2 for patients aged ≥70 years, those with Eastern Cooperative Oncology Group performance status [ECOG PS] of 2, or those with prior pelvic/abdominal irradiation) every 3 weeks in both treatment arms, starting 1 hour after completing cetuximab infusion for patients in the cetuximab arm. Patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. There were no poststudy treatment limitations (supplemental online Methods).
Extended RAS Analysis
For retrospective biomarker analysis, available DNA samples were reanalyzed for mutations in KRAS and NRAS exons 2, 3, and 4 using BEAMing (beads, emulsion, amplification, magnetics) technology. RAS‐wt status was defined as having all relevant alleles analyzable and a sum of mutated RAS allele frequencies across all tested mutations of ≤5%. The number of DNA samples included in this analysis was higher than the number of tumor samples available for the earlier retrospective analysis of the EPIC trial by KRAS status, which analyzed samples from U.S. sites only (23% of all randomized patients) and was therefore not representative of the overall study population [13]. Baseline characteristics, efficacy, safety, and poststudy therapy were also assessed (additional information for assessments and statistical analysis are provided in the supplemental online Methods).
Results
Baseline Characteristics
From May 2003 to February 2006, 1,298 RAS‐unselected patients with EGFR‐detectable mCRC who had previously progressed on first‐line fluoropyrimidine and oxaliplatin–based chemotherapy were enrolled (Fig. 1). Among the enrolled patients, RAS status could not be determined in 101 patients (7.8%), and 134 patients (10.3%) had no sample available. Of the 452 patients with RAS‐wt mCRC who were randomized, 446 (98.7%) received treatment: 229 of 231 patients (99.1%) in the cetuximab plus irinotecan arm and 217 of 221 patients (98.2%) in the irinotecan arm. Among patients in the cetuximab plus irinotecan and irinotecan arms, only 27 patients (11.7%) and 28 patients (12.7%), respectively, had received previous bevacizumab therapy; bevacizumab had not been approved in many participating countries at the time of this study.
Figure 1 Patient disposition. Abbreviation: wt, wild type.
Baseline characteristics in the randomized population were comparable to those of the unselected population and reasonably balanced between treatment arms within the RAS‐wt subgroup (Table 1). Most patients in the RAS‐wt subgroup were men (62.8%) and had an ECOG PS of 0 or 1 (93.5%). Median age was 61 years, and 38.7% were aged >65 years.
Table 1 Baseline characteristics of the RAS‐wt and RAS‐unselected populations in the EPIC study
Characteristic
RAS‐wt
RAS‐unselected [2]Total (n = 1,298), n (%)
Irinotecan (n = 221), n (%) Cetuximab plus irinotecan (n = 231), n (%) Total (n = 452), n (%)
Sex
Female 74 (33.5) 86 (37.2) 160 (35.4) 482 (37.1)
Male 147 (66.5) 145 (62.8) 292 (64.6) 816 (62.9)
Median age (range), years 60.0 (23–82) 61.0 (33–85) 61.0 (23–85) 62 (21–90)
ECOG PS
0 112 (50.7) 126 (54.5) 238 (52.7) 664 (51.2)
1 101 (45.7) 90 (39.0) 191 (42.3) 555 (42.8)
2 7 (3.2) 15 (6.5) 22 (4.9) 70 (5.4)
Not reported 1 (0.5) 0 1 (0.2) 9 (0.7)
Prior therapy
Radiotherapy 44 (19.9) 46 (19.9) 90 (19.9) 249 (19.2)
Adjuvant 19 (8.6) 15 (6.5) 34 (7.5) 102 (7.9)
Metastatic 8 (3.6) 17 (7.4) 25 (5.5) 70 (5.4)
Neoadjuvant 18 (8.1) 17 (7.4) 35 (7.7) 90 (69.3)
Chemotherapy 221 (100) 231 (100) 452 (100) 1,298 (100)
Adjuvant 55 (24.9) 54 (23.4) 109 (24.1) 646 (49.8)
Metastatic 219 (99.1) 231 (100) 450 (99.6) 1,289 (99.3)
Neoadjuvant 14 (6.3) 17 (7.4) 31 (6.9) 80 (6.2)
First‐line therapy
Fluoropyrimidine 216 (97.7) 225 (97.4) 441 (97.6) 1,266 (97.5)
Oxaliplatin 219 (99.1) 229 (99.1) 448 (99.1) 1,280 (98.6)
Reason for discontinuation
Disease progression 143 (64.7) 144 (62.3) 287 (63.5) 843 (64.9)
Toxicity 29 (13.1) 36 (15.6) 65 (14.4) 207 (15.9)
Other 44 (19.9) 45 (19.5) 89 (19.7) 225 (17.3)
Unknown 3 (1.4) 5 (2.2) 8 (1.8) 11 (0.8)
Tumor type
Colon 160 (72.4) 149 (64.5) 309 (68.4) 902 (69.5)
Rectum 61 (27.6) 82 (35.5) 143 (31.6) 395 (30.4)
Unknown 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.1)
Number of disease sites
1 69 (31.2) 81 (35.1) 150 (33.2) 415 (32.0)
≥ 2 150 (67.9) 149 (64.5) 299 (66.2) 871 (67.1)
Missing 2 (0.9) 1 (0.4) 3 (0.7) 12 (0.9)
EGFR‐positive CRC
Yes 221 (100) 230 (99.6) 451 (99.8) 1,275 (98.2)
No 0 (0.0) 1 (0.4) 1 (0.2) 2 (0.2)
Liver metastases
Yes 170 (76.9) 176 (76.2) 346 (76.5) 989 (76.2)
No 49 (22.2) 54 (23.4) 103 (22.8) 297 (22.9)
Abbreviations: CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; wt, wild type.
Treatment Adherence and Exposure
Patients in the RAS‐wt group received irinotecan for a median duration of 18.0 weeks (range, 0.7–89.1) in the cetuximab plus irinotecan arm and 10.0 weeks (range, 1.1–71.0) in the irinotecan arm; the median cumulative irinotecan doses were 1,798.4 mg/m2 (range, 266.1–7,204.8) and 1,056.8 mg/m2 (range, 173.6–7,150.3), respectively. Median duration of cetuximab treatment was 19.0 weeks (range, 0.7–97.9), and median cumulative dose was 4,524.0 mg/m2 (range, 159.6–22,086.3). In the cetuximab plus irinotecan arm, 79.0% of patients received ≥80% of the planned dose intensity of irinotecan versus 85.7% of patients in the irinotecan arm. For cetuximab treatment, ≥80% of the planned dose intensity was administered in 72.9% of patients.
In the irinotecan arm, 104 patients (47.1%) received cetuximab in a subsequent line of therapy after the EPIC study; 90 (40.7%) received cetuximab plus irinotecan (Fig. 2). In the cetuximab plus irinotecan arm, 26 patients (11.3%) received cetuximab after the study.
Figure 2 Overall survival by subsequent therapy in the RAS–wild‐type population. (A): In the cetuximab plus irinotecan arm of the EPIC study. (B): In the irinotecan arm of the EPIC study. Abbreviation: CI, confidence interval.
Efficacy
Median OS was 12.3 versus 12.0 months (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.71–1.17; p = .4645) in the cetuximab plus irinotecan versus irinotecan arms, respectively (Table 2; Fig. 3A); median PFS was 5.4 versus 2.6 months (HR, 0.57; 95% CI, 0.46–0.69; p < .0001; Table 2; Fig. 3B). ORR was higher in the cetuximab plus irinotecan arm than in the irinotecan arm: 29.4% versus 5.0% (odds ratio [OR], 8.12; 95% CI, 4.04–17.40; p < .0001) (Table 2). An analysis of OS by poststudy treatment within the RAS‐wt population showed improved median OS in patients who received poststudy cetuximab compared with those not receiving cetuximab or any subsequent therapy in both treatment arms (Fig. 2; supplemental online Table 1). In the cetuximab plus irinotecan arm, median OS in patients who had previously received bevacizumab (n = 27) versus those without prior bevacizumab therapy (n = 204) was 10.2 (95% CI, 4.53–14.09) versus 12.8 months (95% CI, 11.47–15.70), respectively. In the irinotecan arm, median OS was not estimable (95% CI, 11.73 months–not estimable) in patients who had received previous bevacizumab (n = 28) versus 11.8 months (95% CI, 9.00–13.31) in patients without prior bevacizumab therapy (n = 193). ORR in patients who had previously received bevacizumab was 18.5% in the cetuximab plus irinotecan arm (n = 27) and 3.6% in the irinotecan arm (n = 28).
Table 2 Summary of efficacy results in the RAS‐wt and RAS‐unselected populations in the EPIC study
RAS‐wt population
RAS‐unselected population [2]
Irinotecan (n = 221) Cetuximab plus irinotecan (n = 231) Irinotecan (n = 650) Cetuximab plus irinotecan (n = 648)
Median duration of therapy (range), weeks
Cetuximab NA 19.0 (0.7–97.9) NA 14.0 (0.7–97.9)
Irinotecan 10.0 (1.1–71.0) 18.0 (0.7–89.1) 9.9 (0.4–71.0) 13.1 (0.7–89.1)
OS
Number of events, n (%) 126 (57.0) 133 (57.6) 429 (66.0) 445 (68.8)
Median (95% CI), months 12.0 (9.36–14.92) 12.3 (11.37–14.09) 9.99 (9.13–11.33) 10.71 (9.59–11.30)
HR (95% CI) 0.91 (0.71–1.17) 0.975 (0.854–1.114)
Log‐rank p value .4645 .7114
PFS
Number of events, n (%) 201 (91.0) 212 (91.8) 598 (92.0) 610 (94.1)
Median (95% CI), months 2.6 (2.30–2.83) 5.4 (4.24–5.75) 2.56 (2.1–2.69) 3.98 (3.15–4.14)
HR (95% CI) 0.57 (0.46–0.69) 0.692 (0.617–0.776)
Log‐rank p value <.0001 <.0001
Response
Primary definition, n (%)
Complete response 0 4 (1.7) 1 (0.2) 9 (1.4)
Partial response 11 (5.0) 64 (27.7) 26 (4.0) 97 (15.0)
Stable disease 100 (45.2) 90 (39.0) 271 (41.7) 292 (45.1)
Progressive disease 71 (32.1) 46 (19.9) 243 (37.4) 174 (26.9)
Not assessable 39 (17.6) 27 (11.7) 109 (16.8) 76 (11.7)
ORR (CR + PR), n (%) [95% CI] 11 (5.0) [2.51–8.73] 68 (29.4) [23.63–35.77] 27 (4.2) [2.75–5.99] 106 (16.4) [13.59–19.44]
Abbreviations: CI, confidence interval; CR, complete response; HR, hazard ratio; NA, not applicable; ORR, overall response rate; OS, overall survival; PFS, progression‐free survival; PR, partial response; wt, wild type.
Figure 3 Survival in the RAS–wild‐type population of the EPIC study. (A): Overall survival. (B): Progression‐free survival. Abbreviations: CI, confidence interval; HR, hazard ratio.
Safety
Adverse events (AEs) in the RAS‐wt population were consistent with the safety profile observed in the overall EPIC safety population and in other cetuximab studies [2, 8, 9], and no new or unexpected safety signals were observed in either treatment arm. In the cetuximab plus irinotecan and irinotecan arms, 76.4% and 61.8% of patients, respectively, experienced a grade ≥ 3 treatment‐emergent AE. Grade ≥ 3 treatment‐related AEs (TRAEs) were observed in 67.7% and 45.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively; the most common grade 3/4 TRAEs (occurring in ≥20 patients in any treatment arm) were diarrhea (32.3% vs. 17.1%) and neutropenia (20.5% vs. 14.3%). In the cetuximab plus irinotecan arm, grade ≥ 3 drug‐related skin reactions were observed in 12.2% of patients, and grade ≥ 3 acne‐like dermatitis occurred in 1.7%. These TRAEs account for the overall higher TRAE rate in the cetuximab plus irinotecan group.
Serious TRAEs occurred in 29.3% and 21.2% of patients in the cetuximab plus irinotecan and irinotecan arms, respectively. Cetuximab‐related serious AEs (SAEs) occurred in 14.4% of patients in the cetuximab plus irinotecan arm. Irinotecan‐related SAEs were observed in 26.6% versus 21.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively. The most common grade ≥ 3 serious TRAEs (occurring in ≥5% of patients) in both treatment arms were febrile neutropenia and diarrhea. Furthermore, serious TRAEs leading to death occurred in eight patients in the cetuximab plus irinotecan arm and were cetuximab‐related in five patients (dyspnea [n = 1], disease progression [n = 1], cardiac failure and renal failure [n = 1], vomiting and sudden death [n = 1], sepsis [n = 1]) and irinotecan‐related in seven patients (diarrhea, cardiac failure and renal failure [n = 1], pneumonia aspiration and respiratory arrest [n = 1], disease progression [n = 1], gastroenteritis [n = 1], neutropenia [n = 1], vomiting and sudden death [n = 1], intestinal perforation, peritonitis and sepsis [n = 1]) versus three patients in the irinotecan arm (febrile neutropenia [n = 1]; intestinal obstruction [n = 1]; neutropenia [n = 1]). AEs resulting in discontinuation of cetuximab occurred in 20.5% of patients in the cetuximab plus irinotecan arm. AEs leading to irinotecan discontinuation were similar in both arms (22.3% vs. 19.4% in the cetuximab plus irinotecan vs. irinotecan arms).
QoL
Compliance rates for the QoL questionnaire in the RAS‐wt population at baseline were 86.1% and 90.0% in the cetuximab plus irinotecan and irinotecan arms, respectively. The on‐study completion rate subsequently decreased over time, stabilizing at approximately 50% at week 21 in each arm and remaining at this level until weeks 51 and 45 in the cetuximab plus irinotecan and irinotecan arms, respectively. Patients who completed the QoL assessment questionnaire answered 96.7% to 100% of the questions. Baseline scores were similar between treatment arms for 13 of 15 QoL scales. For the symptom scale fatigue and the single item insomnia, differences from baseline scores favored cetuximab plus irinotecan over irinotecan (p < .1). A longitudinal model (truncated at week 45) was used to compare change from baseline scores over time between treatment arms. During the course of the study, improved QoL was reported by patients in the cetuximab plus irinotecan arm compared with those in the irinotecan arm for several multi‐item and single‐item scales (supplemental online Table 2). The model also showed advantages for cetuximab treatment for two functioning scales (physical functioning and role functioning), two symptom scales (fatigue and nausea/vomiting), and two single‐item scales (pain and appetite loss), all in favor of the combination treatment (p < .05). A trend for improved cognitive functioning, global health status, and constipation was also observed in the cetuximab plus irinotecan arm (p < .1). The remaining multi‐item and single‐items scales showed no significant differences between the two treatment arms.
Discussion
This retrospective analysis of the RAS‐wt population of the EPIC study reiterates that the addition of cetuximab to irinotecan did not prolong OS—consistent with results of the primary analysis in the non–biomarker‐defined population [2] as well as those of a previous subgroup analysis in the KRAS‐wt population [13]. The lack of change in OS is possibly due to the high rate of poststudy crossover to cetuximab therapy in patients in the irinotecan arm, as suggested by Sobrero et al [2]. Indeed, nearly half of the patients with RAS‐wt tumors in the irinotecan arm received cetuximab in a subsequent line of therapy after the study, potentially masking any OS benefit of the addition of cetuximab to irinotecan. This hypothesis is supported by results from the CO.17 study of cetuximab versus best supportive care (BSC) in pretreated advanced RAS‐ and BRAF‐wt CRC, in which OS was significantly improved with cetuximab compared with BSC (10.1 vs. 4.8 months), with only 7.0% of patients who received BSC subsequently receiving cetuximab [14, 15].
Interestingly, patients in both treatment arms of EPIC who received poststudy cetuximab had improved OS compared with those who received a subsequent therapy without cetuximab or no poststudy therapy, suggesting that the administration of cetuximab at any point in the second or later line may improve survival. Furthermore, these data suggest that cetuximab‐based therapy may be a suitable standard treatment in the rechallenge setting (i.e., retreatment with cetuximab after progression in a subsequent therapy line without cetuximab) as well as beyond progression for patients with RAS‐wt mCRC. Thus, although guidelines recommend the use of cetuximab in the first‐line treatment setting [3, 4, 5], data from this trial support the use of cetuximab in second or subsequent line treatment settings. Of note, limitations of this analysis include a potential bias because of the differences in the proportion of subsequent therapies with and without cetuximab in the two treatment arms. Another possible bias arises from the observation that patients who live longer are more likely to receive cetuximab in any subsequent therapy line.
In contrast to OS, PFS was more than doubled and ORR was approximately sixfold higher in the cetuximab plus irinotecan arm than in the irinotecan arm (p < .0001 each), and this improvement was more prominent than that in the primary analysis [2] and in the analysis of the KRAS‐wt population [13]. These results suggest that second‐line cetuximab may have a clinically meaningful therapeutic benefit in patients with mCRC—considering their survival prognosis of approximately 1 year, which is supported by the improvements observed in the patients’ QoL. Furthermore, patients who received cetuximab continued treatment for longer, likely because of the prolonged PFS. In both this retrospective analysis and the initial results of the EPIC study [2], the longer PFS and higher ORR observed upon the addition of cetuximab to irinotecan may be a better indicator of the additional benefit conferred by cetuximab than OS, because these endpoints are directly related to the study period and are therefore unaffected by subsequent therapies and are clinically relevant in patients with mCRC.
Similar to the results of the primary analysis of the EPIC study, no new or unexpected safety signals in the RAS‐wt population were observed in either treatment arm. Furthermore, the improved QoL, as demonstrated for several single‐ and multi‐item scales in the cetuximab plus irinotecan arm compared with that in the irinotecan arm, is also reflected in the observed treatment duration, which was almost twice as long in the cetuximab plus irinotecan arm than in the irinotecan arm. Although an analysis for efficacy in left‐sided versus right‐sided tumors was not feasible in this retrospective study because of missing data on primary tumor location, the ORR for the RAS‐wt population in this study was among the highest observed to date in the second‐line setting when compared with that reported for other regimens, such as bevacizumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4), as reported for the E3200 study (ORR, 22.7%) [16], and panitumumab plus combination chemotherapy (ORR, 41% for panitumumab plus 5‐fluorouracil, leucovorin, and irinotecan (FOLFIRI) vs. 10% for FOLFIRI in patients with RAS‐wt tumors) [17]. Notably, although ORR and PFS increased from 16.4% to 29.4% and from 4.0 to 5.4 months, respectively, in the RAS‐unselected and the RAS‐wt populations with cetuximab plus irinotecan, the efficacy outcomes for patients receiving irinotecan did not differ between the RAS‐unselected and RAS‐wt populations (PFS, 2.6 months in both populations; ORR: 4.2% and 5.0%, respectively). These findings, as well as the improved QoL observed in the cetuximab plus irinotecan arm, further confirm the increased efficacy of cetuximab in patients with RAS‐wt tumors in second‐line treatment and confirm that RAS testing is predictive of clinical benefit.
Conclusion
This retrospective analysis of RAS‐wt patients enrolled in the EPIC study emphasizes the role of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC.
Author Contributions
Conception/design: Alberto Sobrero, Heinz‐Josef Lenz, Regina Esser, Johannes Nippgen, Howard Burris
Provision of study material or patients: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Collection and/or assembly of data: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Data analysis and interpretation: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Manuscript writing: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Final approval of manuscript: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Werner Scheithauer, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Disclosures
Alberto Sobrero: Amgen, Bayer, Bristol Myers Squibb, Celgene, Eli Lilly & Co., EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany), Roche, Sanofi, Takeda (C/A); Heinz‐Josef Lenz: Bayer, Bristol Myers Squibb, EMD Serono, Roche (C/A), Bayer, Bristol Myers Squibb, EMD Serono, Roche, Takeda (H), Bayer, EMD Serono (other—travel support); Cathy Eng: Bayer, LSK Global PS, Roche, Sirtex, Taiho (C/A); Wenfeng Chen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Regina Esser: Merck KGaA (Darmstadt, Germany) (E, OI); Johannes Nippgen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Howard Burris: AstraZeneca, Celgene, Daiichi Sankyo, FORMA Therapeutics, Incyte, Pfizer (C/A), Agios, AstraZeneca, Arch, Array BioPharma, Arvinas, Bayer, BIND Therapeutics, BioAtla, BioMed Valley, Boehringer‐Ingelheim, Bristol Myers Squibb, CicloMed, CytomX, eFFECTOR, Eli Lilly & Co., Roche/Genentech, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Incyte, Janssen, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck KGaA, Millennium Pharmaceuticals, Mirna Therapeutics, Moderna, Novartis, Pfizer, Revolution Medicine, Seattle Genetics, Tesaro, TG Therapeutics, Verastem, Vertex Pharmaceuticals (RF—institution), HCA/Sarah Cannon (OI). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Appendix S1 Supporting Information.
Click here for additional data file.
Table S1 Median OS by Subsequent Therapy in the RAS wt Population in the EPIC Study
Table S2: Comparison of QoL Between Treatment Arms Using a Longitudinal Analysis
Click here for additional data file.
Acknowledgments
Medical writing assistance was provided by Eleanor Green of ClinicalThinking, Manchester, U.K., and funded by Merck KGaA, Darmstadt, Germany. This assistance consisted of copyediting, editorial and production assistance. This study was sponsored by Bristol Myers Squibb, New York, NY; ImClone Systems, Bridgewater, NJ; Eli Lilly & Co., Indianapolis, IN; and Merck KGaA. Protocol design and funding of medical writing support by ClinicalThinking, Inc., was provided by Merck KGaA. Data interpretation and the final decision to submit for publication was conducted by Merck KGaA and the coordinating investigators.
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Extended RAS Analysis of the Phase III EPIC Trial: Irinotecan + Cetuximab Versus Irinotecan as Second-Line Treatment for Patients with Metastatic Colorectal Cancer.
The multicenter, open-label, randomized, phase III EPIC study (EMR 062202-025) investigated cetuximab plus irinotecan versus irinotecan in patients with epidermal growth factor receptor-detectable metastatic colorectal cancer (mCRC) that progressed on first-line fluoropyrimidine- and oxaliplatin-based chemotherapy; we report the outcomes of patients with RAS-wild-type (wt) disease.
Available DNA samples from RAS-unselected patients (n = 1,164 of 1,298 [89.7%]) were reanalyzed for RAS mutations using beads, emulsion, amplification, and magnetics. Baseline characteristics, efficacy, safety, and poststudy therapy were assessed. RAS-wt status was defined as a mutated RAS allele frequency of ≤5%, with all relevant alleles being analyzable.
Baseline characteristics were comparable between the groups (n = 452 patients with RAS-wt mCRC; cetuximab plus irinotecan n = 231, irinotecan n = 221) and between the RAS-wt and RAS-unselected populations. In the cetuximab plus irinotecan versus irinotecan arms, median overall survival was 12.3 versus 12.0 months, median progression-free survival (PFS) was 5.4 versus 2.6 months, and objective response rate (ORR) was 29.4% versus 5.0%, respectively. Quality of life (QoL) was improved in the cetuximab plus irinotecan arm. Serious adverse events occurred in 45.4% (cetuximab plus irinotecan) and 42.4% (irinotecan) of patients. In total, 47.1% of patients in the irinotecan arm received subsequent cetuximab therapy.
PFS, ORR, and QoL were improved with cetuximab plus irinotecan as a second-line treatment in patients with RAS-wt mCRC, confirming that cetuximab-based therapy is suitable in this population. Almost half of patients in the irinotecan arm received poststudy cetuximab, masking a potential overall survival benefit of cetuximab addition.
Cetuximab is approved for the treatment of RAS-wild-type metastatic colorectal cancer (mCRC). In this retrospective analysis of the phase III EPIC study (cetuximab plus irinotecan vs. irinotecan alone as second-line treatment in patients with RAS-unselected mCRC), the subgroup of patients with RAS-wild-type mCRC who received cetuximab plus irinotecan had improved progression-free survival, objective response rate, and quality of life compared with the RAS-unselected population. These findings suggest that cetuximab-based therapy is a suitable second-line treatment for patients with RAS-wild-type mCRC.
Introduction
Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer‐related deaths globally, with approximately 1.8 million new cases and almost 900,000 deaths annually [1].
Cetuximab, an immunoglobulin G subtype 1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) [2], in combination with oxaliplatin‐ or irinotecan‐based doublet chemotherapy, is a first‐line standard‐of‐care treatment for patients with RAS‐wild‐type (wt) metastatic CRC (mCRC) [3, 4, 5]. Later‐line therapies in mCRC tend to include a biological agent in combination with chemotherapy and are selected based on which prior therapies the patient has received [6].
The randomized phase III study EPIC (Erbitux plus Irinotecan for the Treatment of mCRC; EMR 062202‐025), initiated in May 2003, was designed to determine whether the combination of cetuximab and irinotecan as a second‐line therapy would result in longer overall survival (OS) than that with irinotecan alone in irinotecan‐naïve patients with mCRC unselected for RAS mutational status. The original findings of the EPIC trial revealed statistically significantly improved progression‐free survival (PFS) and objective response rate (ORR) with cetuximab plus irinotecan compared with irinotecan, but there was no difference in OS [2]. The observed improvement in PFS and ORR suggests that cetuximab provides tumor control and thus has clinically relevant therapeutic benefit in this patient population. The lack of improvement in OS upon the addition of cetuximab to irinotecan may be attributed to the high crossover rate in the irinotecan arm because cetuximab was already approved in the third‐ and later‐line setting when the EPIC trial was conducted.
At the time this study was initiated, tumor EGFR expression was considered the only potentially relevant biomarker of response for anti‐EGFR inhibitors. This assumption has now been dispelled, and evidence of EGFR expression is no longer an eligibility requirement for anti‐EGFR therapy [3, 4, 5]. Instead, RAS mutations have been established as a much more evidence‐based predictive biomarker [7]. Retrospective analyses of pivotal studies with cetuximab plus chemotherapy, such as CRYSTAL and OPUS, found that ORR, PFS, and OS were significantly improved in patients with RAS‐wt tumors compared with those in patients with RAS‐mutant tumors [8, 9]; thus, extended RAS testing was included in treatment guidelines and product labels [4, 5, 10, 11], and the phase III TAILOR trial became the first to prospectively enroll a RAS‐wt population [12].
Because the EPIC trial was conducted before RAS was identified as a relevant biomarker for selecting patients for cetuximab treatment, a retrospective analysis of the RAS‐wt population was necessary to confirm the increased benefit of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC. We retrospectively analyzed the outcomes of patients with RAS‐wt mCRC in the EPIC study population. An analysis of the KRAS‐mutant population, a small proportion of the total population (n = 108 [8.3%]), has been reported previously [13].
Materials and Methods
EPIC was a multicenter, open‐label, randomized, phase III study that enrolled patients from 221 sites globally. Eligibility criteria have been described previously [2]. Briefly, eligible patients had histologically documented mCRC and immunohistochemical evidence of EGFR expression. Disease progression or discontinuation due to toxicity within 6 months of the last dose of first‐line fluoropyrimidine and oxaliplatin–based treatment for metastatic disease was required. Patients who had previously received irinotecan or anti‐EGFR therapies were not eligible. Patients were randomly assigned 1:1 to receive cetuximab plus irinotecan or irinotecan. The primary endpoint was OS; secondary endpoints included PFS, ORR, and quality of life (QoL). The trial was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the ethics committees of all participating centers, and all patients provided written informed consent.
Treatment
Patients assigned to the cetuximab plus irinotecan arm received an initial cetuximab dose of 400 mg/m2 (2‐hour i.v. infusion) and then 250 mg/m2 (1‐hour i.v. infusion) weekly. Pretreatment with an antihistamine was required prior to the first dose of cetuximab and was administered at the investigator's discretion prior to subsequent doses. Irinotecan was administered at 350 mg/m2 (90‐minute i.v. infusion; 300 mg/m2 for patients aged ≥70 years, those with Eastern Cooperative Oncology Group performance status [ECOG PS] of 2, or those with prior pelvic/abdominal irradiation) every 3 weeks in both treatment arms, starting 1 hour after completing cetuximab infusion for patients in the cetuximab arm. Patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. There were no poststudy treatment limitations (supplemental online Methods).
Extended RAS Analysis
For retrospective biomarker analysis, available DNA samples were reanalyzed for mutations in KRAS and NRAS exons 2, 3, and 4 using BEAMing (beads, emulsion, amplification, magnetics) technology. RAS‐wt status was defined as having all relevant alleles analyzable and a sum of mutated RAS allele frequencies across all tested mutations of ≤5%. The number of DNA samples included in this analysis was higher than the number of tumor samples available for the earlier retrospective analysis of the EPIC trial by KRAS status, which analyzed samples from U.S. sites only (23% of all randomized patients) and was therefore not representative of the overall study population [13]. Baseline characteristics, efficacy, safety, and poststudy therapy were also assessed (additional information for assessments and statistical analysis are provided in the supplemental online Methods).
Results
Baseline Characteristics
From May 2003 to February 2006, 1,298 RAS‐unselected patients with EGFR‐detectable mCRC who had previously progressed on first‐line fluoropyrimidine and oxaliplatin–based chemotherapy were enrolled (Fig. 1). Among the enrolled patients, RAS status could not be determined in 101 patients (7.8%), and 134 patients (10.3%) had no sample available. Of the 452 patients with RAS‐wt mCRC who were randomized, 446 (98.7%) received treatment: 229 of 231 patients (99.1%) in the cetuximab plus irinotecan arm and 217 of 221 patients (98.2%) in the irinotecan arm. Among patients in the cetuximab plus irinotecan and irinotecan arms, only 27 patients (11.7%) and 28 patients (12.7%), respectively, had received previous bevacizumab therapy; bevacizumab had not been approved in many participating countries at the time of this study.
Figure 1 Patient disposition. Abbreviation: wt, wild type.
Baseline characteristics in the randomized population were comparable to those of the unselected population and reasonably balanced between treatment arms within the RAS‐wt subgroup (Table 1). Most patients in the RAS‐wt subgroup were men (62.8%) and had an ECOG PS of 0 or 1 (93.5%). Median age was 61 years, and 38.7% were aged >65 years.
Table 1 Baseline characteristics of the RAS‐wt and RAS‐unselected populations in the EPIC study
Characteristic
RAS‐wt
RAS‐unselected [2]Total (n = 1,298), n (%)
Irinotecan (n = 221), n (%) Cetuximab plus irinotecan (n = 231), n (%) Total (n = 452), n (%)
Sex
Female 74 (33.5) 86 (37.2) 160 (35.4) 482 (37.1)
Male 147 (66.5) 145 (62.8) 292 (64.6) 816 (62.9)
Median age (range), years 60.0 (23–82) 61.0 (33–85) 61.0 (23–85) 62 (21–90)
ECOG PS
0 112 (50.7) 126 (54.5) 238 (52.7) 664 (51.2)
1 101 (45.7) 90 (39.0) 191 (42.3) 555 (42.8)
2 7 (3.2) 15 (6.5) 22 (4.9) 70 (5.4)
Not reported 1 (0.5) 0 1 (0.2) 9 (0.7)
Prior therapy
Radiotherapy 44 (19.9) 46 (19.9) 90 (19.9) 249 (19.2)
Adjuvant 19 (8.6) 15 (6.5) 34 (7.5) 102 (7.9)
Metastatic 8 (3.6) 17 (7.4) 25 (5.5) 70 (5.4)
Neoadjuvant 18 (8.1) 17 (7.4) 35 (7.7) 90 (69.3)
Chemotherapy 221 (100) 231 (100) 452 (100) 1,298 (100)
Adjuvant 55 (24.9) 54 (23.4) 109 (24.1) 646 (49.8)
Metastatic 219 (99.1) 231 (100) 450 (99.6) 1,289 (99.3)
Neoadjuvant 14 (6.3) 17 (7.4) 31 (6.9) 80 (6.2)
First‐line therapy
Fluoropyrimidine 216 (97.7) 225 (97.4) 441 (97.6) 1,266 (97.5)
Oxaliplatin 219 (99.1) 229 (99.1) 448 (99.1) 1,280 (98.6)
Reason for discontinuation
Disease progression 143 (64.7) 144 (62.3) 287 (63.5) 843 (64.9)
Toxicity 29 (13.1) 36 (15.6) 65 (14.4) 207 (15.9)
Other 44 (19.9) 45 (19.5) 89 (19.7) 225 (17.3)
Unknown 3 (1.4) 5 (2.2) 8 (1.8) 11 (0.8)
Tumor type
Colon 160 (72.4) 149 (64.5) 309 (68.4) 902 (69.5)
Rectum 61 (27.6) 82 (35.5) 143 (31.6) 395 (30.4)
Unknown 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.1)
Number of disease sites
1 69 (31.2) 81 (35.1) 150 (33.2) 415 (32.0)
≥ 2 150 (67.9) 149 (64.5) 299 (66.2) 871 (67.1)
Missing 2 (0.9) 1 (0.4) 3 (0.7) 12 (0.9)
EGFR‐positive CRC
Yes 221 (100) 230 (99.6) 451 (99.8) 1,275 (98.2)
No 0 (0.0) 1 (0.4) 1 (0.2) 2 (0.2)
Liver metastases
Yes 170 (76.9) 176 (76.2) 346 (76.5) 989 (76.2)
No 49 (22.2) 54 (23.4) 103 (22.8) 297 (22.9)
Abbreviations: CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; wt, wild type.
Treatment Adherence and Exposure
Patients in the RAS‐wt group received irinotecan for a median duration of 18.0 weeks (range, 0.7–89.1) in the cetuximab plus irinotecan arm and 10.0 weeks (range, 1.1–71.0) in the irinotecan arm; the median cumulative irinotecan doses were 1,798.4 mg/m2 (range, 266.1–7,204.8) and 1,056.8 mg/m2 (range, 173.6–7,150.3), respectively. Median duration of cetuximab treatment was 19.0 weeks (range, 0.7–97.9), and median cumulative dose was 4,524.0 mg/m2 (range, 159.6–22,086.3). In the cetuximab plus irinotecan arm, 79.0% of patients received ≥80% of the planned dose intensity of irinotecan versus 85.7% of patients in the irinotecan arm. For cetuximab treatment, ≥80% of the planned dose intensity was administered in 72.9% of patients.
In the irinotecan arm, 104 patients (47.1%) received cetuximab in a subsequent line of therapy after the EPIC study; 90 (40.7%) received cetuximab plus irinotecan (Fig. 2). In the cetuximab plus irinotecan arm, 26 patients (11.3%) received cetuximab after the study.
Figure 2 Overall survival by subsequent therapy in the RAS–wild‐type population. (A): In the cetuximab plus irinotecan arm of the EPIC study. (B): In the irinotecan arm of the EPIC study. Abbreviation: CI, confidence interval.
Efficacy
Median OS was 12.3 versus 12.0 months (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.71–1.17; p = .4645) in the cetuximab plus irinotecan versus irinotecan arms, respectively (Table 2; Fig. 3A); median PFS was 5.4 versus 2.6 months (HR, 0.57; 95% CI, 0.46–0.69; p < .0001; Table 2; Fig. 3B). ORR was higher in the cetuximab plus irinotecan arm than in the irinotecan arm: 29.4% versus 5.0% (odds ratio [OR], 8.12; 95% CI, 4.04–17.40; p < .0001) (Table 2). An analysis of OS by poststudy treatment within the RAS‐wt population showed improved median OS in patients who received poststudy cetuximab compared with those not receiving cetuximab or any subsequent therapy in both treatment arms (Fig. 2; supplemental online Table 1). In the cetuximab plus irinotecan arm, median OS in patients who had previously received bevacizumab (n = 27) versus those without prior bevacizumab therapy (n = 204) was 10.2 (95% CI, 4.53–14.09) versus 12.8 months (95% CI, 11.47–15.70), respectively. In the irinotecan arm, median OS was not estimable (95% CI, 11.73 months–not estimable) in patients who had received previous bevacizumab (n = 28) versus 11.8 months (95% CI, 9.00–13.31) in patients without prior bevacizumab therapy (n = 193). ORR in patients who had previously received bevacizumab was 18.5% in the cetuximab plus irinotecan arm (n = 27) and 3.6% in the irinotecan arm (n = 28).
Table 2 Summary of efficacy results in the RAS‐wt and RAS‐unselected populations in the EPIC study
RAS‐wt population
RAS‐unselected population [2]
Irinotecan (n = 221) Cetuximab plus irinotecan (n = 231) Irinotecan (n = 650) Cetuximab plus irinotecan (n = 648)
Median duration of therapy (range), weeks
Cetuximab NA 19.0 (0.7–97.9) NA 14.0 (0.7–97.9)
Irinotecan 10.0 (1.1–71.0) 18.0 (0.7–89.1) 9.9 (0.4–71.0) 13.1 (0.7–89.1)
OS
Number of events, n (%) 126 (57.0) 133 (57.6) 429 (66.0) 445 (68.8)
Median (95% CI), months 12.0 (9.36–14.92) 12.3 (11.37–14.09) 9.99 (9.13–11.33) 10.71 (9.59–11.30)
HR (95% CI) 0.91 (0.71–1.17) 0.975 (0.854–1.114)
Log‐rank p value .4645 .7114
PFS
Number of events, n (%) 201 (91.0) 212 (91.8) 598 (92.0) 610 (94.1)
Median (95% CI), months 2.6 (2.30–2.83) 5.4 (4.24–5.75) 2.56 (2.1–2.69) 3.98 (3.15–4.14)
HR (95% CI) 0.57 (0.46–0.69) 0.692 (0.617–0.776)
Log‐rank p value <.0001 <.0001
Response
Primary definition, n (%)
Complete response 0 4 (1.7) 1 (0.2) 9 (1.4)
Partial response 11 (5.0) 64 (27.7) 26 (4.0) 97 (15.0)
Stable disease 100 (45.2) 90 (39.0) 271 (41.7) 292 (45.1)
Progressive disease 71 (32.1) 46 (19.9) 243 (37.4) 174 (26.9)
Not assessable 39 (17.6) 27 (11.7) 109 (16.8) 76 (11.7)
ORR (CR + PR), n (%) [95% CI] 11 (5.0) [2.51–8.73] 68 (29.4) [23.63–35.77] 27 (4.2) [2.75–5.99] 106 (16.4) [13.59–19.44]
Abbreviations: CI, confidence interval; CR, complete response; HR, hazard ratio; NA, not applicable; ORR, overall response rate; OS, overall survival; PFS, progression‐free survival; PR, partial response; wt, wild type.
Figure 3 Survival in the RAS–wild‐type population of the EPIC study. (A): Overall survival. (B): Progression‐free survival. Abbreviations: CI, confidence interval; HR, hazard ratio.
Safety
Adverse events (AEs) in the RAS‐wt population were consistent with the safety profile observed in the overall EPIC safety population and in other cetuximab studies [2, 8, 9], and no new or unexpected safety signals were observed in either treatment arm. In the cetuximab plus irinotecan and irinotecan arms, 76.4% and 61.8% of patients, respectively, experienced a grade ≥ 3 treatment‐emergent AE. Grade ≥ 3 treatment‐related AEs (TRAEs) were observed in 67.7% and 45.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively; the most common grade 3/4 TRAEs (occurring in ≥20 patients in any treatment arm) were diarrhea (32.3% vs. 17.1%) and neutropenia (20.5% vs. 14.3%). In the cetuximab plus irinotecan arm, grade ≥ 3 drug‐related skin reactions were observed in 12.2% of patients, and grade ≥ 3 acne‐like dermatitis occurred in 1.7%. These TRAEs account for the overall higher TRAE rate in the cetuximab plus irinotecan group.
Serious TRAEs occurred in 29.3% and 21.2% of patients in the cetuximab plus irinotecan and irinotecan arms, respectively. Cetuximab‐related serious AEs (SAEs) occurred in 14.4% of patients in the cetuximab plus irinotecan arm. Irinotecan‐related SAEs were observed in 26.6% versus 21.2% of patients in the cetuximab plus irinotecan versus irinotecan arms, respectively. The most common grade ≥ 3 serious TRAEs (occurring in ≥5% of patients) in both treatment arms were febrile neutropenia and diarrhea. Furthermore, serious TRAEs leading to death occurred in eight patients in the cetuximab plus irinotecan arm and were cetuximab‐related in five patients (dyspnea [n = 1], disease progression [n = 1], cardiac failure and renal failure [n = 1], vomiting and sudden death [n = 1], sepsis [n = 1]) and irinotecan‐related in seven patients (diarrhea, cardiac failure and renal failure [n = 1], pneumonia aspiration and respiratory arrest [n = 1], disease progression [n = 1], gastroenteritis [n = 1], neutropenia [n = 1], vomiting and sudden death [n = 1], intestinal perforation, peritonitis and sepsis [n = 1]) versus three patients in the irinotecan arm (febrile neutropenia [n = 1]; intestinal obstruction [n = 1]; neutropenia [n = 1]). AEs resulting in discontinuation of cetuximab occurred in 20.5% of patients in the cetuximab plus irinotecan arm. AEs leading to irinotecan discontinuation were similar in both arms (22.3% vs. 19.4% in the cetuximab plus irinotecan vs. irinotecan arms).
QoL
Compliance rates for the QoL questionnaire in the RAS‐wt population at baseline were 86.1% and 90.0% in the cetuximab plus irinotecan and irinotecan arms, respectively. The on‐study completion rate subsequently decreased over time, stabilizing at approximately 50% at week 21 in each arm and remaining at this level until weeks 51 and 45 in the cetuximab plus irinotecan and irinotecan arms, respectively. Patients who completed the QoL assessment questionnaire answered 96.7% to 100% of the questions. Baseline scores were similar between treatment arms for 13 of 15 QoL scales. For the symptom scale fatigue and the single item insomnia, differences from baseline scores favored cetuximab plus irinotecan over irinotecan (p < .1). A longitudinal model (truncated at week 45) was used to compare change from baseline scores over time between treatment arms. During the course of the study, improved QoL was reported by patients in the cetuximab plus irinotecan arm compared with those in the irinotecan arm for several multi‐item and single‐item scales (supplemental online Table 2). The model also showed advantages for cetuximab treatment for two functioning scales (physical functioning and role functioning), two symptom scales (fatigue and nausea/vomiting), and two single‐item scales (pain and appetite loss), all in favor of the combination treatment (p < .05). A trend for improved cognitive functioning, global health status, and constipation was also observed in the cetuximab plus irinotecan arm (p < .1). The remaining multi‐item and single‐items scales showed no significant differences between the two treatment arms.
Discussion
This retrospective analysis of the RAS‐wt population of the EPIC study reiterates that the addition of cetuximab to irinotecan did not prolong OS—consistent with results of the primary analysis in the non–biomarker‐defined population [2] as well as those of a previous subgroup analysis in the KRAS‐wt population [13]. The lack of change in OS is possibly due to the high rate of poststudy crossover to cetuximab therapy in patients in the irinotecan arm, as suggested by Sobrero et al [2]. Indeed, nearly half of the patients with RAS‐wt tumors in the irinotecan arm received cetuximab in a subsequent line of therapy after the study, potentially masking any OS benefit of the addition of cetuximab to irinotecan. This hypothesis is supported by results from the CO.17 study of cetuximab versus best supportive care (BSC) in pretreated advanced RAS‐ and BRAF‐wt CRC, in which OS was significantly improved with cetuximab compared with BSC (10.1 vs. 4.8 months), with only 7.0% of patients who received BSC subsequently receiving cetuximab [14, 15].
Interestingly, patients in both treatment arms of EPIC who received poststudy cetuximab had improved OS compared with those who received a subsequent therapy without cetuximab or no poststudy therapy, suggesting that the administration of cetuximab at any point in the second or later line may improve survival. Furthermore, these data suggest that cetuximab‐based therapy may be a suitable standard treatment in the rechallenge setting (i.e., retreatment with cetuximab after progression in a subsequent therapy line without cetuximab) as well as beyond progression for patients with RAS‐wt mCRC. Thus, although guidelines recommend the use of cetuximab in the first‐line treatment setting [3, 4, 5], data from this trial support the use of cetuximab in second or subsequent line treatment settings. Of note, limitations of this analysis include a potential bias because of the differences in the proportion of subsequent therapies with and without cetuximab in the two treatment arms. Another possible bias arises from the observation that patients who live longer are more likely to receive cetuximab in any subsequent therapy line.
In contrast to OS, PFS was more than doubled and ORR was approximately sixfold higher in the cetuximab plus irinotecan arm than in the irinotecan arm (p < .0001 each), and this improvement was more prominent than that in the primary analysis [2] and in the analysis of the KRAS‐wt population [13]. These results suggest that second‐line cetuximab may have a clinically meaningful therapeutic benefit in patients with mCRC—considering their survival prognosis of approximately 1 year, which is supported by the improvements observed in the patients’ QoL. Furthermore, patients who received cetuximab continued treatment for longer, likely because of the prolonged PFS. In both this retrospective analysis and the initial results of the EPIC study [2], the longer PFS and higher ORR observed upon the addition of cetuximab to irinotecan may be a better indicator of the additional benefit conferred by cetuximab than OS, because these endpoints are directly related to the study period and are therefore unaffected by subsequent therapies and are clinically relevant in patients with mCRC.
Similar to the results of the primary analysis of the EPIC study, no new or unexpected safety signals in the RAS‐wt population were observed in either treatment arm. Furthermore, the improved QoL, as demonstrated for several single‐ and multi‐item scales in the cetuximab plus irinotecan arm compared with that in the irinotecan arm, is also reflected in the observed treatment duration, which was almost twice as long in the cetuximab plus irinotecan arm than in the irinotecan arm. Although an analysis for efficacy in left‐sided versus right‐sided tumors was not feasible in this retrospective study because of missing data on primary tumor location, the ORR for the RAS‐wt population in this study was among the highest observed to date in the second‐line setting when compared with that reported for other regimens, such as bevacizumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4), as reported for the E3200 study (ORR, 22.7%) [16], and panitumumab plus combination chemotherapy (ORR, 41% for panitumumab plus 5‐fluorouracil, leucovorin, and irinotecan (FOLFIRI) vs. 10% for FOLFIRI in patients with RAS‐wt tumors) [17]. Notably, although ORR and PFS increased from 16.4% to 29.4% and from 4.0 to 5.4 months, respectively, in the RAS‐unselected and the RAS‐wt populations with cetuximab plus irinotecan, the efficacy outcomes for patients receiving irinotecan did not differ between the RAS‐unselected and RAS‐wt populations (PFS, 2.6 months in both populations; ORR: 4.2% and 5.0%, respectively). These findings, as well as the improved QoL observed in the cetuximab plus irinotecan arm, further confirm the increased efficacy of cetuximab in patients with RAS‐wt tumors in second‐line treatment and confirm that RAS testing is predictive of clinical benefit.
Conclusion
This retrospective analysis of RAS‐wt patients enrolled in the EPIC study emphasizes the role of cetuximab‐based therapy as a standard second‐line treatment for patients with RAS‐wt mCRC.
Author Contributions
Conception/design: Alberto Sobrero, Heinz‐Josef Lenz, Regina Esser, Johannes Nippgen, Howard Burris
Provision of study material or patients: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Collection and/or assembly of data: Cathy Eng, Werner Scheithauer, Gary Middleton, Howard Burris
Data analysis and interpretation: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Manuscript writing: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Final approval of manuscript: Alberto Sobrero, Heinz‐Josef Lenz, Cathy Eng, Werner Scheithauer, Gary Middleton, Wenfeng Chen, Regina Esser, Johannes Nippgen, Howard Burris
Disclosures
Alberto Sobrero: Amgen, Bayer, Bristol Myers Squibb, Celgene, Eli Lilly & Co., EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany), Roche, Sanofi, Takeda (C/A); Heinz‐Josef Lenz: Bayer, Bristol Myers Squibb, EMD Serono, Roche (C/A), Bayer, Bristol Myers Squibb, EMD Serono, Roche, Takeda (H), Bayer, EMD Serono (other—travel support); Cathy Eng: Bayer, LSK Global PS, Roche, Sirtex, Taiho (C/A); Wenfeng Chen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Regina Esser: Merck KGaA (Darmstadt, Germany) (E, OI); Johannes Nippgen: Merck Serono Co., Ltd., China, an affiliate of Merck KGaA, Darmstadt, Germany (E); Howard Burris: AstraZeneca, Celgene, Daiichi Sankyo, FORMA Therapeutics, Incyte, Pfizer (C/A), Agios, AstraZeneca, Arch, Array BioPharma, Arvinas, Bayer, BIND Therapeutics, BioAtla, BioMed Valley, Boehringer‐Ingelheim, Bristol Myers Squibb, CicloMed, CytomX, eFFECTOR, Eli Lilly & Co., Roche/Genentech, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Incyte, Janssen, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck KGaA, Millennium Pharmaceuticals, Mirna Therapeutics, Moderna, Novartis, Pfizer, Revolution Medicine, Seattle Genetics, Tesaro, TG Therapeutics, Verastem, Vertex Pharmaceuticals (RF—institution), HCA/Sarah Cannon (OI). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Appendix S1 Supporting Information.
Click here for additional data file.
Table S1 Median OS by Subsequent Therapy in the RAS wt Population in the EPIC Study
Table S2: Comparison of QoL Between Treatment Arms Using a Longitudinal Analysis
Click here for additional data file.
Acknowledgments
Medical writing assistance was provided by Eleanor Green of ClinicalThinking, Manchester, U.K., and funded by Merck KGaA, Darmstadt, Germany. This assistance consisted of copyediting, editorial and production assistance. This study was sponsored by Bristol Myers Squibb, New York, NY; ImClone Systems, Bridgewater, NJ; Eli Lilly & Co., Indianapolis, IN; and Merck KGaA. Protocol design and funding of medical writing support by ClinicalThinking, Inc., was provided by Merck KGaA. Data interpretation and the final decision to submit for publication was conducted by Merck KGaA and the coordinating investigators.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood 1,25-dihydroxycholecalciferol increased'.
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Hypophosphatemia and FGF23 tumor-induced osteomalacia in two cases of metastatic breast cancer.
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by factor-induced dysregulation of phosphate and vitamin D metabolism resulting in alterations in bone formation, leading to bone pain and fractures. While the true incidence is likely underestimated, less than 500 cases of TIO have been reported since initial description in 1947. TIO cases have classically been associated with mesenchymal tumors of bone and soft tissue, but have also rarely been linked to malignant tumors, with scant reports implicating non-mesenchymal tumors. TIO is mediated through inappropriate tumor overproduction of fibroblast growth factor 23 (FGF23). Increased FGF23 secretion leads to hypophosphatemia by (1) reduced phosphate reabsorption via activation of the proximal renal tubular epithelial cells to internalize sodium phosphate cotransporters and (2) reduced activation of vitamin D3 via inhibition of the renal enzyme 1-α hydroxylase. Low circulating levels of active vitamin D lead to reduced intestinal phosphate absorption and impaired mineralization of osteoid matrix. TIO in breast cancer poses a distinct diagnostic challenge due to the common adjunct oncologic management with bone protection therapy such as denosumab or bisphosphonates. These agents can be culprits of hypophosphatemia and hypocalcemia, rendering timely diagnosis of TIO difficult. Delay of diagnosis of TIO can result in worsening functional status, and early morbidity and mortality. To date, there has been one prior case report of TIO in breast cancer, and herein we describe two additional cases of TIO in this setting.
pmcIntroduction
Fibroblast growth factor-23 (FGF23) is a phosphaturic humoral factor produced by osteoblasts and osteocytes [1]. First identified two decades ago, mutations in the cleavage of FGF23 cause several inherited renal phosphate wasting diseases leading to rickets in children or osteomalacia in adults [2, 3]. In the paraneoplastic setting, FGF23 oversecretion leads to tumor-induced rickets/osteomalacia (TIO) also known as oncogenic osteomalacia [4]. TIO is typically reported with mesenchymal tumors [5, 6], and is starting to become recognized in patients with liquid [7] and solid organ malignancies [8, 9, 10] as well.
FGF23 is a key regulator of phosphate metabolism. The primary physiologic function is to lower serum phosphate levels which is mediated by FGF receptors (FGFR) and klotho complexes [3]. FGF23 downregulates the expression of cotransporters in the kidney that are essential for the reabsorption of phosphate. Additionally, FGF23 downregulates the expression of enzymes that activate vitamin D which increases intestinal phosphate absorption, thereby indirectly lowering serum phosphate levels [11].
Phosphate is primarily found in bone and is responsible for skeletal strength and rigidity. Low phosphate levels manifest as general muscle weakness, fatigue, and in extreme cases impaired cardiac and respiratory function [12]. These symptoms, in patients with cancer, may be attributed to their malignancy, and the potential diagnosis of TIO may be overlooked, especially with the rarer non-mesenchymal origin tumors. Below are examples of two case reports of patients with metastatic breast cancer with severe hypophosphatemia, phosphaturia and elevated serum FGF23, consistent with TIO. To the best of our knowledge, there is only one other case report of TIO associated with metastatic breast cancer [13]. These cases are particularly challenging given the use of antiresorptive therapy in patients with bone metastasis which can trigger FGF23 overexpression [13] and worsen underlying oncologic osteomalacia.
Case 1
A 47-year-old woman with metastatic breast cancer with liver and bone involvement was referred to the nephrology clinic for persistent hypophosphatemia. Seven years ago patient was diagnosed with left mammary duct carcinoma and underwent partial mastectomy followed by chemotherapy with paclitaxel and tamoxifen. She had a reoccurrence 3 years later and failed multiple lines of chemotherapy including eribulin and vinorelbine with last positron emission tomography (PET) scan showing metastasis to the liver, sternum, and sclerotic osseous lesions to the spine and right iliac (Figure 1).
The patient was initiated on monthly denosumab for 1 year (12 doses in total) prior to the current nephrology visit, with last dose 1 month ago, to address metastatic bone involvement. Phosphorous level on consultation was < 0.9 mg/dL (2.5 – 4.5 mg/dL) with no prior levels. Remainder of bloodwork is shown in Table 1 which highlights low calcium 7.4 mg/dL (8.5 – 10.5 mg/dL) and elevated alkaline phosphatase (ALP) of 738 U/L (≤ 130 U/L). The fractional excretion of phosphate (FePhos) in the urine was elevated at 56% (< 5 – 10%).
Etiology for hypophosphatemia was initially thought to be secondary hyperparathyroidism given elevated parathyroid hormone (PTH) of 488 pg/mL (12 – 88 pg/mL) due to hypocalcemia in the setting of recent denosumab administration. Phosphorous levels remained low despite oral calcium and phosphate repletion and oral calcitriol administration (Table 1). Given persistent hypophosphatemia, FGF23 was checked, and levels returned strikingly elevated at 2,430 RU/mL (≤ 180 RU/mL) suggesting an FGF23 secreting tumor as the most likely cause for severe hypophosphatemia. Unfortunately, the patient passed away within 1 month due to disease progression.
Case 2
A 55-year-old woman with triple negative invasive ductal breast cancer, who achieved remission 10 years ago presented with progressive weakness. She was found to have relapsed disease involving the liver, lung, and bone (vertebral, acetabulum, and ilium) 1 year ago (Figure 2), and subsequently received chemotherapy including palbociclib, nivolumab, and abraxane as well as 4 monthly doses of zoledronate, followed by 10 monthly treatments of denosumab. She last received bone-stimulating therapy and chemotherapy 3 months prior to admission. She had no other comorbidities, nor a history of additional medications or herbal supplements. She was a lifetime nonsmoker. She was admitted for obstructive jaundice due to progression of disease. During the course of her admission, she complained of severe lower extremity bone pain limiting ambulation. Prior to admission, the patient’s electrolytes were within normal limits.
Upon admission, she was cachectic (body mass index < 18), with hypophosphatemia of 1.6 mmol/L (2.5 – 4.5 mmol/L). Nephrology was called for further evaluation. Remainder of lab studies are shown in Table 2 and include a normal corrected calcium of 9.5 mmol/L (8.5 – 10.5 mmol/L), low 25-hydroxyvitamin D of 15 ng/dL (20 – 50 ng/dL), elevated PTH of 287.3 pg/mL (12 – 88 pg/mL), and elevated ALP of 635 U/L (≤ 130U/L). FePhos was 78% (< 5 – 10%), consistent with phosphate wasting. Of note, 1,25-dihydroxyvitamin D was elevated at 83 pg/mL (20 – 50 pg/mL) despite not being on calcitriol.
Given elevated urine phosphate, an oncologic osteomalacia was suspected and FGF23 was checked and was elevated at 548 (< 180) RU/mL. Due to aggressive supplementation, serum phosphate increased to a peak value of 3.8 mmol/L; PTH decreased to 44, but FGF23 and FePhos remained elevated at 424 and 72%, respectively. The patient continued to decline and passed away within 2 weeks.
Discussion
FGF23 is a glycoprotein part of the FGF family which is subdivided into 7 subfamilies with 22 members reported in humans [14]. FGF23 belongs to the FGF19 subfamily which has also been called the endocrine FGFs due to the inner protein structure allowing it to function as a circulating hormone [15]. FGF23 is derived from bones, and under physiologic conditions, its production is stimulated by extracellular phosphate. Once secreted from osteoblasts and osteocytes, FGF23 plays a pleiotropic role which links the bone with several organ systems including the kidney, heart, and cells part of the immune system [1]. FGF23 signaling contributes to regulation in cellular proliferation, survival, and differentiation making it an attractive pathway to hijack by cancer cells [16].
FGF23 renal pathophysiology
With respect to the kidney, the main function of FGF23 is to lower serum phosphate levels as shown in Figure 3. This is established through direct inhibition of phosphate reabsorption at the level of the proximal tubular cells, and indirectly by downregulation of enzymes necessary to activate vitamin D. Direct actions involve the binding of circulating FGF23 to FGF receptors (FGFRs) and coreceptor klotho on the basolateral surface of the proximal tubular cells. This results in decreased expression of two sodium-phosphate cotransporters called NaPi-2a and NaPi-2c. These transporters, located on the apical surface of the proximal tubular cell are responsible for renal phosphate reabsorption. Decreased expression of NaPi-2a and NaPi-2c is therefore a direct cause of phosphaturia [17].
FGF23 also indirectly lowers serum phosphate levels by inhibiting renal 1-α-hydroxylase which is necessary to activate vitamin D. Further, FGF23 also increases the expression of 24-hydroxylase which degrades the active form of vitamin D into inactive metabolites. These actions collectively reduce active levels of vitamin D leading to decreased intestinal reabsorption of phosphate [18]. This relationship has been demonstrated in animal studies where a single injection of recombinant FGF23 resulted in reduction of serum phosphate and 1,25 (OH) 2D levels independent of PTH levels [11]. During the experiment, PTH levels remained low, and the hypophosphatemia was reproduced by injection of FGF23 in parathyroidectomized rats [11].
FGF23 mode of inheritance
Both genetic and acquired mechanisms of FGF23-related hypophosphatemic disease have been described. Genetic mechanisms vary by mode of inheritance. Autosomal dominant hypophosphatemic rickets (ADHR) is caused by mutations in FGF23 gene [2]. The autosomal recessive variant is caused by mutations in dentrin matrix protein 1 (DMP1) [19]. The X-linked dominant form occurs due to mutations in phosphate-regulating gene (PHEX) [20].
An acquired FGF23 hypophosphatemic disease is associated with the administration of intravenous iron, specifically the saccharated ferric oxide and iron polymaltose. Evaluation of these patients showed elevated FGF23 levels with the exact mechanism not known [21]. TIO is another example of an acquired form of FGF23 hypophosphatemic disease [17] which is reviewed in greater detail below.
Tumor-induced osteomalacia
TIO is a rare paraneoplastic disease, first described in 1947 by Robert McCance who reported a patient with pain and weakness in the setting of low phosphate levels. His symptoms persisted despite being treated with vitamin D, and eventually improved only after a tumor found in the femur bone was resected [22]. Animal experiments have supported the presence of the humoral factor leading to hypophosphatemia [23]. The earliest evidence to support this in humans was done by Miyauchi et al. [24] where tumor removal in a patient with osteomalacia and injection into healthy mice lead to hypophosphatemia.
Tumors associated with TIO are usually mesenchymal in origin [17]. Within the reported cases of TIO, 40% occur in the bone and 55% occur in soft tissues. The thigh and femur are the most common sites of involvement with the pelvis reported in only 8% of cases, and only 2% of cases reported as involving more than one site [25]. These tumors can be histologically polymorphous, but in 1991 Weidner [26] proposed a classification system to divide them into four morphologic patterns including phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT), osteoblastoma-like variant, non-ossifying fibroma-like variant, and ossifying fibroma-like variant. PMTMCT comprises 70 – 80% of cases of TIO and typically begins in bone or soft tissues [5].
Non-mesenchymal tumors with TIO manifestations are now being recognized and reported in leukemia [7], B cell non-Hodgkin’s lymphoma [8], sarcoma [10], and other solid organ cancers including lung [27], prostate [28], and colon cancer [29]. There is only one case of TIO reported in metastatic breast cancer [13] with the two cases above resulting in a total of three. During malignancy, abnormal FGF signaling has been shown to induce cell proliferation and angiogenesis thereby promoting metastasis [16]. In breast cancer specifically, molecular alternations in FGFR1 and FGFR2 receptors are the most common reported [16]. Clinical trials support this data where phase I trials showed hyperphosphatemia as the most common adverse effect when novel tyrosine kinase inhibitors targeted FGF signaling [30].
Diagnostic evaluation of TIO should start with a comprehensive metabolic panel to check serum phosphorous and calcium levels which are typically low. Alkaline phosphatase may be elevated as in case 1 (738 U/L) and case 2 (635 U/L) due to osteoblast hyperactivity. Vitamin D levels should be checked and are typically low due to the inhibitory effect of FGF23. This was seen in our cases where vitamin D levels were 8 ng/mL and 15 ng/mL in case 1 and 2, respectively. PTH levels may be variable and increased at times as part of a normal feedback response to low vitamin D levels and subsequently hypocalcemia. In both cases, the elevation in PTH (488 pg/mL and 287 pg/mL) was likely multifactorial; initially as a feedback to hypocalcemia in the setting of denosumab. Secondary hyperparathyroidism has been demonstrated in patients receiving denosumab as a result of prolonged hypocalcemia caused by this drug [31], leading to renal phosphate wasting in some patients. This mechanism may have contributed to pathogenesis of hypophosphatemia in our patients. However in case 1, phosphorus remained low despite aggressive supplementation. Persistent hypophosphatemia however should also raise concern for an FGF23 secreting tumor. For case 2, denosumab was given 3 months prior to recognition of hypophosphatemia. Furthermore, FGF23 remained elevated, and phosphaturia continued despite PTH normalization. Therefore, denosumab likely did not play a major role in the FGF23 elevation or renal phosphate wasting. Along with serum FGF23, urine studies including urine creatinine and urine phosphorous must be checked to calculate the fractional excretion of phosphate and tubular reabsorption of phosphate. In the setting of TIO, one would expect a high fractional excretion of phosphate (> 10%) and low tubular reabsorption of phosphate (< 75%) due to inhibition of sodium phosphate transporters at the proximal tubules and low vitamin D. Dihydroxyvitamin D-1,25 was low in case 1 as expected due to suppressed activation by FGF23. However, in case 2, dihydroxyvitamin D-1,25 was elevated in the absence of calcitriol. Although in patients with chronic kidney disease and hyperphosphatemia FGF23 is elevated leading to suppression of vitamin D 1,25 production, we hypothesize that perhaps in some patients with hypophosphatemia, other mechanisms may be responsible for higher vitamin D 1,25 levels to counteract effects of low phosphorus levels.
Several imaging modalities can be used to identify the tumor, including magnetic resonance imaging (MRI) and PET scan. Somatostatin receptors (SSTR) based functioning imaging can also be performed since some of these tumors express SSTRs [32]. However, clinicians have to be mindful that inflammatory reactions can cause a false positive SSTR imaging [32]. In cases where tumor is identified, the treatment of choice is resection. Once FGF23 levels decline in circulation, serum phosphate levels return to normal, as early as five days post operatively [33]. In cases where the tumor is inoperable, medical management may be attempted with phosphate supplementation and calcitriol as recommended in our cases of metastatic disease. Octreotide is another potential treatment, given link with SSTR. Targeted antibodies against FGF23 have shown promise in animal models [34].
Conclusion
TIO can be a challenging diagnosis to make, especially in patients with malignancy other than mesenchymal origin, as symptoms of hypophosphatemia are nonspecific and could be easily attributed to the underlying cancer. In fact, the average time from recognition of osteomalacia to identifying the associated tumor is ~ 5 years [35]. We recommend more frequent testing of serum phosphorous since it is not part of the routine basic metabolic panel. Furthermore, in breast cancer specifically, patients are frequently managed with bone-targeted therapy such as bisphosphonates and denosumab which can further exacerbate hypophosphatemia. Antiresorptive therapy during malignancies should be carefully weighed with degree of hypophosphatemia and risk of skeletal-related events. Patients with TIO should be evaluated for resection, which can be curative when involving a solitary lesion. It is reasonable to check FGF23 levels in oncologic patients with persistent hypophosphatemia despite adequate supplementation of phosphorus and vitamin D and discontinuation of the drugs known to cause renal phosphate wasting. In patients with several lesions or metastatic cancer such as described above, systemic oncologic therapy and supplementation of phosphorous, calcium, and vitamin D can be attempted to improve the quality of life.
Funding
This research was supported by National Institute of Health grant award P30CA008748.
Conflict of interest
Ilya Glezerman owns Pfizer Stock. Remaining authors have nothing to disclose.
Figure 1 PET scan showing progression of disease for case 1. Metastasis to the liver, sternum, and sclerotic osseous lesions to the spine and right iliac.
Table 1. Case 1. Sequence of laboratory findings and treatment for hypophosphatemia.
–12 months to –1 month –10 days –4 days Nephrology
consult (day 0) +10 days
Treatment
Denosumab (mg) 120 mg/monthly × 10 doses
Potassium-phosphate/sodium-phosphate (mg) 250-45-298
t.i.d. 250-45-298
t.i.d.
Calcitriol (mcg) 0.25 b.i.d. 0.25 b.i.d.
Laboratory studies
Serum phosphate (mg/dL) < 0.9 1 1.1
Serum calcium* (mg/dL) Range 8.7 – 10.5 8.1 8.4 7.9 9.1
Alkaline phosphatase (U/L) Range 97 – 506 504 690 738 619
Serum PTH (pg/mL) 488
Serum FGF23 (RU/mL) 2,430
Serum 25-OH Vit D (ng/mL) 8
Urine sodium (mEq/L) 22
Urine calcium (mg/dL) < 1
Urine phosphate (mg/dL) 214
Urine creatinine (mg/dL) 229
FePhos** 56%
*Corrected calcium = total calcium (mg/dL) + 0.8 (4.0-serum albumin [g/dL]), where 4.0 represents the average albumin level. **FePhos = (urine phosphorus/serum phosphorus) × (serum creatinine/urine creatinine). PTH = parathyroid hormone; FGF23 = fibroblast growth factor 23; FePhos = fractional excretion of phosphorus.
Table 2. Case 2. Sequence of laboratory findings and treatment for hypophosphatemia,
–12 months to –3 months –10 days –4 days Nephrology
consult (day 0) +3 days +4 days
Treatment
Denosumab (mg) 120 mg/monthly
× 10 doses
Potassium-phosphate/Sodium-phosphate (mg) 250-45-298 once 250-45-298
TID 250-45-298
QID
IV Phosphate (mmol) 30 30 15
PO calcium citrate (g) 3.8
IV calcium gluconate (g) 4 2
Laboratory studies
Serum phosphate (mg/dL) 2.6 (month –3) 1.6 1.4 1.4 3.8 2.4
*Serum calcium (mg/dL) 9.2 – 10.1 range 9.0 8.7 8.0 9.4 9.3
Alkaline phosphatase (U/L) 138 – 253 range 516 581 712 677 664
Serum PTH (pg/mL) 287.3 44.3
Serum FGF23 (RU/mL) 548 424
Serum 25-OH Vit D (ng/mL) 15
Serum 1,25-Dihydroxyvitamin D (pg/mL) 82
Urine sodium (mEq/L) < 20
Urine calcium (mg/dL) 3.1
Urine phosphate (mg/dL) 175 416
Urine creatinine (mg/dL) 80 99
**FePhos 78% 72%
*Corrected calcium = total calcium (mg/dL) + 0.8 (4.0-serum albumin [g/dL]), where 4.0 represents the average albumin level. **FePhos = (urine phosphorus/serum phosphorus) × (serum creatinine/urine creatinine). PTH = parathyroid hormone; FGF23 = fibroblast growth factor 23; FePhos = fractional excretion of phosphorus.
Figure 2 PET Scan showing progression of disease for case 2. Metastasis to the liver, right acetabulum, thoracic vertebrae, and right ilium.
Figure 3 Bone-kidney axis and phosphaturic effects of FGF23. FGF23 is produced in bone by osteocytes in response to high serum phosphorous. In malignant bone, FGF23 is produced regardless of serum phosphorous. One of FGF23 targets is the kidney. FGF23 binds to FGR receptors and complexes with klotho on the basolateral surface of proximal tubular cells. This causes a decrease in expression of sodium-phosphorus co-transporters (Na-PO42-) whose role is renal phosphate reabsorption. Indirect effects include inhibition of 1-α-hydroxylase levels which are necessary to activate vitamin D and increased expression of 24-hydroxylase which degrades active vitamin D. The net effect is a decrease in serum phosphorous.
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DENOSUMAB, NIVOLUMAB, PACLITAXEL, PALBOCICLIB, ZOLEDRONIC ACID
|
DrugsGivenReaction
|
CC BY
|
33191899
| 17,820,365
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood 25-hydroxycholecalciferol decreased'.
|
Hypophosphatemia and FGF23 tumor-induced osteomalacia in two cases of metastatic breast cancer.
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by factor-induced dysregulation of phosphate and vitamin D metabolism resulting in alterations in bone formation, leading to bone pain and fractures. While the true incidence is likely underestimated, less than 500 cases of TIO have been reported since initial description in 1947. TIO cases have classically been associated with mesenchymal tumors of bone and soft tissue, but have also rarely been linked to malignant tumors, with scant reports implicating non-mesenchymal tumors. TIO is mediated through inappropriate tumor overproduction of fibroblast growth factor 23 (FGF23). Increased FGF23 secretion leads to hypophosphatemia by (1) reduced phosphate reabsorption via activation of the proximal renal tubular epithelial cells to internalize sodium phosphate cotransporters and (2) reduced activation of vitamin D3 via inhibition of the renal enzyme 1-α hydroxylase. Low circulating levels of active vitamin D lead to reduced intestinal phosphate absorption and impaired mineralization of osteoid matrix. TIO in breast cancer poses a distinct diagnostic challenge due to the common adjunct oncologic management with bone protection therapy such as denosumab or bisphosphonates. These agents can be culprits of hypophosphatemia and hypocalcemia, rendering timely diagnosis of TIO difficult. Delay of diagnosis of TIO can result in worsening functional status, and early morbidity and mortality. To date, there has been one prior case report of TIO in breast cancer, and herein we describe two additional cases of TIO in this setting.
pmcIntroduction
Fibroblast growth factor-23 (FGF23) is a phosphaturic humoral factor produced by osteoblasts and osteocytes [1]. First identified two decades ago, mutations in the cleavage of FGF23 cause several inherited renal phosphate wasting diseases leading to rickets in children or osteomalacia in adults [2, 3]. In the paraneoplastic setting, FGF23 oversecretion leads to tumor-induced rickets/osteomalacia (TIO) also known as oncogenic osteomalacia [4]. TIO is typically reported with mesenchymal tumors [5, 6], and is starting to become recognized in patients with liquid [7] and solid organ malignancies [8, 9, 10] as well.
FGF23 is a key regulator of phosphate metabolism. The primary physiologic function is to lower serum phosphate levels which is mediated by FGF receptors (FGFR) and klotho complexes [3]. FGF23 downregulates the expression of cotransporters in the kidney that are essential for the reabsorption of phosphate. Additionally, FGF23 downregulates the expression of enzymes that activate vitamin D which increases intestinal phosphate absorption, thereby indirectly lowering serum phosphate levels [11].
Phosphate is primarily found in bone and is responsible for skeletal strength and rigidity. Low phosphate levels manifest as general muscle weakness, fatigue, and in extreme cases impaired cardiac and respiratory function [12]. These symptoms, in patients with cancer, may be attributed to their malignancy, and the potential diagnosis of TIO may be overlooked, especially with the rarer non-mesenchymal origin tumors. Below are examples of two case reports of patients with metastatic breast cancer with severe hypophosphatemia, phosphaturia and elevated serum FGF23, consistent with TIO. To the best of our knowledge, there is only one other case report of TIO associated with metastatic breast cancer [13]. These cases are particularly challenging given the use of antiresorptive therapy in patients with bone metastasis which can trigger FGF23 overexpression [13] and worsen underlying oncologic osteomalacia.
Case 1
A 47-year-old woman with metastatic breast cancer with liver and bone involvement was referred to the nephrology clinic for persistent hypophosphatemia. Seven years ago patient was diagnosed with left mammary duct carcinoma and underwent partial mastectomy followed by chemotherapy with paclitaxel and tamoxifen. She had a reoccurrence 3 years later and failed multiple lines of chemotherapy including eribulin and vinorelbine with last positron emission tomography (PET) scan showing metastasis to the liver, sternum, and sclerotic osseous lesions to the spine and right iliac (Figure 1).
The patient was initiated on monthly denosumab for 1 year (12 doses in total) prior to the current nephrology visit, with last dose 1 month ago, to address metastatic bone involvement. Phosphorous level on consultation was < 0.9 mg/dL (2.5 – 4.5 mg/dL) with no prior levels. Remainder of bloodwork is shown in Table 1 which highlights low calcium 7.4 mg/dL (8.5 – 10.5 mg/dL) and elevated alkaline phosphatase (ALP) of 738 U/L (≤ 130 U/L). The fractional excretion of phosphate (FePhos) in the urine was elevated at 56% (< 5 – 10%).
Etiology for hypophosphatemia was initially thought to be secondary hyperparathyroidism given elevated parathyroid hormone (PTH) of 488 pg/mL (12 – 88 pg/mL) due to hypocalcemia in the setting of recent denosumab administration. Phosphorous levels remained low despite oral calcium and phosphate repletion and oral calcitriol administration (Table 1). Given persistent hypophosphatemia, FGF23 was checked, and levels returned strikingly elevated at 2,430 RU/mL (≤ 180 RU/mL) suggesting an FGF23 secreting tumor as the most likely cause for severe hypophosphatemia. Unfortunately, the patient passed away within 1 month due to disease progression.
Case 2
A 55-year-old woman with triple negative invasive ductal breast cancer, who achieved remission 10 years ago presented with progressive weakness. She was found to have relapsed disease involving the liver, lung, and bone (vertebral, acetabulum, and ilium) 1 year ago (Figure 2), and subsequently received chemotherapy including palbociclib, nivolumab, and abraxane as well as 4 monthly doses of zoledronate, followed by 10 monthly treatments of denosumab. She last received bone-stimulating therapy and chemotherapy 3 months prior to admission. She had no other comorbidities, nor a history of additional medications or herbal supplements. She was a lifetime nonsmoker. She was admitted for obstructive jaundice due to progression of disease. During the course of her admission, she complained of severe lower extremity bone pain limiting ambulation. Prior to admission, the patient’s electrolytes were within normal limits.
Upon admission, she was cachectic (body mass index < 18), with hypophosphatemia of 1.6 mmol/L (2.5 – 4.5 mmol/L). Nephrology was called for further evaluation. Remainder of lab studies are shown in Table 2 and include a normal corrected calcium of 9.5 mmol/L (8.5 – 10.5 mmol/L), low 25-hydroxyvitamin D of 15 ng/dL (20 – 50 ng/dL), elevated PTH of 287.3 pg/mL (12 – 88 pg/mL), and elevated ALP of 635 U/L (≤ 130U/L). FePhos was 78% (< 5 – 10%), consistent with phosphate wasting. Of note, 1,25-dihydroxyvitamin D was elevated at 83 pg/mL (20 – 50 pg/mL) despite not being on calcitriol.
Given elevated urine phosphate, an oncologic osteomalacia was suspected and FGF23 was checked and was elevated at 548 (< 180) RU/mL. Due to aggressive supplementation, serum phosphate increased to a peak value of 3.8 mmol/L; PTH decreased to 44, but FGF23 and FePhos remained elevated at 424 and 72%, respectively. The patient continued to decline and passed away within 2 weeks.
Discussion
FGF23 is a glycoprotein part of the FGF family which is subdivided into 7 subfamilies with 22 members reported in humans [14]. FGF23 belongs to the FGF19 subfamily which has also been called the endocrine FGFs due to the inner protein structure allowing it to function as a circulating hormone [15]. FGF23 is derived from bones, and under physiologic conditions, its production is stimulated by extracellular phosphate. Once secreted from osteoblasts and osteocytes, FGF23 plays a pleiotropic role which links the bone with several organ systems including the kidney, heart, and cells part of the immune system [1]. FGF23 signaling contributes to regulation in cellular proliferation, survival, and differentiation making it an attractive pathway to hijack by cancer cells [16].
FGF23 renal pathophysiology
With respect to the kidney, the main function of FGF23 is to lower serum phosphate levels as shown in Figure 3. This is established through direct inhibition of phosphate reabsorption at the level of the proximal tubular cells, and indirectly by downregulation of enzymes necessary to activate vitamin D. Direct actions involve the binding of circulating FGF23 to FGF receptors (FGFRs) and coreceptor klotho on the basolateral surface of the proximal tubular cells. This results in decreased expression of two sodium-phosphate cotransporters called NaPi-2a and NaPi-2c. These transporters, located on the apical surface of the proximal tubular cell are responsible for renal phosphate reabsorption. Decreased expression of NaPi-2a and NaPi-2c is therefore a direct cause of phosphaturia [17].
FGF23 also indirectly lowers serum phosphate levels by inhibiting renal 1-α-hydroxylase which is necessary to activate vitamin D. Further, FGF23 also increases the expression of 24-hydroxylase which degrades the active form of vitamin D into inactive metabolites. These actions collectively reduce active levels of vitamin D leading to decreased intestinal reabsorption of phosphate [18]. This relationship has been demonstrated in animal studies where a single injection of recombinant FGF23 resulted in reduction of serum phosphate and 1,25 (OH) 2D levels independent of PTH levels [11]. During the experiment, PTH levels remained low, and the hypophosphatemia was reproduced by injection of FGF23 in parathyroidectomized rats [11].
FGF23 mode of inheritance
Both genetic and acquired mechanisms of FGF23-related hypophosphatemic disease have been described. Genetic mechanisms vary by mode of inheritance. Autosomal dominant hypophosphatemic rickets (ADHR) is caused by mutations in FGF23 gene [2]. The autosomal recessive variant is caused by mutations in dentrin matrix protein 1 (DMP1) [19]. The X-linked dominant form occurs due to mutations in phosphate-regulating gene (PHEX) [20].
An acquired FGF23 hypophosphatemic disease is associated with the administration of intravenous iron, specifically the saccharated ferric oxide and iron polymaltose. Evaluation of these patients showed elevated FGF23 levels with the exact mechanism not known [21]. TIO is another example of an acquired form of FGF23 hypophosphatemic disease [17] which is reviewed in greater detail below.
Tumor-induced osteomalacia
TIO is a rare paraneoplastic disease, first described in 1947 by Robert McCance who reported a patient with pain and weakness in the setting of low phosphate levels. His symptoms persisted despite being treated with vitamin D, and eventually improved only after a tumor found in the femur bone was resected [22]. Animal experiments have supported the presence of the humoral factor leading to hypophosphatemia [23]. The earliest evidence to support this in humans was done by Miyauchi et al. [24] where tumor removal in a patient with osteomalacia and injection into healthy mice lead to hypophosphatemia.
Tumors associated with TIO are usually mesenchymal in origin [17]. Within the reported cases of TIO, 40% occur in the bone and 55% occur in soft tissues. The thigh and femur are the most common sites of involvement with the pelvis reported in only 8% of cases, and only 2% of cases reported as involving more than one site [25]. These tumors can be histologically polymorphous, but in 1991 Weidner [26] proposed a classification system to divide them into four morphologic patterns including phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT), osteoblastoma-like variant, non-ossifying fibroma-like variant, and ossifying fibroma-like variant. PMTMCT comprises 70 – 80% of cases of TIO and typically begins in bone or soft tissues [5].
Non-mesenchymal tumors with TIO manifestations are now being recognized and reported in leukemia [7], B cell non-Hodgkin’s lymphoma [8], sarcoma [10], and other solid organ cancers including lung [27], prostate [28], and colon cancer [29]. There is only one case of TIO reported in metastatic breast cancer [13] with the two cases above resulting in a total of three. During malignancy, abnormal FGF signaling has been shown to induce cell proliferation and angiogenesis thereby promoting metastasis [16]. In breast cancer specifically, molecular alternations in FGFR1 and FGFR2 receptors are the most common reported [16]. Clinical trials support this data where phase I trials showed hyperphosphatemia as the most common adverse effect when novel tyrosine kinase inhibitors targeted FGF signaling [30].
Diagnostic evaluation of TIO should start with a comprehensive metabolic panel to check serum phosphorous and calcium levels which are typically low. Alkaline phosphatase may be elevated as in case 1 (738 U/L) and case 2 (635 U/L) due to osteoblast hyperactivity. Vitamin D levels should be checked and are typically low due to the inhibitory effect of FGF23. This was seen in our cases where vitamin D levels were 8 ng/mL and 15 ng/mL in case 1 and 2, respectively. PTH levels may be variable and increased at times as part of a normal feedback response to low vitamin D levels and subsequently hypocalcemia. In both cases, the elevation in PTH (488 pg/mL and 287 pg/mL) was likely multifactorial; initially as a feedback to hypocalcemia in the setting of denosumab. Secondary hyperparathyroidism has been demonstrated in patients receiving denosumab as a result of prolonged hypocalcemia caused by this drug [31], leading to renal phosphate wasting in some patients. This mechanism may have contributed to pathogenesis of hypophosphatemia in our patients. However in case 1, phosphorus remained low despite aggressive supplementation. Persistent hypophosphatemia however should also raise concern for an FGF23 secreting tumor. For case 2, denosumab was given 3 months prior to recognition of hypophosphatemia. Furthermore, FGF23 remained elevated, and phosphaturia continued despite PTH normalization. Therefore, denosumab likely did not play a major role in the FGF23 elevation or renal phosphate wasting. Along with serum FGF23, urine studies including urine creatinine and urine phosphorous must be checked to calculate the fractional excretion of phosphate and tubular reabsorption of phosphate. In the setting of TIO, one would expect a high fractional excretion of phosphate (> 10%) and low tubular reabsorption of phosphate (< 75%) due to inhibition of sodium phosphate transporters at the proximal tubules and low vitamin D. Dihydroxyvitamin D-1,25 was low in case 1 as expected due to suppressed activation by FGF23. However, in case 2, dihydroxyvitamin D-1,25 was elevated in the absence of calcitriol. Although in patients with chronic kidney disease and hyperphosphatemia FGF23 is elevated leading to suppression of vitamin D 1,25 production, we hypothesize that perhaps in some patients with hypophosphatemia, other mechanisms may be responsible for higher vitamin D 1,25 levels to counteract effects of low phosphorus levels.
Several imaging modalities can be used to identify the tumor, including magnetic resonance imaging (MRI) and PET scan. Somatostatin receptors (SSTR) based functioning imaging can also be performed since some of these tumors express SSTRs [32]. However, clinicians have to be mindful that inflammatory reactions can cause a false positive SSTR imaging [32]. In cases where tumor is identified, the treatment of choice is resection. Once FGF23 levels decline in circulation, serum phosphate levels return to normal, as early as five days post operatively [33]. In cases where the tumor is inoperable, medical management may be attempted with phosphate supplementation and calcitriol as recommended in our cases of metastatic disease. Octreotide is another potential treatment, given link with SSTR. Targeted antibodies against FGF23 have shown promise in animal models [34].
Conclusion
TIO can be a challenging diagnosis to make, especially in patients with malignancy other than mesenchymal origin, as symptoms of hypophosphatemia are nonspecific and could be easily attributed to the underlying cancer. In fact, the average time from recognition of osteomalacia to identifying the associated tumor is ~ 5 years [35]. We recommend more frequent testing of serum phosphorous since it is not part of the routine basic metabolic panel. Furthermore, in breast cancer specifically, patients are frequently managed with bone-targeted therapy such as bisphosphonates and denosumab which can further exacerbate hypophosphatemia. Antiresorptive therapy during malignancies should be carefully weighed with degree of hypophosphatemia and risk of skeletal-related events. Patients with TIO should be evaluated for resection, which can be curative when involving a solitary lesion. It is reasonable to check FGF23 levels in oncologic patients with persistent hypophosphatemia despite adequate supplementation of phosphorus and vitamin D and discontinuation of the drugs known to cause renal phosphate wasting. In patients with several lesions or metastatic cancer such as described above, systemic oncologic therapy and supplementation of phosphorous, calcium, and vitamin D can be attempted to improve the quality of life.
Funding
This research was supported by National Institute of Health grant award P30CA008748.
Conflict of interest
Ilya Glezerman owns Pfizer Stock. Remaining authors have nothing to disclose.
Figure 1 PET scan showing progression of disease for case 1. Metastasis to the liver, sternum, and sclerotic osseous lesions to the spine and right iliac.
Table 1. Case 1. Sequence of laboratory findings and treatment for hypophosphatemia.
–12 months to –1 month –10 days –4 days Nephrology
consult (day 0) +10 days
Treatment
Denosumab (mg) 120 mg/monthly × 10 doses
Potassium-phosphate/sodium-phosphate (mg) 250-45-298
t.i.d. 250-45-298
t.i.d.
Calcitriol (mcg) 0.25 b.i.d. 0.25 b.i.d.
Laboratory studies
Serum phosphate (mg/dL) < 0.9 1 1.1
Serum calcium* (mg/dL) Range 8.7 – 10.5 8.1 8.4 7.9 9.1
Alkaline phosphatase (U/L) Range 97 – 506 504 690 738 619
Serum PTH (pg/mL) 488
Serum FGF23 (RU/mL) 2,430
Serum 25-OH Vit D (ng/mL) 8
Urine sodium (mEq/L) 22
Urine calcium (mg/dL) < 1
Urine phosphate (mg/dL) 214
Urine creatinine (mg/dL) 229
FePhos** 56%
*Corrected calcium = total calcium (mg/dL) + 0.8 (4.0-serum albumin [g/dL]), where 4.0 represents the average albumin level. **FePhos = (urine phosphorus/serum phosphorus) × (serum creatinine/urine creatinine). PTH = parathyroid hormone; FGF23 = fibroblast growth factor 23; FePhos = fractional excretion of phosphorus.
Table 2. Case 2. Sequence of laboratory findings and treatment for hypophosphatemia,
–12 months to –3 months –10 days –4 days Nephrology
consult (day 0) +3 days +4 days
Treatment
Denosumab (mg) 120 mg/monthly
× 10 doses
Potassium-phosphate/Sodium-phosphate (mg) 250-45-298 once 250-45-298
TID 250-45-298
QID
IV Phosphate (mmol) 30 30 15
PO calcium citrate (g) 3.8
IV calcium gluconate (g) 4 2
Laboratory studies
Serum phosphate (mg/dL) 2.6 (month –3) 1.6 1.4 1.4 3.8 2.4
*Serum calcium (mg/dL) 9.2 – 10.1 range 9.0 8.7 8.0 9.4 9.3
Alkaline phosphatase (U/L) 138 – 253 range 516 581 712 677 664
Serum PTH (pg/mL) 287.3 44.3
Serum FGF23 (RU/mL) 548 424
Serum 25-OH Vit D (ng/mL) 15
Serum 1,25-Dihydroxyvitamin D (pg/mL) 82
Urine sodium (mEq/L) < 20
Urine calcium (mg/dL) 3.1
Urine phosphate (mg/dL) 175 416
Urine creatinine (mg/dL) 80 99
**FePhos 78% 72%
*Corrected calcium = total calcium (mg/dL) + 0.8 (4.0-serum albumin [g/dL]), where 4.0 represents the average albumin level. **FePhos = (urine phosphorus/serum phosphorus) × (serum creatinine/urine creatinine). PTH = parathyroid hormone; FGF23 = fibroblast growth factor 23; FePhos = fractional excretion of phosphorus.
Figure 2 PET Scan showing progression of disease for case 2. Metastasis to the liver, right acetabulum, thoracic vertebrae, and right ilium.
Figure 3 Bone-kidney axis and phosphaturic effects of FGF23. FGF23 is produced in bone by osteocytes in response to high serum phosphorous. In malignant bone, FGF23 is produced regardless of serum phosphorous. One of FGF23 targets is the kidney. FGF23 binds to FGR receptors and complexes with klotho on the basolateral surface of proximal tubular cells. This causes a decrease in expression of sodium-phosphorus co-transporters (Na-PO42-) whose role is renal phosphate reabsorption. Indirect effects include inhibition of 1-α-hydroxylase levels which are necessary to activate vitamin D and increased expression of 24-hydroxylase which degrades active vitamin D. The net effect is a decrease in serum phosphorous.
|
DENOSUMAB, NIVOLUMAB, PACLITAXEL, PALBOCICLIB, ZOLEDRONIC ACID
|
DrugsGivenReaction
|
CC BY
|
33191899
| 17,820,365
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood alkaline phosphatase increased'.
|
Hypophosphatemia and FGF23 tumor-induced osteomalacia in two cases of metastatic breast cancer.
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by factor-induced dysregulation of phosphate and vitamin D metabolism resulting in alterations in bone formation, leading to bone pain and fractures. While the true incidence is likely underestimated, less than 500 cases of TIO have been reported since initial description in 1947. TIO cases have classically been associated with mesenchymal tumors of bone and soft tissue, but have also rarely been linked to malignant tumors, with scant reports implicating non-mesenchymal tumors. TIO is mediated through inappropriate tumor overproduction of fibroblast growth factor 23 (FGF23). Increased FGF23 secretion leads to hypophosphatemia by (1) reduced phosphate reabsorption via activation of the proximal renal tubular epithelial cells to internalize sodium phosphate cotransporters and (2) reduced activation of vitamin D3 via inhibition of the renal enzyme 1-α hydroxylase. Low circulating levels of active vitamin D lead to reduced intestinal phosphate absorption and impaired mineralization of osteoid matrix. TIO in breast cancer poses a distinct diagnostic challenge due to the common adjunct oncologic management with bone protection therapy such as denosumab or bisphosphonates. These agents can be culprits of hypophosphatemia and hypocalcemia, rendering timely diagnosis of TIO difficult. Delay of diagnosis of TIO can result in worsening functional status, and early morbidity and mortality. To date, there has been one prior case report of TIO in breast cancer, and herein we describe two additional cases of TIO in this setting.
pmcIntroduction
Fibroblast growth factor-23 (FGF23) is a phosphaturic humoral factor produced by osteoblasts and osteocytes [1]. First identified two decades ago, mutations in the cleavage of FGF23 cause several inherited renal phosphate wasting diseases leading to rickets in children or osteomalacia in adults [2, 3]. In the paraneoplastic setting, FGF23 oversecretion leads to tumor-induced rickets/osteomalacia (TIO) also known as oncogenic osteomalacia [4]. TIO is typically reported with mesenchymal tumors [5, 6], and is starting to become recognized in patients with liquid [7] and solid organ malignancies [8, 9, 10] as well.
FGF23 is a key regulator of phosphate metabolism. The primary physiologic function is to lower serum phosphate levels which is mediated by FGF receptors (FGFR) and klotho complexes [3]. FGF23 downregulates the expression of cotransporters in the kidney that are essential for the reabsorption of phosphate. Additionally, FGF23 downregulates the expression of enzymes that activate vitamin D which increases intestinal phosphate absorption, thereby indirectly lowering serum phosphate levels [11].
Phosphate is primarily found in bone and is responsible for skeletal strength and rigidity. Low phosphate levels manifest as general muscle weakness, fatigue, and in extreme cases impaired cardiac and respiratory function [12]. These symptoms, in patients with cancer, may be attributed to their malignancy, and the potential diagnosis of TIO may be overlooked, especially with the rarer non-mesenchymal origin tumors. Below are examples of two case reports of patients with metastatic breast cancer with severe hypophosphatemia, phosphaturia and elevated serum FGF23, consistent with TIO. To the best of our knowledge, there is only one other case report of TIO associated with metastatic breast cancer [13]. These cases are particularly challenging given the use of antiresorptive therapy in patients with bone metastasis which can trigger FGF23 overexpression [13] and worsen underlying oncologic osteomalacia.
Case 1
A 47-year-old woman with metastatic breast cancer with liver and bone involvement was referred to the nephrology clinic for persistent hypophosphatemia. Seven years ago patient was diagnosed with left mammary duct carcinoma and underwent partial mastectomy followed by chemotherapy with paclitaxel and tamoxifen. She had a reoccurrence 3 years later and failed multiple lines of chemotherapy including eribulin and vinorelbine with last positron emission tomography (PET) scan showing metastasis to the liver, sternum, and sclerotic osseous lesions to the spine and right iliac (Figure 1).
The patient was initiated on monthly denosumab for 1 year (12 doses in total) prior to the current nephrology visit, with last dose 1 month ago, to address metastatic bone involvement. Phosphorous level on consultation was < 0.9 mg/dL (2.5 – 4.5 mg/dL) with no prior levels. Remainder of bloodwork is shown in Table 1 which highlights low calcium 7.4 mg/dL (8.5 – 10.5 mg/dL) and elevated alkaline phosphatase (ALP) of 738 U/L (≤ 130 U/L). The fractional excretion of phosphate (FePhos) in the urine was elevated at 56% (< 5 – 10%).
Etiology for hypophosphatemia was initially thought to be secondary hyperparathyroidism given elevated parathyroid hormone (PTH) of 488 pg/mL (12 – 88 pg/mL) due to hypocalcemia in the setting of recent denosumab administration. Phosphorous levels remained low despite oral calcium and phosphate repletion and oral calcitriol administration (Table 1). Given persistent hypophosphatemia, FGF23 was checked, and levels returned strikingly elevated at 2,430 RU/mL (≤ 180 RU/mL) suggesting an FGF23 secreting tumor as the most likely cause for severe hypophosphatemia. Unfortunately, the patient passed away within 1 month due to disease progression.
Case 2
A 55-year-old woman with triple negative invasive ductal breast cancer, who achieved remission 10 years ago presented with progressive weakness. She was found to have relapsed disease involving the liver, lung, and bone (vertebral, acetabulum, and ilium) 1 year ago (Figure 2), and subsequently received chemotherapy including palbociclib, nivolumab, and abraxane as well as 4 monthly doses of zoledronate, followed by 10 monthly treatments of denosumab. She last received bone-stimulating therapy and chemotherapy 3 months prior to admission. She had no other comorbidities, nor a history of additional medications or herbal supplements. She was a lifetime nonsmoker. She was admitted for obstructive jaundice due to progression of disease. During the course of her admission, she complained of severe lower extremity bone pain limiting ambulation. Prior to admission, the patient’s electrolytes were within normal limits.
Upon admission, she was cachectic (body mass index < 18), with hypophosphatemia of 1.6 mmol/L (2.5 – 4.5 mmol/L). Nephrology was called for further evaluation. Remainder of lab studies are shown in Table 2 and include a normal corrected calcium of 9.5 mmol/L (8.5 – 10.5 mmol/L), low 25-hydroxyvitamin D of 15 ng/dL (20 – 50 ng/dL), elevated PTH of 287.3 pg/mL (12 – 88 pg/mL), and elevated ALP of 635 U/L (≤ 130U/L). FePhos was 78% (< 5 – 10%), consistent with phosphate wasting. Of note, 1,25-dihydroxyvitamin D was elevated at 83 pg/mL (20 – 50 pg/mL) despite not being on calcitriol.
Given elevated urine phosphate, an oncologic osteomalacia was suspected and FGF23 was checked and was elevated at 548 (< 180) RU/mL. Due to aggressive supplementation, serum phosphate increased to a peak value of 3.8 mmol/L; PTH decreased to 44, but FGF23 and FePhos remained elevated at 424 and 72%, respectively. The patient continued to decline and passed away within 2 weeks.
Discussion
FGF23 is a glycoprotein part of the FGF family which is subdivided into 7 subfamilies with 22 members reported in humans [14]. FGF23 belongs to the FGF19 subfamily which has also been called the endocrine FGFs due to the inner protein structure allowing it to function as a circulating hormone [15]. FGF23 is derived from bones, and under physiologic conditions, its production is stimulated by extracellular phosphate. Once secreted from osteoblasts and osteocytes, FGF23 plays a pleiotropic role which links the bone with several organ systems including the kidney, heart, and cells part of the immune system [1]. FGF23 signaling contributes to regulation in cellular proliferation, survival, and differentiation making it an attractive pathway to hijack by cancer cells [16].
FGF23 renal pathophysiology
With respect to the kidney, the main function of FGF23 is to lower serum phosphate levels as shown in Figure 3. This is established through direct inhibition of phosphate reabsorption at the level of the proximal tubular cells, and indirectly by downregulation of enzymes necessary to activate vitamin D. Direct actions involve the binding of circulating FGF23 to FGF receptors (FGFRs) and coreceptor klotho on the basolateral surface of the proximal tubular cells. This results in decreased expression of two sodium-phosphate cotransporters called NaPi-2a and NaPi-2c. These transporters, located on the apical surface of the proximal tubular cell are responsible for renal phosphate reabsorption. Decreased expression of NaPi-2a and NaPi-2c is therefore a direct cause of phosphaturia [17].
FGF23 also indirectly lowers serum phosphate levels by inhibiting renal 1-α-hydroxylase which is necessary to activate vitamin D. Further, FGF23 also increases the expression of 24-hydroxylase which degrades the active form of vitamin D into inactive metabolites. These actions collectively reduce active levels of vitamin D leading to decreased intestinal reabsorption of phosphate [18]. This relationship has been demonstrated in animal studies where a single injection of recombinant FGF23 resulted in reduction of serum phosphate and 1,25 (OH) 2D levels independent of PTH levels [11]. During the experiment, PTH levels remained low, and the hypophosphatemia was reproduced by injection of FGF23 in parathyroidectomized rats [11].
FGF23 mode of inheritance
Both genetic and acquired mechanisms of FGF23-related hypophosphatemic disease have been described. Genetic mechanisms vary by mode of inheritance. Autosomal dominant hypophosphatemic rickets (ADHR) is caused by mutations in FGF23 gene [2]. The autosomal recessive variant is caused by mutations in dentrin matrix protein 1 (DMP1) [19]. The X-linked dominant form occurs due to mutations in phosphate-regulating gene (PHEX) [20].
An acquired FGF23 hypophosphatemic disease is associated with the administration of intravenous iron, specifically the saccharated ferric oxide and iron polymaltose. Evaluation of these patients showed elevated FGF23 levels with the exact mechanism not known [21]. TIO is another example of an acquired form of FGF23 hypophosphatemic disease [17] which is reviewed in greater detail below.
Tumor-induced osteomalacia
TIO is a rare paraneoplastic disease, first described in 1947 by Robert McCance who reported a patient with pain and weakness in the setting of low phosphate levels. His symptoms persisted despite being treated with vitamin D, and eventually improved only after a tumor found in the femur bone was resected [22]. Animal experiments have supported the presence of the humoral factor leading to hypophosphatemia [23]. The earliest evidence to support this in humans was done by Miyauchi et al. [24] where tumor removal in a patient with osteomalacia and injection into healthy mice lead to hypophosphatemia.
Tumors associated with TIO are usually mesenchymal in origin [17]. Within the reported cases of TIO, 40% occur in the bone and 55% occur in soft tissues. The thigh and femur are the most common sites of involvement with the pelvis reported in only 8% of cases, and only 2% of cases reported as involving more than one site [25]. These tumors can be histologically polymorphous, but in 1991 Weidner [26] proposed a classification system to divide them into four morphologic patterns including phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT), osteoblastoma-like variant, non-ossifying fibroma-like variant, and ossifying fibroma-like variant. PMTMCT comprises 70 – 80% of cases of TIO and typically begins in bone or soft tissues [5].
Non-mesenchymal tumors with TIO manifestations are now being recognized and reported in leukemia [7], B cell non-Hodgkin’s lymphoma [8], sarcoma [10], and other solid organ cancers including lung [27], prostate [28], and colon cancer [29]. There is only one case of TIO reported in metastatic breast cancer [13] with the two cases above resulting in a total of three. During malignancy, abnormal FGF signaling has been shown to induce cell proliferation and angiogenesis thereby promoting metastasis [16]. In breast cancer specifically, molecular alternations in FGFR1 and FGFR2 receptors are the most common reported [16]. Clinical trials support this data where phase I trials showed hyperphosphatemia as the most common adverse effect when novel tyrosine kinase inhibitors targeted FGF signaling [30].
Diagnostic evaluation of TIO should start with a comprehensive metabolic panel to check serum phosphorous and calcium levels which are typically low. Alkaline phosphatase may be elevated as in case 1 (738 U/L) and case 2 (635 U/L) due to osteoblast hyperactivity. Vitamin D levels should be checked and are typically low due to the inhibitory effect of FGF23. This was seen in our cases where vitamin D levels were 8 ng/mL and 15 ng/mL in case 1 and 2, respectively. PTH levels may be variable and increased at times as part of a normal feedback response to low vitamin D levels and subsequently hypocalcemia. In both cases, the elevation in PTH (488 pg/mL and 287 pg/mL) was likely multifactorial; initially as a feedback to hypocalcemia in the setting of denosumab. Secondary hyperparathyroidism has been demonstrated in patients receiving denosumab as a result of prolonged hypocalcemia caused by this drug [31], leading to renal phosphate wasting in some patients. This mechanism may have contributed to pathogenesis of hypophosphatemia in our patients. However in case 1, phosphorus remained low despite aggressive supplementation. Persistent hypophosphatemia however should also raise concern for an FGF23 secreting tumor. For case 2, denosumab was given 3 months prior to recognition of hypophosphatemia. Furthermore, FGF23 remained elevated, and phosphaturia continued despite PTH normalization. Therefore, denosumab likely did not play a major role in the FGF23 elevation or renal phosphate wasting. Along with serum FGF23, urine studies including urine creatinine and urine phosphorous must be checked to calculate the fractional excretion of phosphate and tubular reabsorption of phosphate. In the setting of TIO, one would expect a high fractional excretion of phosphate (> 10%) and low tubular reabsorption of phosphate (< 75%) due to inhibition of sodium phosphate transporters at the proximal tubules and low vitamin D. Dihydroxyvitamin D-1,25 was low in case 1 as expected due to suppressed activation by FGF23. However, in case 2, dihydroxyvitamin D-1,25 was elevated in the absence of calcitriol. Although in patients with chronic kidney disease and hyperphosphatemia FGF23 is elevated leading to suppression of vitamin D 1,25 production, we hypothesize that perhaps in some patients with hypophosphatemia, other mechanisms may be responsible for higher vitamin D 1,25 levels to counteract effects of low phosphorus levels.
Several imaging modalities can be used to identify the tumor, including magnetic resonance imaging (MRI) and PET scan. Somatostatin receptors (SSTR) based functioning imaging can also be performed since some of these tumors express SSTRs [32]. However, clinicians have to be mindful that inflammatory reactions can cause a false positive SSTR imaging [32]. In cases where tumor is identified, the treatment of choice is resection. Once FGF23 levels decline in circulation, serum phosphate levels return to normal, as early as five days post operatively [33]. In cases where the tumor is inoperable, medical management may be attempted with phosphate supplementation and calcitriol as recommended in our cases of metastatic disease. Octreotide is another potential treatment, given link with SSTR. Targeted antibodies against FGF23 have shown promise in animal models [34].
Conclusion
TIO can be a challenging diagnosis to make, especially in patients with malignancy other than mesenchymal origin, as symptoms of hypophosphatemia are nonspecific and could be easily attributed to the underlying cancer. In fact, the average time from recognition of osteomalacia to identifying the associated tumor is ~ 5 years [35]. We recommend more frequent testing of serum phosphorous since it is not part of the routine basic metabolic panel. Furthermore, in breast cancer specifically, patients are frequently managed with bone-targeted therapy such as bisphosphonates and denosumab which can further exacerbate hypophosphatemia. Antiresorptive therapy during malignancies should be carefully weighed with degree of hypophosphatemia and risk of skeletal-related events. Patients with TIO should be evaluated for resection, which can be curative when involving a solitary lesion. It is reasonable to check FGF23 levels in oncologic patients with persistent hypophosphatemia despite adequate supplementation of phosphorus and vitamin D and discontinuation of the drugs known to cause renal phosphate wasting. In patients with several lesions or metastatic cancer such as described above, systemic oncologic therapy and supplementation of phosphorous, calcium, and vitamin D can be attempted to improve the quality of life.
Funding
This research was supported by National Institute of Health grant award P30CA008748.
Conflict of interest
Ilya Glezerman owns Pfizer Stock. Remaining authors have nothing to disclose.
Figure 1 PET scan showing progression of disease for case 1. Metastasis to the liver, sternum, and sclerotic osseous lesions to the spine and right iliac.
Table 1. Case 1. Sequence of laboratory findings and treatment for hypophosphatemia.
–12 months to –1 month –10 days –4 days Nephrology
consult (day 0) +10 days
Treatment
Denosumab (mg) 120 mg/monthly × 10 doses
Potassium-phosphate/sodium-phosphate (mg) 250-45-298
t.i.d. 250-45-298
t.i.d.
Calcitriol (mcg) 0.25 b.i.d. 0.25 b.i.d.
Laboratory studies
Serum phosphate (mg/dL) < 0.9 1 1.1
Serum calcium* (mg/dL) Range 8.7 – 10.5 8.1 8.4 7.9 9.1
Alkaline phosphatase (U/L) Range 97 – 506 504 690 738 619
Serum PTH (pg/mL) 488
Serum FGF23 (RU/mL) 2,430
Serum 25-OH Vit D (ng/mL) 8
Urine sodium (mEq/L) 22
Urine calcium (mg/dL) < 1
Urine phosphate (mg/dL) 214
Urine creatinine (mg/dL) 229
FePhos** 56%
*Corrected calcium = total calcium (mg/dL) + 0.8 (4.0-serum albumin [g/dL]), where 4.0 represents the average albumin level. **FePhos = (urine phosphorus/serum phosphorus) × (serum creatinine/urine creatinine). PTH = parathyroid hormone; FGF23 = fibroblast growth factor 23; FePhos = fractional excretion of phosphorus.
Table 2. Case 2. Sequence of laboratory findings and treatment for hypophosphatemia,
–12 months to –3 months –10 days –4 days Nephrology
consult (day 0) +3 days +4 days
Treatment
Denosumab (mg) 120 mg/monthly
× 10 doses
Potassium-phosphate/Sodium-phosphate (mg) 250-45-298 once 250-45-298
TID 250-45-298
QID
IV Phosphate (mmol) 30 30 15
PO calcium citrate (g) 3.8
IV calcium gluconate (g) 4 2
Laboratory studies
Serum phosphate (mg/dL) 2.6 (month –3) 1.6 1.4 1.4 3.8 2.4
*Serum calcium (mg/dL) 9.2 – 10.1 range 9.0 8.7 8.0 9.4 9.3
Alkaline phosphatase (U/L) 138 – 253 range 516 581 712 677 664
Serum PTH (pg/mL) 287.3 44.3
Serum FGF23 (RU/mL) 548 424
Serum 25-OH Vit D (ng/mL) 15
Serum 1,25-Dihydroxyvitamin D (pg/mL) 82
Urine sodium (mEq/L) < 20
Urine calcium (mg/dL) 3.1
Urine phosphate (mg/dL) 175 416
Urine creatinine (mg/dL) 80 99
**FePhos 78% 72%
*Corrected calcium = total calcium (mg/dL) + 0.8 (4.0-serum albumin [g/dL]), where 4.0 represents the average albumin level. **FePhos = (urine phosphorus/serum phosphorus) × (serum creatinine/urine creatinine). PTH = parathyroid hormone; FGF23 = fibroblast growth factor 23; FePhos = fractional excretion of phosphorus.
Figure 2 PET Scan showing progression of disease for case 2. Metastasis to the liver, right acetabulum, thoracic vertebrae, and right ilium.
Figure 3 Bone-kidney axis and phosphaturic effects of FGF23. FGF23 is produced in bone by osteocytes in response to high serum phosphorous. In malignant bone, FGF23 is produced regardless of serum phosphorous. One of FGF23 targets is the kidney. FGF23 binds to FGR receptors and complexes with klotho on the basolateral surface of proximal tubular cells. This causes a decrease in expression of sodium-phosphorus co-transporters (Na-PO42-) whose role is renal phosphate reabsorption. Indirect effects include inhibition of 1-α-hydroxylase levels which are necessary to activate vitamin D and increased expression of 24-hydroxylase which degrades active vitamin D. The net effect is a decrease in serum phosphorous.
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DENOSUMAB, NIVOLUMAB, PACLITAXEL, PALBOCICLIB, ZOLEDRONIC ACID
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DrugsGivenReaction
|
CC BY
|
33191899
| 17,820,365
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood parathyroid hormone decreased'.
|
Hypophosphatemia and FGF23 tumor-induced osteomalacia in two cases of metastatic breast cancer.
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by factor-induced dysregulation of phosphate and vitamin D metabolism resulting in alterations in bone formation, leading to bone pain and fractures. While the true incidence is likely underestimated, less than 500 cases of TIO have been reported since initial description in 1947. TIO cases have classically been associated with mesenchymal tumors of bone and soft tissue, but have also rarely been linked to malignant tumors, with scant reports implicating non-mesenchymal tumors. TIO is mediated through inappropriate tumor overproduction of fibroblast growth factor 23 (FGF23). Increased FGF23 secretion leads to hypophosphatemia by (1) reduced phosphate reabsorption via activation of the proximal renal tubular epithelial cells to internalize sodium phosphate cotransporters and (2) reduced activation of vitamin D3 via inhibition of the renal enzyme 1-α hydroxylase. Low circulating levels of active vitamin D lead to reduced intestinal phosphate absorption and impaired mineralization of osteoid matrix. TIO in breast cancer poses a distinct diagnostic challenge due to the common adjunct oncologic management with bone protection therapy such as denosumab or bisphosphonates. These agents can be culprits of hypophosphatemia and hypocalcemia, rendering timely diagnosis of TIO difficult. Delay of diagnosis of TIO can result in worsening functional status, and early morbidity and mortality. To date, there has been one prior case report of TIO in breast cancer, and herein we describe two additional cases of TIO in this setting.
pmcIntroduction
Fibroblast growth factor-23 (FGF23) is a phosphaturic humoral factor produced by osteoblasts and osteocytes [1]. First identified two decades ago, mutations in the cleavage of FGF23 cause several inherited renal phosphate wasting diseases leading to rickets in children or osteomalacia in adults [2, 3]. In the paraneoplastic setting, FGF23 oversecretion leads to tumor-induced rickets/osteomalacia (TIO) also known as oncogenic osteomalacia [4]. TIO is typically reported with mesenchymal tumors [5, 6], and is starting to become recognized in patients with liquid [7] and solid organ malignancies [8, 9, 10] as well.
FGF23 is a key regulator of phosphate metabolism. The primary physiologic function is to lower serum phosphate levels which is mediated by FGF receptors (FGFR) and klotho complexes [3]. FGF23 downregulates the expression of cotransporters in the kidney that are essential for the reabsorption of phosphate. Additionally, FGF23 downregulates the expression of enzymes that activate vitamin D which increases intestinal phosphate absorption, thereby indirectly lowering serum phosphate levels [11].
Phosphate is primarily found in bone and is responsible for skeletal strength and rigidity. Low phosphate levels manifest as general muscle weakness, fatigue, and in extreme cases impaired cardiac and respiratory function [12]. These symptoms, in patients with cancer, may be attributed to their malignancy, and the potential diagnosis of TIO may be overlooked, especially with the rarer non-mesenchymal origin tumors. Below are examples of two case reports of patients with metastatic breast cancer with severe hypophosphatemia, phosphaturia and elevated serum FGF23, consistent with TIO. To the best of our knowledge, there is only one other case report of TIO associated with metastatic breast cancer [13]. These cases are particularly challenging given the use of antiresorptive therapy in patients with bone metastasis which can trigger FGF23 overexpression [13] and worsen underlying oncologic osteomalacia.
Case 1
A 47-year-old woman with metastatic breast cancer with liver and bone involvement was referred to the nephrology clinic for persistent hypophosphatemia. Seven years ago patient was diagnosed with left mammary duct carcinoma and underwent partial mastectomy followed by chemotherapy with paclitaxel and tamoxifen. She had a reoccurrence 3 years later and failed multiple lines of chemotherapy including eribulin and vinorelbine with last positron emission tomography (PET) scan showing metastasis to the liver, sternum, and sclerotic osseous lesions to the spine and right iliac (Figure 1).
The patient was initiated on monthly denosumab for 1 year (12 doses in total) prior to the current nephrology visit, with last dose 1 month ago, to address metastatic bone involvement. Phosphorous level on consultation was < 0.9 mg/dL (2.5 – 4.5 mg/dL) with no prior levels. Remainder of bloodwork is shown in Table 1 which highlights low calcium 7.4 mg/dL (8.5 – 10.5 mg/dL) and elevated alkaline phosphatase (ALP) of 738 U/L (≤ 130 U/L). The fractional excretion of phosphate (FePhos) in the urine was elevated at 56% (< 5 – 10%).
Etiology for hypophosphatemia was initially thought to be secondary hyperparathyroidism given elevated parathyroid hormone (PTH) of 488 pg/mL (12 – 88 pg/mL) due to hypocalcemia in the setting of recent denosumab administration. Phosphorous levels remained low despite oral calcium and phosphate repletion and oral calcitriol administration (Table 1). Given persistent hypophosphatemia, FGF23 was checked, and levels returned strikingly elevated at 2,430 RU/mL (≤ 180 RU/mL) suggesting an FGF23 secreting tumor as the most likely cause for severe hypophosphatemia. Unfortunately, the patient passed away within 1 month due to disease progression.
Case 2
A 55-year-old woman with triple negative invasive ductal breast cancer, who achieved remission 10 years ago presented with progressive weakness. She was found to have relapsed disease involving the liver, lung, and bone (vertebral, acetabulum, and ilium) 1 year ago (Figure 2), and subsequently received chemotherapy including palbociclib, nivolumab, and abraxane as well as 4 monthly doses of zoledronate, followed by 10 monthly treatments of denosumab. She last received bone-stimulating therapy and chemotherapy 3 months prior to admission. She had no other comorbidities, nor a history of additional medications or herbal supplements. She was a lifetime nonsmoker. She was admitted for obstructive jaundice due to progression of disease. During the course of her admission, she complained of severe lower extremity bone pain limiting ambulation. Prior to admission, the patient’s electrolytes were within normal limits.
Upon admission, she was cachectic (body mass index < 18), with hypophosphatemia of 1.6 mmol/L (2.5 – 4.5 mmol/L). Nephrology was called for further evaluation. Remainder of lab studies are shown in Table 2 and include a normal corrected calcium of 9.5 mmol/L (8.5 – 10.5 mmol/L), low 25-hydroxyvitamin D of 15 ng/dL (20 – 50 ng/dL), elevated PTH of 287.3 pg/mL (12 – 88 pg/mL), and elevated ALP of 635 U/L (≤ 130U/L). FePhos was 78% (< 5 – 10%), consistent with phosphate wasting. Of note, 1,25-dihydroxyvitamin D was elevated at 83 pg/mL (20 – 50 pg/mL) despite not being on calcitriol.
Given elevated urine phosphate, an oncologic osteomalacia was suspected and FGF23 was checked and was elevated at 548 (< 180) RU/mL. Due to aggressive supplementation, serum phosphate increased to a peak value of 3.8 mmol/L; PTH decreased to 44, but FGF23 and FePhos remained elevated at 424 and 72%, respectively. The patient continued to decline and passed away within 2 weeks.
Discussion
FGF23 is a glycoprotein part of the FGF family which is subdivided into 7 subfamilies with 22 members reported in humans [14]. FGF23 belongs to the FGF19 subfamily which has also been called the endocrine FGFs due to the inner protein structure allowing it to function as a circulating hormone [15]. FGF23 is derived from bones, and under physiologic conditions, its production is stimulated by extracellular phosphate. Once secreted from osteoblasts and osteocytes, FGF23 plays a pleiotropic role which links the bone with several organ systems including the kidney, heart, and cells part of the immune system [1]. FGF23 signaling contributes to regulation in cellular proliferation, survival, and differentiation making it an attractive pathway to hijack by cancer cells [16].
FGF23 renal pathophysiology
With respect to the kidney, the main function of FGF23 is to lower serum phosphate levels as shown in Figure 3. This is established through direct inhibition of phosphate reabsorption at the level of the proximal tubular cells, and indirectly by downregulation of enzymes necessary to activate vitamin D. Direct actions involve the binding of circulating FGF23 to FGF receptors (FGFRs) and coreceptor klotho on the basolateral surface of the proximal tubular cells. This results in decreased expression of two sodium-phosphate cotransporters called NaPi-2a and NaPi-2c. These transporters, located on the apical surface of the proximal tubular cell are responsible for renal phosphate reabsorption. Decreased expression of NaPi-2a and NaPi-2c is therefore a direct cause of phosphaturia [17].
FGF23 also indirectly lowers serum phosphate levels by inhibiting renal 1-α-hydroxylase which is necessary to activate vitamin D. Further, FGF23 also increases the expression of 24-hydroxylase which degrades the active form of vitamin D into inactive metabolites. These actions collectively reduce active levels of vitamin D leading to decreased intestinal reabsorption of phosphate [18]. This relationship has been demonstrated in animal studies where a single injection of recombinant FGF23 resulted in reduction of serum phosphate and 1,25 (OH) 2D levels independent of PTH levels [11]. During the experiment, PTH levels remained low, and the hypophosphatemia was reproduced by injection of FGF23 in parathyroidectomized rats [11].
FGF23 mode of inheritance
Both genetic and acquired mechanisms of FGF23-related hypophosphatemic disease have been described. Genetic mechanisms vary by mode of inheritance. Autosomal dominant hypophosphatemic rickets (ADHR) is caused by mutations in FGF23 gene [2]. The autosomal recessive variant is caused by mutations in dentrin matrix protein 1 (DMP1) [19]. The X-linked dominant form occurs due to mutations in phosphate-regulating gene (PHEX) [20].
An acquired FGF23 hypophosphatemic disease is associated with the administration of intravenous iron, specifically the saccharated ferric oxide and iron polymaltose. Evaluation of these patients showed elevated FGF23 levels with the exact mechanism not known [21]. TIO is another example of an acquired form of FGF23 hypophosphatemic disease [17] which is reviewed in greater detail below.
Tumor-induced osteomalacia
TIO is a rare paraneoplastic disease, first described in 1947 by Robert McCance who reported a patient with pain and weakness in the setting of low phosphate levels. His symptoms persisted despite being treated with vitamin D, and eventually improved only after a tumor found in the femur bone was resected [22]. Animal experiments have supported the presence of the humoral factor leading to hypophosphatemia [23]. The earliest evidence to support this in humans was done by Miyauchi et al. [24] where tumor removal in a patient with osteomalacia and injection into healthy mice lead to hypophosphatemia.
Tumors associated with TIO are usually mesenchymal in origin [17]. Within the reported cases of TIO, 40% occur in the bone and 55% occur in soft tissues. The thigh and femur are the most common sites of involvement with the pelvis reported in only 8% of cases, and only 2% of cases reported as involving more than one site [25]. These tumors can be histologically polymorphous, but in 1991 Weidner [26] proposed a classification system to divide them into four morphologic patterns including phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT), osteoblastoma-like variant, non-ossifying fibroma-like variant, and ossifying fibroma-like variant. PMTMCT comprises 70 – 80% of cases of TIO and typically begins in bone or soft tissues [5].
Non-mesenchymal tumors with TIO manifestations are now being recognized and reported in leukemia [7], B cell non-Hodgkin’s lymphoma [8], sarcoma [10], and other solid organ cancers including lung [27], prostate [28], and colon cancer [29]. There is only one case of TIO reported in metastatic breast cancer [13] with the two cases above resulting in a total of three. During malignancy, abnormal FGF signaling has been shown to induce cell proliferation and angiogenesis thereby promoting metastasis [16]. In breast cancer specifically, molecular alternations in FGFR1 and FGFR2 receptors are the most common reported [16]. Clinical trials support this data where phase I trials showed hyperphosphatemia as the most common adverse effect when novel tyrosine kinase inhibitors targeted FGF signaling [30].
Diagnostic evaluation of TIO should start with a comprehensive metabolic panel to check serum phosphorous and calcium levels which are typically low. Alkaline phosphatase may be elevated as in case 1 (738 U/L) and case 2 (635 U/L) due to osteoblast hyperactivity. Vitamin D levels should be checked and are typically low due to the inhibitory effect of FGF23. This was seen in our cases where vitamin D levels were 8 ng/mL and 15 ng/mL in case 1 and 2, respectively. PTH levels may be variable and increased at times as part of a normal feedback response to low vitamin D levels and subsequently hypocalcemia. In both cases, the elevation in PTH (488 pg/mL and 287 pg/mL) was likely multifactorial; initially as a feedback to hypocalcemia in the setting of denosumab. Secondary hyperparathyroidism has been demonstrated in patients receiving denosumab as a result of prolonged hypocalcemia caused by this drug [31], leading to renal phosphate wasting in some patients. This mechanism may have contributed to pathogenesis of hypophosphatemia in our patients. However in case 1, phosphorus remained low despite aggressive supplementation. Persistent hypophosphatemia however should also raise concern for an FGF23 secreting tumor. For case 2, denosumab was given 3 months prior to recognition of hypophosphatemia. Furthermore, FGF23 remained elevated, and phosphaturia continued despite PTH normalization. Therefore, denosumab likely did not play a major role in the FGF23 elevation or renal phosphate wasting. Along with serum FGF23, urine studies including urine creatinine and urine phosphorous must be checked to calculate the fractional excretion of phosphate and tubular reabsorption of phosphate. In the setting of TIO, one would expect a high fractional excretion of phosphate (> 10%) and low tubular reabsorption of phosphate (< 75%) due to inhibition of sodium phosphate transporters at the proximal tubules and low vitamin D. Dihydroxyvitamin D-1,25 was low in case 1 as expected due to suppressed activation by FGF23. However, in case 2, dihydroxyvitamin D-1,25 was elevated in the absence of calcitriol. Although in patients with chronic kidney disease and hyperphosphatemia FGF23 is elevated leading to suppression of vitamin D 1,25 production, we hypothesize that perhaps in some patients with hypophosphatemia, other mechanisms may be responsible for higher vitamin D 1,25 levels to counteract effects of low phosphorus levels.
Several imaging modalities can be used to identify the tumor, including magnetic resonance imaging (MRI) and PET scan. Somatostatin receptors (SSTR) based functioning imaging can also be performed since some of these tumors express SSTRs [32]. However, clinicians have to be mindful that inflammatory reactions can cause a false positive SSTR imaging [32]. In cases where tumor is identified, the treatment of choice is resection. Once FGF23 levels decline in circulation, serum phosphate levels return to normal, as early as five days post operatively [33]. In cases where the tumor is inoperable, medical management may be attempted with phosphate supplementation and calcitriol as recommended in our cases of metastatic disease. Octreotide is another potential treatment, given link with SSTR. Targeted antibodies against FGF23 have shown promise in animal models [34].
Conclusion
TIO can be a challenging diagnosis to make, especially in patients with malignancy other than mesenchymal origin, as symptoms of hypophosphatemia are nonspecific and could be easily attributed to the underlying cancer. In fact, the average time from recognition of osteomalacia to identifying the associated tumor is ~ 5 years [35]. We recommend more frequent testing of serum phosphorous since it is not part of the routine basic metabolic panel. Furthermore, in breast cancer specifically, patients are frequently managed with bone-targeted therapy such as bisphosphonates and denosumab which can further exacerbate hypophosphatemia. Antiresorptive therapy during malignancies should be carefully weighed with degree of hypophosphatemia and risk of skeletal-related events. Patients with TIO should be evaluated for resection, which can be curative when involving a solitary lesion. It is reasonable to check FGF23 levels in oncologic patients with persistent hypophosphatemia despite adequate supplementation of phosphorus and vitamin D and discontinuation of the drugs known to cause renal phosphate wasting. In patients with several lesions or metastatic cancer such as described above, systemic oncologic therapy and supplementation of phosphorous, calcium, and vitamin D can be attempted to improve the quality of life.
Funding
This research was supported by National Institute of Health grant award P30CA008748.
Conflict of interest
Ilya Glezerman owns Pfizer Stock. Remaining authors have nothing to disclose.
Figure 1 PET scan showing progression of disease for case 1. Metastasis to the liver, sternum, and sclerotic osseous lesions to the spine and right iliac.
Table 1. Case 1. Sequence of laboratory findings and treatment for hypophosphatemia.
–12 months to –1 month –10 days –4 days Nephrology
consult (day 0) +10 days
Treatment
Denosumab (mg) 120 mg/monthly × 10 doses
Potassium-phosphate/sodium-phosphate (mg) 250-45-298
t.i.d. 250-45-298
t.i.d.
Calcitriol (mcg) 0.25 b.i.d. 0.25 b.i.d.
Laboratory studies
Serum phosphate (mg/dL) < 0.9 1 1.1
Serum calcium* (mg/dL) Range 8.7 – 10.5 8.1 8.4 7.9 9.1
Alkaline phosphatase (U/L) Range 97 – 506 504 690 738 619
Serum PTH (pg/mL) 488
Serum FGF23 (RU/mL) 2,430
Serum 25-OH Vit D (ng/mL) 8
Urine sodium (mEq/L) 22
Urine calcium (mg/dL) < 1
Urine phosphate (mg/dL) 214
Urine creatinine (mg/dL) 229
FePhos** 56%
*Corrected calcium = total calcium (mg/dL) + 0.8 (4.0-serum albumin [g/dL]), where 4.0 represents the average albumin level. **FePhos = (urine phosphorus/serum phosphorus) × (serum creatinine/urine creatinine). PTH = parathyroid hormone; FGF23 = fibroblast growth factor 23; FePhos = fractional excretion of phosphorus.
Table 2. Case 2. Sequence of laboratory findings and treatment for hypophosphatemia,
–12 months to –3 months –10 days –4 days Nephrology
consult (day 0) +3 days +4 days
Treatment
Denosumab (mg) 120 mg/monthly
× 10 doses
Potassium-phosphate/Sodium-phosphate (mg) 250-45-298 once 250-45-298
TID 250-45-298
QID
IV Phosphate (mmol) 30 30 15
PO calcium citrate (g) 3.8
IV calcium gluconate (g) 4 2
Laboratory studies
Serum phosphate (mg/dL) 2.6 (month –3) 1.6 1.4 1.4 3.8 2.4
*Serum calcium (mg/dL) 9.2 – 10.1 range 9.0 8.7 8.0 9.4 9.3
Alkaline phosphatase (U/L) 138 – 253 range 516 581 712 677 664
Serum PTH (pg/mL) 287.3 44.3
Serum FGF23 (RU/mL) 548 424
Serum 25-OH Vit D (ng/mL) 15
Serum 1,25-Dihydroxyvitamin D (pg/mL) 82
Urine sodium (mEq/L) < 20
Urine calcium (mg/dL) 3.1
Urine phosphate (mg/dL) 175 416
Urine creatinine (mg/dL) 80 99
**FePhos 78% 72%
*Corrected calcium = total calcium (mg/dL) + 0.8 (4.0-serum albumin [g/dL]), where 4.0 represents the average albumin level. **FePhos = (urine phosphorus/serum phosphorus) × (serum creatinine/urine creatinine). PTH = parathyroid hormone; FGF23 = fibroblast growth factor 23; FePhos = fractional excretion of phosphorus.
Figure 2 PET Scan showing progression of disease for case 2. Metastasis to the liver, right acetabulum, thoracic vertebrae, and right ilium.
Figure 3 Bone-kidney axis and phosphaturic effects of FGF23. FGF23 is produced in bone by osteocytes in response to high serum phosphorous. In malignant bone, FGF23 is produced regardless of serum phosphorous. One of FGF23 targets is the kidney. FGF23 binds to FGR receptors and complexes with klotho on the basolateral surface of proximal tubular cells. This causes a decrease in expression of sodium-phosphorus co-transporters (Na-PO42-) whose role is renal phosphate reabsorption. Indirect effects include inhibition of 1-α-hydroxylase levels which are necessary to activate vitamin D and increased expression of 24-hydroxylase which degrades active vitamin D. The net effect is a decrease in serum phosphorous.
|
CALCIUM CITRATE, CALCIUM GLUCONATE, POTASSIUM PHOSPHATE\SODIUM PHOSPHATE, SODIUM PHOSPHATE
|
DrugsGivenReaction
|
CC BY
|
33191899
| 19,139,574
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood parathyroid hormone increased'.
|
Hypophosphatemia and FGF23 tumor-induced osteomalacia in two cases of metastatic breast cancer.
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by factor-induced dysregulation of phosphate and vitamin D metabolism resulting in alterations in bone formation, leading to bone pain and fractures. While the true incidence is likely underestimated, less than 500 cases of TIO have been reported since initial description in 1947. TIO cases have classically been associated with mesenchymal tumors of bone and soft tissue, but have also rarely been linked to malignant tumors, with scant reports implicating non-mesenchymal tumors. TIO is mediated through inappropriate tumor overproduction of fibroblast growth factor 23 (FGF23). Increased FGF23 secretion leads to hypophosphatemia by (1) reduced phosphate reabsorption via activation of the proximal renal tubular epithelial cells to internalize sodium phosphate cotransporters and (2) reduced activation of vitamin D3 via inhibition of the renal enzyme 1-α hydroxylase. Low circulating levels of active vitamin D lead to reduced intestinal phosphate absorption and impaired mineralization of osteoid matrix. TIO in breast cancer poses a distinct diagnostic challenge due to the common adjunct oncologic management with bone protection therapy such as denosumab or bisphosphonates. These agents can be culprits of hypophosphatemia and hypocalcemia, rendering timely diagnosis of TIO difficult. Delay of diagnosis of TIO can result in worsening functional status, and early morbidity and mortality. To date, there has been one prior case report of TIO in breast cancer, and herein we describe two additional cases of TIO in this setting.
pmcIntroduction
Fibroblast growth factor-23 (FGF23) is a phosphaturic humoral factor produced by osteoblasts and osteocytes [1]. First identified two decades ago, mutations in the cleavage of FGF23 cause several inherited renal phosphate wasting diseases leading to rickets in children or osteomalacia in adults [2, 3]. In the paraneoplastic setting, FGF23 oversecretion leads to tumor-induced rickets/osteomalacia (TIO) also known as oncogenic osteomalacia [4]. TIO is typically reported with mesenchymal tumors [5, 6], and is starting to become recognized in patients with liquid [7] and solid organ malignancies [8, 9, 10] as well.
FGF23 is a key regulator of phosphate metabolism. The primary physiologic function is to lower serum phosphate levels which is mediated by FGF receptors (FGFR) and klotho complexes [3]. FGF23 downregulates the expression of cotransporters in the kidney that are essential for the reabsorption of phosphate. Additionally, FGF23 downregulates the expression of enzymes that activate vitamin D which increases intestinal phosphate absorption, thereby indirectly lowering serum phosphate levels [11].
Phosphate is primarily found in bone and is responsible for skeletal strength and rigidity. Low phosphate levels manifest as general muscle weakness, fatigue, and in extreme cases impaired cardiac and respiratory function [12]. These symptoms, in patients with cancer, may be attributed to their malignancy, and the potential diagnosis of TIO may be overlooked, especially with the rarer non-mesenchymal origin tumors. Below are examples of two case reports of patients with metastatic breast cancer with severe hypophosphatemia, phosphaturia and elevated serum FGF23, consistent with TIO. To the best of our knowledge, there is only one other case report of TIO associated with metastatic breast cancer [13]. These cases are particularly challenging given the use of antiresorptive therapy in patients with bone metastasis which can trigger FGF23 overexpression [13] and worsen underlying oncologic osteomalacia.
Case 1
A 47-year-old woman with metastatic breast cancer with liver and bone involvement was referred to the nephrology clinic for persistent hypophosphatemia. Seven years ago patient was diagnosed with left mammary duct carcinoma and underwent partial mastectomy followed by chemotherapy with paclitaxel and tamoxifen. She had a reoccurrence 3 years later and failed multiple lines of chemotherapy including eribulin and vinorelbine with last positron emission tomography (PET) scan showing metastasis to the liver, sternum, and sclerotic osseous lesions to the spine and right iliac (Figure 1).
The patient was initiated on monthly denosumab for 1 year (12 doses in total) prior to the current nephrology visit, with last dose 1 month ago, to address metastatic bone involvement. Phosphorous level on consultation was < 0.9 mg/dL (2.5 – 4.5 mg/dL) with no prior levels. Remainder of bloodwork is shown in Table 1 which highlights low calcium 7.4 mg/dL (8.5 – 10.5 mg/dL) and elevated alkaline phosphatase (ALP) of 738 U/L (≤ 130 U/L). The fractional excretion of phosphate (FePhos) in the urine was elevated at 56% (< 5 – 10%).
Etiology for hypophosphatemia was initially thought to be secondary hyperparathyroidism given elevated parathyroid hormone (PTH) of 488 pg/mL (12 – 88 pg/mL) due to hypocalcemia in the setting of recent denosumab administration. Phosphorous levels remained low despite oral calcium and phosphate repletion and oral calcitriol administration (Table 1). Given persistent hypophosphatemia, FGF23 was checked, and levels returned strikingly elevated at 2,430 RU/mL (≤ 180 RU/mL) suggesting an FGF23 secreting tumor as the most likely cause for severe hypophosphatemia. Unfortunately, the patient passed away within 1 month due to disease progression.
Case 2
A 55-year-old woman with triple negative invasive ductal breast cancer, who achieved remission 10 years ago presented with progressive weakness. She was found to have relapsed disease involving the liver, lung, and bone (vertebral, acetabulum, and ilium) 1 year ago (Figure 2), and subsequently received chemotherapy including palbociclib, nivolumab, and abraxane as well as 4 monthly doses of zoledronate, followed by 10 monthly treatments of denosumab. She last received bone-stimulating therapy and chemotherapy 3 months prior to admission. She had no other comorbidities, nor a history of additional medications or herbal supplements. She was a lifetime nonsmoker. She was admitted for obstructive jaundice due to progression of disease. During the course of her admission, she complained of severe lower extremity bone pain limiting ambulation. Prior to admission, the patient’s electrolytes were within normal limits.
Upon admission, she was cachectic (body mass index < 18), with hypophosphatemia of 1.6 mmol/L (2.5 – 4.5 mmol/L). Nephrology was called for further evaluation. Remainder of lab studies are shown in Table 2 and include a normal corrected calcium of 9.5 mmol/L (8.5 – 10.5 mmol/L), low 25-hydroxyvitamin D of 15 ng/dL (20 – 50 ng/dL), elevated PTH of 287.3 pg/mL (12 – 88 pg/mL), and elevated ALP of 635 U/L (≤ 130U/L). FePhos was 78% (< 5 – 10%), consistent with phosphate wasting. Of note, 1,25-dihydroxyvitamin D was elevated at 83 pg/mL (20 – 50 pg/mL) despite not being on calcitriol.
Given elevated urine phosphate, an oncologic osteomalacia was suspected and FGF23 was checked and was elevated at 548 (< 180) RU/mL. Due to aggressive supplementation, serum phosphate increased to a peak value of 3.8 mmol/L; PTH decreased to 44, but FGF23 and FePhos remained elevated at 424 and 72%, respectively. The patient continued to decline and passed away within 2 weeks.
Discussion
FGF23 is a glycoprotein part of the FGF family which is subdivided into 7 subfamilies with 22 members reported in humans [14]. FGF23 belongs to the FGF19 subfamily which has also been called the endocrine FGFs due to the inner protein structure allowing it to function as a circulating hormone [15]. FGF23 is derived from bones, and under physiologic conditions, its production is stimulated by extracellular phosphate. Once secreted from osteoblasts and osteocytes, FGF23 plays a pleiotropic role which links the bone with several organ systems including the kidney, heart, and cells part of the immune system [1]. FGF23 signaling contributes to regulation in cellular proliferation, survival, and differentiation making it an attractive pathway to hijack by cancer cells [16].
FGF23 renal pathophysiology
With respect to the kidney, the main function of FGF23 is to lower serum phosphate levels as shown in Figure 3. This is established through direct inhibition of phosphate reabsorption at the level of the proximal tubular cells, and indirectly by downregulation of enzymes necessary to activate vitamin D. Direct actions involve the binding of circulating FGF23 to FGF receptors (FGFRs) and coreceptor klotho on the basolateral surface of the proximal tubular cells. This results in decreased expression of two sodium-phosphate cotransporters called NaPi-2a and NaPi-2c. These transporters, located on the apical surface of the proximal tubular cell are responsible for renal phosphate reabsorption. Decreased expression of NaPi-2a and NaPi-2c is therefore a direct cause of phosphaturia [17].
FGF23 also indirectly lowers serum phosphate levels by inhibiting renal 1-α-hydroxylase which is necessary to activate vitamin D. Further, FGF23 also increases the expression of 24-hydroxylase which degrades the active form of vitamin D into inactive metabolites. These actions collectively reduce active levels of vitamin D leading to decreased intestinal reabsorption of phosphate [18]. This relationship has been demonstrated in animal studies where a single injection of recombinant FGF23 resulted in reduction of serum phosphate and 1,25 (OH) 2D levels independent of PTH levels [11]. During the experiment, PTH levels remained low, and the hypophosphatemia was reproduced by injection of FGF23 in parathyroidectomized rats [11].
FGF23 mode of inheritance
Both genetic and acquired mechanisms of FGF23-related hypophosphatemic disease have been described. Genetic mechanisms vary by mode of inheritance. Autosomal dominant hypophosphatemic rickets (ADHR) is caused by mutations in FGF23 gene [2]. The autosomal recessive variant is caused by mutations in dentrin matrix protein 1 (DMP1) [19]. The X-linked dominant form occurs due to mutations in phosphate-regulating gene (PHEX) [20].
An acquired FGF23 hypophosphatemic disease is associated with the administration of intravenous iron, specifically the saccharated ferric oxide and iron polymaltose. Evaluation of these patients showed elevated FGF23 levels with the exact mechanism not known [21]. TIO is another example of an acquired form of FGF23 hypophosphatemic disease [17] which is reviewed in greater detail below.
Tumor-induced osteomalacia
TIO is a rare paraneoplastic disease, first described in 1947 by Robert McCance who reported a patient with pain and weakness in the setting of low phosphate levels. His symptoms persisted despite being treated with vitamin D, and eventually improved only after a tumor found in the femur bone was resected [22]. Animal experiments have supported the presence of the humoral factor leading to hypophosphatemia [23]. The earliest evidence to support this in humans was done by Miyauchi et al. [24] where tumor removal in a patient with osteomalacia and injection into healthy mice lead to hypophosphatemia.
Tumors associated with TIO are usually mesenchymal in origin [17]. Within the reported cases of TIO, 40% occur in the bone and 55% occur in soft tissues. The thigh and femur are the most common sites of involvement with the pelvis reported in only 8% of cases, and only 2% of cases reported as involving more than one site [25]. These tumors can be histologically polymorphous, but in 1991 Weidner [26] proposed a classification system to divide them into four morphologic patterns including phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT), osteoblastoma-like variant, non-ossifying fibroma-like variant, and ossifying fibroma-like variant. PMTMCT comprises 70 – 80% of cases of TIO and typically begins in bone or soft tissues [5].
Non-mesenchymal tumors with TIO manifestations are now being recognized and reported in leukemia [7], B cell non-Hodgkin’s lymphoma [8], sarcoma [10], and other solid organ cancers including lung [27], prostate [28], and colon cancer [29]. There is only one case of TIO reported in metastatic breast cancer [13] with the two cases above resulting in a total of three. During malignancy, abnormal FGF signaling has been shown to induce cell proliferation and angiogenesis thereby promoting metastasis [16]. In breast cancer specifically, molecular alternations in FGFR1 and FGFR2 receptors are the most common reported [16]. Clinical trials support this data where phase I trials showed hyperphosphatemia as the most common adverse effect when novel tyrosine kinase inhibitors targeted FGF signaling [30].
Diagnostic evaluation of TIO should start with a comprehensive metabolic panel to check serum phosphorous and calcium levels which are typically low. Alkaline phosphatase may be elevated as in case 1 (738 U/L) and case 2 (635 U/L) due to osteoblast hyperactivity. Vitamin D levels should be checked and are typically low due to the inhibitory effect of FGF23. This was seen in our cases where vitamin D levels were 8 ng/mL and 15 ng/mL in case 1 and 2, respectively. PTH levels may be variable and increased at times as part of a normal feedback response to low vitamin D levels and subsequently hypocalcemia. In both cases, the elevation in PTH (488 pg/mL and 287 pg/mL) was likely multifactorial; initially as a feedback to hypocalcemia in the setting of denosumab. Secondary hyperparathyroidism has been demonstrated in patients receiving denosumab as a result of prolonged hypocalcemia caused by this drug [31], leading to renal phosphate wasting in some patients. This mechanism may have contributed to pathogenesis of hypophosphatemia in our patients. However in case 1, phosphorus remained low despite aggressive supplementation. Persistent hypophosphatemia however should also raise concern for an FGF23 secreting tumor. For case 2, denosumab was given 3 months prior to recognition of hypophosphatemia. Furthermore, FGF23 remained elevated, and phosphaturia continued despite PTH normalization. Therefore, denosumab likely did not play a major role in the FGF23 elevation or renal phosphate wasting. Along with serum FGF23, urine studies including urine creatinine and urine phosphorous must be checked to calculate the fractional excretion of phosphate and tubular reabsorption of phosphate. In the setting of TIO, one would expect a high fractional excretion of phosphate (> 10%) and low tubular reabsorption of phosphate (< 75%) due to inhibition of sodium phosphate transporters at the proximal tubules and low vitamin D. Dihydroxyvitamin D-1,25 was low in case 1 as expected due to suppressed activation by FGF23. However, in case 2, dihydroxyvitamin D-1,25 was elevated in the absence of calcitriol. Although in patients with chronic kidney disease and hyperphosphatemia FGF23 is elevated leading to suppression of vitamin D 1,25 production, we hypothesize that perhaps in some patients with hypophosphatemia, other mechanisms may be responsible for higher vitamin D 1,25 levels to counteract effects of low phosphorus levels.
Several imaging modalities can be used to identify the tumor, including magnetic resonance imaging (MRI) and PET scan. Somatostatin receptors (SSTR) based functioning imaging can also be performed since some of these tumors express SSTRs [32]. However, clinicians have to be mindful that inflammatory reactions can cause a false positive SSTR imaging [32]. In cases where tumor is identified, the treatment of choice is resection. Once FGF23 levels decline in circulation, serum phosphate levels return to normal, as early as five days post operatively [33]. In cases where the tumor is inoperable, medical management may be attempted with phosphate supplementation and calcitriol as recommended in our cases of metastatic disease. Octreotide is another potential treatment, given link with SSTR. Targeted antibodies against FGF23 have shown promise in animal models [34].
Conclusion
TIO can be a challenging diagnosis to make, especially in patients with malignancy other than mesenchymal origin, as symptoms of hypophosphatemia are nonspecific and could be easily attributed to the underlying cancer. In fact, the average time from recognition of osteomalacia to identifying the associated tumor is ~ 5 years [35]. We recommend more frequent testing of serum phosphorous since it is not part of the routine basic metabolic panel. Furthermore, in breast cancer specifically, patients are frequently managed with bone-targeted therapy such as bisphosphonates and denosumab which can further exacerbate hypophosphatemia. Antiresorptive therapy during malignancies should be carefully weighed with degree of hypophosphatemia and risk of skeletal-related events. Patients with TIO should be evaluated for resection, which can be curative when involving a solitary lesion. It is reasonable to check FGF23 levels in oncologic patients with persistent hypophosphatemia despite adequate supplementation of phosphorus and vitamin D and discontinuation of the drugs known to cause renal phosphate wasting. In patients with several lesions or metastatic cancer such as described above, systemic oncologic therapy and supplementation of phosphorous, calcium, and vitamin D can be attempted to improve the quality of life.
Funding
This research was supported by National Institute of Health grant award P30CA008748.
Conflict of interest
Ilya Glezerman owns Pfizer Stock. Remaining authors have nothing to disclose.
Figure 1 PET scan showing progression of disease for case 1. Metastasis to the liver, sternum, and sclerotic osseous lesions to the spine and right iliac.
Table 1. Case 1. Sequence of laboratory findings and treatment for hypophosphatemia.
–12 months to –1 month –10 days –4 days Nephrology
consult (day 0) +10 days
Treatment
Denosumab (mg) 120 mg/monthly × 10 doses
Potassium-phosphate/sodium-phosphate (mg) 250-45-298
t.i.d. 250-45-298
t.i.d.
Calcitriol (mcg) 0.25 b.i.d. 0.25 b.i.d.
Laboratory studies
Serum phosphate (mg/dL) < 0.9 1 1.1
Serum calcium* (mg/dL) Range 8.7 – 10.5 8.1 8.4 7.9 9.1
Alkaline phosphatase (U/L) Range 97 – 506 504 690 738 619
Serum PTH (pg/mL) 488
Serum FGF23 (RU/mL) 2,430
Serum 25-OH Vit D (ng/mL) 8
Urine sodium (mEq/L) 22
Urine calcium (mg/dL) < 1
Urine phosphate (mg/dL) 214
Urine creatinine (mg/dL) 229
FePhos** 56%
*Corrected calcium = total calcium (mg/dL) + 0.8 (4.0-serum albumin [g/dL]), where 4.0 represents the average albumin level. **FePhos = (urine phosphorus/serum phosphorus) × (serum creatinine/urine creatinine). PTH = parathyroid hormone; FGF23 = fibroblast growth factor 23; FePhos = fractional excretion of phosphorus.
Table 2. Case 2. Sequence of laboratory findings and treatment for hypophosphatemia,
–12 months to –3 months –10 days –4 days Nephrology
consult (day 0) +3 days +4 days
Treatment
Denosumab (mg) 120 mg/monthly
× 10 doses
Potassium-phosphate/Sodium-phosphate (mg) 250-45-298 once 250-45-298
TID 250-45-298
QID
IV Phosphate (mmol) 30 30 15
PO calcium citrate (g) 3.8
IV calcium gluconate (g) 4 2
Laboratory studies
Serum phosphate (mg/dL) 2.6 (month –3) 1.6 1.4 1.4 3.8 2.4
*Serum calcium (mg/dL) 9.2 – 10.1 range 9.0 8.7 8.0 9.4 9.3
Alkaline phosphatase (U/L) 138 – 253 range 516 581 712 677 664
Serum PTH (pg/mL) 287.3 44.3
Serum FGF23 (RU/mL) 548 424
Serum 25-OH Vit D (ng/mL) 15
Serum 1,25-Dihydroxyvitamin D (pg/mL) 82
Urine sodium (mEq/L) < 20
Urine calcium (mg/dL) 3.1
Urine phosphate (mg/dL) 175 416
Urine creatinine (mg/dL) 80 99
**FePhos 78% 72%
*Corrected calcium = total calcium (mg/dL) + 0.8 (4.0-serum albumin [g/dL]), where 4.0 represents the average albumin level. **FePhos = (urine phosphorus/serum phosphorus) × (serum creatinine/urine creatinine). PTH = parathyroid hormone; FGF23 = fibroblast growth factor 23; FePhos = fractional excretion of phosphorus.
Figure 2 PET Scan showing progression of disease for case 2. Metastasis to the liver, right acetabulum, thoracic vertebrae, and right ilium.
Figure 3 Bone-kidney axis and phosphaturic effects of FGF23. FGF23 is produced in bone by osteocytes in response to high serum phosphorous. In malignant bone, FGF23 is produced regardless of serum phosphorous. One of FGF23 targets is the kidney. FGF23 binds to FGR receptors and complexes with klotho on the basolateral surface of proximal tubular cells. This causes a decrease in expression of sodium-phosphorus co-transporters (Na-PO42-) whose role is renal phosphate reabsorption. Indirect effects include inhibition of 1-α-hydroxylase levels which are necessary to activate vitamin D and increased expression of 24-hydroxylase which degrades active vitamin D. The net effect is a decrease in serum phosphorous.
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DENOSUMAB, NIVOLUMAB, PACLITAXEL, PALBOCICLIB, ZOLEDRONIC ACID
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DrugsGivenReaction
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CC BY
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33191899
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2021-02
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood phosphorus increased'.
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Hypophosphatemia and FGF23 tumor-induced osteomalacia in two cases of metastatic breast cancer.
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by factor-induced dysregulation of phosphate and vitamin D metabolism resulting in alterations in bone formation, leading to bone pain and fractures. While the true incidence is likely underestimated, less than 500 cases of TIO have been reported since initial description in 1947. TIO cases have classically been associated with mesenchymal tumors of bone and soft tissue, but have also rarely been linked to malignant tumors, with scant reports implicating non-mesenchymal tumors. TIO is mediated through inappropriate tumor overproduction of fibroblast growth factor 23 (FGF23). Increased FGF23 secretion leads to hypophosphatemia by (1) reduced phosphate reabsorption via activation of the proximal renal tubular epithelial cells to internalize sodium phosphate cotransporters and (2) reduced activation of vitamin D3 via inhibition of the renal enzyme 1-α hydroxylase. Low circulating levels of active vitamin D lead to reduced intestinal phosphate absorption and impaired mineralization of osteoid matrix. TIO in breast cancer poses a distinct diagnostic challenge due to the common adjunct oncologic management with bone protection therapy such as denosumab or bisphosphonates. These agents can be culprits of hypophosphatemia and hypocalcemia, rendering timely diagnosis of TIO difficult. Delay of diagnosis of TIO can result in worsening functional status, and early morbidity and mortality. To date, there has been one prior case report of TIO in breast cancer, and herein we describe two additional cases of TIO in this setting.
pmcIntroduction
Fibroblast growth factor-23 (FGF23) is a phosphaturic humoral factor produced by osteoblasts and osteocytes [1]. First identified two decades ago, mutations in the cleavage of FGF23 cause several inherited renal phosphate wasting diseases leading to rickets in children or osteomalacia in adults [2, 3]. In the paraneoplastic setting, FGF23 oversecretion leads to tumor-induced rickets/osteomalacia (TIO) also known as oncogenic osteomalacia [4]. TIO is typically reported with mesenchymal tumors [5, 6], and is starting to become recognized in patients with liquid [7] and solid organ malignancies [8, 9, 10] as well.
FGF23 is a key regulator of phosphate metabolism. The primary physiologic function is to lower serum phosphate levels which is mediated by FGF receptors (FGFR) and klotho complexes [3]. FGF23 downregulates the expression of cotransporters in the kidney that are essential for the reabsorption of phosphate. Additionally, FGF23 downregulates the expression of enzymes that activate vitamin D which increases intestinal phosphate absorption, thereby indirectly lowering serum phosphate levels [11].
Phosphate is primarily found in bone and is responsible for skeletal strength and rigidity. Low phosphate levels manifest as general muscle weakness, fatigue, and in extreme cases impaired cardiac and respiratory function [12]. These symptoms, in patients with cancer, may be attributed to their malignancy, and the potential diagnosis of TIO may be overlooked, especially with the rarer non-mesenchymal origin tumors. Below are examples of two case reports of patients with metastatic breast cancer with severe hypophosphatemia, phosphaturia and elevated serum FGF23, consistent with TIO. To the best of our knowledge, there is only one other case report of TIO associated with metastatic breast cancer [13]. These cases are particularly challenging given the use of antiresorptive therapy in patients with bone metastasis which can trigger FGF23 overexpression [13] and worsen underlying oncologic osteomalacia.
Case 1
A 47-year-old woman with metastatic breast cancer with liver and bone involvement was referred to the nephrology clinic for persistent hypophosphatemia. Seven years ago patient was diagnosed with left mammary duct carcinoma and underwent partial mastectomy followed by chemotherapy with paclitaxel and tamoxifen. She had a reoccurrence 3 years later and failed multiple lines of chemotherapy including eribulin and vinorelbine with last positron emission tomography (PET) scan showing metastasis to the liver, sternum, and sclerotic osseous lesions to the spine and right iliac (Figure 1).
The patient was initiated on monthly denosumab for 1 year (12 doses in total) prior to the current nephrology visit, with last dose 1 month ago, to address metastatic bone involvement. Phosphorous level on consultation was < 0.9 mg/dL (2.5 – 4.5 mg/dL) with no prior levels. Remainder of bloodwork is shown in Table 1 which highlights low calcium 7.4 mg/dL (8.5 – 10.5 mg/dL) and elevated alkaline phosphatase (ALP) of 738 U/L (≤ 130 U/L). The fractional excretion of phosphate (FePhos) in the urine was elevated at 56% (< 5 – 10%).
Etiology for hypophosphatemia was initially thought to be secondary hyperparathyroidism given elevated parathyroid hormone (PTH) of 488 pg/mL (12 – 88 pg/mL) due to hypocalcemia in the setting of recent denosumab administration. Phosphorous levels remained low despite oral calcium and phosphate repletion and oral calcitriol administration (Table 1). Given persistent hypophosphatemia, FGF23 was checked, and levels returned strikingly elevated at 2,430 RU/mL (≤ 180 RU/mL) suggesting an FGF23 secreting tumor as the most likely cause for severe hypophosphatemia. Unfortunately, the patient passed away within 1 month due to disease progression.
Case 2
A 55-year-old woman with triple negative invasive ductal breast cancer, who achieved remission 10 years ago presented with progressive weakness. She was found to have relapsed disease involving the liver, lung, and bone (vertebral, acetabulum, and ilium) 1 year ago (Figure 2), and subsequently received chemotherapy including palbociclib, nivolumab, and abraxane as well as 4 monthly doses of zoledronate, followed by 10 monthly treatments of denosumab. She last received bone-stimulating therapy and chemotherapy 3 months prior to admission. She had no other comorbidities, nor a history of additional medications or herbal supplements. She was a lifetime nonsmoker. She was admitted for obstructive jaundice due to progression of disease. During the course of her admission, she complained of severe lower extremity bone pain limiting ambulation. Prior to admission, the patient’s electrolytes were within normal limits.
Upon admission, she was cachectic (body mass index < 18), with hypophosphatemia of 1.6 mmol/L (2.5 – 4.5 mmol/L). Nephrology was called for further evaluation. Remainder of lab studies are shown in Table 2 and include a normal corrected calcium of 9.5 mmol/L (8.5 – 10.5 mmol/L), low 25-hydroxyvitamin D of 15 ng/dL (20 – 50 ng/dL), elevated PTH of 287.3 pg/mL (12 – 88 pg/mL), and elevated ALP of 635 U/L (≤ 130U/L). FePhos was 78% (< 5 – 10%), consistent with phosphate wasting. Of note, 1,25-dihydroxyvitamin D was elevated at 83 pg/mL (20 – 50 pg/mL) despite not being on calcitriol.
Given elevated urine phosphate, an oncologic osteomalacia was suspected and FGF23 was checked and was elevated at 548 (< 180) RU/mL. Due to aggressive supplementation, serum phosphate increased to a peak value of 3.8 mmol/L; PTH decreased to 44, but FGF23 and FePhos remained elevated at 424 and 72%, respectively. The patient continued to decline and passed away within 2 weeks.
Discussion
FGF23 is a glycoprotein part of the FGF family which is subdivided into 7 subfamilies with 22 members reported in humans [14]. FGF23 belongs to the FGF19 subfamily which has also been called the endocrine FGFs due to the inner protein structure allowing it to function as a circulating hormone [15]. FGF23 is derived from bones, and under physiologic conditions, its production is stimulated by extracellular phosphate. Once secreted from osteoblasts and osteocytes, FGF23 plays a pleiotropic role which links the bone with several organ systems including the kidney, heart, and cells part of the immune system [1]. FGF23 signaling contributes to regulation in cellular proliferation, survival, and differentiation making it an attractive pathway to hijack by cancer cells [16].
FGF23 renal pathophysiology
With respect to the kidney, the main function of FGF23 is to lower serum phosphate levels as shown in Figure 3. This is established through direct inhibition of phosphate reabsorption at the level of the proximal tubular cells, and indirectly by downregulation of enzymes necessary to activate vitamin D. Direct actions involve the binding of circulating FGF23 to FGF receptors (FGFRs) and coreceptor klotho on the basolateral surface of the proximal tubular cells. This results in decreased expression of two sodium-phosphate cotransporters called NaPi-2a and NaPi-2c. These transporters, located on the apical surface of the proximal tubular cell are responsible for renal phosphate reabsorption. Decreased expression of NaPi-2a and NaPi-2c is therefore a direct cause of phosphaturia [17].
FGF23 also indirectly lowers serum phosphate levels by inhibiting renal 1-α-hydroxylase which is necessary to activate vitamin D. Further, FGF23 also increases the expression of 24-hydroxylase which degrades the active form of vitamin D into inactive metabolites. These actions collectively reduce active levels of vitamin D leading to decreased intestinal reabsorption of phosphate [18]. This relationship has been demonstrated in animal studies where a single injection of recombinant FGF23 resulted in reduction of serum phosphate and 1,25 (OH) 2D levels independent of PTH levels [11]. During the experiment, PTH levels remained low, and the hypophosphatemia was reproduced by injection of FGF23 in parathyroidectomized rats [11].
FGF23 mode of inheritance
Both genetic and acquired mechanisms of FGF23-related hypophosphatemic disease have been described. Genetic mechanisms vary by mode of inheritance. Autosomal dominant hypophosphatemic rickets (ADHR) is caused by mutations in FGF23 gene [2]. The autosomal recessive variant is caused by mutations in dentrin matrix protein 1 (DMP1) [19]. The X-linked dominant form occurs due to mutations in phosphate-regulating gene (PHEX) [20].
An acquired FGF23 hypophosphatemic disease is associated with the administration of intravenous iron, specifically the saccharated ferric oxide and iron polymaltose. Evaluation of these patients showed elevated FGF23 levels with the exact mechanism not known [21]. TIO is another example of an acquired form of FGF23 hypophosphatemic disease [17] which is reviewed in greater detail below.
Tumor-induced osteomalacia
TIO is a rare paraneoplastic disease, first described in 1947 by Robert McCance who reported a patient with pain and weakness in the setting of low phosphate levels. His symptoms persisted despite being treated with vitamin D, and eventually improved only after a tumor found in the femur bone was resected [22]. Animal experiments have supported the presence of the humoral factor leading to hypophosphatemia [23]. The earliest evidence to support this in humans was done by Miyauchi et al. [24] where tumor removal in a patient with osteomalacia and injection into healthy mice lead to hypophosphatemia.
Tumors associated with TIO are usually mesenchymal in origin [17]. Within the reported cases of TIO, 40% occur in the bone and 55% occur in soft tissues. The thigh and femur are the most common sites of involvement with the pelvis reported in only 8% of cases, and only 2% of cases reported as involving more than one site [25]. These tumors can be histologically polymorphous, but in 1991 Weidner [26] proposed a classification system to divide them into four morphologic patterns including phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT), osteoblastoma-like variant, non-ossifying fibroma-like variant, and ossifying fibroma-like variant. PMTMCT comprises 70 – 80% of cases of TIO and typically begins in bone or soft tissues [5].
Non-mesenchymal tumors with TIO manifestations are now being recognized and reported in leukemia [7], B cell non-Hodgkin’s lymphoma [8], sarcoma [10], and other solid organ cancers including lung [27], prostate [28], and colon cancer [29]. There is only one case of TIO reported in metastatic breast cancer [13] with the two cases above resulting in a total of three. During malignancy, abnormal FGF signaling has been shown to induce cell proliferation and angiogenesis thereby promoting metastasis [16]. In breast cancer specifically, molecular alternations in FGFR1 and FGFR2 receptors are the most common reported [16]. Clinical trials support this data where phase I trials showed hyperphosphatemia as the most common adverse effect when novel tyrosine kinase inhibitors targeted FGF signaling [30].
Diagnostic evaluation of TIO should start with a comprehensive metabolic panel to check serum phosphorous and calcium levels which are typically low. Alkaline phosphatase may be elevated as in case 1 (738 U/L) and case 2 (635 U/L) due to osteoblast hyperactivity. Vitamin D levels should be checked and are typically low due to the inhibitory effect of FGF23. This was seen in our cases where vitamin D levels were 8 ng/mL and 15 ng/mL in case 1 and 2, respectively. PTH levels may be variable and increased at times as part of a normal feedback response to low vitamin D levels and subsequently hypocalcemia. In both cases, the elevation in PTH (488 pg/mL and 287 pg/mL) was likely multifactorial; initially as a feedback to hypocalcemia in the setting of denosumab. Secondary hyperparathyroidism has been demonstrated in patients receiving denosumab as a result of prolonged hypocalcemia caused by this drug [31], leading to renal phosphate wasting in some patients. This mechanism may have contributed to pathogenesis of hypophosphatemia in our patients. However in case 1, phosphorus remained low despite aggressive supplementation. Persistent hypophosphatemia however should also raise concern for an FGF23 secreting tumor. For case 2, denosumab was given 3 months prior to recognition of hypophosphatemia. Furthermore, FGF23 remained elevated, and phosphaturia continued despite PTH normalization. Therefore, denosumab likely did not play a major role in the FGF23 elevation or renal phosphate wasting. Along with serum FGF23, urine studies including urine creatinine and urine phosphorous must be checked to calculate the fractional excretion of phosphate and tubular reabsorption of phosphate. In the setting of TIO, one would expect a high fractional excretion of phosphate (> 10%) and low tubular reabsorption of phosphate (< 75%) due to inhibition of sodium phosphate transporters at the proximal tubules and low vitamin D. Dihydroxyvitamin D-1,25 was low in case 1 as expected due to suppressed activation by FGF23. However, in case 2, dihydroxyvitamin D-1,25 was elevated in the absence of calcitriol. Although in patients with chronic kidney disease and hyperphosphatemia FGF23 is elevated leading to suppression of vitamin D 1,25 production, we hypothesize that perhaps in some patients with hypophosphatemia, other mechanisms may be responsible for higher vitamin D 1,25 levels to counteract effects of low phosphorus levels.
Several imaging modalities can be used to identify the tumor, including magnetic resonance imaging (MRI) and PET scan. Somatostatin receptors (SSTR) based functioning imaging can also be performed since some of these tumors express SSTRs [32]. However, clinicians have to be mindful that inflammatory reactions can cause a false positive SSTR imaging [32]. In cases where tumor is identified, the treatment of choice is resection. Once FGF23 levels decline in circulation, serum phosphate levels return to normal, as early as five days post operatively [33]. In cases where the tumor is inoperable, medical management may be attempted with phosphate supplementation and calcitriol as recommended in our cases of metastatic disease. Octreotide is another potential treatment, given link with SSTR. Targeted antibodies against FGF23 have shown promise in animal models [34].
Conclusion
TIO can be a challenging diagnosis to make, especially in patients with malignancy other than mesenchymal origin, as symptoms of hypophosphatemia are nonspecific and could be easily attributed to the underlying cancer. In fact, the average time from recognition of osteomalacia to identifying the associated tumor is ~ 5 years [35]. We recommend more frequent testing of serum phosphorous since it is not part of the routine basic metabolic panel. Furthermore, in breast cancer specifically, patients are frequently managed with bone-targeted therapy such as bisphosphonates and denosumab which can further exacerbate hypophosphatemia. Antiresorptive therapy during malignancies should be carefully weighed with degree of hypophosphatemia and risk of skeletal-related events. Patients with TIO should be evaluated for resection, which can be curative when involving a solitary lesion. It is reasonable to check FGF23 levels in oncologic patients with persistent hypophosphatemia despite adequate supplementation of phosphorus and vitamin D and discontinuation of the drugs known to cause renal phosphate wasting. In patients with several lesions or metastatic cancer such as described above, systemic oncologic therapy and supplementation of phosphorous, calcium, and vitamin D can be attempted to improve the quality of life.
Funding
This research was supported by National Institute of Health grant award P30CA008748.
Conflict of interest
Ilya Glezerman owns Pfizer Stock. Remaining authors have nothing to disclose.
Figure 1 PET scan showing progression of disease for case 1. Metastasis to the liver, sternum, and sclerotic osseous lesions to the spine and right iliac.
Table 1. Case 1. Sequence of laboratory findings and treatment for hypophosphatemia.
–12 months to –1 month –10 days –4 days Nephrology
consult (day 0) +10 days
Treatment
Denosumab (mg) 120 mg/monthly × 10 doses
Potassium-phosphate/sodium-phosphate (mg) 250-45-298
t.i.d. 250-45-298
t.i.d.
Calcitriol (mcg) 0.25 b.i.d. 0.25 b.i.d.
Laboratory studies
Serum phosphate (mg/dL) < 0.9 1 1.1
Serum calcium* (mg/dL) Range 8.7 – 10.5 8.1 8.4 7.9 9.1
Alkaline phosphatase (U/L) Range 97 – 506 504 690 738 619
Serum PTH (pg/mL) 488
Serum FGF23 (RU/mL) 2,430
Serum 25-OH Vit D (ng/mL) 8
Urine sodium (mEq/L) 22
Urine calcium (mg/dL) < 1
Urine phosphate (mg/dL) 214
Urine creatinine (mg/dL) 229
FePhos** 56%
*Corrected calcium = total calcium (mg/dL) + 0.8 (4.0-serum albumin [g/dL]), where 4.0 represents the average albumin level. **FePhos = (urine phosphorus/serum phosphorus) × (serum creatinine/urine creatinine). PTH = parathyroid hormone; FGF23 = fibroblast growth factor 23; FePhos = fractional excretion of phosphorus.
Table 2. Case 2. Sequence of laboratory findings and treatment for hypophosphatemia,
–12 months to –3 months –10 days –4 days Nephrology
consult (day 0) +3 days +4 days
Treatment
Denosumab (mg) 120 mg/monthly
× 10 doses
Potassium-phosphate/Sodium-phosphate (mg) 250-45-298 once 250-45-298
TID 250-45-298
QID
IV Phosphate (mmol) 30 30 15
PO calcium citrate (g) 3.8
IV calcium gluconate (g) 4 2
Laboratory studies
Serum phosphate (mg/dL) 2.6 (month –3) 1.6 1.4 1.4 3.8 2.4
*Serum calcium (mg/dL) 9.2 – 10.1 range 9.0 8.7 8.0 9.4 9.3
Alkaline phosphatase (U/L) 138 – 253 range 516 581 712 677 664
Serum PTH (pg/mL) 287.3 44.3
Serum FGF23 (RU/mL) 548 424
Serum 25-OH Vit D (ng/mL) 15
Serum 1,25-Dihydroxyvitamin D (pg/mL) 82
Urine sodium (mEq/L) < 20
Urine calcium (mg/dL) 3.1
Urine phosphate (mg/dL) 175 416
Urine creatinine (mg/dL) 80 99
**FePhos 78% 72%
*Corrected calcium = total calcium (mg/dL) + 0.8 (4.0-serum albumin [g/dL]), where 4.0 represents the average albumin level. **FePhos = (urine phosphorus/serum phosphorus) × (serum creatinine/urine creatinine). PTH = parathyroid hormone; FGF23 = fibroblast growth factor 23; FePhos = fractional excretion of phosphorus.
Figure 2 PET Scan showing progression of disease for case 2. Metastasis to the liver, right acetabulum, thoracic vertebrae, and right ilium.
Figure 3 Bone-kidney axis and phosphaturic effects of FGF23. FGF23 is produced in bone by osteocytes in response to high serum phosphorous. In malignant bone, FGF23 is produced regardless of serum phosphorous. One of FGF23 targets is the kidney. FGF23 binds to FGR receptors and complexes with klotho on the basolateral surface of proximal tubular cells. This causes a decrease in expression of sodium-phosphorus co-transporters (Na-PO42-) whose role is renal phosphate reabsorption. Indirect effects include inhibition of 1-α-hydroxylase levels which are necessary to activate vitamin D and increased expression of 24-hydroxylase which degrades active vitamin D. The net effect is a decrease in serum phosphorous.
|
CALCIUM CITRATE, CALCIUM GLUCONATE, POTASSIUM PHOSPHATE\SODIUM PHOSPHATE, SODIUM PHOSPHATE
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DrugsGivenReaction
|
CC BY
|
33191899
| 19,139,574
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Breast cancer metastatic'.
|
Hypophosphatemia and FGF23 tumor-induced osteomalacia in two cases of metastatic breast cancer.
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by factor-induced dysregulation of phosphate and vitamin D metabolism resulting in alterations in bone formation, leading to bone pain and fractures. While the true incidence is likely underestimated, less than 500 cases of TIO have been reported since initial description in 1947. TIO cases have classically been associated with mesenchymal tumors of bone and soft tissue, but have also rarely been linked to malignant tumors, with scant reports implicating non-mesenchymal tumors. TIO is mediated through inappropriate tumor overproduction of fibroblast growth factor 23 (FGF23). Increased FGF23 secretion leads to hypophosphatemia by (1) reduced phosphate reabsorption via activation of the proximal renal tubular epithelial cells to internalize sodium phosphate cotransporters and (2) reduced activation of vitamin D3 via inhibition of the renal enzyme 1-α hydroxylase. Low circulating levels of active vitamin D lead to reduced intestinal phosphate absorption and impaired mineralization of osteoid matrix. TIO in breast cancer poses a distinct diagnostic challenge due to the common adjunct oncologic management with bone protection therapy such as denosumab or bisphosphonates. These agents can be culprits of hypophosphatemia and hypocalcemia, rendering timely diagnosis of TIO difficult. Delay of diagnosis of TIO can result in worsening functional status, and early morbidity and mortality. To date, there has been one prior case report of TIO in breast cancer, and herein we describe two additional cases of TIO in this setting.
pmcIntroduction
Fibroblast growth factor-23 (FGF23) is a phosphaturic humoral factor produced by osteoblasts and osteocytes [1]. First identified two decades ago, mutations in the cleavage of FGF23 cause several inherited renal phosphate wasting diseases leading to rickets in children or osteomalacia in adults [2, 3]. In the paraneoplastic setting, FGF23 oversecretion leads to tumor-induced rickets/osteomalacia (TIO) also known as oncogenic osteomalacia [4]. TIO is typically reported with mesenchymal tumors [5, 6], and is starting to become recognized in patients with liquid [7] and solid organ malignancies [8, 9, 10] as well.
FGF23 is a key regulator of phosphate metabolism. The primary physiologic function is to lower serum phosphate levels which is mediated by FGF receptors (FGFR) and klotho complexes [3]. FGF23 downregulates the expression of cotransporters in the kidney that are essential for the reabsorption of phosphate. Additionally, FGF23 downregulates the expression of enzymes that activate vitamin D which increases intestinal phosphate absorption, thereby indirectly lowering serum phosphate levels [11].
Phosphate is primarily found in bone and is responsible for skeletal strength and rigidity. Low phosphate levels manifest as general muscle weakness, fatigue, and in extreme cases impaired cardiac and respiratory function [12]. These symptoms, in patients with cancer, may be attributed to their malignancy, and the potential diagnosis of TIO may be overlooked, especially with the rarer non-mesenchymal origin tumors. Below are examples of two case reports of patients with metastatic breast cancer with severe hypophosphatemia, phosphaturia and elevated serum FGF23, consistent with TIO. To the best of our knowledge, there is only one other case report of TIO associated with metastatic breast cancer [13]. These cases are particularly challenging given the use of antiresorptive therapy in patients with bone metastasis which can trigger FGF23 overexpression [13] and worsen underlying oncologic osteomalacia.
Case 1
A 47-year-old woman with metastatic breast cancer with liver and bone involvement was referred to the nephrology clinic for persistent hypophosphatemia. Seven years ago patient was diagnosed with left mammary duct carcinoma and underwent partial mastectomy followed by chemotherapy with paclitaxel and tamoxifen. She had a reoccurrence 3 years later and failed multiple lines of chemotherapy including eribulin and vinorelbine with last positron emission tomography (PET) scan showing metastasis to the liver, sternum, and sclerotic osseous lesions to the spine and right iliac (Figure 1).
The patient was initiated on monthly denosumab for 1 year (12 doses in total) prior to the current nephrology visit, with last dose 1 month ago, to address metastatic bone involvement. Phosphorous level on consultation was < 0.9 mg/dL (2.5 – 4.5 mg/dL) with no prior levels. Remainder of bloodwork is shown in Table 1 which highlights low calcium 7.4 mg/dL (8.5 – 10.5 mg/dL) and elevated alkaline phosphatase (ALP) of 738 U/L (≤ 130 U/L). The fractional excretion of phosphate (FePhos) in the urine was elevated at 56% (< 5 – 10%).
Etiology for hypophosphatemia was initially thought to be secondary hyperparathyroidism given elevated parathyroid hormone (PTH) of 488 pg/mL (12 – 88 pg/mL) due to hypocalcemia in the setting of recent denosumab administration. Phosphorous levels remained low despite oral calcium and phosphate repletion and oral calcitriol administration (Table 1). Given persistent hypophosphatemia, FGF23 was checked, and levels returned strikingly elevated at 2,430 RU/mL (≤ 180 RU/mL) suggesting an FGF23 secreting tumor as the most likely cause for severe hypophosphatemia. Unfortunately, the patient passed away within 1 month due to disease progression.
Case 2
A 55-year-old woman with triple negative invasive ductal breast cancer, who achieved remission 10 years ago presented with progressive weakness. She was found to have relapsed disease involving the liver, lung, and bone (vertebral, acetabulum, and ilium) 1 year ago (Figure 2), and subsequently received chemotherapy including palbociclib, nivolumab, and abraxane as well as 4 monthly doses of zoledronate, followed by 10 monthly treatments of denosumab. She last received bone-stimulating therapy and chemotherapy 3 months prior to admission. She had no other comorbidities, nor a history of additional medications or herbal supplements. She was a lifetime nonsmoker. She was admitted for obstructive jaundice due to progression of disease. During the course of her admission, she complained of severe lower extremity bone pain limiting ambulation. Prior to admission, the patient’s electrolytes were within normal limits.
Upon admission, she was cachectic (body mass index < 18), with hypophosphatemia of 1.6 mmol/L (2.5 – 4.5 mmol/L). Nephrology was called for further evaluation. Remainder of lab studies are shown in Table 2 and include a normal corrected calcium of 9.5 mmol/L (8.5 – 10.5 mmol/L), low 25-hydroxyvitamin D of 15 ng/dL (20 – 50 ng/dL), elevated PTH of 287.3 pg/mL (12 – 88 pg/mL), and elevated ALP of 635 U/L (≤ 130U/L). FePhos was 78% (< 5 – 10%), consistent with phosphate wasting. Of note, 1,25-dihydroxyvitamin D was elevated at 83 pg/mL (20 – 50 pg/mL) despite not being on calcitriol.
Given elevated urine phosphate, an oncologic osteomalacia was suspected and FGF23 was checked and was elevated at 548 (< 180) RU/mL. Due to aggressive supplementation, serum phosphate increased to a peak value of 3.8 mmol/L; PTH decreased to 44, but FGF23 and FePhos remained elevated at 424 and 72%, respectively. The patient continued to decline and passed away within 2 weeks.
Discussion
FGF23 is a glycoprotein part of the FGF family which is subdivided into 7 subfamilies with 22 members reported in humans [14]. FGF23 belongs to the FGF19 subfamily which has also been called the endocrine FGFs due to the inner protein structure allowing it to function as a circulating hormone [15]. FGF23 is derived from bones, and under physiologic conditions, its production is stimulated by extracellular phosphate. Once secreted from osteoblasts and osteocytes, FGF23 plays a pleiotropic role which links the bone with several organ systems including the kidney, heart, and cells part of the immune system [1]. FGF23 signaling contributes to regulation in cellular proliferation, survival, and differentiation making it an attractive pathway to hijack by cancer cells [16].
FGF23 renal pathophysiology
With respect to the kidney, the main function of FGF23 is to lower serum phosphate levels as shown in Figure 3. This is established through direct inhibition of phosphate reabsorption at the level of the proximal tubular cells, and indirectly by downregulation of enzymes necessary to activate vitamin D. Direct actions involve the binding of circulating FGF23 to FGF receptors (FGFRs) and coreceptor klotho on the basolateral surface of the proximal tubular cells. This results in decreased expression of two sodium-phosphate cotransporters called NaPi-2a and NaPi-2c. These transporters, located on the apical surface of the proximal tubular cell are responsible for renal phosphate reabsorption. Decreased expression of NaPi-2a and NaPi-2c is therefore a direct cause of phosphaturia [17].
FGF23 also indirectly lowers serum phosphate levels by inhibiting renal 1-α-hydroxylase which is necessary to activate vitamin D. Further, FGF23 also increases the expression of 24-hydroxylase which degrades the active form of vitamin D into inactive metabolites. These actions collectively reduce active levels of vitamin D leading to decreased intestinal reabsorption of phosphate [18]. This relationship has been demonstrated in animal studies where a single injection of recombinant FGF23 resulted in reduction of serum phosphate and 1,25 (OH) 2D levels independent of PTH levels [11]. During the experiment, PTH levels remained low, and the hypophosphatemia was reproduced by injection of FGF23 in parathyroidectomized rats [11].
FGF23 mode of inheritance
Both genetic and acquired mechanisms of FGF23-related hypophosphatemic disease have been described. Genetic mechanisms vary by mode of inheritance. Autosomal dominant hypophosphatemic rickets (ADHR) is caused by mutations in FGF23 gene [2]. The autosomal recessive variant is caused by mutations in dentrin matrix protein 1 (DMP1) [19]. The X-linked dominant form occurs due to mutations in phosphate-regulating gene (PHEX) [20].
An acquired FGF23 hypophosphatemic disease is associated with the administration of intravenous iron, specifically the saccharated ferric oxide and iron polymaltose. Evaluation of these patients showed elevated FGF23 levels with the exact mechanism not known [21]. TIO is another example of an acquired form of FGF23 hypophosphatemic disease [17] which is reviewed in greater detail below.
Tumor-induced osteomalacia
TIO is a rare paraneoplastic disease, first described in 1947 by Robert McCance who reported a patient with pain and weakness in the setting of low phosphate levels. His symptoms persisted despite being treated with vitamin D, and eventually improved only after a tumor found in the femur bone was resected [22]. Animal experiments have supported the presence of the humoral factor leading to hypophosphatemia [23]. The earliest evidence to support this in humans was done by Miyauchi et al. [24] where tumor removal in a patient with osteomalacia and injection into healthy mice lead to hypophosphatemia.
Tumors associated with TIO are usually mesenchymal in origin [17]. Within the reported cases of TIO, 40% occur in the bone and 55% occur in soft tissues. The thigh and femur are the most common sites of involvement with the pelvis reported in only 8% of cases, and only 2% of cases reported as involving more than one site [25]. These tumors can be histologically polymorphous, but in 1991 Weidner [26] proposed a classification system to divide them into four morphologic patterns including phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT), osteoblastoma-like variant, non-ossifying fibroma-like variant, and ossifying fibroma-like variant. PMTMCT comprises 70 – 80% of cases of TIO and typically begins in bone or soft tissues [5].
Non-mesenchymal tumors with TIO manifestations are now being recognized and reported in leukemia [7], B cell non-Hodgkin’s lymphoma [8], sarcoma [10], and other solid organ cancers including lung [27], prostate [28], and colon cancer [29]. There is only one case of TIO reported in metastatic breast cancer [13] with the two cases above resulting in a total of three. During malignancy, abnormal FGF signaling has been shown to induce cell proliferation and angiogenesis thereby promoting metastasis [16]. In breast cancer specifically, molecular alternations in FGFR1 and FGFR2 receptors are the most common reported [16]. Clinical trials support this data where phase I trials showed hyperphosphatemia as the most common adverse effect when novel tyrosine kinase inhibitors targeted FGF signaling [30].
Diagnostic evaluation of TIO should start with a comprehensive metabolic panel to check serum phosphorous and calcium levels which are typically low. Alkaline phosphatase may be elevated as in case 1 (738 U/L) and case 2 (635 U/L) due to osteoblast hyperactivity. Vitamin D levels should be checked and are typically low due to the inhibitory effect of FGF23. This was seen in our cases where vitamin D levels were 8 ng/mL and 15 ng/mL in case 1 and 2, respectively. PTH levels may be variable and increased at times as part of a normal feedback response to low vitamin D levels and subsequently hypocalcemia. In both cases, the elevation in PTH (488 pg/mL and 287 pg/mL) was likely multifactorial; initially as a feedback to hypocalcemia in the setting of denosumab. Secondary hyperparathyroidism has been demonstrated in patients receiving denosumab as a result of prolonged hypocalcemia caused by this drug [31], leading to renal phosphate wasting in some patients. This mechanism may have contributed to pathogenesis of hypophosphatemia in our patients. However in case 1, phosphorus remained low despite aggressive supplementation. Persistent hypophosphatemia however should also raise concern for an FGF23 secreting tumor. For case 2, denosumab was given 3 months prior to recognition of hypophosphatemia. Furthermore, FGF23 remained elevated, and phosphaturia continued despite PTH normalization. Therefore, denosumab likely did not play a major role in the FGF23 elevation or renal phosphate wasting. Along with serum FGF23, urine studies including urine creatinine and urine phosphorous must be checked to calculate the fractional excretion of phosphate and tubular reabsorption of phosphate. In the setting of TIO, one would expect a high fractional excretion of phosphate (> 10%) and low tubular reabsorption of phosphate (< 75%) due to inhibition of sodium phosphate transporters at the proximal tubules and low vitamin D. Dihydroxyvitamin D-1,25 was low in case 1 as expected due to suppressed activation by FGF23. However, in case 2, dihydroxyvitamin D-1,25 was elevated in the absence of calcitriol. Although in patients with chronic kidney disease and hyperphosphatemia FGF23 is elevated leading to suppression of vitamin D 1,25 production, we hypothesize that perhaps in some patients with hypophosphatemia, other mechanisms may be responsible for higher vitamin D 1,25 levels to counteract effects of low phosphorus levels.
Several imaging modalities can be used to identify the tumor, including magnetic resonance imaging (MRI) and PET scan. Somatostatin receptors (SSTR) based functioning imaging can also be performed since some of these tumors express SSTRs [32]. However, clinicians have to be mindful that inflammatory reactions can cause a false positive SSTR imaging [32]. In cases where tumor is identified, the treatment of choice is resection. Once FGF23 levels decline in circulation, serum phosphate levels return to normal, as early as five days post operatively [33]. In cases where the tumor is inoperable, medical management may be attempted with phosphate supplementation and calcitriol as recommended in our cases of metastatic disease. Octreotide is another potential treatment, given link with SSTR. Targeted antibodies against FGF23 have shown promise in animal models [34].
Conclusion
TIO can be a challenging diagnosis to make, especially in patients with malignancy other than mesenchymal origin, as symptoms of hypophosphatemia are nonspecific and could be easily attributed to the underlying cancer. In fact, the average time from recognition of osteomalacia to identifying the associated tumor is ~ 5 years [35]. We recommend more frequent testing of serum phosphorous since it is not part of the routine basic metabolic panel. Furthermore, in breast cancer specifically, patients are frequently managed with bone-targeted therapy such as bisphosphonates and denosumab which can further exacerbate hypophosphatemia. Antiresorptive therapy during malignancies should be carefully weighed with degree of hypophosphatemia and risk of skeletal-related events. Patients with TIO should be evaluated for resection, which can be curative when involving a solitary lesion. It is reasonable to check FGF23 levels in oncologic patients with persistent hypophosphatemia despite adequate supplementation of phosphorus and vitamin D and discontinuation of the drugs known to cause renal phosphate wasting. In patients with several lesions or metastatic cancer such as described above, systemic oncologic therapy and supplementation of phosphorous, calcium, and vitamin D can be attempted to improve the quality of life.
Funding
This research was supported by National Institute of Health grant award P30CA008748.
Conflict of interest
Ilya Glezerman owns Pfizer Stock. Remaining authors have nothing to disclose.
Figure 1 PET scan showing progression of disease for case 1. Metastasis to the liver, sternum, and sclerotic osseous lesions to the spine and right iliac.
Table 1. Case 1. Sequence of laboratory findings and treatment for hypophosphatemia.
–12 months to –1 month –10 days –4 days Nephrology
consult (day 0) +10 days
Treatment
Denosumab (mg) 120 mg/monthly × 10 doses
Potassium-phosphate/sodium-phosphate (mg) 250-45-298
t.i.d. 250-45-298
t.i.d.
Calcitriol (mcg) 0.25 b.i.d. 0.25 b.i.d.
Laboratory studies
Serum phosphate (mg/dL) < 0.9 1 1.1
Serum calcium* (mg/dL) Range 8.7 – 10.5 8.1 8.4 7.9 9.1
Alkaline phosphatase (U/L) Range 97 – 506 504 690 738 619
Serum PTH (pg/mL) 488
Serum FGF23 (RU/mL) 2,430
Serum 25-OH Vit D (ng/mL) 8
Urine sodium (mEq/L) 22
Urine calcium (mg/dL) < 1
Urine phosphate (mg/dL) 214
Urine creatinine (mg/dL) 229
FePhos** 56%
*Corrected calcium = total calcium (mg/dL) + 0.8 (4.0-serum albumin [g/dL]), where 4.0 represents the average albumin level. **FePhos = (urine phosphorus/serum phosphorus) × (serum creatinine/urine creatinine). PTH = parathyroid hormone; FGF23 = fibroblast growth factor 23; FePhos = fractional excretion of phosphorus.
Table 2. Case 2. Sequence of laboratory findings and treatment for hypophosphatemia,
–12 months to –3 months –10 days –4 days Nephrology
consult (day 0) +3 days +4 days
Treatment
Denosumab (mg) 120 mg/monthly
× 10 doses
Potassium-phosphate/Sodium-phosphate (mg) 250-45-298 once 250-45-298
TID 250-45-298
QID
IV Phosphate (mmol) 30 30 15
PO calcium citrate (g) 3.8
IV calcium gluconate (g) 4 2
Laboratory studies
Serum phosphate (mg/dL) 2.6 (month –3) 1.6 1.4 1.4 3.8 2.4
*Serum calcium (mg/dL) 9.2 – 10.1 range 9.0 8.7 8.0 9.4 9.3
Alkaline phosphatase (U/L) 138 – 253 range 516 581 712 677 664
Serum PTH (pg/mL) 287.3 44.3
Serum FGF23 (RU/mL) 548 424
Serum 25-OH Vit D (ng/mL) 15
Serum 1,25-Dihydroxyvitamin D (pg/mL) 82
Urine sodium (mEq/L) < 20
Urine calcium (mg/dL) 3.1
Urine phosphate (mg/dL) 175 416
Urine creatinine (mg/dL) 80 99
**FePhos 78% 72%
*Corrected calcium = total calcium (mg/dL) + 0.8 (4.0-serum albumin [g/dL]), where 4.0 represents the average albumin level. **FePhos = (urine phosphorus/serum phosphorus) × (serum creatinine/urine creatinine). PTH = parathyroid hormone; FGF23 = fibroblast growth factor 23; FePhos = fractional excretion of phosphorus.
Figure 2 PET Scan showing progression of disease for case 2. Metastasis to the liver, right acetabulum, thoracic vertebrae, and right ilium.
Figure 3 Bone-kidney axis and phosphaturic effects of FGF23. FGF23 is produced in bone by osteocytes in response to high serum phosphorous. In malignant bone, FGF23 is produced regardless of serum phosphorous. One of FGF23 targets is the kidney. FGF23 binds to FGR receptors and complexes with klotho on the basolateral surface of proximal tubular cells. This causes a decrease in expression of sodium-phosphorus co-transporters (Na-PO42-) whose role is renal phosphate reabsorption. Indirect effects include inhibition of 1-α-hydroxylase levels which are necessary to activate vitamin D and increased expression of 24-hydroxylase which degrades active vitamin D. The net effect is a decrease in serum phosphorous.
|
DENOSUMAB, NIVOLUMAB, PACLITAXEL, PALBOCICLIB, ZOLEDRONIC ACID
|
DrugsGivenReaction
|
CC BY
|
33191899
| 17,820,365
|
2021-02
|
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