instruction
stringlengths 34
186
| input
stringlengths 2.02k
93.8k
| output
stringlengths 2
418
| meta_questiontype
stringclasses 6
values | meta_inputlicense
stringclasses 6
values | meta_pmid
stringlengths 8
8
| meta_safetyreportid
int64 9.51M
21M
| meta_articlepubdate
stringlengths 4
10
|
|---|---|---|---|---|---|---|---|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neoplasm progression'.
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
CARBOPLATIN, DOCETAXEL, DURVALUMAB, GIMERACIL\OTERACIL\TEGAFUR, PACLITAXEL
|
DrugsGivenReaction
|
CC BY
|
33118287
| 18,511,771
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Non-small cell lung cancer stage IIIA'.
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
CARBOPLATIN, DOCETAXEL, DURVALUMAB, GIMERACIL\OTERACIL\TEGAFUR, PACLITAXEL
|
DrugsGivenReaction
|
CC BY
|
33118287
| 18,516,222
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Non-small cell lung cancer'.
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
ACYCLOVIR, CARBOPLATIN, GIMERACIL\OTERACIL\TEGAFUR, RADIATION THERAPY
|
DrugsGivenReaction
|
CC BY
|
33118287
| 18,760,944
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pleural effusion'.
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
ACYCLOVIR, CARBOPLATIN, GIMERACIL\OTERACIL\TEGAFUR, RADIATION THERAPY
|
DrugsGivenReaction
|
CC BY
|
33118287
| 18,760,944
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'.
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
CARBOPLATIN, DOCETAXEL, DURVALUMAB, GIMERACIL\OTERACIL\TEGAFUR, PACLITAXEL
|
DrugsGivenReaction
|
CC BY
|
33118287
| 18,516,222
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory failure'.
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
ACYCLOVIR, CARBOPLATIN, GIMERACIL\OTERACIL\TEGAFUR, RADIATION THERAPY
|
DrugsGivenReaction
|
CC BY
|
33118287
| 18,760,944
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Skin mass'.
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
DOCETAXEL
|
DrugsGivenReaction
|
CC BY
|
33118287
| 18,485,283
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Viral rash'.
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
DOCETAXEL
|
DrugsGivenReaction
|
CC BY
|
33118287
| 18,485,283
|
2021-01
|
What was the administration route of drug 'ACYCLOVIR'?
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
Intravenous (not otherwise specified)
|
DrugAdministrationRoute
|
CC BY
|
33118287
| 18,760,944
|
2021-01
|
What was the administration route of drug 'VALACYCLOVIR HYDROCHLORIDE'?
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
Oral
|
DrugAdministrationRoute
|
CC BY
|
33118287
| 18,544,968
|
2021-01
|
What was the outcome of reaction 'Condition aggravated'?
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
Recovering
|
ReactionOutcome
|
CC BY
|
33118287
| 18,485,283
|
2021-01
|
What was the outcome of reaction 'Herpes zoster'?
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
Recovered
|
ReactionOutcome
|
CC BY
|
33118287
| 18,516,222
|
2021-01
|
What was the outcome of reaction 'Metastases to skin'?
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
Not recovered
|
ReactionOutcome
|
CC BY
|
33118287
| 18,544,968
|
2021-01
|
What was the outcome of reaction 'Neoplasm progression'?
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
Fatal
|
ReactionOutcome
|
CC BY
|
33118287
| 18,511,771
|
2021-01
|
What was the outcome of reaction 'Non-small cell lung cancer'?
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
Fatal
|
ReactionOutcome
|
CC BY
|
33118287
| 18,760,944
|
2021-01
|
What was the outcome of reaction 'Pleural effusion'?
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
Fatal
|
ReactionOutcome
|
CC BY
|
33118287
| 18,760,944
|
2021-01
|
What was the outcome of reaction 'Respiratory failure'?
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
Fatal
|
ReactionOutcome
|
CC BY
|
33118287
| 18,760,944
|
2021-01
|
What was the outcome of reaction 'Viral rash'?
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
Recovering
|
ReactionOutcome
|
CC BY
|
33118287
| 18,485,283
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombophlebitis'.
|
Myelopreservation with Trilaciclib in Patients Receiving Topotecan for Small Cell Lung Cancer: Results from a Randomized, Double-Blind, Placebo-Controlled Phase II Study.
Multilineage myelosuppression is an acute toxicity of cytotoxic chemotherapy, resulting in serious complications and dose modifications. Current therapies are lineage specific and administered after chemotherapy damage has occurred. Trilaciclib is a cyclin-dependent kinase 4/6 inhibitor that is administered prior to chemotherapy to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy (myelopreservation).
In this randomized, double-blind, placebo-controlled phase II trial, patients with previously treated extensive-stage small cell lung cancer (ES-SCLC) were randomized to receive intravenous trilaciclib 240 mg/m2 or placebo before topotecan 1.5 mg/m2 on days 1-5 of each 21-day cycle. Primary endpoints were duration of severe neutropenia (DSN) in cycle 1 and occurrence of severe neutropenia (SN). Additional endpoints were prespecified to further assess the effect of trilaciclib on myelopreservation, safety, patient-reported outcomes (PROs), and antitumor efficacy.
Thirty-two patients received trilaciclib, and 29 patients received placebo. Compared with placebo, administration of trilaciclib prior to topotecan resulted in statistically significant and clinically meaningful decreases in DSN in cycle 1 (mean [standard deviation] 2 [3.9] versus 7 [6.2] days; adjusted one-sided P < 0.0001) and occurrence of SN (40.6% versus 75.9%; adjusted one-sided P = 0.016), with numerical improvements in additional neutrophil, red blood cell, and platelet measures. Patients receiving trilaciclib had fewer grade ≥ 3 hematologic adverse events than patients receiving placebo, particularly neutropenia (75.0% versus 85.7%) and anemia (28.1% versus 60.7%). Myelopreservation benefits extended to improvements in PROs, specifically in those related to fatigue. Antitumor efficacy was comparable between treatment arms.
Compared with placebo, the addition of trilaciclib prior to topotecan for the treatment of patients with previously treated ES-SCLC improves the patient experience of receiving chemotherapy, as demonstrated by a reduction in chemotherapy-induced myelosuppression, improved safety profile, improved quality of life and no detrimental effects on antitumor efficacy.
ClinicalTrials.gov: NCT02514447.
Key Summary Points
Why carry out this study?
Topotecan is an intravenous (IV) topoisomerase I inhibitor indicated for the treatment of small cell lung cancer (SCLC) in patients with platinum-sensitive disease after failure of first-line chemotherapy.
Although topotecan remains an important treatment option for patients with relapsed SCLC, it is commonly associated with chemotherapy-induced myelosuppression (CIM), which results in complications such as increased risk of infection, fatigue, and bleeding and the associated need for dose reductions and delays.
Trilaciclib is an IV cyclin-dependent kinase 4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells in the G1 phase of the cell cycle during chemotherapy exposure, thereby preserving them from chemotherapy-induced damage (myelopreservation).
In this randomized, placebo-controlled phase II study, the myelopreservation effects of trilaciclib administered prior to topotecan for the treatment of patients with previously treated extensive-stage SCLC (ES-SCLC) were evaluated.
What was learned from the study?
Compared with placebo, administering trilaciclib prior to topotecan reduced CIM and the need for supportive care interventions, improved the safety profile of topotecan, and improved the quality of life of patients, particularly with regard to endpoints associated with fatigue.
The data extend the evidence for the clinical benefits of trilaciclib as a first-in-class myelopreservation agent for patients with ES-SCLC treated with chemotherapy and demonstrate that trilaciclib can reduce the risk of CIM that might otherwise result in a substantial risk of additional intervention, hospitalization, and even death.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.13078844.
Introduction
Small cell lung cancer (SCLC) is highly sensitive to chemotherapeutic agents given in the first-line setting. However, despite high response rates to initial chemotherapy with etoposide plus cisplatin or carboplatin, irinotecan, or combination therapy with cyclophosphamide, vincristine, and an anthracycline, most patients relapse [1]. For > 15 years, the topoisomerase I inhibitor, topotecan, has been the only United States Food and Drug Administration-approved standard of care for patients with relapsed SCLC after failure of front-line chemotherapy, and it continues to be an important treatment option in this setting, both in the US and globally [2, 3]. However, topotecan is associated with significant chemotherapy-induced myelosuppression (CIM), which has long been a major concern to clinicians using this agent. The standard 5-day schedule of intravenous (IV) topotecan 1.5 mg/m2 results in high rates of grade 3 and 4 neutropenia, anemia, and thrombocytopenia [4–6], which increase the risk of infection, fatigue and bleeding among patients with SCLC and reduce patient quality of life. Furthermore, clinical concerns raised by CIM commonly lead to chemotherapy dose reductions and/or delays, which limit therapeutic dose intensity and, potentially, its intended antitumor efficacy [6–8]. CIM is currently managed with supportive care interventions such as hematopoietic growth factors and transfusions [9–12]. However, these are often administered reactively when signs or symptoms appear, are specific to individual hematopoietic lineages and impart their own set of risks for adverse reactions, highlighting the need for alternative approaches that can proactively prevent CIM.
Trilaciclib is a selective, reversible cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is administered intravenously prior to chemotherapy to preserve hematopoietic stem and progenitor cells (HSPCs) and lymphocytes during chemotherapy (myelopreservation). Because HSPCs and lymphocytes are dependent on CDK4/6 activity for proliferation, they are arrested in the G1 phase of the cell cycle upon exposure to trilaciclib. This transient, drug-induced cell cycle arrest prevents HSPCs and lymphocytes from proliferating in the presence of cytotoxic chemotherapy, thereby protecting them from chemotherapy-induced damage [13–15]. The myelopreservation effects of trilaciclib are in contrast to the myelosuppressive effects of oral CDK4/6 inhibitors currently approved for the treatment of hormone receptor-positive breast cancer. Oral CDK4/6 inhibitors are dosed chronically to inhibit CDK4/6-dependent tumor proliferation, with the continued blockade of HSPC proliferation in the bone marrow resulting in myelosuppression (most commonly neutropenia) [16]. By contrast, trilaciclib is administered intravenously and intermittently (i.e., only prior to the administration of chemotherapy) to prevent damage to HSPCs. This allows for more precise control over the period of HSPC cycle arrest and the avoidance of lingering myelosuppressive effects [13].
Clinically, the myelopreservation benefits of trilaciclib have primarily been studied in patients with extensive stage (ES)-SCLC. SCLC tumor cells replicate independently of CDK4/6 through the obligate loss of the retinoblastoma protein [17], thereby allowing assessment of trilaciclib’s effects on the host without any potential direct effects on the tumor. In a randomized, double-blind, placebo-controlled phase II trial in patients with newly diagnosed ES-SCLC, administration of trilaciclib prior to etoposide plus carboplatin (E/P) improved myelosuppression endpoints across multiple hematopoietic lineages, without impairing chemotherapy efficacy [18]. Compared with the placebo arm, fewer supportive care interventions and dose reductions were required in the trilaciclib arm. Furthermore, safety was improved, with fewer grade ≥ 3 adverse events (AEs) reported with trilaciclib, primarily because of less high-grade hematologic toxicity [18].
Here, we report the myelopreservation, safety, health-related quality of life (HRQoL) and antitumor efficacy results from a randomized, double-blind, placebo-controlled phase II trial of trilaciclib administered prior to topotecan in patients with previously treated ES-SCLC. The current study was performed to assess the myelopreservation effects of trilaciclib in the setting of a chemotherapy regimen that is associated with significant hematologic toxicity and to evaluate the effects of trilaciclib when administered to patients with HSPCs that have already been damaged by prior lines of chemotherapy.
Methods
Study Design and Participants
This was a global, multicenter, phase Ib/IIa study (NCT02514447) of trilaciclib administered prior to topotecan for patients with ES-SCLC being treated in a second-/third-line setting. Data from the phase II portion of the study are presented.
Eligible patients were aged ≥ 18 years, with a confirmed diagnosis of ES-SCLC. Patients must have had disease progression during or after first- or second-line chemotherapy and been eligible to receive topotecan. Additional inclusion criteria (Supplementary Methods) included ≥ 1 measurable target lesion per Response Evaluable Criteria in Solid Tumors Version 1.1 (RECIST v1.1), adequate organ function, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2. Patients were excluded if they had a history of topotecan treatment for SCLC or brain metastases requiring immediate treatment.
The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonisation. The protocol and all study-related materials were approved by the institutional review board or independent ethics committee of each participating center. All patients provided written informed consent.
Patients were randomized to receive trilaciclib or placebo by an interactive web response system according to a randomization schedule generated by an unblinded statistician (Supplementary Methods). Randomization was stratified based on ECOG PS (0/1 versus 2) and sensitivity to first-line treatment, as defined by the investigator (sensitive versus resistant, whereby sensitivity was defined as having a complete response, partial response or stable disease with first-line treatment, and a progression-free interval ≥ 90 days after completion of first-line treatment; resistance was defined as a best response of progressive disease or a progression-free interval < 90 days). The sponsor, patients, investigators, and other staff were blinded to the treatment arm.
All patients received trilaciclib 240 mg/m2 or placebo administered as a 30-min IV infusion ≤ 4 h prior to topotecan 1.5 mg/m2 on each day that chemotherapy was administered. Treatment was administered on days 1–5 of each 21-day cycle. Patients were treated until progression, unacceptable toxicity, withdrawal of consent, or discontinuation by the patient or investigator. No dose modifications of trilaciclib were allowed. Topotecan dose reductions were only allowed twice for any patient and were permanent. To ensure an unconfounded assessment of trilaciclib’s ability to prevent CIM, administration of erythropoiesis-stimulating agents (ESAs) and primary prophylaxis with granulocyte colony-stimulating factors (G-CSFs) was prohibited in cycle 1, although therapeutic G-CSF was allowed in all cycles. As the risk of febrile neutropenia (FN) is predicted to be > 20% with topotecan, primary prophylaxis with G-CSF during cycle 1 would be indicated per standard guidelines. However, the safety monitoring committee agreed that for this study, prohibiting primary prophylaxis with G-CSF was permissible as long as the risk to patients receiving placebo was minimized by implementing a 2:1 (trilaciclib: placebo) randomization ratio, allowing the therapeutic use of G-CSF in cycle 1 and allowing investigators to only enroll those patients whose safety (as assessed by the treating physician) was not substantially compromised by this approach. Following completion of cycle 1, supportive care measures, including ESAs and G-CSF, were permitted per American Society of Clinical Oncology guidelines [19] and current prescribing information. Red blood cell (RBC) and platelet transfusions were allowed per investigator discretion throughout the entire treatment period.
Objectives, Endpoints, and Assessments
The primary objective was to assess the safety and tolerability of trilaciclib administered prior to topotecan. Unless otherwise specified, myelosuppression endpoints were measured using hematologic laboratory parameters (e.g., complete blood counts) and their derivatives rather than AEs. Primary endpoints were the duration of severe neutropenia (DSN) in cycle 1 and occurrence (percent of patients) of severe neutropenia (SN), whereby SN was defined as absolute neutrophil count < 0.5 × 109 cells/l. Key secondary endpoints were the occurrence of RBC transfusions on/after week 5, G-CSF administration, platelet transfusions, and number of all-cause dose reductions. Supportive secondary endpoints were the occurrence of FN AEs, ESA administration, IV antibiotic use, and infection serious AEs (SAEs) as well as overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Additional endpoints included patient-reported outcomes (PRO; exploratory), the occurrence and incidence (per 100 cycles) of hospitalization (all cause and due to CIM [neutropenia, anemia, thrombocytopenia] or sepsis), AEs, and additional safety endpoints. AEs were monitored throughout the study and were graded according to National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.03. Hematologic AEs were defined as neutropenia, neutrophil count decreased, anemia, anemia macrocytic, RBC count decreased, hemoglobin decreased, thrombocytopenia, and platelet count decreased. Exploratory assessment of trilaciclib’s effects on HRQoL was based on validated PRO instruments (e.g., Functional Assessment of Cancer Therapy [FACT]-Anemia [An], and FACT-Lung [FACT-L]), using literature-based thresholds of meaningful within-patient change [20–23]. Antitumor efficacy evaluation was based on responses derived from investigator measurements, as per RECIST v1.1.
Statistical Analysis
The sample size was determined based on having ≥ 90% power to detect treatment effects between trilaciclib versus placebo with respect to each of the primary endpoints, at a significance level of two-sided 0.20 (Supplementary Methods).
The intent-to-treat (ITT) analysis set, used for myelopreservation, PRO and PFS/OS endpoints, included all randomized patients, with data analyzed by randomly assigned treatment. Safety analyses included all patients who received ≥ 1 dose of any study drug, with data analyzed by actual received treatment. Analyses of tumor response were performed in patients who had measurable disease at the baseline tumor assessment, and had ≥ 1 post-baseline tumor assessment, clinical progression as noted by the investigator before their first post-baseline tumor scan, or died because of disease progression before their first post-baseline tumor scan.
Continuous variables were summarized by descriptive statistics, and categorical variables summarized in frequency tables. DSN in cycle 1 was assessed using a nonparametric analysis of covariance, and occurrence of SN was evaluated using a modified Poisson model. Both models included the stratification factors of ECOG PS (0/1 versus 2), sensitivity to first-line treatment (sensitive or resistant), and treatment as fixed effects, with baseline absolute neutrophil count as a covariate. For counting variables, treatment effects were evaluated using a negative binomial model with the same fixed terms, using corresponding baseline laboratory values as covariates.
For the two primary endpoints and key secondary endpoints, a Hochberg-based gatekeeping procedure was used to control the family-wise error rate across the multiple null hypotheses at the one-sided level of 0.1.
For PFS and OS, median time to event was estimated using the Kaplan-Meier method. Treatment group differences were tested using a stratified log-rank test, and a Cox regression model was used to estimate the hazard ratio (HR) and 80% confidence interval (CI) for trilaciclib versus placebo, with stratification factors as covariates.
Analyses were implemented using SAS® version 9.4. Final myelopreservation and PRO analyses were conducted after all patients had had the opportunity to receive ≥ 12 weeks of treatment or had discontinued from study treatment prior to week 12 (database lock 1; data cutoff September 28, 2018). Safety, hospitalization, and antitumor endpoint analyses were conducted when ≥ 70% of patients had died (database lock 2; data cut-off May 31, 2019).
Results
Patients and Treatment
Patients were enrolled at 17 sites in the US, 5 in Serbia, and 1 each in Belgium, Croatia, and Republic of Macedonia. Sixty-one patients were randomized (ITT population; 32 to trilaciclib and 29 to placebo), and 60 were treated per protocol (Fig. S1). Of the 60 treated patients, 59 (98.3%) discontinued study treatment, usually because of disease progression (37 patients; 61.7%). Of the ITT population, 60 patients (98.4%) discontinued the study, including 53 patients (86.9%) who discontinued because of death, most commonly attributed to lung cancer.
Baseline demographics and disease characteristics were generally comparable between the trilaciclib and placebo arms, except that there were more male patients (68.8% versus 41.4%), more ex-US patients (56.3% versus 37.9%), more current smokers (40.6% versus 24.1%), and more patients with brain metastases (25.0% versus 17.2%) enrolled in the trilaciclib arm (Table 1).Table 1 Baseline demographics and disease characteristics
Category Trilaciclib prior to topotecan 1.5 mg/m2 (n = 32) Placebo prior to topotecan 1.5 mg/m2 (n = 29)
Age, median, (min, max) years 62 (47, 77) 64 (47, 82)
Age group, n (%)
18– < 65 years 20 (62.5) 18 (62.1)
≥ 65 years 12 (37.5) 11 (37.9)
Gender, n (%)
Male 22 (68.8) 12 (41.4)
Female 10 (31.3) 17 (58.6)
Region, n (%)
US 14 (43.8) 18 (62.1)
Ex-US 18 (56.3) 11 (37.9)
ECOG PS, n (%)
0/1 29 (90.6) 27 (93.1)
2 3 (9.4) 2 (6.9)
Smoking history, n (%)
Never 3 (9.4) 2 (6.9)
Former 16 (50.0) 20 (69.0)
Current 13 (40.6) 7 (24.1)
Treatment line, n (%)
Second 26 (81.2) 24 (82.8)
Third 6 (18.8) 5 (17.2)
Sensitivity to first-line treatment, n (%)
Sensitive 14 (43.8) 13 (44.8)
Resistant 18 (56.3) 16 (55.2)
Brain metastases at baseline, n (%) 8 (25.0) 5 (17.2)
Baseline LDH, n (%)
≤ ULN 15 (46.9) 15 (51.7)
> ULN 16 (50.0) 13 (44.8)
Missing 1 (3.1) 1 (3.4)
Weight loss ≥ 6 months prior to randomization, n (%)
No 22 (68.8) 21 (72.4)
Yes 10 (31.3) 8 (27.6)
Weight loss > 5% 9 (90.0) 6 (75.0)
Weight loss ≤ 5% 1 (10.0) 2 (25.0)
ECOG PS Eastern Cooperative Oncology Group performance status, LDH lactate dehydrogenase, max maximum, min minimum, SCLC small cell lung cancer, ULN upper limit of normal, US United States
Myelopreservation
The addition of trilaciclib decreased CIM relative to placebo when administered prior to topotecan, as measured by statistically significant improvements in the primary endpoints of DSN in cycle 1 (P < 0.0001) and occurrence of SN (P = 0.016; Fig. 1 and Table S1). Fewer patients receiving trilaciclib required RBC and platelet transfusions, the use of G-CSFs and ESAs, and all-cause chemotherapy dose reductions compared with placebo (Fig. 1; Table S1).Fig. 1 Myelopreservation outcomes. DSN duration of severe neutropenia, ESA erythropoiesis-stimulating agent, FN febrile neutropenia, G-CSF granulocyte colony-stimulating factor, IV intravenous, RBC red blood cell, SAE serious adverse event, SN severe neutropenia
Patient Experience
PRO completion rates were high (> 80% in both arms) throughout the study. At baseline, mean PRO scores were higher in the placebo arm (indicating better HRQoL) than in the trilaciclib arm. Patients receiving trilaciclib consistently showed improvement or remained stable from baseline to the end of cycle 4 in all domains except emotional wellbeing, whereas patients receiving placebo showed deterioration (Fig. S2A). From baseline to the end of each of the first four cycles, a larger proportion of patients receiving trilaciclib had improvement and a smaller proportion had deterioration in fatigue subscale scores (symptoms and functional limitations) than in the placebo arm (Fig. S2B). Benefits with trilaciclib were seen for each measure of patient functioning and symptoms, in particular for fatigue, anemia symptoms, and functional limitations. Median time to deterioration for patients receiving trilaciclib was longer than for patients receiving placebo (HR range: 0.25–0.75; Fig. 2). The time to deterioration among patients receiving trilaciclib was approximately 5.5 months longer than placebo for functional wellbeing, 3 months longer for fatigue, and 2 months longer for Anemia-Trial Outcome Index.Fig. 2 Median time to confirmed deterioration in patient-reported outcomes. CI confidence interval, EWB emotional wellbeing, FACT-An Functional Assessment of Cancer Therapy-Anemia [An], FACT-G Functional Assessment of Cancer Therapy-General, FACT-L Functional Assessment of Cancer Therapy-Lung, FWB functional wellbeing, LCS lung cancer symptoms, NYR not yet reached, PWB physical wellbeing, SWB social wellbeing, TOI trial outcome index, TTD time to confirmed deterioration, Worsening decrease from baseline by a clinically meaningful threshold for two consecutive visits: ≤ 3 points for PWB, SWB, EWB, FWB, LCS, and fatigue; ≤ 6 points for FACT-L, lung TOI, and anemia TOI points; ≤ 7 points for FACT-G and FACT-An total scores
Safety
On average, patients in the trilaciclib and placebo arms completed five and four cycles of topotecan, respectively. Fewer patients receiving trilaciclib (18.8%) had per-protocol chemotherapy dose reductions compared with those receiving placebo (32.1%; Table S2). The incidence of dose delays was similar across the trilaciclib and placebo arms (65.6% versus 60.7%).
Almost all patients experienced ≥ 1 AE (Table 2). Compared with placebo, patients receiving trilaciclib had fewer high-grade (grade 3 and 4) AEs overall, including fewer high-grade hematologic AEs (Table 2). Hematologic AEs were the most commonly reported high-grade events (Table 2). Grade 3 or 4 FN AEs were reported in 6.3% of patients receiving trilaciclib compared with 17.9% of patients receiving placebo (Fig. 1). Among patients receiving trilaciclib, three (9.4%) were hospitalized for CIM or sepsis versus six patients (21.4%) receiving placebo (P = 0.1879). The incidence of hospitalization due to CIM or sepsis was 1.97/100 cycles with trilaciclib versus 9.73/100 cycles with placebo (Table S1).Table 2 Overall safety summary and most common adverse events (≥ 5 patients with any grade adverse event in either treatment arm)
Trilaciclib prior to topotecan 1.5 mg/m2
(n = 32) Placebo prior to topotecan 1.5 mg/m2
(n = 28)*
Patients with any AE, n (%) 32 (100) 27 (96.4)
Patients with AE related to any study drug, n (%) 30 (93.8) 27 (96.4)
Trilaciclib-/placebo-related 8 (25.0) 12 (42.9)
Topotecan-related 30 (93.8) 27 (96.4)
Patients with AE leading to discontinuation, n (%) 1 (3.1) 7 (25.0)
Patients with any grade ≥ 3 AE 28 (87.5) 27 (96.4)
Patients with any grade ≥ 4 AE 18 (56.3) 21 (75.0)
Patients with grade ≥ 3 AE related to any study drug, n (%) 25 (78.1) 27 (96.4)
Trilaciclib-/placebo-related 7 (21.9) 6 (21.4)
Topotecan-related 24 (75.0) 27 (96.4)
Patients with grade ≥ 3 hematologic AE, n (%) 26 (81.3) 26 (92.9)
Patients with grade ≥ 4 hematologic AE, n (%) 16 (50.0) 21 (75.0)
Patients with any serious AE, n (%) 12 (37.5) 7 (25.0)
Patients with any serious AE related to any study drug, n (%) 5 (15.6) 6 (21.4)
Trilaciclib-/placebo-related 1 (3.1) 0
Topotecan-related 5 (15.6) 6 (21.4)
Patients with AE leading to death, n (%) 3 (9.4)† 1 (3.6)
Most common AEs Trilaciclib prior to topotecan 1.5 mg/m2
(n = 32) Placebo prior to topotecan 1.5 mg/m2
(n = 28)*
Any grade Grade 3 Grade 4 Any grade Grade 3 Grade 4
Neutropenia 24 (75.0) 15 (46.9) 7 (21.9) 24 (85.7) 4 (14.3) 20 (71.4)
Thrombocytopenia 20 (62.5) 8 (25.0) 9 (28.1) 19 (67.9) 5 (17.9) 11 (39.3)
Anemia 17 (53.1) 9 (28.1) 0 (0) 24 (85.7) 17 (60.7) 0 (0)
Fatigue 13 (40.6) 2 (6.3) 0 (0) 10 (35.7) 2 (7.1) 0 (0)
Nausea 9 (28.1) 0 (0) 0 (0) 14 (50.0) 1 (3.6) 0 (0)
Pyrexia 8 (25.0) 0 (0) 0 (0) 5 (17.9) 0 (0) 0 (0)
Hypokalemia 7 (21.9) 0 (0) 1 (3.1) 5 (17.9) 2 (7.1) 0 (0)
Decreased appetite 6 (18.8) 1 (3.1) 0 (0) 5 (17.9) 0 (0) 0 (0)
Diarrhea 5 (15.6) 0 (0) 0 (0) 8 (28.6) 0 (0) 1 (3.6)
Leukopenia 4 (12.5) 1 (3.1) 1 (3.1) 9 (32.1) 4 (14.3) 3 (10.7)
Dyspnea 4 (12.5) 1 (3.1) 0 (0) 5 (17.9) 2 (7.1) 0 (0)
Cough 3 (9.4) 0 (0) 0 (0) 6 (21.4) 0 (0) 0 (0)
Vomiting 2 (6.3) 0 (0) 0 (0) 9 (32.1) 1 (3.6) 0 (0)
Dehydration 2 (6.3) 0 (0) 0 (0) 7 (25.0) 1 (3.6) 0 (0)
Febrile neutropenia 2 (6.3) 0 (0) 2 (6.3) 5 (17.9) 2 (7.1) 3 (10.7)
Dizziness 2 (6.3) 0 (0) 0 (0) 5 (17.9) 0 (0) 0 (0)
AE adverse event
*One patient randomized to the placebo arm was not treated
†One AE that led to death was considered related to topotecan; none were considered related to trilaciclib
One patient in the trilaciclib arm had an AE leading to treatment discontinuation versus seven patients receiving placebo. Fatal AEs were reported in three patients in the trilaciclib arm (respiratory failure, acute respiratory failure, and cerebrovascular accident); none were considered related to trilaciclib. One patient in the placebo arm had a fatal AE (sepsis). One trilaciclib-related SAE was reported (infusion-related grade 3 thrombophlebitis), which was also considered by the investigator to be related to topotecan. Infusion-related reactions/injection site reactions or phlebitis AEs were reported in four patients in the trilaciclib arm and no patients in the placebo arm; all were grade 1 or 2 in severity.
Antitumor Efficacy
The ORR was comparable between the trilaciclib and placebo arms (16.7% [5/30 patients] versus 23.1% [6/26 patients]; P = 0.5494; Table S3). Median duration of response was numerically longer with trilaciclib (6.8 months) than with placebo (4.9 months), with overlapping CIs. Investigator-assessed PFS and OS were comparable between the trilaciclib and placebo arms; median PFS was 4.2 versus 4.2 months (HR [80% CI] 0.88 [0.61, 1.27]; P = 0.5886]), and median OS was 6.2 versus 6.5 months (HR 1.38 [0.95, 2.01]; P = 0.3377), respectively (Fig. 3).Fig. 3 Kaplan-Meier estimates of the probability of progression-free survival and overall survival. a PFS in the ITT population. b OS in the ITT population. CI confidence interval, HR hazard ratio, ITT intent-to-treat, OS overall survival, PFS progression-free survival
Discussion
Data from this study indicate that trilaciclib demonstrates myelopreservation efficacy in previously treated patients with ES-SCLC, whose bone marrow was damaged by first- or second-line chemotherapy. Myelopreservation benefits manifested as statistically significant, clinically meaningful improvements in the primary endpoints of DSN in cycle 1 and occurrence of SN, consistent with the results of the previous phase II trial of trilaciclib in patients who received E/P chemotherapy for newly diagnosed ES-SCLC [18]. These measures are clinically relevant since the severity and duration of SN are associated with an increased risk of FN, infection, IV antibiotic use, and hospitalizations [24–26]. Indeed, consistent with the significant reduction in DSN in cycle 1, and occurrence of SN, there was an approximately threefold decrease in the occurrence of FN AEs among patients receiving trilaciclib compared with placebo, although the total number of events was small. Patients receiving trilaciclib also experienced less chemotherapy-induced anemia, consistent with the observation that fewer patients receiving trilaciclib needed RBC transfusions and ESA administrations. This finding is also clinically meaningful; not only does anemia negatively impact patients’ HRQoL, but it is also associated with decreased survival, decreased tumor response, delays in therapy, and reduced patient compliance and therefore contributes to considerable morbidity and mortality among patients with cancer [7, 27]. Additional myelopreservation endpoints also consistently favored trilaciclib over placebo, with improvements observed in the use of other supportive care measures, namely G-CSF and ESA administration, and platelet transfusions. This finding is particularly pertinent, as current supportive care interventions for myelosuppression are associated with additional risks, such as bone pain with G-CSF, thromboembolic events with ESAs, and hemolytic reactions with platelet transfusions [11, 12, 28]. Also important is the finding that trilaciclib reduced the occurrence of chemotherapy dose reductions compared with placebo, allowing the standard dose of topotecan to be maintained. Of note, > 50% of patients diagnosed with SCLC are aged > 65 years [29]. Older patients often present with additional comorbidities, meaning they are particularly vulnerable to CIM and more likely to experience clinically significant side effects leading to clinical intervention and delayed chemotherapy treatment and/or dose reductions. The proactive management of CIM in elderly patients with SCLC is therefore essential to ensure delivery of standard-of-care chemotherapy regimens while improving the patient experience [30].
Patients with ES-SCLC who received trilaciclib prior to topotecan had a better experience receiving chemotherapy than patients receiving placebo. PRO assessments, using validated instruments, demonstrated that trilaciclib administered prior to topotecan resulted in meaningful delays in deterioration and even showed signs of improvement in fatigue, as well as other symptoms and functional limitations associated with cancer and CIM. Given the poor prognosis associated with relapsed SCLC, some patients may consider improved HRQoL a more important therapeutic goal than traditional efficacy outcomes [31]. The benefit of trilaciclib was particularly apparent in endpoints associated with anemia and fatigue, providing further evidence that trilaciclib may reduce the burden of CIM and its associated symptoms among patients with ES-SCLC. The fact that these data were collected in a randomized, placebo-controlled, double-blind study, with limited missing data, supports the robustness of these findings.
In line with previous findings [18], an improved overall safety profile for topotecan was evidenced by a reduction in high-grade hematologic AEs (neutropenia and anemia), which are commonly associated with CIM, providing further evidence for the myelopreservation effects of trilaciclib. Rates of thrombocytopenia, particularly high-grade events, were reported at a similarly low frequency in the trilaciclib and placebo arms. Among patients receiving trilaciclib, there was a 56% decrease in the number of patients hospitalized for CIM or sepsis compared with placebo (9.4% versus 21.4%). No discontinuations or deaths due to AEs were considered to be related to trilaciclib treatment. AEs of special interest with trilaciclib were primarily low grade and included injection-site reactions and phlebitis/thrombophlebitis.
Differences in measures of antitumor efficacy (ORR, PFS, and OS) between trilaciclib and placebo were nonsignificant; however, for OS, there was a trend for the HRs to favor placebo for both the ITT population and most subgroups. The trend appears to reflect an imbalance between prognostic factors for antitumor efficacy between the treatment arms (Supplementary Methods; Table S4). Compared with the placebo arm, for example, more patients in the trilaciclib arm were male and were current smokers, both of which are poor prognostic factors for survival [32, 33]. Survival outcomes in this study were similar to those seen in other studies of topotecan, where median survival times rarely exceed 6 months [2, 3]. The data reiterate the dismal prognosis of patients with relapsed or refractory ES-SCLC and highlight the urgent need for more effective treatment options in this setting. In June 2020, lurbinectedin was approved for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. Approval was based on efficacy data from a single-arm, phase II basket trial of 105 patients treated with IV lurbinectedin every 21 days [34]. In this study, the ORR (primary endpoint) was 35.2%, with a median response duration of 5.1 months. The most common grade 3/4 AEs were hematologic abnormalities. Eleven patients had SAEs, including five patients with neutropenia and five patients with FN [34]. Considering the efficacy and safety profile of lurbinectedin, it would be interesting to investigate whether trilaciclib might be advantageously combined with lurbinectedin, and/or other emerging agents, to improve patient outcomes. Importantly, however, comparable antitumor efficacy outcomes between the two treatment arms corroborate previous findings that trilaciclib does not negatively impact the antitumor efficacy of chemotherapy [18].
A limitation of this study is that, due to the small sample size, only large differences in OS would be detected. Therefore, although trilaciclib reduced the occurrence of chemotherapy dose reductions compared with placebo, detecting the impact of any potential differences in topotecan dose intensity on survival outcomes would be limited. Studies in patients with SCLC have shown, however, that increasing the relative dose intensity of chemotherapy beyond the standard of care rarely translates into significant improvements in response rates or survival [35]. The small sample size may have also reduced the ability to observe statistically significant differences in secondary myelopreservation measures, such as the occurrence of FN AEs, infection SAEs, and IV antibiotic use. However, large treatment effects were not expected for these endpoints given that patients in both arms could receive supportive care interventions, with the exception of prophylactic G-CSF in cycle 1. Further investigation of the effects of trilaciclib on CIM and antitumor efficacy in larger studies is needed, including in tumor types or settings that may be more responsive to dose intensification. Studies to further delineate the effects of trilaciclib compared with other supportive care interventions, such as prophylactic G-CSF, would also be of interest to establish the real-world impact of trilaciclib on CIM.
Conclusions
Overall, these data extend the evidence for the clinical benefits of trilaciclib as a first-in-class myelopreservation agent for patients with SCLC treated with myelotoxic chemotherapy. The study demonstrates that trilaciclib reduces the risk of CIM in patients with HSPCs that have been damaged by prior lines of cytotoxic chemotherapy who are being treated with a chemotherapy regimen associated with significant hematologic toxicity.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 414 kb)
Supplementary file2 (PDF 418 kb)
Supplementary file3 (DOCX 195 kb)
Acknowledgements
We thank and acknowledge all the patients, their families, and study personnel for participating in the study.
Funding
This study and medical writing support, along with the Rapid Service and Open Access fees, were funded by G1 Therapeutics, Inc. (Research Triangle Park, NC).
Medical Writing Assistance
Medical writing assistance was provided by Fiona Scott, contracted by Alligent Europe (Envision Pharma Group), funded by G1 Therapeutics, Inc.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The submitted work was sponsored and funded by G1 Therapeutics, Inc., Research Triangle Park, NC, USA. Jie Xiao and Joyce M. Antal are employees of, and have stock ownership in, G1 Therapeutics, Inc. Shannon R. Morris was a paid employee of, and had stock ownership in, G1 Therapeutics, Inc., at the time of study completion and manuscript preparation and submission, and is currently a paid consultant to G1 Therapeutics, Inc., via SRM Consulting LLC. Outside of the submitted work, Renata Ferrarotto reports personal fees from Regeneron-Sanofi, Ayala Pharma, Klus Pharma, Medscape, Cellestia Biotech, Carevive and Prelude, and grants from AstraZeneca, Merck, Genentech, Pfizer, Oropharynx Program Stiefel clinical trials, ASCO Career Development Award, and the MD Anderson Khalifa Award. Maen A. Hussein is on the speaker bureau for Bristol-Myers Squibb, Incyte, and Pfizer. Lowell L. Hart reports personal consulting fees from Genentech, Novartis, Lilly, Nanostring, Astra Zeneca and Daiichi Sankyo outside of the scope of the current work. Zoran G. Andric, J. Thaddeus Beck, Janakiraman Subramanian, Davorin Z. Radosavljevic, Bojan Zaric, Wahid T. Hanna, Raid Aljumaily, Taofeek K. Owonikoko, and Didier Verhoeven have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonisation. The protocol and all study-related materials were approved by the institutional review board or independent ethics committee of each participating center. All patients provided written informed consent.
Data Availability
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
|
TOPOTECAN HYDROCHLORIDE
|
DrugsGivenReaction
|
CC BY-NC
|
33123968
| 18,528,230
|
2021-01
|
What was the administration route of drug 'TOPOTECAN HYDROCHLORIDE'?
|
Myelopreservation with Trilaciclib in Patients Receiving Topotecan for Small Cell Lung Cancer: Results from a Randomized, Double-Blind, Placebo-Controlled Phase II Study.
Multilineage myelosuppression is an acute toxicity of cytotoxic chemotherapy, resulting in serious complications and dose modifications. Current therapies are lineage specific and administered after chemotherapy damage has occurred. Trilaciclib is a cyclin-dependent kinase 4/6 inhibitor that is administered prior to chemotherapy to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy (myelopreservation).
In this randomized, double-blind, placebo-controlled phase II trial, patients with previously treated extensive-stage small cell lung cancer (ES-SCLC) were randomized to receive intravenous trilaciclib 240 mg/m2 or placebo before topotecan 1.5 mg/m2 on days 1-5 of each 21-day cycle. Primary endpoints were duration of severe neutropenia (DSN) in cycle 1 and occurrence of severe neutropenia (SN). Additional endpoints were prespecified to further assess the effect of trilaciclib on myelopreservation, safety, patient-reported outcomes (PROs), and antitumor efficacy.
Thirty-two patients received trilaciclib, and 29 patients received placebo. Compared with placebo, administration of trilaciclib prior to topotecan resulted in statistically significant and clinically meaningful decreases in DSN in cycle 1 (mean [standard deviation] 2 [3.9] versus 7 [6.2] days; adjusted one-sided P < 0.0001) and occurrence of SN (40.6% versus 75.9%; adjusted one-sided P = 0.016), with numerical improvements in additional neutrophil, red blood cell, and platelet measures. Patients receiving trilaciclib had fewer grade ≥ 3 hematologic adverse events than patients receiving placebo, particularly neutropenia (75.0% versus 85.7%) and anemia (28.1% versus 60.7%). Myelopreservation benefits extended to improvements in PROs, specifically in those related to fatigue. Antitumor efficacy was comparable between treatment arms.
Compared with placebo, the addition of trilaciclib prior to topotecan for the treatment of patients with previously treated ES-SCLC improves the patient experience of receiving chemotherapy, as demonstrated by a reduction in chemotherapy-induced myelosuppression, improved safety profile, improved quality of life and no detrimental effects on antitumor efficacy.
ClinicalTrials.gov: NCT02514447.
Key Summary Points
Why carry out this study?
Topotecan is an intravenous (IV) topoisomerase I inhibitor indicated for the treatment of small cell lung cancer (SCLC) in patients with platinum-sensitive disease after failure of first-line chemotherapy.
Although topotecan remains an important treatment option for patients with relapsed SCLC, it is commonly associated with chemotherapy-induced myelosuppression (CIM), which results in complications such as increased risk of infection, fatigue, and bleeding and the associated need for dose reductions and delays.
Trilaciclib is an IV cyclin-dependent kinase 4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells in the G1 phase of the cell cycle during chemotherapy exposure, thereby preserving them from chemotherapy-induced damage (myelopreservation).
In this randomized, placebo-controlled phase II study, the myelopreservation effects of trilaciclib administered prior to topotecan for the treatment of patients with previously treated extensive-stage SCLC (ES-SCLC) were evaluated.
What was learned from the study?
Compared with placebo, administering trilaciclib prior to topotecan reduced CIM and the need for supportive care interventions, improved the safety profile of topotecan, and improved the quality of life of patients, particularly with regard to endpoints associated with fatigue.
The data extend the evidence for the clinical benefits of trilaciclib as a first-in-class myelopreservation agent for patients with ES-SCLC treated with chemotherapy and demonstrate that trilaciclib can reduce the risk of CIM that might otherwise result in a substantial risk of additional intervention, hospitalization, and even death.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.13078844.
Introduction
Small cell lung cancer (SCLC) is highly sensitive to chemotherapeutic agents given in the first-line setting. However, despite high response rates to initial chemotherapy with etoposide plus cisplatin or carboplatin, irinotecan, or combination therapy with cyclophosphamide, vincristine, and an anthracycline, most patients relapse [1]. For > 15 years, the topoisomerase I inhibitor, topotecan, has been the only United States Food and Drug Administration-approved standard of care for patients with relapsed SCLC after failure of front-line chemotherapy, and it continues to be an important treatment option in this setting, both in the US and globally [2, 3]. However, topotecan is associated with significant chemotherapy-induced myelosuppression (CIM), which has long been a major concern to clinicians using this agent. The standard 5-day schedule of intravenous (IV) topotecan 1.5 mg/m2 results in high rates of grade 3 and 4 neutropenia, anemia, and thrombocytopenia [4–6], which increase the risk of infection, fatigue and bleeding among patients with SCLC and reduce patient quality of life. Furthermore, clinical concerns raised by CIM commonly lead to chemotherapy dose reductions and/or delays, which limit therapeutic dose intensity and, potentially, its intended antitumor efficacy [6–8]. CIM is currently managed with supportive care interventions such as hematopoietic growth factors and transfusions [9–12]. However, these are often administered reactively when signs or symptoms appear, are specific to individual hematopoietic lineages and impart their own set of risks for adverse reactions, highlighting the need for alternative approaches that can proactively prevent CIM.
Trilaciclib is a selective, reversible cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is administered intravenously prior to chemotherapy to preserve hematopoietic stem and progenitor cells (HSPCs) and lymphocytes during chemotherapy (myelopreservation). Because HSPCs and lymphocytes are dependent on CDK4/6 activity for proliferation, they are arrested in the G1 phase of the cell cycle upon exposure to trilaciclib. This transient, drug-induced cell cycle arrest prevents HSPCs and lymphocytes from proliferating in the presence of cytotoxic chemotherapy, thereby protecting them from chemotherapy-induced damage [13–15]. The myelopreservation effects of trilaciclib are in contrast to the myelosuppressive effects of oral CDK4/6 inhibitors currently approved for the treatment of hormone receptor-positive breast cancer. Oral CDK4/6 inhibitors are dosed chronically to inhibit CDK4/6-dependent tumor proliferation, with the continued blockade of HSPC proliferation in the bone marrow resulting in myelosuppression (most commonly neutropenia) [16]. By contrast, trilaciclib is administered intravenously and intermittently (i.e., only prior to the administration of chemotherapy) to prevent damage to HSPCs. This allows for more precise control over the period of HSPC cycle arrest and the avoidance of lingering myelosuppressive effects [13].
Clinically, the myelopreservation benefits of trilaciclib have primarily been studied in patients with extensive stage (ES)-SCLC. SCLC tumor cells replicate independently of CDK4/6 through the obligate loss of the retinoblastoma protein [17], thereby allowing assessment of trilaciclib’s effects on the host without any potential direct effects on the tumor. In a randomized, double-blind, placebo-controlled phase II trial in patients with newly diagnosed ES-SCLC, administration of trilaciclib prior to etoposide plus carboplatin (E/P) improved myelosuppression endpoints across multiple hematopoietic lineages, without impairing chemotherapy efficacy [18]. Compared with the placebo arm, fewer supportive care interventions and dose reductions were required in the trilaciclib arm. Furthermore, safety was improved, with fewer grade ≥ 3 adverse events (AEs) reported with trilaciclib, primarily because of less high-grade hematologic toxicity [18].
Here, we report the myelopreservation, safety, health-related quality of life (HRQoL) and antitumor efficacy results from a randomized, double-blind, placebo-controlled phase II trial of trilaciclib administered prior to topotecan in patients with previously treated ES-SCLC. The current study was performed to assess the myelopreservation effects of trilaciclib in the setting of a chemotherapy regimen that is associated with significant hematologic toxicity and to evaluate the effects of trilaciclib when administered to patients with HSPCs that have already been damaged by prior lines of chemotherapy.
Methods
Study Design and Participants
This was a global, multicenter, phase Ib/IIa study (NCT02514447) of trilaciclib administered prior to topotecan for patients with ES-SCLC being treated in a second-/third-line setting. Data from the phase II portion of the study are presented.
Eligible patients were aged ≥ 18 years, with a confirmed diagnosis of ES-SCLC. Patients must have had disease progression during or after first- or second-line chemotherapy and been eligible to receive topotecan. Additional inclusion criteria (Supplementary Methods) included ≥ 1 measurable target lesion per Response Evaluable Criteria in Solid Tumors Version 1.1 (RECIST v1.1), adequate organ function, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2. Patients were excluded if they had a history of topotecan treatment for SCLC or brain metastases requiring immediate treatment.
The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonisation. The protocol and all study-related materials were approved by the institutional review board or independent ethics committee of each participating center. All patients provided written informed consent.
Patients were randomized to receive trilaciclib or placebo by an interactive web response system according to a randomization schedule generated by an unblinded statistician (Supplementary Methods). Randomization was stratified based on ECOG PS (0/1 versus 2) and sensitivity to first-line treatment, as defined by the investigator (sensitive versus resistant, whereby sensitivity was defined as having a complete response, partial response or stable disease with first-line treatment, and a progression-free interval ≥ 90 days after completion of first-line treatment; resistance was defined as a best response of progressive disease or a progression-free interval < 90 days). The sponsor, patients, investigators, and other staff were blinded to the treatment arm.
All patients received trilaciclib 240 mg/m2 or placebo administered as a 30-min IV infusion ≤ 4 h prior to topotecan 1.5 mg/m2 on each day that chemotherapy was administered. Treatment was administered on days 1–5 of each 21-day cycle. Patients were treated until progression, unacceptable toxicity, withdrawal of consent, or discontinuation by the patient or investigator. No dose modifications of trilaciclib were allowed. Topotecan dose reductions were only allowed twice for any patient and were permanent. To ensure an unconfounded assessment of trilaciclib’s ability to prevent CIM, administration of erythropoiesis-stimulating agents (ESAs) and primary prophylaxis with granulocyte colony-stimulating factors (G-CSFs) was prohibited in cycle 1, although therapeutic G-CSF was allowed in all cycles. As the risk of febrile neutropenia (FN) is predicted to be > 20% with topotecan, primary prophylaxis with G-CSF during cycle 1 would be indicated per standard guidelines. However, the safety monitoring committee agreed that for this study, prohibiting primary prophylaxis with G-CSF was permissible as long as the risk to patients receiving placebo was minimized by implementing a 2:1 (trilaciclib: placebo) randomization ratio, allowing the therapeutic use of G-CSF in cycle 1 and allowing investigators to only enroll those patients whose safety (as assessed by the treating physician) was not substantially compromised by this approach. Following completion of cycle 1, supportive care measures, including ESAs and G-CSF, were permitted per American Society of Clinical Oncology guidelines [19] and current prescribing information. Red blood cell (RBC) and platelet transfusions were allowed per investigator discretion throughout the entire treatment period.
Objectives, Endpoints, and Assessments
The primary objective was to assess the safety and tolerability of trilaciclib administered prior to topotecan. Unless otherwise specified, myelosuppression endpoints were measured using hematologic laboratory parameters (e.g., complete blood counts) and their derivatives rather than AEs. Primary endpoints were the duration of severe neutropenia (DSN) in cycle 1 and occurrence (percent of patients) of severe neutropenia (SN), whereby SN was defined as absolute neutrophil count < 0.5 × 109 cells/l. Key secondary endpoints were the occurrence of RBC transfusions on/after week 5, G-CSF administration, platelet transfusions, and number of all-cause dose reductions. Supportive secondary endpoints were the occurrence of FN AEs, ESA administration, IV antibiotic use, and infection serious AEs (SAEs) as well as overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Additional endpoints included patient-reported outcomes (PRO; exploratory), the occurrence and incidence (per 100 cycles) of hospitalization (all cause and due to CIM [neutropenia, anemia, thrombocytopenia] or sepsis), AEs, and additional safety endpoints. AEs were monitored throughout the study and were graded according to National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.03. Hematologic AEs were defined as neutropenia, neutrophil count decreased, anemia, anemia macrocytic, RBC count decreased, hemoglobin decreased, thrombocytopenia, and platelet count decreased. Exploratory assessment of trilaciclib’s effects on HRQoL was based on validated PRO instruments (e.g., Functional Assessment of Cancer Therapy [FACT]-Anemia [An], and FACT-Lung [FACT-L]), using literature-based thresholds of meaningful within-patient change [20–23]. Antitumor efficacy evaluation was based on responses derived from investigator measurements, as per RECIST v1.1.
Statistical Analysis
The sample size was determined based on having ≥ 90% power to detect treatment effects between trilaciclib versus placebo with respect to each of the primary endpoints, at a significance level of two-sided 0.20 (Supplementary Methods).
The intent-to-treat (ITT) analysis set, used for myelopreservation, PRO and PFS/OS endpoints, included all randomized patients, with data analyzed by randomly assigned treatment. Safety analyses included all patients who received ≥ 1 dose of any study drug, with data analyzed by actual received treatment. Analyses of tumor response were performed in patients who had measurable disease at the baseline tumor assessment, and had ≥ 1 post-baseline tumor assessment, clinical progression as noted by the investigator before their first post-baseline tumor scan, or died because of disease progression before their first post-baseline tumor scan.
Continuous variables were summarized by descriptive statistics, and categorical variables summarized in frequency tables. DSN in cycle 1 was assessed using a nonparametric analysis of covariance, and occurrence of SN was evaluated using a modified Poisson model. Both models included the stratification factors of ECOG PS (0/1 versus 2), sensitivity to first-line treatment (sensitive or resistant), and treatment as fixed effects, with baseline absolute neutrophil count as a covariate. For counting variables, treatment effects were evaluated using a negative binomial model with the same fixed terms, using corresponding baseline laboratory values as covariates.
For the two primary endpoints and key secondary endpoints, a Hochberg-based gatekeeping procedure was used to control the family-wise error rate across the multiple null hypotheses at the one-sided level of 0.1.
For PFS and OS, median time to event was estimated using the Kaplan-Meier method. Treatment group differences were tested using a stratified log-rank test, and a Cox regression model was used to estimate the hazard ratio (HR) and 80% confidence interval (CI) for trilaciclib versus placebo, with stratification factors as covariates.
Analyses were implemented using SAS® version 9.4. Final myelopreservation and PRO analyses were conducted after all patients had had the opportunity to receive ≥ 12 weeks of treatment or had discontinued from study treatment prior to week 12 (database lock 1; data cutoff September 28, 2018). Safety, hospitalization, and antitumor endpoint analyses were conducted when ≥ 70% of patients had died (database lock 2; data cut-off May 31, 2019).
Results
Patients and Treatment
Patients were enrolled at 17 sites in the US, 5 in Serbia, and 1 each in Belgium, Croatia, and Republic of Macedonia. Sixty-one patients were randomized (ITT population; 32 to trilaciclib and 29 to placebo), and 60 were treated per protocol (Fig. S1). Of the 60 treated patients, 59 (98.3%) discontinued study treatment, usually because of disease progression (37 patients; 61.7%). Of the ITT population, 60 patients (98.4%) discontinued the study, including 53 patients (86.9%) who discontinued because of death, most commonly attributed to lung cancer.
Baseline demographics and disease characteristics were generally comparable between the trilaciclib and placebo arms, except that there were more male patients (68.8% versus 41.4%), more ex-US patients (56.3% versus 37.9%), more current smokers (40.6% versus 24.1%), and more patients with brain metastases (25.0% versus 17.2%) enrolled in the trilaciclib arm (Table 1).Table 1 Baseline demographics and disease characteristics
Category Trilaciclib prior to topotecan 1.5 mg/m2 (n = 32) Placebo prior to topotecan 1.5 mg/m2 (n = 29)
Age, median, (min, max) years 62 (47, 77) 64 (47, 82)
Age group, n (%)
18– < 65 years 20 (62.5) 18 (62.1)
≥ 65 years 12 (37.5) 11 (37.9)
Gender, n (%)
Male 22 (68.8) 12 (41.4)
Female 10 (31.3) 17 (58.6)
Region, n (%)
US 14 (43.8) 18 (62.1)
Ex-US 18 (56.3) 11 (37.9)
ECOG PS, n (%)
0/1 29 (90.6) 27 (93.1)
2 3 (9.4) 2 (6.9)
Smoking history, n (%)
Never 3 (9.4) 2 (6.9)
Former 16 (50.0) 20 (69.0)
Current 13 (40.6) 7 (24.1)
Treatment line, n (%)
Second 26 (81.2) 24 (82.8)
Third 6 (18.8) 5 (17.2)
Sensitivity to first-line treatment, n (%)
Sensitive 14 (43.8) 13 (44.8)
Resistant 18 (56.3) 16 (55.2)
Brain metastases at baseline, n (%) 8 (25.0) 5 (17.2)
Baseline LDH, n (%)
≤ ULN 15 (46.9) 15 (51.7)
> ULN 16 (50.0) 13 (44.8)
Missing 1 (3.1) 1 (3.4)
Weight loss ≥ 6 months prior to randomization, n (%)
No 22 (68.8) 21 (72.4)
Yes 10 (31.3) 8 (27.6)
Weight loss > 5% 9 (90.0) 6 (75.0)
Weight loss ≤ 5% 1 (10.0) 2 (25.0)
ECOG PS Eastern Cooperative Oncology Group performance status, LDH lactate dehydrogenase, max maximum, min minimum, SCLC small cell lung cancer, ULN upper limit of normal, US United States
Myelopreservation
The addition of trilaciclib decreased CIM relative to placebo when administered prior to topotecan, as measured by statistically significant improvements in the primary endpoints of DSN in cycle 1 (P < 0.0001) and occurrence of SN (P = 0.016; Fig. 1 and Table S1). Fewer patients receiving trilaciclib required RBC and platelet transfusions, the use of G-CSFs and ESAs, and all-cause chemotherapy dose reductions compared with placebo (Fig. 1; Table S1).Fig. 1 Myelopreservation outcomes. DSN duration of severe neutropenia, ESA erythropoiesis-stimulating agent, FN febrile neutropenia, G-CSF granulocyte colony-stimulating factor, IV intravenous, RBC red blood cell, SAE serious adverse event, SN severe neutropenia
Patient Experience
PRO completion rates were high (> 80% in both arms) throughout the study. At baseline, mean PRO scores were higher in the placebo arm (indicating better HRQoL) than in the trilaciclib arm. Patients receiving trilaciclib consistently showed improvement or remained stable from baseline to the end of cycle 4 in all domains except emotional wellbeing, whereas patients receiving placebo showed deterioration (Fig. S2A). From baseline to the end of each of the first four cycles, a larger proportion of patients receiving trilaciclib had improvement and a smaller proportion had deterioration in fatigue subscale scores (symptoms and functional limitations) than in the placebo arm (Fig. S2B). Benefits with trilaciclib were seen for each measure of patient functioning and symptoms, in particular for fatigue, anemia symptoms, and functional limitations. Median time to deterioration for patients receiving trilaciclib was longer than for patients receiving placebo (HR range: 0.25–0.75; Fig. 2). The time to deterioration among patients receiving trilaciclib was approximately 5.5 months longer than placebo for functional wellbeing, 3 months longer for fatigue, and 2 months longer for Anemia-Trial Outcome Index.Fig. 2 Median time to confirmed deterioration in patient-reported outcomes. CI confidence interval, EWB emotional wellbeing, FACT-An Functional Assessment of Cancer Therapy-Anemia [An], FACT-G Functional Assessment of Cancer Therapy-General, FACT-L Functional Assessment of Cancer Therapy-Lung, FWB functional wellbeing, LCS lung cancer symptoms, NYR not yet reached, PWB physical wellbeing, SWB social wellbeing, TOI trial outcome index, TTD time to confirmed deterioration, Worsening decrease from baseline by a clinically meaningful threshold for two consecutive visits: ≤ 3 points for PWB, SWB, EWB, FWB, LCS, and fatigue; ≤ 6 points for FACT-L, lung TOI, and anemia TOI points; ≤ 7 points for FACT-G and FACT-An total scores
Safety
On average, patients in the trilaciclib and placebo arms completed five and four cycles of topotecan, respectively. Fewer patients receiving trilaciclib (18.8%) had per-protocol chemotherapy dose reductions compared with those receiving placebo (32.1%; Table S2). The incidence of dose delays was similar across the trilaciclib and placebo arms (65.6% versus 60.7%).
Almost all patients experienced ≥ 1 AE (Table 2). Compared with placebo, patients receiving trilaciclib had fewer high-grade (grade 3 and 4) AEs overall, including fewer high-grade hematologic AEs (Table 2). Hematologic AEs were the most commonly reported high-grade events (Table 2). Grade 3 or 4 FN AEs were reported in 6.3% of patients receiving trilaciclib compared with 17.9% of patients receiving placebo (Fig. 1). Among patients receiving trilaciclib, three (9.4%) were hospitalized for CIM or sepsis versus six patients (21.4%) receiving placebo (P = 0.1879). The incidence of hospitalization due to CIM or sepsis was 1.97/100 cycles with trilaciclib versus 9.73/100 cycles with placebo (Table S1).Table 2 Overall safety summary and most common adverse events (≥ 5 patients with any grade adverse event in either treatment arm)
Trilaciclib prior to topotecan 1.5 mg/m2
(n = 32) Placebo prior to topotecan 1.5 mg/m2
(n = 28)*
Patients with any AE, n (%) 32 (100) 27 (96.4)
Patients with AE related to any study drug, n (%) 30 (93.8) 27 (96.4)
Trilaciclib-/placebo-related 8 (25.0) 12 (42.9)
Topotecan-related 30 (93.8) 27 (96.4)
Patients with AE leading to discontinuation, n (%) 1 (3.1) 7 (25.0)
Patients with any grade ≥ 3 AE 28 (87.5) 27 (96.4)
Patients with any grade ≥ 4 AE 18 (56.3) 21 (75.0)
Patients with grade ≥ 3 AE related to any study drug, n (%) 25 (78.1) 27 (96.4)
Trilaciclib-/placebo-related 7 (21.9) 6 (21.4)
Topotecan-related 24 (75.0) 27 (96.4)
Patients with grade ≥ 3 hematologic AE, n (%) 26 (81.3) 26 (92.9)
Patients with grade ≥ 4 hematologic AE, n (%) 16 (50.0) 21 (75.0)
Patients with any serious AE, n (%) 12 (37.5) 7 (25.0)
Patients with any serious AE related to any study drug, n (%) 5 (15.6) 6 (21.4)
Trilaciclib-/placebo-related 1 (3.1) 0
Topotecan-related 5 (15.6) 6 (21.4)
Patients with AE leading to death, n (%) 3 (9.4)† 1 (3.6)
Most common AEs Trilaciclib prior to topotecan 1.5 mg/m2
(n = 32) Placebo prior to topotecan 1.5 mg/m2
(n = 28)*
Any grade Grade 3 Grade 4 Any grade Grade 3 Grade 4
Neutropenia 24 (75.0) 15 (46.9) 7 (21.9) 24 (85.7) 4 (14.3) 20 (71.4)
Thrombocytopenia 20 (62.5) 8 (25.0) 9 (28.1) 19 (67.9) 5 (17.9) 11 (39.3)
Anemia 17 (53.1) 9 (28.1) 0 (0) 24 (85.7) 17 (60.7) 0 (0)
Fatigue 13 (40.6) 2 (6.3) 0 (0) 10 (35.7) 2 (7.1) 0 (0)
Nausea 9 (28.1) 0 (0) 0 (0) 14 (50.0) 1 (3.6) 0 (0)
Pyrexia 8 (25.0) 0 (0) 0 (0) 5 (17.9) 0 (0) 0 (0)
Hypokalemia 7 (21.9) 0 (0) 1 (3.1) 5 (17.9) 2 (7.1) 0 (0)
Decreased appetite 6 (18.8) 1 (3.1) 0 (0) 5 (17.9) 0 (0) 0 (0)
Diarrhea 5 (15.6) 0 (0) 0 (0) 8 (28.6) 0 (0) 1 (3.6)
Leukopenia 4 (12.5) 1 (3.1) 1 (3.1) 9 (32.1) 4 (14.3) 3 (10.7)
Dyspnea 4 (12.5) 1 (3.1) 0 (0) 5 (17.9) 2 (7.1) 0 (0)
Cough 3 (9.4) 0 (0) 0 (0) 6 (21.4) 0 (0) 0 (0)
Vomiting 2 (6.3) 0 (0) 0 (0) 9 (32.1) 1 (3.6) 0 (0)
Dehydration 2 (6.3) 0 (0) 0 (0) 7 (25.0) 1 (3.6) 0 (0)
Febrile neutropenia 2 (6.3) 0 (0) 2 (6.3) 5 (17.9) 2 (7.1) 3 (10.7)
Dizziness 2 (6.3) 0 (0) 0 (0) 5 (17.9) 0 (0) 0 (0)
AE adverse event
*One patient randomized to the placebo arm was not treated
†One AE that led to death was considered related to topotecan; none were considered related to trilaciclib
One patient in the trilaciclib arm had an AE leading to treatment discontinuation versus seven patients receiving placebo. Fatal AEs were reported in three patients in the trilaciclib arm (respiratory failure, acute respiratory failure, and cerebrovascular accident); none were considered related to trilaciclib. One patient in the placebo arm had a fatal AE (sepsis). One trilaciclib-related SAE was reported (infusion-related grade 3 thrombophlebitis), which was also considered by the investigator to be related to topotecan. Infusion-related reactions/injection site reactions or phlebitis AEs were reported in four patients in the trilaciclib arm and no patients in the placebo arm; all were grade 1 or 2 in severity.
Antitumor Efficacy
The ORR was comparable between the trilaciclib and placebo arms (16.7% [5/30 patients] versus 23.1% [6/26 patients]; P = 0.5494; Table S3). Median duration of response was numerically longer with trilaciclib (6.8 months) than with placebo (4.9 months), with overlapping CIs. Investigator-assessed PFS and OS were comparable between the trilaciclib and placebo arms; median PFS was 4.2 versus 4.2 months (HR [80% CI] 0.88 [0.61, 1.27]; P = 0.5886]), and median OS was 6.2 versus 6.5 months (HR 1.38 [0.95, 2.01]; P = 0.3377), respectively (Fig. 3).Fig. 3 Kaplan-Meier estimates of the probability of progression-free survival and overall survival. a PFS in the ITT population. b OS in the ITT population. CI confidence interval, HR hazard ratio, ITT intent-to-treat, OS overall survival, PFS progression-free survival
Discussion
Data from this study indicate that trilaciclib demonstrates myelopreservation efficacy in previously treated patients with ES-SCLC, whose bone marrow was damaged by first- or second-line chemotherapy. Myelopreservation benefits manifested as statistically significant, clinically meaningful improvements in the primary endpoints of DSN in cycle 1 and occurrence of SN, consistent with the results of the previous phase II trial of trilaciclib in patients who received E/P chemotherapy for newly diagnosed ES-SCLC [18]. These measures are clinically relevant since the severity and duration of SN are associated with an increased risk of FN, infection, IV antibiotic use, and hospitalizations [24–26]. Indeed, consistent with the significant reduction in DSN in cycle 1, and occurrence of SN, there was an approximately threefold decrease in the occurrence of FN AEs among patients receiving trilaciclib compared with placebo, although the total number of events was small. Patients receiving trilaciclib also experienced less chemotherapy-induced anemia, consistent with the observation that fewer patients receiving trilaciclib needed RBC transfusions and ESA administrations. This finding is also clinically meaningful; not only does anemia negatively impact patients’ HRQoL, but it is also associated with decreased survival, decreased tumor response, delays in therapy, and reduced patient compliance and therefore contributes to considerable morbidity and mortality among patients with cancer [7, 27]. Additional myelopreservation endpoints also consistently favored trilaciclib over placebo, with improvements observed in the use of other supportive care measures, namely G-CSF and ESA administration, and platelet transfusions. This finding is particularly pertinent, as current supportive care interventions for myelosuppression are associated with additional risks, such as bone pain with G-CSF, thromboembolic events with ESAs, and hemolytic reactions with platelet transfusions [11, 12, 28]. Also important is the finding that trilaciclib reduced the occurrence of chemotherapy dose reductions compared with placebo, allowing the standard dose of topotecan to be maintained. Of note, > 50% of patients diagnosed with SCLC are aged > 65 years [29]. Older patients often present with additional comorbidities, meaning they are particularly vulnerable to CIM and more likely to experience clinically significant side effects leading to clinical intervention and delayed chemotherapy treatment and/or dose reductions. The proactive management of CIM in elderly patients with SCLC is therefore essential to ensure delivery of standard-of-care chemotherapy regimens while improving the patient experience [30].
Patients with ES-SCLC who received trilaciclib prior to topotecan had a better experience receiving chemotherapy than patients receiving placebo. PRO assessments, using validated instruments, demonstrated that trilaciclib administered prior to topotecan resulted in meaningful delays in deterioration and even showed signs of improvement in fatigue, as well as other symptoms and functional limitations associated with cancer and CIM. Given the poor prognosis associated with relapsed SCLC, some patients may consider improved HRQoL a more important therapeutic goal than traditional efficacy outcomes [31]. The benefit of trilaciclib was particularly apparent in endpoints associated with anemia and fatigue, providing further evidence that trilaciclib may reduce the burden of CIM and its associated symptoms among patients with ES-SCLC. The fact that these data were collected in a randomized, placebo-controlled, double-blind study, with limited missing data, supports the robustness of these findings.
In line with previous findings [18], an improved overall safety profile for topotecan was evidenced by a reduction in high-grade hematologic AEs (neutropenia and anemia), which are commonly associated with CIM, providing further evidence for the myelopreservation effects of trilaciclib. Rates of thrombocytopenia, particularly high-grade events, were reported at a similarly low frequency in the trilaciclib and placebo arms. Among patients receiving trilaciclib, there was a 56% decrease in the number of patients hospitalized for CIM or sepsis compared with placebo (9.4% versus 21.4%). No discontinuations or deaths due to AEs were considered to be related to trilaciclib treatment. AEs of special interest with trilaciclib were primarily low grade and included injection-site reactions and phlebitis/thrombophlebitis.
Differences in measures of antitumor efficacy (ORR, PFS, and OS) between trilaciclib and placebo were nonsignificant; however, for OS, there was a trend for the HRs to favor placebo for both the ITT population and most subgroups. The trend appears to reflect an imbalance between prognostic factors for antitumor efficacy between the treatment arms (Supplementary Methods; Table S4). Compared with the placebo arm, for example, more patients in the trilaciclib arm were male and were current smokers, both of which are poor prognostic factors for survival [32, 33]. Survival outcomes in this study were similar to those seen in other studies of topotecan, where median survival times rarely exceed 6 months [2, 3]. The data reiterate the dismal prognosis of patients with relapsed or refractory ES-SCLC and highlight the urgent need for more effective treatment options in this setting. In June 2020, lurbinectedin was approved for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. Approval was based on efficacy data from a single-arm, phase II basket trial of 105 patients treated with IV lurbinectedin every 21 days [34]. In this study, the ORR (primary endpoint) was 35.2%, with a median response duration of 5.1 months. The most common grade 3/4 AEs were hematologic abnormalities. Eleven patients had SAEs, including five patients with neutropenia and five patients with FN [34]. Considering the efficacy and safety profile of lurbinectedin, it would be interesting to investigate whether trilaciclib might be advantageously combined with lurbinectedin, and/or other emerging agents, to improve patient outcomes. Importantly, however, comparable antitumor efficacy outcomes between the two treatment arms corroborate previous findings that trilaciclib does not negatively impact the antitumor efficacy of chemotherapy [18].
A limitation of this study is that, due to the small sample size, only large differences in OS would be detected. Therefore, although trilaciclib reduced the occurrence of chemotherapy dose reductions compared with placebo, detecting the impact of any potential differences in topotecan dose intensity on survival outcomes would be limited. Studies in patients with SCLC have shown, however, that increasing the relative dose intensity of chemotherapy beyond the standard of care rarely translates into significant improvements in response rates or survival [35]. The small sample size may have also reduced the ability to observe statistically significant differences in secondary myelopreservation measures, such as the occurrence of FN AEs, infection SAEs, and IV antibiotic use. However, large treatment effects were not expected for these endpoints given that patients in both arms could receive supportive care interventions, with the exception of prophylactic G-CSF in cycle 1. Further investigation of the effects of trilaciclib on CIM and antitumor efficacy in larger studies is needed, including in tumor types or settings that may be more responsive to dose intensification. Studies to further delineate the effects of trilaciclib compared with other supportive care interventions, such as prophylactic G-CSF, would also be of interest to establish the real-world impact of trilaciclib on CIM.
Conclusions
Overall, these data extend the evidence for the clinical benefits of trilaciclib as a first-in-class myelopreservation agent for patients with SCLC treated with myelotoxic chemotherapy. The study demonstrates that trilaciclib reduces the risk of CIM in patients with HSPCs that have been damaged by prior lines of cytotoxic chemotherapy who are being treated with a chemotherapy regimen associated with significant hematologic toxicity.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 414 kb)
Supplementary file2 (PDF 418 kb)
Supplementary file3 (DOCX 195 kb)
Acknowledgements
We thank and acknowledge all the patients, their families, and study personnel for participating in the study.
Funding
This study and medical writing support, along with the Rapid Service and Open Access fees, were funded by G1 Therapeutics, Inc. (Research Triangle Park, NC).
Medical Writing Assistance
Medical writing assistance was provided by Fiona Scott, contracted by Alligent Europe (Envision Pharma Group), funded by G1 Therapeutics, Inc.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The submitted work was sponsored and funded by G1 Therapeutics, Inc., Research Triangle Park, NC, USA. Jie Xiao and Joyce M. Antal are employees of, and have stock ownership in, G1 Therapeutics, Inc. Shannon R. Morris was a paid employee of, and had stock ownership in, G1 Therapeutics, Inc., at the time of study completion and manuscript preparation and submission, and is currently a paid consultant to G1 Therapeutics, Inc., via SRM Consulting LLC. Outside of the submitted work, Renata Ferrarotto reports personal fees from Regeneron-Sanofi, Ayala Pharma, Klus Pharma, Medscape, Cellestia Biotech, Carevive and Prelude, and grants from AstraZeneca, Merck, Genentech, Pfizer, Oropharynx Program Stiefel clinical trials, ASCO Career Development Award, and the MD Anderson Khalifa Award. Maen A. Hussein is on the speaker bureau for Bristol-Myers Squibb, Incyte, and Pfizer. Lowell L. Hart reports personal consulting fees from Genentech, Novartis, Lilly, Nanostring, Astra Zeneca and Daiichi Sankyo outside of the scope of the current work. Zoran G. Andric, J. Thaddeus Beck, Janakiraman Subramanian, Davorin Z. Radosavljevic, Bojan Zaric, Wahid T. Hanna, Raid Aljumaily, Taofeek K. Owonikoko, and Didier Verhoeven have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonisation. The protocol and all study-related materials were approved by the institutional review board or independent ethics committee of each participating center. All patients provided written informed consent.
Data Availability
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
|
Intravenous drip
|
DrugAdministrationRoute
|
CC BY-NC
|
33123968
| 18,528,230
|
2021-01
|
What was the dosage of drug 'TOPOTECAN HYDROCHLORIDE'?
|
Myelopreservation with Trilaciclib in Patients Receiving Topotecan for Small Cell Lung Cancer: Results from a Randomized, Double-Blind, Placebo-Controlled Phase II Study.
Multilineage myelosuppression is an acute toxicity of cytotoxic chemotherapy, resulting in serious complications and dose modifications. Current therapies are lineage specific and administered after chemotherapy damage has occurred. Trilaciclib is a cyclin-dependent kinase 4/6 inhibitor that is administered prior to chemotherapy to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy (myelopreservation).
In this randomized, double-blind, placebo-controlled phase II trial, patients with previously treated extensive-stage small cell lung cancer (ES-SCLC) were randomized to receive intravenous trilaciclib 240 mg/m2 or placebo before topotecan 1.5 mg/m2 on days 1-5 of each 21-day cycle. Primary endpoints were duration of severe neutropenia (DSN) in cycle 1 and occurrence of severe neutropenia (SN). Additional endpoints were prespecified to further assess the effect of trilaciclib on myelopreservation, safety, patient-reported outcomes (PROs), and antitumor efficacy.
Thirty-two patients received trilaciclib, and 29 patients received placebo. Compared with placebo, administration of trilaciclib prior to topotecan resulted in statistically significant and clinically meaningful decreases in DSN in cycle 1 (mean [standard deviation] 2 [3.9] versus 7 [6.2] days; adjusted one-sided P < 0.0001) and occurrence of SN (40.6% versus 75.9%; adjusted one-sided P = 0.016), with numerical improvements in additional neutrophil, red blood cell, and platelet measures. Patients receiving trilaciclib had fewer grade ≥ 3 hematologic adverse events than patients receiving placebo, particularly neutropenia (75.0% versus 85.7%) and anemia (28.1% versus 60.7%). Myelopreservation benefits extended to improvements in PROs, specifically in those related to fatigue. Antitumor efficacy was comparable between treatment arms.
Compared with placebo, the addition of trilaciclib prior to topotecan for the treatment of patients with previously treated ES-SCLC improves the patient experience of receiving chemotherapy, as demonstrated by a reduction in chemotherapy-induced myelosuppression, improved safety profile, improved quality of life and no detrimental effects on antitumor efficacy.
ClinicalTrials.gov: NCT02514447.
Key Summary Points
Why carry out this study?
Topotecan is an intravenous (IV) topoisomerase I inhibitor indicated for the treatment of small cell lung cancer (SCLC) in patients with platinum-sensitive disease after failure of first-line chemotherapy.
Although topotecan remains an important treatment option for patients with relapsed SCLC, it is commonly associated with chemotherapy-induced myelosuppression (CIM), which results in complications such as increased risk of infection, fatigue, and bleeding and the associated need for dose reductions and delays.
Trilaciclib is an IV cyclin-dependent kinase 4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells in the G1 phase of the cell cycle during chemotherapy exposure, thereby preserving them from chemotherapy-induced damage (myelopreservation).
In this randomized, placebo-controlled phase II study, the myelopreservation effects of trilaciclib administered prior to topotecan for the treatment of patients with previously treated extensive-stage SCLC (ES-SCLC) were evaluated.
What was learned from the study?
Compared with placebo, administering trilaciclib prior to topotecan reduced CIM and the need for supportive care interventions, improved the safety profile of topotecan, and improved the quality of life of patients, particularly with regard to endpoints associated with fatigue.
The data extend the evidence for the clinical benefits of trilaciclib as a first-in-class myelopreservation agent for patients with ES-SCLC treated with chemotherapy and demonstrate that trilaciclib can reduce the risk of CIM that might otherwise result in a substantial risk of additional intervention, hospitalization, and even death.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.13078844.
Introduction
Small cell lung cancer (SCLC) is highly sensitive to chemotherapeutic agents given in the first-line setting. However, despite high response rates to initial chemotherapy with etoposide plus cisplatin or carboplatin, irinotecan, or combination therapy with cyclophosphamide, vincristine, and an anthracycline, most patients relapse [1]. For > 15 years, the topoisomerase I inhibitor, topotecan, has been the only United States Food and Drug Administration-approved standard of care for patients with relapsed SCLC after failure of front-line chemotherapy, and it continues to be an important treatment option in this setting, both in the US and globally [2, 3]. However, topotecan is associated with significant chemotherapy-induced myelosuppression (CIM), which has long been a major concern to clinicians using this agent. The standard 5-day schedule of intravenous (IV) topotecan 1.5 mg/m2 results in high rates of grade 3 and 4 neutropenia, anemia, and thrombocytopenia [4–6], which increase the risk of infection, fatigue and bleeding among patients with SCLC and reduce patient quality of life. Furthermore, clinical concerns raised by CIM commonly lead to chemotherapy dose reductions and/or delays, which limit therapeutic dose intensity and, potentially, its intended antitumor efficacy [6–8]. CIM is currently managed with supportive care interventions such as hematopoietic growth factors and transfusions [9–12]. However, these are often administered reactively when signs or symptoms appear, are specific to individual hematopoietic lineages and impart their own set of risks for adverse reactions, highlighting the need for alternative approaches that can proactively prevent CIM.
Trilaciclib is a selective, reversible cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is administered intravenously prior to chemotherapy to preserve hematopoietic stem and progenitor cells (HSPCs) and lymphocytes during chemotherapy (myelopreservation). Because HSPCs and lymphocytes are dependent on CDK4/6 activity for proliferation, they are arrested in the G1 phase of the cell cycle upon exposure to trilaciclib. This transient, drug-induced cell cycle arrest prevents HSPCs and lymphocytes from proliferating in the presence of cytotoxic chemotherapy, thereby protecting them from chemotherapy-induced damage [13–15]. The myelopreservation effects of trilaciclib are in contrast to the myelosuppressive effects of oral CDK4/6 inhibitors currently approved for the treatment of hormone receptor-positive breast cancer. Oral CDK4/6 inhibitors are dosed chronically to inhibit CDK4/6-dependent tumor proliferation, with the continued blockade of HSPC proliferation in the bone marrow resulting in myelosuppression (most commonly neutropenia) [16]. By contrast, trilaciclib is administered intravenously and intermittently (i.e., only prior to the administration of chemotherapy) to prevent damage to HSPCs. This allows for more precise control over the period of HSPC cycle arrest and the avoidance of lingering myelosuppressive effects [13].
Clinically, the myelopreservation benefits of trilaciclib have primarily been studied in patients with extensive stage (ES)-SCLC. SCLC tumor cells replicate independently of CDK4/6 through the obligate loss of the retinoblastoma protein [17], thereby allowing assessment of trilaciclib’s effects on the host without any potential direct effects on the tumor. In a randomized, double-blind, placebo-controlled phase II trial in patients with newly diagnosed ES-SCLC, administration of trilaciclib prior to etoposide plus carboplatin (E/P) improved myelosuppression endpoints across multiple hematopoietic lineages, without impairing chemotherapy efficacy [18]. Compared with the placebo arm, fewer supportive care interventions and dose reductions were required in the trilaciclib arm. Furthermore, safety was improved, with fewer grade ≥ 3 adverse events (AEs) reported with trilaciclib, primarily because of less high-grade hematologic toxicity [18].
Here, we report the myelopreservation, safety, health-related quality of life (HRQoL) and antitumor efficacy results from a randomized, double-blind, placebo-controlled phase II trial of trilaciclib administered prior to topotecan in patients with previously treated ES-SCLC. The current study was performed to assess the myelopreservation effects of trilaciclib in the setting of a chemotherapy regimen that is associated with significant hematologic toxicity and to evaluate the effects of trilaciclib when administered to patients with HSPCs that have already been damaged by prior lines of chemotherapy.
Methods
Study Design and Participants
This was a global, multicenter, phase Ib/IIa study (NCT02514447) of trilaciclib administered prior to topotecan for patients with ES-SCLC being treated in a second-/third-line setting. Data from the phase II portion of the study are presented.
Eligible patients were aged ≥ 18 years, with a confirmed diagnosis of ES-SCLC. Patients must have had disease progression during or after first- or second-line chemotherapy and been eligible to receive topotecan. Additional inclusion criteria (Supplementary Methods) included ≥ 1 measurable target lesion per Response Evaluable Criteria in Solid Tumors Version 1.1 (RECIST v1.1), adequate organ function, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2. Patients were excluded if they had a history of topotecan treatment for SCLC or brain metastases requiring immediate treatment.
The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonisation. The protocol and all study-related materials were approved by the institutional review board or independent ethics committee of each participating center. All patients provided written informed consent.
Patients were randomized to receive trilaciclib or placebo by an interactive web response system according to a randomization schedule generated by an unblinded statistician (Supplementary Methods). Randomization was stratified based on ECOG PS (0/1 versus 2) and sensitivity to first-line treatment, as defined by the investigator (sensitive versus resistant, whereby sensitivity was defined as having a complete response, partial response or stable disease with first-line treatment, and a progression-free interval ≥ 90 days after completion of first-line treatment; resistance was defined as a best response of progressive disease or a progression-free interval < 90 days). The sponsor, patients, investigators, and other staff were blinded to the treatment arm.
All patients received trilaciclib 240 mg/m2 or placebo administered as a 30-min IV infusion ≤ 4 h prior to topotecan 1.5 mg/m2 on each day that chemotherapy was administered. Treatment was administered on days 1–5 of each 21-day cycle. Patients were treated until progression, unacceptable toxicity, withdrawal of consent, or discontinuation by the patient or investigator. No dose modifications of trilaciclib were allowed. Topotecan dose reductions were only allowed twice for any patient and were permanent. To ensure an unconfounded assessment of trilaciclib’s ability to prevent CIM, administration of erythropoiesis-stimulating agents (ESAs) and primary prophylaxis with granulocyte colony-stimulating factors (G-CSFs) was prohibited in cycle 1, although therapeutic G-CSF was allowed in all cycles. As the risk of febrile neutropenia (FN) is predicted to be > 20% with topotecan, primary prophylaxis with G-CSF during cycle 1 would be indicated per standard guidelines. However, the safety monitoring committee agreed that for this study, prohibiting primary prophylaxis with G-CSF was permissible as long as the risk to patients receiving placebo was minimized by implementing a 2:1 (trilaciclib: placebo) randomization ratio, allowing the therapeutic use of G-CSF in cycle 1 and allowing investigators to only enroll those patients whose safety (as assessed by the treating physician) was not substantially compromised by this approach. Following completion of cycle 1, supportive care measures, including ESAs and G-CSF, were permitted per American Society of Clinical Oncology guidelines [19] and current prescribing information. Red blood cell (RBC) and platelet transfusions were allowed per investigator discretion throughout the entire treatment period.
Objectives, Endpoints, and Assessments
The primary objective was to assess the safety and tolerability of trilaciclib administered prior to topotecan. Unless otherwise specified, myelosuppression endpoints were measured using hematologic laboratory parameters (e.g., complete blood counts) and their derivatives rather than AEs. Primary endpoints were the duration of severe neutropenia (DSN) in cycle 1 and occurrence (percent of patients) of severe neutropenia (SN), whereby SN was defined as absolute neutrophil count < 0.5 × 109 cells/l. Key secondary endpoints were the occurrence of RBC transfusions on/after week 5, G-CSF administration, platelet transfusions, and number of all-cause dose reductions. Supportive secondary endpoints were the occurrence of FN AEs, ESA administration, IV antibiotic use, and infection serious AEs (SAEs) as well as overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Additional endpoints included patient-reported outcomes (PRO; exploratory), the occurrence and incidence (per 100 cycles) of hospitalization (all cause and due to CIM [neutropenia, anemia, thrombocytopenia] or sepsis), AEs, and additional safety endpoints. AEs were monitored throughout the study and were graded according to National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.03. Hematologic AEs were defined as neutropenia, neutrophil count decreased, anemia, anemia macrocytic, RBC count decreased, hemoglobin decreased, thrombocytopenia, and platelet count decreased. Exploratory assessment of trilaciclib’s effects on HRQoL was based on validated PRO instruments (e.g., Functional Assessment of Cancer Therapy [FACT]-Anemia [An], and FACT-Lung [FACT-L]), using literature-based thresholds of meaningful within-patient change [20–23]. Antitumor efficacy evaluation was based on responses derived from investigator measurements, as per RECIST v1.1.
Statistical Analysis
The sample size was determined based on having ≥ 90% power to detect treatment effects between trilaciclib versus placebo with respect to each of the primary endpoints, at a significance level of two-sided 0.20 (Supplementary Methods).
The intent-to-treat (ITT) analysis set, used for myelopreservation, PRO and PFS/OS endpoints, included all randomized patients, with data analyzed by randomly assigned treatment. Safety analyses included all patients who received ≥ 1 dose of any study drug, with data analyzed by actual received treatment. Analyses of tumor response were performed in patients who had measurable disease at the baseline tumor assessment, and had ≥ 1 post-baseline tumor assessment, clinical progression as noted by the investigator before their first post-baseline tumor scan, or died because of disease progression before their first post-baseline tumor scan.
Continuous variables were summarized by descriptive statistics, and categorical variables summarized in frequency tables. DSN in cycle 1 was assessed using a nonparametric analysis of covariance, and occurrence of SN was evaluated using a modified Poisson model. Both models included the stratification factors of ECOG PS (0/1 versus 2), sensitivity to first-line treatment (sensitive or resistant), and treatment as fixed effects, with baseline absolute neutrophil count as a covariate. For counting variables, treatment effects were evaluated using a negative binomial model with the same fixed terms, using corresponding baseline laboratory values as covariates.
For the two primary endpoints and key secondary endpoints, a Hochberg-based gatekeeping procedure was used to control the family-wise error rate across the multiple null hypotheses at the one-sided level of 0.1.
For PFS and OS, median time to event was estimated using the Kaplan-Meier method. Treatment group differences were tested using a stratified log-rank test, and a Cox regression model was used to estimate the hazard ratio (HR) and 80% confidence interval (CI) for trilaciclib versus placebo, with stratification factors as covariates.
Analyses were implemented using SAS® version 9.4. Final myelopreservation and PRO analyses were conducted after all patients had had the opportunity to receive ≥ 12 weeks of treatment or had discontinued from study treatment prior to week 12 (database lock 1; data cutoff September 28, 2018). Safety, hospitalization, and antitumor endpoint analyses were conducted when ≥ 70% of patients had died (database lock 2; data cut-off May 31, 2019).
Results
Patients and Treatment
Patients were enrolled at 17 sites in the US, 5 in Serbia, and 1 each in Belgium, Croatia, and Republic of Macedonia. Sixty-one patients were randomized (ITT population; 32 to trilaciclib and 29 to placebo), and 60 were treated per protocol (Fig. S1). Of the 60 treated patients, 59 (98.3%) discontinued study treatment, usually because of disease progression (37 patients; 61.7%). Of the ITT population, 60 patients (98.4%) discontinued the study, including 53 patients (86.9%) who discontinued because of death, most commonly attributed to lung cancer.
Baseline demographics and disease characteristics were generally comparable between the trilaciclib and placebo arms, except that there were more male patients (68.8% versus 41.4%), more ex-US patients (56.3% versus 37.9%), more current smokers (40.6% versus 24.1%), and more patients with brain metastases (25.0% versus 17.2%) enrolled in the trilaciclib arm (Table 1).Table 1 Baseline demographics and disease characteristics
Category Trilaciclib prior to topotecan 1.5 mg/m2 (n = 32) Placebo prior to topotecan 1.5 mg/m2 (n = 29)
Age, median, (min, max) years 62 (47, 77) 64 (47, 82)
Age group, n (%)
18– < 65 years 20 (62.5) 18 (62.1)
≥ 65 years 12 (37.5) 11 (37.9)
Gender, n (%)
Male 22 (68.8) 12 (41.4)
Female 10 (31.3) 17 (58.6)
Region, n (%)
US 14 (43.8) 18 (62.1)
Ex-US 18 (56.3) 11 (37.9)
ECOG PS, n (%)
0/1 29 (90.6) 27 (93.1)
2 3 (9.4) 2 (6.9)
Smoking history, n (%)
Never 3 (9.4) 2 (6.9)
Former 16 (50.0) 20 (69.0)
Current 13 (40.6) 7 (24.1)
Treatment line, n (%)
Second 26 (81.2) 24 (82.8)
Third 6 (18.8) 5 (17.2)
Sensitivity to first-line treatment, n (%)
Sensitive 14 (43.8) 13 (44.8)
Resistant 18 (56.3) 16 (55.2)
Brain metastases at baseline, n (%) 8 (25.0) 5 (17.2)
Baseline LDH, n (%)
≤ ULN 15 (46.9) 15 (51.7)
> ULN 16 (50.0) 13 (44.8)
Missing 1 (3.1) 1 (3.4)
Weight loss ≥ 6 months prior to randomization, n (%)
No 22 (68.8) 21 (72.4)
Yes 10 (31.3) 8 (27.6)
Weight loss > 5% 9 (90.0) 6 (75.0)
Weight loss ≤ 5% 1 (10.0) 2 (25.0)
ECOG PS Eastern Cooperative Oncology Group performance status, LDH lactate dehydrogenase, max maximum, min minimum, SCLC small cell lung cancer, ULN upper limit of normal, US United States
Myelopreservation
The addition of trilaciclib decreased CIM relative to placebo when administered prior to topotecan, as measured by statistically significant improvements in the primary endpoints of DSN in cycle 1 (P < 0.0001) and occurrence of SN (P = 0.016; Fig. 1 and Table S1). Fewer patients receiving trilaciclib required RBC and platelet transfusions, the use of G-CSFs and ESAs, and all-cause chemotherapy dose reductions compared with placebo (Fig. 1; Table S1).Fig. 1 Myelopreservation outcomes. DSN duration of severe neutropenia, ESA erythropoiesis-stimulating agent, FN febrile neutropenia, G-CSF granulocyte colony-stimulating factor, IV intravenous, RBC red blood cell, SAE serious adverse event, SN severe neutropenia
Patient Experience
PRO completion rates were high (> 80% in both arms) throughout the study. At baseline, mean PRO scores were higher in the placebo arm (indicating better HRQoL) than in the trilaciclib arm. Patients receiving trilaciclib consistently showed improvement or remained stable from baseline to the end of cycle 4 in all domains except emotional wellbeing, whereas patients receiving placebo showed deterioration (Fig. S2A). From baseline to the end of each of the first four cycles, a larger proportion of patients receiving trilaciclib had improvement and a smaller proportion had deterioration in fatigue subscale scores (symptoms and functional limitations) than in the placebo arm (Fig. S2B). Benefits with trilaciclib were seen for each measure of patient functioning and symptoms, in particular for fatigue, anemia symptoms, and functional limitations. Median time to deterioration for patients receiving trilaciclib was longer than for patients receiving placebo (HR range: 0.25–0.75; Fig. 2). The time to deterioration among patients receiving trilaciclib was approximately 5.5 months longer than placebo for functional wellbeing, 3 months longer for fatigue, and 2 months longer for Anemia-Trial Outcome Index.Fig. 2 Median time to confirmed deterioration in patient-reported outcomes. CI confidence interval, EWB emotional wellbeing, FACT-An Functional Assessment of Cancer Therapy-Anemia [An], FACT-G Functional Assessment of Cancer Therapy-General, FACT-L Functional Assessment of Cancer Therapy-Lung, FWB functional wellbeing, LCS lung cancer symptoms, NYR not yet reached, PWB physical wellbeing, SWB social wellbeing, TOI trial outcome index, TTD time to confirmed deterioration, Worsening decrease from baseline by a clinically meaningful threshold for two consecutive visits: ≤ 3 points for PWB, SWB, EWB, FWB, LCS, and fatigue; ≤ 6 points for FACT-L, lung TOI, and anemia TOI points; ≤ 7 points for FACT-G and FACT-An total scores
Safety
On average, patients in the trilaciclib and placebo arms completed five and four cycles of topotecan, respectively. Fewer patients receiving trilaciclib (18.8%) had per-protocol chemotherapy dose reductions compared with those receiving placebo (32.1%; Table S2). The incidence of dose delays was similar across the trilaciclib and placebo arms (65.6% versus 60.7%).
Almost all patients experienced ≥ 1 AE (Table 2). Compared with placebo, patients receiving trilaciclib had fewer high-grade (grade 3 and 4) AEs overall, including fewer high-grade hematologic AEs (Table 2). Hematologic AEs were the most commonly reported high-grade events (Table 2). Grade 3 or 4 FN AEs were reported in 6.3% of patients receiving trilaciclib compared with 17.9% of patients receiving placebo (Fig. 1). Among patients receiving trilaciclib, three (9.4%) were hospitalized for CIM or sepsis versus six patients (21.4%) receiving placebo (P = 0.1879). The incidence of hospitalization due to CIM or sepsis was 1.97/100 cycles with trilaciclib versus 9.73/100 cycles with placebo (Table S1).Table 2 Overall safety summary and most common adverse events (≥ 5 patients with any grade adverse event in either treatment arm)
Trilaciclib prior to topotecan 1.5 mg/m2
(n = 32) Placebo prior to topotecan 1.5 mg/m2
(n = 28)*
Patients with any AE, n (%) 32 (100) 27 (96.4)
Patients with AE related to any study drug, n (%) 30 (93.8) 27 (96.4)
Trilaciclib-/placebo-related 8 (25.0) 12 (42.9)
Topotecan-related 30 (93.8) 27 (96.4)
Patients with AE leading to discontinuation, n (%) 1 (3.1) 7 (25.0)
Patients with any grade ≥ 3 AE 28 (87.5) 27 (96.4)
Patients with any grade ≥ 4 AE 18 (56.3) 21 (75.0)
Patients with grade ≥ 3 AE related to any study drug, n (%) 25 (78.1) 27 (96.4)
Trilaciclib-/placebo-related 7 (21.9) 6 (21.4)
Topotecan-related 24 (75.0) 27 (96.4)
Patients with grade ≥ 3 hematologic AE, n (%) 26 (81.3) 26 (92.9)
Patients with grade ≥ 4 hematologic AE, n (%) 16 (50.0) 21 (75.0)
Patients with any serious AE, n (%) 12 (37.5) 7 (25.0)
Patients with any serious AE related to any study drug, n (%) 5 (15.6) 6 (21.4)
Trilaciclib-/placebo-related 1 (3.1) 0
Topotecan-related 5 (15.6) 6 (21.4)
Patients with AE leading to death, n (%) 3 (9.4)† 1 (3.6)
Most common AEs Trilaciclib prior to topotecan 1.5 mg/m2
(n = 32) Placebo prior to topotecan 1.5 mg/m2
(n = 28)*
Any grade Grade 3 Grade 4 Any grade Grade 3 Grade 4
Neutropenia 24 (75.0) 15 (46.9) 7 (21.9) 24 (85.7) 4 (14.3) 20 (71.4)
Thrombocytopenia 20 (62.5) 8 (25.0) 9 (28.1) 19 (67.9) 5 (17.9) 11 (39.3)
Anemia 17 (53.1) 9 (28.1) 0 (0) 24 (85.7) 17 (60.7) 0 (0)
Fatigue 13 (40.6) 2 (6.3) 0 (0) 10 (35.7) 2 (7.1) 0 (0)
Nausea 9 (28.1) 0 (0) 0 (0) 14 (50.0) 1 (3.6) 0 (0)
Pyrexia 8 (25.0) 0 (0) 0 (0) 5 (17.9) 0 (0) 0 (0)
Hypokalemia 7 (21.9) 0 (0) 1 (3.1) 5 (17.9) 2 (7.1) 0 (0)
Decreased appetite 6 (18.8) 1 (3.1) 0 (0) 5 (17.9) 0 (0) 0 (0)
Diarrhea 5 (15.6) 0 (0) 0 (0) 8 (28.6) 0 (0) 1 (3.6)
Leukopenia 4 (12.5) 1 (3.1) 1 (3.1) 9 (32.1) 4 (14.3) 3 (10.7)
Dyspnea 4 (12.5) 1 (3.1) 0 (0) 5 (17.9) 2 (7.1) 0 (0)
Cough 3 (9.4) 0 (0) 0 (0) 6 (21.4) 0 (0) 0 (0)
Vomiting 2 (6.3) 0 (0) 0 (0) 9 (32.1) 1 (3.6) 0 (0)
Dehydration 2 (6.3) 0 (0) 0 (0) 7 (25.0) 1 (3.6) 0 (0)
Febrile neutropenia 2 (6.3) 0 (0) 2 (6.3) 5 (17.9) 2 (7.1) 3 (10.7)
Dizziness 2 (6.3) 0 (0) 0 (0) 5 (17.9) 0 (0) 0 (0)
AE adverse event
*One patient randomized to the placebo arm was not treated
†One AE that led to death was considered related to topotecan; none were considered related to trilaciclib
One patient in the trilaciclib arm had an AE leading to treatment discontinuation versus seven patients receiving placebo. Fatal AEs were reported in three patients in the trilaciclib arm (respiratory failure, acute respiratory failure, and cerebrovascular accident); none were considered related to trilaciclib. One patient in the placebo arm had a fatal AE (sepsis). One trilaciclib-related SAE was reported (infusion-related grade 3 thrombophlebitis), which was also considered by the investigator to be related to topotecan. Infusion-related reactions/injection site reactions or phlebitis AEs were reported in four patients in the trilaciclib arm and no patients in the placebo arm; all were grade 1 or 2 in severity.
Antitumor Efficacy
The ORR was comparable between the trilaciclib and placebo arms (16.7% [5/30 patients] versus 23.1% [6/26 patients]; P = 0.5494; Table S3). Median duration of response was numerically longer with trilaciclib (6.8 months) than with placebo (4.9 months), with overlapping CIs. Investigator-assessed PFS and OS were comparable between the trilaciclib and placebo arms; median PFS was 4.2 versus 4.2 months (HR [80% CI] 0.88 [0.61, 1.27]; P = 0.5886]), and median OS was 6.2 versus 6.5 months (HR 1.38 [0.95, 2.01]; P = 0.3377), respectively (Fig. 3).Fig. 3 Kaplan-Meier estimates of the probability of progression-free survival and overall survival. a PFS in the ITT population. b OS in the ITT population. CI confidence interval, HR hazard ratio, ITT intent-to-treat, OS overall survival, PFS progression-free survival
Discussion
Data from this study indicate that trilaciclib demonstrates myelopreservation efficacy in previously treated patients with ES-SCLC, whose bone marrow was damaged by first- or second-line chemotherapy. Myelopreservation benefits manifested as statistically significant, clinically meaningful improvements in the primary endpoints of DSN in cycle 1 and occurrence of SN, consistent with the results of the previous phase II trial of trilaciclib in patients who received E/P chemotherapy for newly diagnosed ES-SCLC [18]. These measures are clinically relevant since the severity and duration of SN are associated with an increased risk of FN, infection, IV antibiotic use, and hospitalizations [24–26]. Indeed, consistent with the significant reduction in DSN in cycle 1, and occurrence of SN, there was an approximately threefold decrease in the occurrence of FN AEs among patients receiving trilaciclib compared with placebo, although the total number of events was small. Patients receiving trilaciclib also experienced less chemotherapy-induced anemia, consistent with the observation that fewer patients receiving trilaciclib needed RBC transfusions and ESA administrations. This finding is also clinically meaningful; not only does anemia negatively impact patients’ HRQoL, but it is also associated with decreased survival, decreased tumor response, delays in therapy, and reduced patient compliance and therefore contributes to considerable morbidity and mortality among patients with cancer [7, 27]. Additional myelopreservation endpoints also consistently favored trilaciclib over placebo, with improvements observed in the use of other supportive care measures, namely G-CSF and ESA administration, and platelet transfusions. This finding is particularly pertinent, as current supportive care interventions for myelosuppression are associated with additional risks, such as bone pain with G-CSF, thromboembolic events with ESAs, and hemolytic reactions with platelet transfusions [11, 12, 28]. Also important is the finding that trilaciclib reduced the occurrence of chemotherapy dose reductions compared with placebo, allowing the standard dose of topotecan to be maintained. Of note, > 50% of patients diagnosed with SCLC are aged > 65 years [29]. Older patients often present with additional comorbidities, meaning they are particularly vulnerable to CIM and more likely to experience clinically significant side effects leading to clinical intervention and delayed chemotherapy treatment and/or dose reductions. The proactive management of CIM in elderly patients with SCLC is therefore essential to ensure delivery of standard-of-care chemotherapy regimens while improving the patient experience [30].
Patients with ES-SCLC who received trilaciclib prior to topotecan had a better experience receiving chemotherapy than patients receiving placebo. PRO assessments, using validated instruments, demonstrated that trilaciclib administered prior to topotecan resulted in meaningful delays in deterioration and even showed signs of improvement in fatigue, as well as other symptoms and functional limitations associated with cancer and CIM. Given the poor prognosis associated with relapsed SCLC, some patients may consider improved HRQoL a more important therapeutic goal than traditional efficacy outcomes [31]. The benefit of trilaciclib was particularly apparent in endpoints associated with anemia and fatigue, providing further evidence that trilaciclib may reduce the burden of CIM and its associated symptoms among patients with ES-SCLC. The fact that these data were collected in a randomized, placebo-controlled, double-blind study, with limited missing data, supports the robustness of these findings.
In line with previous findings [18], an improved overall safety profile for topotecan was evidenced by a reduction in high-grade hematologic AEs (neutropenia and anemia), which are commonly associated with CIM, providing further evidence for the myelopreservation effects of trilaciclib. Rates of thrombocytopenia, particularly high-grade events, were reported at a similarly low frequency in the trilaciclib and placebo arms. Among patients receiving trilaciclib, there was a 56% decrease in the number of patients hospitalized for CIM or sepsis compared with placebo (9.4% versus 21.4%). No discontinuations or deaths due to AEs were considered to be related to trilaciclib treatment. AEs of special interest with trilaciclib were primarily low grade and included injection-site reactions and phlebitis/thrombophlebitis.
Differences in measures of antitumor efficacy (ORR, PFS, and OS) between trilaciclib and placebo were nonsignificant; however, for OS, there was a trend for the HRs to favor placebo for both the ITT population and most subgroups. The trend appears to reflect an imbalance between prognostic factors for antitumor efficacy between the treatment arms (Supplementary Methods; Table S4). Compared with the placebo arm, for example, more patients in the trilaciclib arm were male and were current smokers, both of which are poor prognostic factors for survival [32, 33]. Survival outcomes in this study were similar to those seen in other studies of topotecan, where median survival times rarely exceed 6 months [2, 3]. The data reiterate the dismal prognosis of patients with relapsed or refractory ES-SCLC and highlight the urgent need for more effective treatment options in this setting. In June 2020, lurbinectedin was approved for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. Approval was based on efficacy data from a single-arm, phase II basket trial of 105 patients treated with IV lurbinectedin every 21 days [34]. In this study, the ORR (primary endpoint) was 35.2%, with a median response duration of 5.1 months. The most common grade 3/4 AEs were hematologic abnormalities. Eleven patients had SAEs, including five patients with neutropenia and five patients with FN [34]. Considering the efficacy and safety profile of lurbinectedin, it would be interesting to investigate whether trilaciclib might be advantageously combined with lurbinectedin, and/or other emerging agents, to improve patient outcomes. Importantly, however, comparable antitumor efficacy outcomes between the two treatment arms corroborate previous findings that trilaciclib does not negatively impact the antitumor efficacy of chemotherapy [18].
A limitation of this study is that, due to the small sample size, only large differences in OS would be detected. Therefore, although trilaciclib reduced the occurrence of chemotherapy dose reductions compared with placebo, detecting the impact of any potential differences in topotecan dose intensity on survival outcomes would be limited. Studies in patients with SCLC have shown, however, that increasing the relative dose intensity of chemotherapy beyond the standard of care rarely translates into significant improvements in response rates or survival [35]. The small sample size may have also reduced the ability to observe statistically significant differences in secondary myelopreservation measures, such as the occurrence of FN AEs, infection SAEs, and IV antibiotic use. However, large treatment effects were not expected for these endpoints given that patients in both arms could receive supportive care interventions, with the exception of prophylactic G-CSF in cycle 1. Further investigation of the effects of trilaciclib on CIM and antitumor efficacy in larger studies is needed, including in tumor types or settings that may be more responsive to dose intensification. Studies to further delineate the effects of trilaciclib compared with other supportive care interventions, such as prophylactic G-CSF, would also be of interest to establish the real-world impact of trilaciclib on CIM.
Conclusions
Overall, these data extend the evidence for the clinical benefits of trilaciclib as a first-in-class myelopreservation agent for patients with SCLC treated with myelotoxic chemotherapy. The study demonstrates that trilaciclib reduces the risk of CIM in patients with HSPCs that have been damaged by prior lines of cytotoxic chemotherapy who are being treated with a chemotherapy regimen associated with significant hematologic toxicity.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 414 kb)
Supplementary file2 (PDF 418 kb)
Supplementary file3 (DOCX 195 kb)
Acknowledgements
We thank and acknowledge all the patients, their families, and study personnel for participating in the study.
Funding
This study and medical writing support, along with the Rapid Service and Open Access fees, were funded by G1 Therapeutics, Inc. (Research Triangle Park, NC).
Medical Writing Assistance
Medical writing assistance was provided by Fiona Scott, contracted by Alligent Europe (Envision Pharma Group), funded by G1 Therapeutics, Inc.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The submitted work was sponsored and funded by G1 Therapeutics, Inc., Research Triangle Park, NC, USA. Jie Xiao and Joyce M. Antal are employees of, and have stock ownership in, G1 Therapeutics, Inc. Shannon R. Morris was a paid employee of, and had stock ownership in, G1 Therapeutics, Inc., at the time of study completion and manuscript preparation and submission, and is currently a paid consultant to G1 Therapeutics, Inc., via SRM Consulting LLC. Outside of the submitted work, Renata Ferrarotto reports personal fees from Regeneron-Sanofi, Ayala Pharma, Klus Pharma, Medscape, Cellestia Biotech, Carevive and Prelude, and grants from AstraZeneca, Merck, Genentech, Pfizer, Oropharynx Program Stiefel clinical trials, ASCO Career Development Award, and the MD Anderson Khalifa Award. Maen A. Hussein is on the speaker bureau for Bristol-Myers Squibb, Incyte, and Pfizer. Lowell L. Hart reports personal consulting fees from Genentech, Novartis, Lilly, Nanostring, Astra Zeneca and Daiichi Sankyo outside of the scope of the current work. Zoran G. Andric, J. Thaddeus Beck, Janakiraman Subramanian, Davorin Z. Radosavljevic, Bojan Zaric, Wahid T. Hanna, Raid Aljumaily, Taofeek K. Owonikoko, and Didier Verhoeven have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonisation. The protocol and all study-related materials were approved by the institutional review board or independent ethics committee of each participating center. All patients provided written informed consent.
Data Availability
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
|
1.5 MG/M2 (ON DAYS 1?5 OF EACH 21-DAY CYCLE)
|
DrugDosageText
|
CC BY-NC
|
33123968
| 18,528,230
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure during pregnancy'.
|
Comanagement Strategy Between Academic Institutions and Community Practices to Reduce Induction Mortality in Acute Promyelocytic Leukemia.
Acute promyelocytic leukemia (APL) is a curable leukemia with > 90% survival in clinical trials. Population-based studies from Sweden and US SEER data have shown long-term survival rates of 62% and 65.7%, with the lower rate being from a higher percentage of early deaths.
In this prospective, multicenter trial, we developed a simplified algorithm that focused on prevention and early treatment of the three main causes of death: bleeding, differentiation syndrome, and infection. All patients with a diagnosis of APL were included. The initial 6 months were spent educating oncologists about early deaths in APL. At the time of suspicion of an APL, an expert was contacted. The algorithm was made available followed by discussion of the treatment plan. Communication between expert and treating physician was frequent in the first 2 weeks, during which time most deaths take place.
Between September 2013 and April 2016, 120 patients enrolled in the study from 32 hospitals. The median age was 52.5 years, with 39% > 60 years and 25% with an age-adjusted Charlson comorbidity index > 4. Sixty-three percent of patients were managed at community centers. Two patients did not meet the criteria for analysis, and of 118 evaluable patients, 10 died, with an early mortality rate of 8.5%. With a median follow-up of 27.3 months, the overall survival was 84.5%.
Induction mortality can be decreased and population-wide survival improved in APL with the use of standardized treatment guidelines. Support from experts who have more experience with induction therapy is crucial and helps to improve the outcomes.
pmcINTRODUCTION
Large multicenter trials in the United States and around the world using combinations of anthracyclines, arsenic trioxide (ATO), and all-trans retinoic acid (ATRA) have reported cure rates for patients with acute promyelocytic leukemia (APL) > 85%.1-6 Early deaths during induction in clinical trials have been reported to occur in 5%-10% of patients. Contrary to this excellent outcome in trials, reports from single institutions, pooled data from multiple institutions, and large population-based registries have reported induction mortality rates (ie, during the first 30 days after the start of therapy) of 17.3%-40%.7-14 In this study, we report the implementation of a standardized treatment algorithm for standard treatment in a network of leukemia treatment centers and comanagement by community oncologists and APL experts.
METHODS
Trial Design
This study was designed to comanage patients with APL at their local/regional practices between the community oncologists and an APL expert in an academic institution. Patients age > 18 years with a confirmed diagnosis of APL and receiving standard therapy were eligible; there were no exclusion criteria. Confirmation of promyelocytic leukemia/retinoic acid receptor-α by fluorescence in situ hybridization was required before enrolling the patient. Patients were consented to collect treatment data, which were stored at Emory University. At the lead sites, an institutional review board (IRB)–approved consent was used, and at community sites, an Emory IRB-approved consent was signed after discussing the study over the phone. Patients diagnosed at the community centers were treated at their local hospitals; no patient was transferred to an academic center. Patients managed at the larger academic centers did not initiate therapy before transfer (Fig 1).
FIG 1. CONSORT diagram showing 120 patients accrued from 32 hospitals. APL, acute promyelocytic leukemia.
Study Treatments and Supportive Care
The available guidelines15 for the management of APL and its complications were simplified into a two-page treatment algorithm. Emphasis was on prevention and early identification of disease complications and APL-directed therapy. Standard-of-care APL therapy was recommended but not directed by the study. Adherence to standard APL therapy as recommended by established guidelines was encouraged, with modifications allowed to account for age or comorbid conditions at the discretion of the treating physician in consultation with the APL expert. Suggested regimens were ATRA and ATO for non–high-risk patients and ATRA and idarubicin for high-risk patients.15 After five instances of early death occurred in elderly patients who had received ATRA 45 mg/m2 and developed severe differentiation syndrome (DS), it was recommended that all patients > 60 years of age and/or with significant comorbidities receive dose-reduced ATRA at 25 mg/m2,16 with ATO added after 10-14 days of therapy.
Prednisone at 0.5 mg/kg was recommended at diagnosis in non–high-risk patients, and dexamethasone at 10 mg twice a day was started in high-risk patients per previously published protocols.17 At the first sign of DS, the corticosteroid dose was increased, and ATRA, ATO, or both were held. Hyperleukocytosis was managed with hydroxyurea and rarely with chemotherapy per published studies.6 Patients were weighed at admission on a standing bedside scale, and aggressive diuresis was used to maintain patients at baseline weight. (Treatment guidelines are provided in the Data Supplement, online only.)
Network
The trial included a 6-month period of education of health care providers in Georgia and South Carolina to increase awareness of causes of early death in APL and the strategies being implemented to reduce mortality by a collaborative approach. Because of increased referrals from other neighboring states (predominantly Florida and North Carolina) after growing awareness of the trial, the trial was expanded to these regions. This involved sending e-mail communications and physically visiting and presenting the strategy in 15 community centers. Four large leukemia centers were identified as lead sites, and experts from the four expert sites were engaged in identifying and establishing communication with leukemia treatment centers in the four states. Cell phone numbers of APL experts were made available 24/7 during the entire study period for all necessary communications. Patients with APL who presented to the lead centers were managed with supervision by an APL expert at the site or with discussions among APL experts. Patients who presented to community leukemia centers were enrolled if an APL expert was contacted at the time of diagnosis. After the initial contact, the patient’s presentation and comorbid conditions were discussed by the treating physician with A.P.J., V.K.K., or both. Patient progress was discussed by phone, e-mail, or text messaging on a daily basis in the first 2 weeks and then every 2-3 days until discharge. In all patients, a consolidation plan and follow-up plan were also recommended at the time of completion of the induction period.
Statistical Methods
We defined early death as mortality from the time of diagnosis until the end of induction. Deaths after 30 days as a result of complications from induction were also included as early deaths for the purpose of this analysis. We estimated that a sample size of 120 patients would have 98% power to detect a difference of 15% at the end of 30 days with an α of 0.05 compared with a control group identified through the SEER database. This control group consisted of patients from the SEER database in the 3 years from 2010 to 2012. Secondary end points were survival at 1 year and relapse rates at 12 months.
Statistical analysis was conducted using SAS 9.4 software (SAS Institute, Cary, NC). Descriptive statistics for each variable were reported. For numeric covariates, the mean and standard deviation were calculated and presented. Frequency and percentage were shown for categorical variables. The univariable association of each covariate on overall survival (OS) was assessed using the Cox proportional hazards regression model. A multivariable Cox model was fit by a backward variable selection method with an α = 0.20 removal criterion. OS was represented in a Kaplan-Meier plot.
RESULTS
Patient and Hospital Characteristics
Between September 2013 and April 2016, 120 patients were enrolled. Two patients were excluded from the analysis: one because of refusal of transfusion support for religious reasons and a second enrolled 12 days after initiation of therapy and already with multiorgan failure at the time expert consultation was requested. This analysis includes all 118 eligible patients. Median age was 52.5 years (range, 21-84 years); 46 patients (39%) were ≥ 60 years. Sixty-eight patients (57%) were female, 23 (19.5%) were high risk,18 and 25% had an age-adjusted Charlson comorbidity index of > 4.19 Patient characteristics are listed in Table 1. Patients were treated at 32 hospitals; 16 hospitals treated only one patient during the observation period, five hospitals managed two patients, four hospitals managed three patients, and two hospitals managed four patients. The remaining five hospitals managed five, six, 10, 12, and 39 patients. Overall, 73 patients (62%) were treated in community centers and 45 (38%) in academic centers.
TABLE 1. Patient Characteristics
Induction Therapy and Supportive Care
ATRA was initiated at the time of suspicion of APL in 100% of patients. Of the 23 high-risk patients, four received ATRA alone as induction therapy. ATRA was initiated at 45 mg/m2 in two patients: one diagnosed with postmyocardial infarction with an ejection fraction of 20% and the other on the day of admission with a non–ST-elevation myocardial infarction. Cytarabine was used for reducing leukocytosis. The patients underwent consolidation therapy with ATRA/ATO postinduction and were in molecular remission at 19 and 32 months. In two patients who were > 70 years of age and had multiple comorbid conditions, ATRA was initiated at 25 mg/m2 and continued throughout their hospital stay at the same dose. Both these patients died as a result of complications from multiorgan failure and DS on days 16 and 18, respectively. In five high-risk patients, ATRA/ATO was initiated for induction in place of chemotherapy because of age or comorbid conditions precluding the use of chemotherapy (n = 4) or patient preference (n = 1). All five patients achieved hematological remission. One of these five patients (age 77 years) died as a result of recurrence of ovarian cancer 9 months after diagnosis of APL. The other four were in molecular remission at 19, 29, 38, and 40 months from diagnosis. In the remaining 14 patients, ATRA/idarubicin was the induction regimen. Two of them died during induction (days 5 and 6), both as a result of disease-related coagulopathy. Overall, 19 (82.6%) of the 23 high-risk patients achieved complete hematological remission after induction, with an induction mortality rate of 17.4%.
In the 95 non–high-risk patients, two received ATRA/chemotherapy per physician preference. One patient died on day 24 as a result of gram-negative sepsis and the other achieved complete hematological remission. In eight patients, ATRA was used as a single agent because of age and/or multiple comorbidities. One of them (age 32 years) presented with intracranial bleed and despite aggressive supportive measures, died on day 6 after initiating ATRA. Among the other seven patients receiving single-agent ATRA, one died on day 19 as a result of DS, and the other six are in molecular remission after dose-reduced ATRA/ATO consolidation. The other 85 patients received induction with ATRA/ATO. This included three patients who were pregnant with 10, 16, and 32 weeks gestation at the time of diagnosis. Two patients in their first trimester opted for termination and initiated therapy with dose-reduced ATRA at 25 mg/m2 to correct the coagulopathy, and ATO was added post-termination. The patient in her third trimester started ATRA alone but required a caesarean section for toxemia of pregnancy and then received ATO postsurgery. At 18 months of follow-up, the baby is in good health. All three patients achieved complete hematological remission after induction and molecular remission after ATRA/ATO consolidation. Thus, of the 95 low-risk patients, 89 (93.6%) achieved remission after induction, with an induction mortality rate of 6.4%. Despite adherence to transfusion guidelines, the targets could not be achieved in a few patients, especially during the initial period, because of florid coagulopathy, but there were no early deaths as a result of inadequate transfusion support.
Early Deaths
Ten patients (six non–high risk and four high risk) died, for an early death rate of 8.5%. Median age in the patients with early death was 67 years (range, 21-84 years). The cause of death was DS in five, coagulopathy in three, DS and infection in one, and infection in one. The median time to death in these 10 patients was 17 days (range, 1-36 days). In the three patients with early death as a result of coagulopathy, two (ages 32 and 40 years) died as a result of intracranial bleeding on days 1 and 6. One patient (age 21 years) presented with brain infarcts and died on day 5. All patients who died as a result of DS and/or infection were older, with a median age of 67 years (range, 61-84 years). Two patients (ages 76 and 72 years) died as a result of gram-negative sepsis (one also had DS) on days 16 and 24.
Consolidation Therapy
At the end of induction therapy, recommendations were given to the treating physicians on the best choice of consolidation therapy. Patients were managed per published regimens.1,6
Relapse and Late Deaths
Of the 108 patients who achieved a remission, seven (6.4%) experienced a relapsed (three of whom were high risk). The three high-risk patients experienced relapse at 12, 29, and 32 months while on maintenance therapy per established protocol1 at the time of relapse. Two of them died at the time of relapse, one as a result of intracranial bleed on day 4 of re-induction and the other after refusal of therapy. The patient who experienced relapse at 32 months underwent re-induction followed by an autologous hematopoietic stem-cell transplantation (HSCT) but had a molecular relapse 4 months after HSCT. ATO was given for disease control followed by a haploidentical HSCT, and the patient was in remission at 4 months after HSCT.
Three of the four non–high-risk patients who experienced relapse received inadequate consolidation with ATO because of social issues and nonadherence to therapy. All four patients received re-induction therapy with ATRA/ATO/chemotherapy and achieved a second remission. Two underwent autologous HSCT and are in remission at 6 and 7 months after transplantation. The other two patients refused HSCT and are in remission after consolidation with ATRA/ATO 4 and 30 months after achieving remission. The causes of late deaths were APL relapse (n = 2), relapse of ovarian cancer (n = 1), relapsed bladder cancer (n = 1), and complications from preexisting chronic medical problems and unrelated to APL or therapy (n = 4).
Survival
The 1-year survival probability for the entire cohort was 87.3%. After 18 months from last patient first visit and a median follow-up of 27.3 months, the OS rate was 84.5%, with an early death rate of 8.5% (Fig 2). In addition to the risk classification at diagnosis (by WBC count), age-adjusted comorbidity index and the presence of moderate to severe DS during induction were statistically significant independent predictors of OS on multivariable analysis (Table 2).
FIG 2. Kaplan-Meier graph of overall survival (OS), with 118 patients included in the survival analysis. The 1-month mortality rate was 7.6%. There were eight late deaths as a result of relapse (n = 2), ovarian cancer (n = 1), relapsed bladder cancer (n = 1), and other chronic medical conditions (n = 4). Data in parentheses are the rate (CI, %).
TABLE 2. Univariable and Multivariable Analyses
Outcomes in Community Versus Academic Centers
Seventy-three patients (61.8%) were managed at the community centers. Patients were registered under an academic center if they were transferred for management at the time of diagnosis. The median age (52 v 52.5 years) and comorbidity index (3 v 3) were similar at the academic and community centers, respectively. There was no difference in induction mortality, irrespective of where the patient was managed. Of the 73 managed at community centers, there were six deaths (three in low-risk patients and three in high-risk patients), with an induction mortality rate of 8.2%. This was similar to the 8.8% (four of 45 patients, with one high-risk patient) mortality rate seen in the academic centers. Similarly, there was no difference in survival at 1 year depending on location of therapy.
DISCUSSION
Our study shows that a high proportion of patients with APL are managed in the community similar to what is observed with other cancers. Recent population-based studies have shown that outcomes in acute myeloid leukemia were worse when managed in community centers compared with academic centers.20 In this study, we show that it is possible to improve 1-year survival in patients treated in community clinics when comanaged by an APL expert and the local treating physician. The outcomes in 29 community centers were similar to the three academic centers both at the end of induction (early death rate, 8.2% v 8.8%, respectively) and at 1 year. Overall, the 1-year survival rate in this study of 87.3% is superior to the US SEER data that showed a relative survival rate of 70.7%.8 The overall long-term survival of 84.5% with a median follow-up of 27.3 months is higher than what is seen in published population-based studies.8,9,12
APL is an uncommon disease, with approximately 3,000 cases diagnosed annually in the United States.21 The high incidence of complications, such as bleeding, thrombosis, and DS, has resulted in a recommendation that patients with APL should be referred to specialized centers. During the course of this study, 16 hospitals managed only one patient each over 3 years. Published data suggest that most large cancer centers may only see three to four patients per year.22,23 The Swedish and Canadian registry data showed that the outcomes were superior in academic centers.11,24 With our approach, using a simple algorithm along with frequent expert advice, revealed an excellent outcome overall and with no difference between community centers and academic institutions. The early death rate was similar at 8.8% in academic institutions and 8.2% in nonacademic community centers.
Elderly patients and patients with comorbidities are generally excluded from clinical trials. These patients have a significantly higher risk and early mortality than those eligible for clinical trials. In a review of patients not enrolled in trials from Germany, the early death rate in noneligible patients was 48%.14 Similarly, population-based data have shown that older age is a high-risk factor.7,9,18 These patients frequently have to be managed differently because this is a vulnerable population. The superiority of ATO-containing regimens over chemotherapy6 offers the chance of cure if early death can be reduced in most patients, including those ineligible for chemotherapy and who are elderly. In our study, there was no age- or comorbidity-based exclusion criteria. In fact, while the median age of patients in most clinical trials is in the low- to mid-40s,1,6 the median age in our study was 52.5 years, which is similar to the Swedish registry data (54 years). Forty-six patients (39%) were > 60 years of age with a median age-adjusted Charlson comorbidity index19 score of 5 in this group. There were 24 patients age > 70 years, including six who were age ≥ 80 years.
Our study does have limitations. Our comparator arm being SEER is a limitation. Our study primary end point was to compare our outcomes to SEER data. The data from SEER cover only 27% of the US population. In addition, patient and treatment data are not clearly available. Despite these issues, we wanted to include all patients who we were called about and attempted to improve outcomes in this heterogeneous group. SEER data provided us the only source of outcomes in such a heterogeneous group of patients. We did exclude two patients in our analysis: one for not being involved in the care from the diagnosis and the other who refused treatment for religious reasons. Even with including these two patients, our results are comparable to that of selected populations of clinical trials, which was our main aim of the study. Another major limitation is the lack of data on the total number of patients diagnosed with APL in the same hospitals during the study period. The majority of the patients enrolled came from Georgia and South Carolina. SEER data themselves are not accurate, and review of SEER data in the same years actually shows that the total number of patients with APL diagnosed was less than what we enrolled. Our accrual did go up in the last part of the study as many referring physicians called us with patients. This also means that we were not called for patients with APL in the earlier part of the trial.
Our algorithm by itself would not be expected to completely eliminate early deaths. Consultation with an APL expert is equally important. Accrual was lower in the first year, but with increased awareness, recruitment improved (two or fewer patients v four patients per month in the first 6 months v last 6 months). This suggests that ongoing communication and education were essential. The significance of networking and its effects on improving APL outcomes was shown by Rego et al25 in Latin America. Across six countries, patients were enrolled up to age 75 years and treated with a standard protocol, with weekly discussion by a centralized group of experts. The early death rate of 32% was decreased to 15% with this approach.
In the present era of targeted therapies in the management of diseases, a decentralized approach might offer better care over a large area and reduce disparities on the basis of geographical location. A similar approach showed remarkable improvements in the management of hepatitis C by primary care physicians under guidance from experts at the University of New Mexico.26 In our opinion, a similar approach to comanaging patients will be valuable in many other oncological conditions. Multiple targeted therapies have been approved in the past decade for various oncology indications, each with peculiar adverse effects. We are exploring the same concept in myeloma and chronic myeloid leukemia.
In summary, we show that a simplified algorithm and partnership between experts and treating community oncologists can significantly decrease early death as a result of APL in both academic and community centers. Our model is presently being implemented as an ECOG-ACRIN study (ClinicalTrials.gov identifier: NCT03253848) across the country. This model also paves the way for use in other conditions where education and academic-community partnerships could lead to better care for patients, even outside a clinical trial.
PRIOR PRESENTATION
SUPPORT
CLINICAL TRIAL INFORMATION
AUTHOR CONTRIBUTIONS
Conception and design: Anand P. Jillella, Martha L. Arellano, Amy A. Langston, Morgan L. McLemore, Chao Zhang, Asad Bashey, Robert K. Stuart, Vamsi K. Kota
Administrative support: Prachi Karkhanis, Shruthi H. Krishnamurthy, Sheldon L. Bolds
Provision of study material or patients: Anand P. Jillella, Martha L. Arellano, Manila Gaddh, Amy A. Langston, Leonard T. Heffner, Elliott F. Winton, Morgan L. McLemore, Chao Zhang, Jose Tongol, Mohamed M. El Geneidy, Asim Pati, Jonathan M. Gerber,Michael R. Grunwald, Jorge Cortes, Asad Bashey, Robert K. Stuart, Vamsi K. Kota
Collection and assembly of data: Manila Gaddh, Sheldon L. Bolds, Stephanie DeBragga, Prachi Karkhanis, Shruthi H. Krishnamurthy, Jose Tongol, Vamsi K. Kota
Data analysis and interpretation: Anand P. Jillella, Martha L. Arellano, Manila Gaddh, Amy A. Langston, Morgan L. McLemore, Chao Zhang, Kathryn S. Simon, Sheldon L. Bolds, Prachi Karkhanis, Jose Tongol, Jonathan M. Gerber, Michael R. Grunwald, Jorge Cortes, Asad Bashey, Robert K. Stuart
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Comanagement Strategy Between Academic Institutions and Community Practices to Reduce Induction Mortality in Acute Promyelocytic Leukemia
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Presented at the 62nd American Society of Hematology Annual Meeting, December 5-8, 2020.
Supported in part by a grant from the Leukemia and Lymphoma Society.
NCT02309333
Conflicts of Interest Statement: Accepted on September 22, 2020.
Martha L. Arellano
Consulting or Advisory Role: Gilead Sciences
Research Funding: Cephalon (Inst)
Manila Gaddh
Consulting or Advisory Role: Agios, Pfizer
Research Funding: MedImmune (Inst), Apellis Pharmaceuticals (Inst), Celgene (Inst), Janssen Pharmaceuticals (Inst), Daiichi Sankyo (Inst)
Travel, Accommodations, Expenses: Agios, Pfizer
Amy A. Langston
Research Funding: Chimerix (Inst), Astellas Pharma (Inst), Incyte (Inst), Takeda Pharmaceuticals (Inst), Jazz Pharmaceuticals (Inst), Kadmon (Inst), Novartis (Inst)
Leonard T. Heffner
Speakers’ Bureau: Kite Pharma
Research Funding: Pharmacyclics (Inst), Genentech (Inst), Kite Pharma (Inst), ADC Therapeutics (Inst), Astex Pharmaceuticals (Inst)
Elliott F. Winton
Research Funding: Incyte, Sierra Oncology, Samus Therapeutics, Blueprint Medicines
Asim Pati
Honoraria: Aptitude Health, ITA Group, AstraZeneca, Bristol Myers Squibb, BeiGene
Michael R. Grunwald
Stock and Other Ownership Interests: Medtronic
Honoraria: OncLive, Med Learning Group, Physicians’ Education Resource
Consulting or Advisory Role: Incyte, Cardinal Health, Pfizer, Agios, AbbVie, Trovagene, Daiichi Sankyo, Bristol-Myers Squibb, Premier, Astellas Pharma
Research Funding: Janssen Pharmaceuticals (Inst), FORMA Therapeutics (Inst), Incyte (Inst), Genentech (Inst), Roche (Inst)
Travel, Accommodations, Expenses: Amgen, Incyte
Jonathan M. Gerber
Patents, Royalties, Other Intellectual Property: US Patent No. 9,012,215, US Patent No. 10,222,376
Jorge Cortes
Consulting or Advisory Role: Bristol Myers Squibb, BioLineRx, Novartis, Pfizer, Amphivena Therapeutics, Daiichi Sankyo, Bio-Path Holdings, Astellas Pharma, Takeda Pharmaceuticals, Jazz Pharmaceuticals
Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Immunogen (Inst), Sun Pharma (Inst), Takeda Pharmaceuticals (Inst), Merus (Inst), Daiichi Sankyo (Inst), Tolero Pharmaceuticals (Inst), Trovagene (Inst), Jazz Pharmaceuticals (Inst)
Robert K. Stuart
Consulting or Advisory Role: Ono Pharmaceutical
Research Funding: Ono Pharmaceutical, Agios, Astellas Pharma
Vamsi K. Kota
Consulting or Advisory Role: Pfizer, Novartis, AbbVie
No other potential conflicts of interest were reported.
Martha L. Arellano
Consulting or Advisory Role: Gilead Sciences
Research Funding: Cephalon (Inst)
Manila Gaddh
Consulting or Advisory Role: Agios, Pfizer
Research Funding: MedImmune (Inst), Apellis Pharmaceuticals (Inst), Celgene (Inst), Janssen Pharmaceuticals (Inst), Daiichi Sankyo (Inst)
Travel, Accommodations, Expenses: Agios, Pfizer
Amy A. Langston
Research Funding: Chimerix (Inst), Astellas Pharma (Inst), Incyte (Inst), Takeda Pharmaceuticals (Inst), Jazz Pharmaceuticals (Inst), Kadmon (Inst), Novartis (Inst)
Leonard T. Heffner
Speakers’ Bureau: Kite Pharma
Research Funding: Pharmacyclics (Inst), Genentech (Inst), Kite Pharma (Inst), ADC Therapeutics (Inst), Astex Pharmaceuticals (Inst)
Elliott F. Winton
Research Funding: Incyte, Sierra Oncology, Samus Therapeutics, Blueprint Medicines
Asim Pati
Honoraria: Aptitude Health, ITA Group, AstraZeneca, Bristol Myers Squibb, BeiGene
Michael R. Grunwald
Stock and Other Ownership Interests: Medtronic
Honoraria: OncLive, Med Learning Group, Physicians’ Education Resource
Consulting or Advisory Role: Incyte, Cardinal Health, Pfizer, Agios, AbbVie, Trovagene, Daiichi Sankyo, Bristol-Myers Squibb, Premier, Astellas Pharma
Research Funding: Janssen Pharmaceuticals (Inst), FORMA Therapeutics (Inst), Incyte (Inst), Genentech (Inst), Roche (Inst)
Travel, Accommodations, Expenses: Amgen, Incyte
Jonathan M. Gerber
Patents, Royalties, Other Intellectual Property: US Patent No. 9,012,215, US Patent No. 10,222,376
Jorge Cortes
Consulting or Advisory Role: Bristol Myers Squibb, BioLineRx, Novartis, Pfizer, Amphivena Therapeutics, Daiichi Sankyo, Bio-Path Holdings, Astellas Pharma, Takeda Pharmaceuticals, Jazz Pharmaceuticals
Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Immunogen (Inst), Sun Pharma (Inst), Takeda Pharmaceuticals (Inst), Merus (Inst), Daiichi Sankyo (Inst), Tolero Pharmaceuticals (Inst), Trovagene (Inst), Jazz Pharmaceuticals (Inst)
Robert K. Stuart
Consulting or Advisory Role: Ono Pharmaceutical
Research Funding: Ono Pharmaceutical, Agios, Astellas Pharma
Vamsi K. Kota
Consulting or Advisory Role: Pfizer, Novartis, AbbVie
No other potential conflicts of interest were reported.
|
TRETINOIN
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33125295
| 20,350,168
|
2021-04
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Normal newborn'.
|
Comanagement Strategy Between Academic Institutions and Community Practices to Reduce Induction Mortality in Acute Promyelocytic Leukemia.
Acute promyelocytic leukemia (APL) is a curable leukemia with > 90% survival in clinical trials. Population-based studies from Sweden and US SEER data have shown long-term survival rates of 62% and 65.7%, with the lower rate being from a higher percentage of early deaths.
In this prospective, multicenter trial, we developed a simplified algorithm that focused on prevention and early treatment of the three main causes of death: bleeding, differentiation syndrome, and infection. All patients with a diagnosis of APL were included. The initial 6 months were spent educating oncologists about early deaths in APL. At the time of suspicion of an APL, an expert was contacted. The algorithm was made available followed by discussion of the treatment plan. Communication between expert and treating physician was frequent in the first 2 weeks, during which time most deaths take place.
Between September 2013 and April 2016, 120 patients enrolled in the study from 32 hospitals. The median age was 52.5 years, with 39% > 60 years and 25% with an age-adjusted Charlson comorbidity index > 4. Sixty-three percent of patients were managed at community centers. Two patients did not meet the criteria for analysis, and of 118 evaluable patients, 10 died, with an early mortality rate of 8.5%. With a median follow-up of 27.3 months, the overall survival was 84.5%.
Induction mortality can be decreased and population-wide survival improved in APL with the use of standardized treatment guidelines. Support from experts who have more experience with induction therapy is crucial and helps to improve the outcomes.
pmcINTRODUCTION
Large multicenter trials in the United States and around the world using combinations of anthracyclines, arsenic trioxide (ATO), and all-trans retinoic acid (ATRA) have reported cure rates for patients with acute promyelocytic leukemia (APL) > 85%.1-6 Early deaths during induction in clinical trials have been reported to occur in 5%-10% of patients. Contrary to this excellent outcome in trials, reports from single institutions, pooled data from multiple institutions, and large population-based registries have reported induction mortality rates (ie, during the first 30 days after the start of therapy) of 17.3%-40%.7-14 In this study, we report the implementation of a standardized treatment algorithm for standard treatment in a network of leukemia treatment centers and comanagement by community oncologists and APL experts.
METHODS
Trial Design
This study was designed to comanage patients with APL at their local/regional practices between the community oncologists and an APL expert in an academic institution. Patients age > 18 years with a confirmed diagnosis of APL and receiving standard therapy were eligible; there were no exclusion criteria. Confirmation of promyelocytic leukemia/retinoic acid receptor-α by fluorescence in situ hybridization was required before enrolling the patient. Patients were consented to collect treatment data, which were stored at Emory University. At the lead sites, an institutional review board (IRB)–approved consent was used, and at community sites, an Emory IRB-approved consent was signed after discussing the study over the phone. Patients diagnosed at the community centers were treated at their local hospitals; no patient was transferred to an academic center. Patients managed at the larger academic centers did not initiate therapy before transfer (Fig 1).
FIG 1. CONSORT diagram showing 120 patients accrued from 32 hospitals. APL, acute promyelocytic leukemia.
Study Treatments and Supportive Care
The available guidelines15 for the management of APL and its complications were simplified into a two-page treatment algorithm. Emphasis was on prevention and early identification of disease complications and APL-directed therapy. Standard-of-care APL therapy was recommended but not directed by the study. Adherence to standard APL therapy as recommended by established guidelines was encouraged, with modifications allowed to account for age or comorbid conditions at the discretion of the treating physician in consultation with the APL expert. Suggested regimens were ATRA and ATO for non–high-risk patients and ATRA and idarubicin for high-risk patients.15 After five instances of early death occurred in elderly patients who had received ATRA 45 mg/m2 and developed severe differentiation syndrome (DS), it was recommended that all patients > 60 years of age and/or with significant comorbidities receive dose-reduced ATRA at 25 mg/m2,16 with ATO added after 10-14 days of therapy.
Prednisone at 0.5 mg/kg was recommended at diagnosis in non–high-risk patients, and dexamethasone at 10 mg twice a day was started in high-risk patients per previously published protocols.17 At the first sign of DS, the corticosteroid dose was increased, and ATRA, ATO, or both were held. Hyperleukocytosis was managed with hydroxyurea and rarely with chemotherapy per published studies.6 Patients were weighed at admission on a standing bedside scale, and aggressive diuresis was used to maintain patients at baseline weight. (Treatment guidelines are provided in the Data Supplement, online only.)
Network
The trial included a 6-month period of education of health care providers in Georgia and South Carolina to increase awareness of causes of early death in APL and the strategies being implemented to reduce mortality by a collaborative approach. Because of increased referrals from other neighboring states (predominantly Florida and North Carolina) after growing awareness of the trial, the trial was expanded to these regions. This involved sending e-mail communications and physically visiting and presenting the strategy in 15 community centers. Four large leukemia centers were identified as lead sites, and experts from the four expert sites were engaged in identifying and establishing communication with leukemia treatment centers in the four states. Cell phone numbers of APL experts were made available 24/7 during the entire study period for all necessary communications. Patients with APL who presented to the lead centers were managed with supervision by an APL expert at the site or with discussions among APL experts. Patients who presented to community leukemia centers were enrolled if an APL expert was contacted at the time of diagnosis. After the initial contact, the patient’s presentation and comorbid conditions were discussed by the treating physician with A.P.J., V.K.K., or both. Patient progress was discussed by phone, e-mail, or text messaging on a daily basis in the first 2 weeks and then every 2-3 days until discharge. In all patients, a consolidation plan and follow-up plan were also recommended at the time of completion of the induction period.
Statistical Methods
We defined early death as mortality from the time of diagnosis until the end of induction. Deaths after 30 days as a result of complications from induction were also included as early deaths for the purpose of this analysis. We estimated that a sample size of 120 patients would have 98% power to detect a difference of 15% at the end of 30 days with an α of 0.05 compared with a control group identified through the SEER database. This control group consisted of patients from the SEER database in the 3 years from 2010 to 2012. Secondary end points were survival at 1 year and relapse rates at 12 months.
Statistical analysis was conducted using SAS 9.4 software (SAS Institute, Cary, NC). Descriptive statistics for each variable were reported. For numeric covariates, the mean and standard deviation were calculated and presented. Frequency and percentage were shown for categorical variables. The univariable association of each covariate on overall survival (OS) was assessed using the Cox proportional hazards regression model. A multivariable Cox model was fit by a backward variable selection method with an α = 0.20 removal criterion. OS was represented in a Kaplan-Meier plot.
RESULTS
Patient and Hospital Characteristics
Between September 2013 and April 2016, 120 patients were enrolled. Two patients were excluded from the analysis: one because of refusal of transfusion support for religious reasons and a second enrolled 12 days after initiation of therapy and already with multiorgan failure at the time expert consultation was requested. This analysis includes all 118 eligible patients. Median age was 52.5 years (range, 21-84 years); 46 patients (39%) were ≥ 60 years. Sixty-eight patients (57%) were female, 23 (19.5%) were high risk,18 and 25% had an age-adjusted Charlson comorbidity index of > 4.19 Patient characteristics are listed in Table 1. Patients were treated at 32 hospitals; 16 hospitals treated only one patient during the observation period, five hospitals managed two patients, four hospitals managed three patients, and two hospitals managed four patients. The remaining five hospitals managed five, six, 10, 12, and 39 patients. Overall, 73 patients (62%) were treated in community centers and 45 (38%) in academic centers.
TABLE 1. Patient Characteristics
Induction Therapy and Supportive Care
ATRA was initiated at the time of suspicion of APL in 100% of patients. Of the 23 high-risk patients, four received ATRA alone as induction therapy. ATRA was initiated at 45 mg/m2 in two patients: one diagnosed with postmyocardial infarction with an ejection fraction of 20% and the other on the day of admission with a non–ST-elevation myocardial infarction. Cytarabine was used for reducing leukocytosis. The patients underwent consolidation therapy with ATRA/ATO postinduction and were in molecular remission at 19 and 32 months. In two patients who were > 70 years of age and had multiple comorbid conditions, ATRA was initiated at 25 mg/m2 and continued throughout their hospital stay at the same dose. Both these patients died as a result of complications from multiorgan failure and DS on days 16 and 18, respectively. In five high-risk patients, ATRA/ATO was initiated for induction in place of chemotherapy because of age or comorbid conditions precluding the use of chemotherapy (n = 4) or patient preference (n = 1). All five patients achieved hematological remission. One of these five patients (age 77 years) died as a result of recurrence of ovarian cancer 9 months after diagnosis of APL. The other four were in molecular remission at 19, 29, 38, and 40 months from diagnosis. In the remaining 14 patients, ATRA/idarubicin was the induction regimen. Two of them died during induction (days 5 and 6), both as a result of disease-related coagulopathy. Overall, 19 (82.6%) of the 23 high-risk patients achieved complete hematological remission after induction, with an induction mortality rate of 17.4%.
In the 95 non–high-risk patients, two received ATRA/chemotherapy per physician preference. One patient died on day 24 as a result of gram-negative sepsis and the other achieved complete hematological remission. In eight patients, ATRA was used as a single agent because of age and/or multiple comorbidities. One of them (age 32 years) presented with intracranial bleed and despite aggressive supportive measures, died on day 6 after initiating ATRA. Among the other seven patients receiving single-agent ATRA, one died on day 19 as a result of DS, and the other six are in molecular remission after dose-reduced ATRA/ATO consolidation. The other 85 patients received induction with ATRA/ATO. This included three patients who were pregnant with 10, 16, and 32 weeks gestation at the time of diagnosis. Two patients in their first trimester opted for termination and initiated therapy with dose-reduced ATRA at 25 mg/m2 to correct the coagulopathy, and ATO was added post-termination. The patient in her third trimester started ATRA alone but required a caesarean section for toxemia of pregnancy and then received ATO postsurgery. At 18 months of follow-up, the baby is in good health. All three patients achieved complete hematological remission after induction and molecular remission after ATRA/ATO consolidation. Thus, of the 95 low-risk patients, 89 (93.6%) achieved remission after induction, with an induction mortality rate of 6.4%. Despite adherence to transfusion guidelines, the targets could not be achieved in a few patients, especially during the initial period, because of florid coagulopathy, but there were no early deaths as a result of inadequate transfusion support.
Early Deaths
Ten patients (six non–high risk and four high risk) died, for an early death rate of 8.5%. Median age in the patients with early death was 67 years (range, 21-84 years). The cause of death was DS in five, coagulopathy in three, DS and infection in one, and infection in one. The median time to death in these 10 patients was 17 days (range, 1-36 days). In the three patients with early death as a result of coagulopathy, two (ages 32 and 40 years) died as a result of intracranial bleeding on days 1 and 6. One patient (age 21 years) presented with brain infarcts and died on day 5. All patients who died as a result of DS and/or infection were older, with a median age of 67 years (range, 61-84 years). Two patients (ages 76 and 72 years) died as a result of gram-negative sepsis (one also had DS) on days 16 and 24.
Consolidation Therapy
At the end of induction therapy, recommendations were given to the treating physicians on the best choice of consolidation therapy. Patients were managed per published regimens.1,6
Relapse and Late Deaths
Of the 108 patients who achieved a remission, seven (6.4%) experienced a relapsed (three of whom were high risk). The three high-risk patients experienced relapse at 12, 29, and 32 months while on maintenance therapy per established protocol1 at the time of relapse. Two of them died at the time of relapse, one as a result of intracranial bleed on day 4 of re-induction and the other after refusal of therapy. The patient who experienced relapse at 32 months underwent re-induction followed by an autologous hematopoietic stem-cell transplantation (HSCT) but had a molecular relapse 4 months after HSCT. ATO was given for disease control followed by a haploidentical HSCT, and the patient was in remission at 4 months after HSCT.
Three of the four non–high-risk patients who experienced relapse received inadequate consolidation with ATO because of social issues and nonadherence to therapy. All four patients received re-induction therapy with ATRA/ATO/chemotherapy and achieved a second remission. Two underwent autologous HSCT and are in remission at 6 and 7 months after transplantation. The other two patients refused HSCT and are in remission after consolidation with ATRA/ATO 4 and 30 months after achieving remission. The causes of late deaths were APL relapse (n = 2), relapse of ovarian cancer (n = 1), relapsed bladder cancer (n = 1), and complications from preexisting chronic medical problems and unrelated to APL or therapy (n = 4).
Survival
The 1-year survival probability for the entire cohort was 87.3%. After 18 months from last patient first visit and a median follow-up of 27.3 months, the OS rate was 84.5%, with an early death rate of 8.5% (Fig 2). In addition to the risk classification at diagnosis (by WBC count), age-adjusted comorbidity index and the presence of moderate to severe DS during induction were statistically significant independent predictors of OS on multivariable analysis (Table 2).
FIG 2. Kaplan-Meier graph of overall survival (OS), with 118 patients included in the survival analysis. The 1-month mortality rate was 7.6%. There were eight late deaths as a result of relapse (n = 2), ovarian cancer (n = 1), relapsed bladder cancer (n = 1), and other chronic medical conditions (n = 4). Data in parentheses are the rate (CI, %).
TABLE 2. Univariable and Multivariable Analyses
Outcomes in Community Versus Academic Centers
Seventy-three patients (61.8%) were managed at the community centers. Patients were registered under an academic center if they were transferred for management at the time of diagnosis. The median age (52 v 52.5 years) and comorbidity index (3 v 3) were similar at the academic and community centers, respectively. There was no difference in induction mortality, irrespective of where the patient was managed. Of the 73 managed at community centers, there were six deaths (three in low-risk patients and three in high-risk patients), with an induction mortality rate of 8.2%. This was similar to the 8.8% (four of 45 patients, with one high-risk patient) mortality rate seen in the academic centers. Similarly, there was no difference in survival at 1 year depending on location of therapy.
DISCUSSION
Our study shows that a high proportion of patients with APL are managed in the community similar to what is observed with other cancers. Recent population-based studies have shown that outcomes in acute myeloid leukemia were worse when managed in community centers compared with academic centers.20 In this study, we show that it is possible to improve 1-year survival in patients treated in community clinics when comanaged by an APL expert and the local treating physician. The outcomes in 29 community centers were similar to the three academic centers both at the end of induction (early death rate, 8.2% v 8.8%, respectively) and at 1 year. Overall, the 1-year survival rate in this study of 87.3% is superior to the US SEER data that showed a relative survival rate of 70.7%.8 The overall long-term survival of 84.5% with a median follow-up of 27.3 months is higher than what is seen in published population-based studies.8,9,12
APL is an uncommon disease, with approximately 3,000 cases diagnosed annually in the United States.21 The high incidence of complications, such as bleeding, thrombosis, and DS, has resulted in a recommendation that patients with APL should be referred to specialized centers. During the course of this study, 16 hospitals managed only one patient each over 3 years. Published data suggest that most large cancer centers may only see three to four patients per year.22,23 The Swedish and Canadian registry data showed that the outcomes were superior in academic centers.11,24 With our approach, using a simple algorithm along with frequent expert advice, revealed an excellent outcome overall and with no difference between community centers and academic institutions. The early death rate was similar at 8.8% in academic institutions and 8.2% in nonacademic community centers.
Elderly patients and patients with comorbidities are generally excluded from clinical trials. These patients have a significantly higher risk and early mortality than those eligible for clinical trials. In a review of patients not enrolled in trials from Germany, the early death rate in noneligible patients was 48%.14 Similarly, population-based data have shown that older age is a high-risk factor.7,9,18 These patients frequently have to be managed differently because this is a vulnerable population. The superiority of ATO-containing regimens over chemotherapy6 offers the chance of cure if early death can be reduced in most patients, including those ineligible for chemotherapy and who are elderly. In our study, there was no age- or comorbidity-based exclusion criteria. In fact, while the median age of patients in most clinical trials is in the low- to mid-40s,1,6 the median age in our study was 52.5 years, which is similar to the Swedish registry data (54 years). Forty-six patients (39%) were > 60 years of age with a median age-adjusted Charlson comorbidity index19 score of 5 in this group. There were 24 patients age > 70 years, including six who were age ≥ 80 years.
Our study does have limitations. Our comparator arm being SEER is a limitation. Our study primary end point was to compare our outcomes to SEER data. The data from SEER cover only 27% of the US population. In addition, patient and treatment data are not clearly available. Despite these issues, we wanted to include all patients who we were called about and attempted to improve outcomes in this heterogeneous group. SEER data provided us the only source of outcomes in such a heterogeneous group of patients. We did exclude two patients in our analysis: one for not being involved in the care from the diagnosis and the other who refused treatment for religious reasons. Even with including these two patients, our results are comparable to that of selected populations of clinical trials, which was our main aim of the study. Another major limitation is the lack of data on the total number of patients diagnosed with APL in the same hospitals during the study period. The majority of the patients enrolled came from Georgia and South Carolina. SEER data themselves are not accurate, and review of SEER data in the same years actually shows that the total number of patients with APL diagnosed was less than what we enrolled. Our accrual did go up in the last part of the study as many referring physicians called us with patients. This also means that we were not called for patients with APL in the earlier part of the trial.
Our algorithm by itself would not be expected to completely eliminate early deaths. Consultation with an APL expert is equally important. Accrual was lower in the first year, but with increased awareness, recruitment improved (two or fewer patients v four patients per month in the first 6 months v last 6 months). This suggests that ongoing communication and education were essential. The significance of networking and its effects on improving APL outcomes was shown by Rego et al25 in Latin America. Across six countries, patients were enrolled up to age 75 years and treated with a standard protocol, with weekly discussion by a centralized group of experts. The early death rate of 32% was decreased to 15% with this approach.
In the present era of targeted therapies in the management of diseases, a decentralized approach might offer better care over a large area and reduce disparities on the basis of geographical location. A similar approach showed remarkable improvements in the management of hepatitis C by primary care physicians under guidance from experts at the University of New Mexico.26 In our opinion, a similar approach to comanaging patients will be valuable in many other oncological conditions. Multiple targeted therapies have been approved in the past decade for various oncology indications, each with peculiar adverse effects. We are exploring the same concept in myeloma and chronic myeloid leukemia.
In summary, we show that a simplified algorithm and partnership between experts and treating community oncologists can significantly decrease early death as a result of APL in both academic and community centers. Our model is presently being implemented as an ECOG-ACRIN study (ClinicalTrials.gov identifier: NCT03253848) across the country. This model also paves the way for use in other conditions where education and academic-community partnerships could lead to better care for patients, even outside a clinical trial.
PRIOR PRESENTATION
SUPPORT
CLINICAL TRIAL INFORMATION
AUTHOR CONTRIBUTIONS
Conception and design: Anand P. Jillella, Martha L. Arellano, Amy A. Langston, Morgan L. McLemore, Chao Zhang, Asad Bashey, Robert K. Stuart, Vamsi K. Kota
Administrative support: Prachi Karkhanis, Shruthi H. Krishnamurthy, Sheldon L. Bolds
Provision of study material or patients: Anand P. Jillella, Martha L. Arellano, Manila Gaddh, Amy A. Langston, Leonard T. Heffner, Elliott F. Winton, Morgan L. McLemore, Chao Zhang, Jose Tongol, Mohamed M. El Geneidy, Asim Pati, Jonathan M. Gerber,Michael R. Grunwald, Jorge Cortes, Asad Bashey, Robert K. Stuart, Vamsi K. Kota
Collection and assembly of data: Manila Gaddh, Sheldon L. Bolds, Stephanie DeBragga, Prachi Karkhanis, Shruthi H. Krishnamurthy, Jose Tongol, Vamsi K. Kota
Data analysis and interpretation: Anand P. Jillella, Martha L. Arellano, Manila Gaddh, Amy A. Langston, Morgan L. McLemore, Chao Zhang, Kathryn S. Simon, Sheldon L. Bolds, Prachi Karkhanis, Jose Tongol, Jonathan M. Gerber, Michael R. Grunwald, Jorge Cortes, Asad Bashey, Robert K. Stuart
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Comanagement Strategy Between Academic Institutions and Community Practices to Reduce Induction Mortality in Acute Promyelocytic Leukemia
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Presented at the 62nd American Society of Hematology Annual Meeting, December 5-8, 2020.
Supported in part by a grant from the Leukemia and Lymphoma Society.
NCT02309333
Conflicts of Interest Statement: Accepted on September 22, 2020.
Martha L. Arellano
Consulting or Advisory Role: Gilead Sciences
Research Funding: Cephalon (Inst)
Manila Gaddh
Consulting or Advisory Role: Agios, Pfizer
Research Funding: MedImmune (Inst), Apellis Pharmaceuticals (Inst), Celgene (Inst), Janssen Pharmaceuticals (Inst), Daiichi Sankyo (Inst)
Travel, Accommodations, Expenses: Agios, Pfizer
Amy A. Langston
Research Funding: Chimerix (Inst), Astellas Pharma (Inst), Incyte (Inst), Takeda Pharmaceuticals (Inst), Jazz Pharmaceuticals (Inst), Kadmon (Inst), Novartis (Inst)
Leonard T. Heffner
Speakers’ Bureau: Kite Pharma
Research Funding: Pharmacyclics (Inst), Genentech (Inst), Kite Pharma (Inst), ADC Therapeutics (Inst), Astex Pharmaceuticals (Inst)
Elliott F. Winton
Research Funding: Incyte, Sierra Oncology, Samus Therapeutics, Blueprint Medicines
Asim Pati
Honoraria: Aptitude Health, ITA Group, AstraZeneca, Bristol Myers Squibb, BeiGene
Michael R. Grunwald
Stock and Other Ownership Interests: Medtronic
Honoraria: OncLive, Med Learning Group, Physicians’ Education Resource
Consulting or Advisory Role: Incyte, Cardinal Health, Pfizer, Agios, AbbVie, Trovagene, Daiichi Sankyo, Bristol-Myers Squibb, Premier, Astellas Pharma
Research Funding: Janssen Pharmaceuticals (Inst), FORMA Therapeutics (Inst), Incyte (Inst), Genentech (Inst), Roche (Inst)
Travel, Accommodations, Expenses: Amgen, Incyte
Jonathan M. Gerber
Patents, Royalties, Other Intellectual Property: US Patent No. 9,012,215, US Patent No. 10,222,376
Jorge Cortes
Consulting or Advisory Role: Bristol Myers Squibb, BioLineRx, Novartis, Pfizer, Amphivena Therapeutics, Daiichi Sankyo, Bio-Path Holdings, Astellas Pharma, Takeda Pharmaceuticals, Jazz Pharmaceuticals
Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Immunogen (Inst), Sun Pharma (Inst), Takeda Pharmaceuticals (Inst), Merus (Inst), Daiichi Sankyo (Inst), Tolero Pharmaceuticals (Inst), Trovagene (Inst), Jazz Pharmaceuticals (Inst)
Robert K. Stuart
Consulting or Advisory Role: Ono Pharmaceutical
Research Funding: Ono Pharmaceutical, Agios, Astellas Pharma
Vamsi K. Kota
Consulting or Advisory Role: Pfizer, Novartis, AbbVie
No other potential conflicts of interest were reported.
Martha L. Arellano
Consulting or Advisory Role: Gilead Sciences
Research Funding: Cephalon (Inst)
Manila Gaddh
Consulting or Advisory Role: Agios, Pfizer
Research Funding: MedImmune (Inst), Apellis Pharmaceuticals (Inst), Celgene (Inst), Janssen Pharmaceuticals (Inst), Daiichi Sankyo (Inst)
Travel, Accommodations, Expenses: Agios, Pfizer
Amy A. Langston
Research Funding: Chimerix (Inst), Astellas Pharma (Inst), Incyte (Inst), Takeda Pharmaceuticals (Inst), Jazz Pharmaceuticals (Inst), Kadmon (Inst), Novartis (Inst)
Leonard T. Heffner
Speakers’ Bureau: Kite Pharma
Research Funding: Pharmacyclics (Inst), Genentech (Inst), Kite Pharma (Inst), ADC Therapeutics (Inst), Astex Pharmaceuticals (Inst)
Elliott F. Winton
Research Funding: Incyte, Sierra Oncology, Samus Therapeutics, Blueprint Medicines
Asim Pati
Honoraria: Aptitude Health, ITA Group, AstraZeneca, Bristol Myers Squibb, BeiGene
Michael R. Grunwald
Stock and Other Ownership Interests: Medtronic
Honoraria: OncLive, Med Learning Group, Physicians’ Education Resource
Consulting or Advisory Role: Incyte, Cardinal Health, Pfizer, Agios, AbbVie, Trovagene, Daiichi Sankyo, Bristol-Myers Squibb, Premier, Astellas Pharma
Research Funding: Janssen Pharmaceuticals (Inst), FORMA Therapeutics (Inst), Incyte (Inst), Genentech (Inst), Roche (Inst)
Travel, Accommodations, Expenses: Amgen, Incyte
Jonathan M. Gerber
Patents, Royalties, Other Intellectual Property: US Patent No. 9,012,215, US Patent No. 10,222,376
Jorge Cortes
Consulting or Advisory Role: Bristol Myers Squibb, BioLineRx, Novartis, Pfizer, Amphivena Therapeutics, Daiichi Sankyo, Bio-Path Holdings, Astellas Pharma, Takeda Pharmaceuticals, Jazz Pharmaceuticals
Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Immunogen (Inst), Sun Pharma (Inst), Takeda Pharmaceuticals (Inst), Merus (Inst), Daiichi Sankyo (Inst), Tolero Pharmaceuticals (Inst), Trovagene (Inst), Jazz Pharmaceuticals (Inst)
Robert K. Stuart
Consulting or Advisory Role: Ono Pharmaceutical
Research Funding: Ono Pharmaceutical, Agios, Astellas Pharma
Vamsi K. Kota
Consulting or Advisory Role: Pfizer, Novartis, AbbVie
No other potential conflicts of interest were reported.
|
TRETINOIN
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33125295
| 20,350,168
|
2021-04
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'.
|
Comanagement Strategy Between Academic Institutions and Community Practices to Reduce Induction Mortality in Acute Promyelocytic Leukemia.
Acute promyelocytic leukemia (APL) is a curable leukemia with > 90% survival in clinical trials. Population-based studies from Sweden and US SEER data have shown long-term survival rates of 62% and 65.7%, with the lower rate being from a higher percentage of early deaths.
In this prospective, multicenter trial, we developed a simplified algorithm that focused on prevention and early treatment of the three main causes of death: bleeding, differentiation syndrome, and infection. All patients with a diagnosis of APL were included. The initial 6 months were spent educating oncologists about early deaths in APL. At the time of suspicion of an APL, an expert was contacted. The algorithm was made available followed by discussion of the treatment plan. Communication between expert and treating physician was frequent in the first 2 weeks, during which time most deaths take place.
Between September 2013 and April 2016, 120 patients enrolled in the study from 32 hospitals. The median age was 52.5 years, with 39% > 60 years and 25% with an age-adjusted Charlson comorbidity index > 4. Sixty-three percent of patients were managed at community centers. Two patients did not meet the criteria for analysis, and of 118 evaluable patients, 10 died, with an early mortality rate of 8.5%. With a median follow-up of 27.3 months, the overall survival was 84.5%.
Induction mortality can be decreased and population-wide survival improved in APL with the use of standardized treatment guidelines. Support from experts who have more experience with induction therapy is crucial and helps to improve the outcomes.
pmcINTRODUCTION
Large multicenter trials in the United States and around the world using combinations of anthracyclines, arsenic trioxide (ATO), and all-trans retinoic acid (ATRA) have reported cure rates for patients with acute promyelocytic leukemia (APL) > 85%.1-6 Early deaths during induction in clinical trials have been reported to occur in 5%-10% of patients. Contrary to this excellent outcome in trials, reports from single institutions, pooled data from multiple institutions, and large population-based registries have reported induction mortality rates (ie, during the first 30 days after the start of therapy) of 17.3%-40%.7-14 In this study, we report the implementation of a standardized treatment algorithm for standard treatment in a network of leukemia treatment centers and comanagement by community oncologists and APL experts.
METHODS
Trial Design
This study was designed to comanage patients with APL at their local/regional practices between the community oncologists and an APL expert in an academic institution. Patients age > 18 years with a confirmed diagnosis of APL and receiving standard therapy were eligible; there were no exclusion criteria. Confirmation of promyelocytic leukemia/retinoic acid receptor-α by fluorescence in situ hybridization was required before enrolling the patient. Patients were consented to collect treatment data, which were stored at Emory University. At the lead sites, an institutional review board (IRB)–approved consent was used, and at community sites, an Emory IRB-approved consent was signed after discussing the study over the phone. Patients diagnosed at the community centers were treated at their local hospitals; no patient was transferred to an academic center. Patients managed at the larger academic centers did not initiate therapy before transfer (Fig 1).
FIG 1. CONSORT diagram showing 120 patients accrued from 32 hospitals. APL, acute promyelocytic leukemia.
Study Treatments and Supportive Care
The available guidelines15 for the management of APL and its complications were simplified into a two-page treatment algorithm. Emphasis was on prevention and early identification of disease complications and APL-directed therapy. Standard-of-care APL therapy was recommended but not directed by the study. Adherence to standard APL therapy as recommended by established guidelines was encouraged, with modifications allowed to account for age or comorbid conditions at the discretion of the treating physician in consultation with the APL expert. Suggested regimens were ATRA and ATO for non–high-risk patients and ATRA and idarubicin for high-risk patients.15 After five instances of early death occurred in elderly patients who had received ATRA 45 mg/m2 and developed severe differentiation syndrome (DS), it was recommended that all patients > 60 years of age and/or with significant comorbidities receive dose-reduced ATRA at 25 mg/m2,16 with ATO added after 10-14 days of therapy.
Prednisone at 0.5 mg/kg was recommended at diagnosis in non–high-risk patients, and dexamethasone at 10 mg twice a day was started in high-risk patients per previously published protocols.17 At the first sign of DS, the corticosteroid dose was increased, and ATRA, ATO, or both were held. Hyperleukocytosis was managed with hydroxyurea and rarely with chemotherapy per published studies.6 Patients were weighed at admission on a standing bedside scale, and aggressive diuresis was used to maintain patients at baseline weight. (Treatment guidelines are provided in the Data Supplement, online only.)
Network
The trial included a 6-month period of education of health care providers in Georgia and South Carolina to increase awareness of causes of early death in APL and the strategies being implemented to reduce mortality by a collaborative approach. Because of increased referrals from other neighboring states (predominantly Florida and North Carolina) after growing awareness of the trial, the trial was expanded to these regions. This involved sending e-mail communications and physically visiting and presenting the strategy in 15 community centers. Four large leukemia centers were identified as lead sites, and experts from the four expert sites were engaged in identifying and establishing communication with leukemia treatment centers in the four states. Cell phone numbers of APL experts were made available 24/7 during the entire study period for all necessary communications. Patients with APL who presented to the lead centers were managed with supervision by an APL expert at the site or with discussions among APL experts. Patients who presented to community leukemia centers were enrolled if an APL expert was contacted at the time of diagnosis. After the initial contact, the patient’s presentation and comorbid conditions were discussed by the treating physician with A.P.J., V.K.K., or both. Patient progress was discussed by phone, e-mail, or text messaging on a daily basis in the first 2 weeks and then every 2-3 days until discharge. In all patients, a consolidation plan and follow-up plan were also recommended at the time of completion of the induction period.
Statistical Methods
We defined early death as mortality from the time of diagnosis until the end of induction. Deaths after 30 days as a result of complications from induction were also included as early deaths for the purpose of this analysis. We estimated that a sample size of 120 patients would have 98% power to detect a difference of 15% at the end of 30 days with an α of 0.05 compared with a control group identified through the SEER database. This control group consisted of patients from the SEER database in the 3 years from 2010 to 2012. Secondary end points were survival at 1 year and relapse rates at 12 months.
Statistical analysis was conducted using SAS 9.4 software (SAS Institute, Cary, NC). Descriptive statistics for each variable were reported. For numeric covariates, the mean and standard deviation were calculated and presented. Frequency and percentage were shown for categorical variables. The univariable association of each covariate on overall survival (OS) was assessed using the Cox proportional hazards regression model. A multivariable Cox model was fit by a backward variable selection method with an α = 0.20 removal criterion. OS was represented in a Kaplan-Meier plot.
RESULTS
Patient and Hospital Characteristics
Between September 2013 and April 2016, 120 patients were enrolled. Two patients were excluded from the analysis: one because of refusal of transfusion support for religious reasons and a second enrolled 12 days after initiation of therapy and already with multiorgan failure at the time expert consultation was requested. This analysis includes all 118 eligible patients. Median age was 52.5 years (range, 21-84 years); 46 patients (39%) were ≥ 60 years. Sixty-eight patients (57%) were female, 23 (19.5%) were high risk,18 and 25% had an age-adjusted Charlson comorbidity index of > 4.19 Patient characteristics are listed in Table 1. Patients were treated at 32 hospitals; 16 hospitals treated only one patient during the observation period, five hospitals managed two patients, four hospitals managed three patients, and two hospitals managed four patients. The remaining five hospitals managed five, six, 10, 12, and 39 patients. Overall, 73 patients (62%) were treated in community centers and 45 (38%) in academic centers.
TABLE 1. Patient Characteristics
Induction Therapy and Supportive Care
ATRA was initiated at the time of suspicion of APL in 100% of patients. Of the 23 high-risk patients, four received ATRA alone as induction therapy. ATRA was initiated at 45 mg/m2 in two patients: one diagnosed with postmyocardial infarction with an ejection fraction of 20% and the other on the day of admission with a non–ST-elevation myocardial infarction. Cytarabine was used for reducing leukocytosis. The patients underwent consolidation therapy with ATRA/ATO postinduction and were in molecular remission at 19 and 32 months. In two patients who were > 70 years of age and had multiple comorbid conditions, ATRA was initiated at 25 mg/m2 and continued throughout their hospital stay at the same dose. Both these patients died as a result of complications from multiorgan failure and DS on days 16 and 18, respectively. In five high-risk patients, ATRA/ATO was initiated for induction in place of chemotherapy because of age or comorbid conditions precluding the use of chemotherapy (n = 4) or patient preference (n = 1). All five patients achieved hematological remission. One of these five patients (age 77 years) died as a result of recurrence of ovarian cancer 9 months after diagnosis of APL. The other four were in molecular remission at 19, 29, 38, and 40 months from diagnosis. In the remaining 14 patients, ATRA/idarubicin was the induction regimen. Two of them died during induction (days 5 and 6), both as a result of disease-related coagulopathy. Overall, 19 (82.6%) of the 23 high-risk patients achieved complete hematological remission after induction, with an induction mortality rate of 17.4%.
In the 95 non–high-risk patients, two received ATRA/chemotherapy per physician preference. One patient died on day 24 as a result of gram-negative sepsis and the other achieved complete hematological remission. In eight patients, ATRA was used as a single agent because of age and/or multiple comorbidities. One of them (age 32 years) presented with intracranial bleed and despite aggressive supportive measures, died on day 6 after initiating ATRA. Among the other seven patients receiving single-agent ATRA, one died on day 19 as a result of DS, and the other six are in molecular remission after dose-reduced ATRA/ATO consolidation. The other 85 patients received induction with ATRA/ATO. This included three patients who were pregnant with 10, 16, and 32 weeks gestation at the time of diagnosis. Two patients in their first trimester opted for termination and initiated therapy with dose-reduced ATRA at 25 mg/m2 to correct the coagulopathy, and ATO was added post-termination. The patient in her third trimester started ATRA alone but required a caesarean section for toxemia of pregnancy and then received ATO postsurgery. At 18 months of follow-up, the baby is in good health. All three patients achieved complete hematological remission after induction and molecular remission after ATRA/ATO consolidation. Thus, of the 95 low-risk patients, 89 (93.6%) achieved remission after induction, with an induction mortality rate of 6.4%. Despite adherence to transfusion guidelines, the targets could not be achieved in a few patients, especially during the initial period, because of florid coagulopathy, but there were no early deaths as a result of inadequate transfusion support.
Early Deaths
Ten patients (six non–high risk and four high risk) died, for an early death rate of 8.5%. Median age in the patients with early death was 67 years (range, 21-84 years). The cause of death was DS in five, coagulopathy in three, DS and infection in one, and infection in one. The median time to death in these 10 patients was 17 days (range, 1-36 days). In the three patients with early death as a result of coagulopathy, two (ages 32 and 40 years) died as a result of intracranial bleeding on days 1 and 6. One patient (age 21 years) presented with brain infarcts and died on day 5. All patients who died as a result of DS and/or infection were older, with a median age of 67 years (range, 61-84 years). Two patients (ages 76 and 72 years) died as a result of gram-negative sepsis (one also had DS) on days 16 and 24.
Consolidation Therapy
At the end of induction therapy, recommendations were given to the treating physicians on the best choice of consolidation therapy. Patients were managed per published regimens.1,6
Relapse and Late Deaths
Of the 108 patients who achieved a remission, seven (6.4%) experienced a relapsed (three of whom were high risk). The three high-risk patients experienced relapse at 12, 29, and 32 months while on maintenance therapy per established protocol1 at the time of relapse. Two of them died at the time of relapse, one as a result of intracranial bleed on day 4 of re-induction and the other after refusal of therapy. The patient who experienced relapse at 32 months underwent re-induction followed by an autologous hematopoietic stem-cell transplantation (HSCT) but had a molecular relapse 4 months after HSCT. ATO was given for disease control followed by a haploidentical HSCT, and the patient was in remission at 4 months after HSCT.
Three of the four non–high-risk patients who experienced relapse received inadequate consolidation with ATO because of social issues and nonadherence to therapy. All four patients received re-induction therapy with ATRA/ATO/chemotherapy and achieved a second remission. Two underwent autologous HSCT and are in remission at 6 and 7 months after transplantation. The other two patients refused HSCT and are in remission after consolidation with ATRA/ATO 4 and 30 months after achieving remission. The causes of late deaths were APL relapse (n = 2), relapse of ovarian cancer (n = 1), relapsed bladder cancer (n = 1), and complications from preexisting chronic medical problems and unrelated to APL or therapy (n = 4).
Survival
The 1-year survival probability for the entire cohort was 87.3%. After 18 months from last patient first visit and a median follow-up of 27.3 months, the OS rate was 84.5%, with an early death rate of 8.5% (Fig 2). In addition to the risk classification at diagnosis (by WBC count), age-adjusted comorbidity index and the presence of moderate to severe DS during induction were statistically significant independent predictors of OS on multivariable analysis (Table 2).
FIG 2. Kaplan-Meier graph of overall survival (OS), with 118 patients included in the survival analysis. The 1-month mortality rate was 7.6%. There were eight late deaths as a result of relapse (n = 2), ovarian cancer (n = 1), relapsed bladder cancer (n = 1), and other chronic medical conditions (n = 4). Data in parentheses are the rate (CI, %).
TABLE 2. Univariable and Multivariable Analyses
Outcomes in Community Versus Academic Centers
Seventy-three patients (61.8%) were managed at the community centers. Patients were registered under an academic center if they were transferred for management at the time of diagnosis. The median age (52 v 52.5 years) and comorbidity index (3 v 3) were similar at the academic and community centers, respectively. There was no difference in induction mortality, irrespective of where the patient was managed. Of the 73 managed at community centers, there were six deaths (three in low-risk patients and three in high-risk patients), with an induction mortality rate of 8.2%. This was similar to the 8.8% (four of 45 patients, with one high-risk patient) mortality rate seen in the academic centers. Similarly, there was no difference in survival at 1 year depending on location of therapy.
DISCUSSION
Our study shows that a high proportion of patients with APL are managed in the community similar to what is observed with other cancers. Recent population-based studies have shown that outcomes in acute myeloid leukemia were worse when managed in community centers compared with academic centers.20 In this study, we show that it is possible to improve 1-year survival in patients treated in community clinics when comanaged by an APL expert and the local treating physician. The outcomes in 29 community centers were similar to the three academic centers both at the end of induction (early death rate, 8.2% v 8.8%, respectively) and at 1 year. Overall, the 1-year survival rate in this study of 87.3% is superior to the US SEER data that showed a relative survival rate of 70.7%.8 The overall long-term survival of 84.5% with a median follow-up of 27.3 months is higher than what is seen in published population-based studies.8,9,12
APL is an uncommon disease, with approximately 3,000 cases diagnosed annually in the United States.21 The high incidence of complications, such as bleeding, thrombosis, and DS, has resulted in a recommendation that patients with APL should be referred to specialized centers. During the course of this study, 16 hospitals managed only one patient each over 3 years. Published data suggest that most large cancer centers may only see three to four patients per year.22,23 The Swedish and Canadian registry data showed that the outcomes were superior in academic centers.11,24 With our approach, using a simple algorithm along with frequent expert advice, revealed an excellent outcome overall and with no difference between community centers and academic institutions. The early death rate was similar at 8.8% in academic institutions and 8.2% in nonacademic community centers.
Elderly patients and patients with comorbidities are generally excluded from clinical trials. These patients have a significantly higher risk and early mortality than those eligible for clinical trials. In a review of patients not enrolled in trials from Germany, the early death rate in noneligible patients was 48%.14 Similarly, population-based data have shown that older age is a high-risk factor.7,9,18 These patients frequently have to be managed differently because this is a vulnerable population. The superiority of ATO-containing regimens over chemotherapy6 offers the chance of cure if early death can be reduced in most patients, including those ineligible for chemotherapy and who are elderly. In our study, there was no age- or comorbidity-based exclusion criteria. In fact, while the median age of patients in most clinical trials is in the low- to mid-40s,1,6 the median age in our study was 52.5 years, which is similar to the Swedish registry data (54 years). Forty-six patients (39%) were > 60 years of age with a median age-adjusted Charlson comorbidity index19 score of 5 in this group. There were 24 patients age > 70 years, including six who were age ≥ 80 years.
Our study does have limitations. Our comparator arm being SEER is a limitation. Our study primary end point was to compare our outcomes to SEER data. The data from SEER cover only 27% of the US population. In addition, patient and treatment data are not clearly available. Despite these issues, we wanted to include all patients who we were called about and attempted to improve outcomes in this heterogeneous group. SEER data provided us the only source of outcomes in such a heterogeneous group of patients. We did exclude two patients in our analysis: one for not being involved in the care from the diagnosis and the other who refused treatment for religious reasons. Even with including these two patients, our results are comparable to that of selected populations of clinical trials, which was our main aim of the study. Another major limitation is the lack of data on the total number of patients diagnosed with APL in the same hospitals during the study period. The majority of the patients enrolled came from Georgia and South Carolina. SEER data themselves are not accurate, and review of SEER data in the same years actually shows that the total number of patients with APL diagnosed was less than what we enrolled. Our accrual did go up in the last part of the study as many referring physicians called us with patients. This also means that we were not called for patients with APL in the earlier part of the trial.
Our algorithm by itself would not be expected to completely eliminate early deaths. Consultation with an APL expert is equally important. Accrual was lower in the first year, but with increased awareness, recruitment improved (two or fewer patients v four patients per month in the first 6 months v last 6 months). This suggests that ongoing communication and education were essential. The significance of networking and its effects on improving APL outcomes was shown by Rego et al25 in Latin America. Across six countries, patients were enrolled up to age 75 years and treated with a standard protocol, with weekly discussion by a centralized group of experts. The early death rate of 32% was decreased to 15% with this approach.
In the present era of targeted therapies in the management of diseases, a decentralized approach might offer better care over a large area and reduce disparities on the basis of geographical location. A similar approach showed remarkable improvements in the management of hepatitis C by primary care physicians under guidance from experts at the University of New Mexico.26 In our opinion, a similar approach to comanaging patients will be valuable in many other oncological conditions. Multiple targeted therapies have been approved in the past decade for various oncology indications, each with peculiar adverse effects. We are exploring the same concept in myeloma and chronic myeloid leukemia.
In summary, we show that a simplified algorithm and partnership between experts and treating community oncologists can significantly decrease early death as a result of APL in both academic and community centers. Our model is presently being implemented as an ECOG-ACRIN study (ClinicalTrials.gov identifier: NCT03253848) across the country. This model also paves the way for use in other conditions where education and academic-community partnerships could lead to better care for patients, even outside a clinical trial.
PRIOR PRESENTATION
SUPPORT
CLINICAL TRIAL INFORMATION
AUTHOR CONTRIBUTIONS
Conception and design: Anand P. Jillella, Martha L. Arellano, Amy A. Langston, Morgan L. McLemore, Chao Zhang, Asad Bashey, Robert K. Stuart, Vamsi K. Kota
Administrative support: Prachi Karkhanis, Shruthi H. Krishnamurthy, Sheldon L. Bolds
Provision of study material or patients: Anand P. Jillella, Martha L. Arellano, Manila Gaddh, Amy A. Langston, Leonard T. Heffner, Elliott F. Winton, Morgan L. McLemore, Chao Zhang, Jose Tongol, Mohamed M. El Geneidy, Asim Pati, Jonathan M. Gerber,Michael R. Grunwald, Jorge Cortes, Asad Bashey, Robert K. Stuart, Vamsi K. Kota
Collection and assembly of data: Manila Gaddh, Sheldon L. Bolds, Stephanie DeBragga, Prachi Karkhanis, Shruthi H. Krishnamurthy, Jose Tongol, Vamsi K. Kota
Data analysis and interpretation: Anand P. Jillella, Martha L. Arellano, Manila Gaddh, Amy A. Langston, Morgan L. McLemore, Chao Zhang, Kathryn S. Simon, Sheldon L. Bolds, Prachi Karkhanis, Jose Tongol, Jonathan M. Gerber, Michael R. Grunwald, Jorge Cortes, Asad Bashey, Robert K. Stuart
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Comanagement Strategy Between Academic Institutions and Community Practices to Reduce Induction Mortality in Acute Promyelocytic Leukemia
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Presented at the 62nd American Society of Hematology Annual Meeting, December 5-8, 2020.
Supported in part by a grant from the Leukemia and Lymphoma Society.
NCT02309333
Conflicts of Interest Statement: Accepted on September 22, 2020.
Martha L. Arellano
Consulting or Advisory Role: Gilead Sciences
Research Funding: Cephalon (Inst)
Manila Gaddh
Consulting or Advisory Role: Agios, Pfizer
Research Funding: MedImmune (Inst), Apellis Pharmaceuticals (Inst), Celgene (Inst), Janssen Pharmaceuticals (Inst), Daiichi Sankyo (Inst)
Travel, Accommodations, Expenses: Agios, Pfizer
Amy A. Langston
Research Funding: Chimerix (Inst), Astellas Pharma (Inst), Incyte (Inst), Takeda Pharmaceuticals (Inst), Jazz Pharmaceuticals (Inst), Kadmon (Inst), Novartis (Inst)
Leonard T. Heffner
Speakers’ Bureau: Kite Pharma
Research Funding: Pharmacyclics (Inst), Genentech (Inst), Kite Pharma (Inst), ADC Therapeutics (Inst), Astex Pharmaceuticals (Inst)
Elliott F. Winton
Research Funding: Incyte, Sierra Oncology, Samus Therapeutics, Blueprint Medicines
Asim Pati
Honoraria: Aptitude Health, ITA Group, AstraZeneca, Bristol Myers Squibb, BeiGene
Michael R. Grunwald
Stock and Other Ownership Interests: Medtronic
Honoraria: OncLive, Med Learning Group, Physicians’ Education Resource
Consulting or Advisory Role: Incyte, Cardinal Health, Pfizer, Agios, AbbVie, Trovagene, Daiichi Sankyo, Bristol-Myers Squibb, Premier, Astellas Pharma
Research Funding: Janssen Pharmaceuticals (Inst), FORMA Therapeutics (Inst), Incyte (Inst), Genentech (Inst), Roche (Inst)
Travel, Accommodations, Expenses: Amgen, Incyte
Jonathan M. Gerber
Patents, Royalties, Other Intellectual Property: US Patent No. 9,012,215, US Patent No. 10,222,376
Jorge Cortes
Consulting or Advisory Role: Bristol Myers Squibb, BioLineRx, Novartis, Pfizer, Amphivena Therapeutics, Daiichi Sankyo, Bio-Path Holdings, Astellas Pharma, Takeda Pharmaceuticals, Jazz Pharmaceuticals
Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Immunogen (Inst), Sun Pharma (Inst), Takeda Pharmaceuticals (Inst), Merus (Inst), Daiichi Sankyo (Inst), Tolero Pharmaceuticals (Inst), Trovagene (Inst), Jazz Pharmaceuticals (Inst)
Robert K. Stuart
Consulting or Advisory Role: Ono Pharmaceutical
Research Funding: Ono Pharmaceutical, Agios, Astellas Pharma
Vamsi K. Kota
Consulting or Advisory Role: Pfizer, Novartis, AbbVie
No other potential conflicts of interest were reported.
Martha L. Arellano
Consulting or Advisory Role: Gilead Sciences
Research Funding: Cephalon (Inst)
Manila Gaddh
Consulting or Advisory Role: Agios, Pfizer
Research Funding: MedImmune (Inst), Apellis Pharmaceuticals (Inst), Celgene (Inst), Janssen Pharmaceuticals (Inst), Daiichi Sankyo (Inst)
Travel, Accommodations, Expenses: Agios, Pfizer
Amy A. Langston
Research Funding: Chimerix (Inst), Astellas Pharma (Inst), Incyte (Inst), Takeda Pharmaceuticals (Inst), Jazz Pharmaceuticals (Inst), Kadmon (Inst), Novartis (Inst)
Leonard T. Heffner
Speakers’ Bureau: Kite Pharma
Research Funding: Pharmacyclics (Inst), Genentech (Inst), Kite Pharma (Inst), ADC Therapeutics (Inst), Astex Pharmaceuticals (Inst)
Elliott F. Winton
Research Funding: Incyte, Sierra Oncology, Samus Therapeutics, Blueprint Medicines
Asim Pati
Honoraria: Aptitude Health, ITA Group, AstraZeneca, Bristol Myers Squibb, BeiGene
Michael R. Grunwald
Stock and Other Ownership Interests: Medtronic
Honoraria: OncLive, Med Learning Group, Physicians’ Education Resource
Consulting or Advisory Role: Incyte, Cardinal Health, Pfizer, Agios, AbbVie, Trovagene, Daiichi Sankyo, Bristol-Myers Squibb, Premier, Astellas Pharma
Research Funding: Janssen Pharmaceuticals (Inst), FORMA Therapeutics (Inst), Incyte (Inst), Genentech (Inst), Roche (Inst)
Travel, Accommodations, Expenses: Amgen, Incyte
Jonathan M. Gerber
Patents, Royalties, Other Intellectual Property: US Patent No. 9,012,215, US Patent No. 10,222,376
Jorge Cortes
Consulting or Advisory Role: Bristol Myers Squibb, BioLineRx, Novartis, Pfizer, Amphivena Therapeutics, Daiichi Sankyo, Bio-Path Holdings, Astellas Pharma, Takeda Pharmaceuticals, Jazz Pharmaceuticals
Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Immunogen (Inst), Sun Pharma (Inst), Takeda Pharmaceuticals (Inst), Merus (Inst), Daiichi Sankyo (Inst), Tolero Pharmaceuticals (Inst), Trovagene (Inst), Jazz Pharmaceuticals (Inst)
Robert K. Stuart
Consulting or Advisory Role: Ono Pharmaceutical
Research Funding: Ono Pharmaceutical, Agios, Astellas Pharma
Vamsi K. Kota
Consulting or Advisory Role: Pfizer, Novartis, AbbVie
No other potential conflicts of interest were reported.
|
TRETINOIN
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33125295
| 20,350,168
|
2021-04
|
What was the outcome of reaction 'Maternal exposure during pregnancy'?
|
Comanagement Strategy Between Academic Institutions and Community Practices to Reduce Induction Mortality in Acute Promyelocytic Leukemia.
Acute promyelocytic leukemia (APL) is a curable leukemia with > 90% survival in clinical trials. Population-based studies from Sweden and US SEER data have shown long-term survival rates of 62% and 65.7%, with the lower rate being from a higher percentage of early deaths.
In this prospective, multicenter trial, we developed a simplified algorithm that focused on prevention and early treatment of the three main causes of death: bleeding, differentiation syndrome, and infection. All patients with a diagnosis of APL were included. The initial 6 months were spent educating oncologists about early deaths in APL. At the time of suspicion of an APL, an expert was contacted. The algorithm was made available followed by discussion of the treatment plan. Communication between expert and treating physician was frequent in the first 2 weeks, during which time most deaths take place.
Between September 2013 and April 2016, 120 patients enrolled in the study from 32 hospitals. The median age was 52.5 years, with 39% > 60 years and 25% with an age-adjusted Charlson comorbidity index > 4. Sixty-three percent of patients were managed at community centers. Two patients did not meet the criteria for analysis, and of 118 evaluable patients, 10 died, with an early mortality rate of 8.5%. With a median follow-up of 27.3 months, the overall survival was 84.5%.
Induction mortality can be decreased and population-wide survival improved in APL with the use of standardized treatment guidelines. Support from experts who have more experience with induction therapy is crucial and helps to improve the outcomes.
pmcINTRODUCTION
Large multicenter trials in the United States and around the world using combinations of anthracyclines, arsenic trioxide (ATO), and all-trans retinoic acid (ATRA) have reported cure rates for patients with acute promyelocytic leukemia (APL) > 85%.1-6 Early deaths during induction in clinical trials have been reported to occur in 5%-10% of patients. Contrary to this excellent outcome in trials, reports from single institutions, pooled data from multiple institutions, and large population-based registries have reported induction mortality rates (ie, during the first 30 days after the start of therapy) of 17.3%-40%.7-14 In this study, we report the implementation of a standardized treatment algorithm for standard treatment in a network of leukemia treatment centers and comanagement by community oncologists and APL experts.
METHODS
Trial Design
This study was designed to comanage patients with APL at their local/regional practices between the community oncologists and an APL expert in an academic institution. Patients age > 18 years with a confirmed diagnosis of APL and receiving standard therapy were eligible; there were no exclusion criteria. Confirmation of promyelocytic leukemia/retinoic acid receptor-α by fluorescence in situ hybridization was required before enrolling the patient. Patients were consented to collect treatment data, which were stored at Emory University. At the lead sites, an institutional review board (IRB)–approved consent was used, and at community sites, an Emory IRB-approved consent was signed after discussing the study over the phone. Patients diagnosed at the community centers were treated at their local hospitals; no patient was transferred to an academic center. Patients managed at the larger academic centers did not initiate therapy before transfer (Fig 1).
FIG 1. CONSORT diagram showing 120 patients accrued from 32 hospitals. APL, acute promyelocytic leukemia.
Study Treatments and Supportive Care
The available guidelines15 for the management of APL and its complications were simplified into a two-page treatment algorithm. Emphasis was on prevention and early identification of disease complications and APL-directed therapy. Standard-of-care APL therapy was recommended but not directed by the study. Adherence to standard APL therapy as recommended by established guidelines was encouraged, with modifications allowed to account for age or comorbid conditions at the discretion of the treating physician in consultation with the APL expert. Suggested regimens were ATRA and ATO for non–high-risk patients and ATRA and idarubicin for high-risk patients.15 After five instances of early death occurred in elderly patients who had received ATRA 45 mg/m2 and developed severe differentiation syndrome (DS), it was recommended that all patients > 60 years of age and/or with significant comorbidities receive dose-reduced ATRA at 25 mg/m2,16 with ATO added after 10-14 days of therapy.
Prednisone at 0.5 mg/kg was recommended at diagnosis in non–high-risk patients, and dexamethasone at 10 mg twice a day was started in high-risk patients per previously published protocols.17 At the first sign of DS, the corticosteroid dose was increased, and ATRA, ATO, or both were held. Hyperleukocytosis was managed with hydroxyurea and rarely with chemotherapy per published studies.6 Patients were weighed at admission on a standing bedside scale, and aggressive diuresis was used to maintain patients at baseline weight. (Treatment guidelines are provided in the Data Supplement, online only.)
Network
The trial included a 6-month period of education of health care providers in Georgia and South Carolina to increase awareness of causes of early death in APL and the strategies being implemented to reduce mortality by a collaborative approach. Because of increased referrals from other neighboring states (predominantly Florida and North Carolina) after growing awareness of the trial, the trial was expanded to these regions. This involved sending e-mail communications and physically visiting and presenting the strategy in 15 community centers. Four large leukemia centers were identified as lead sites, and experts from the four expert sites were engaged in identifying and establishing communication with leukemia treatment centers in the four states. Cell phone numbers of APL experts were made available 24/7 during the entire study period for all necessary communications. Patients with APL who presented to the lead centers were managed with supervision by an APL expert at the site or with discussions among APL experts. Patients who presented to community leukemia centers were enrolled if an APL expert was contacted at the time of diagnosis. After the initial contact, the patient’s presentation and comorbid conditions were discussed by the treating physician with A.P.J., V.K.K., or both. Patient progress was discussed by phone, e-mail, or text messaging on a daily basis in the first 2 weeks and then every 2-3 days until discharge. In all patients, a consolidation plan and follow-up plan were also recommended at the time of completion of the induction period.
Statistical Methods
We defined early death as mortality from the time of diagnosis until the end of induction. Deaths after 30 days as a result of complications from induction were also included as early deaths for the purpose of this analysis. We estimated that a sample size of 120 patients would have 98% power to detect a difference of 15% at the end of 30 days with an α of 0.05 compared with a control group identified through the SEER database. This control group consisted of patients from the SEER database in the 3 years from 2010 to 2012. Secondary end points were survival at 1 year and relapse rates at 12 months.
Statistical analysis was conducted using SAS 9.4 software (SAS Institute, Cary, NC). Descriptive statistics for each variable were reported. For numeric covariates, the mean and standard deviation were calculated and presented. Frequency and percentage were shown for categorical variables. The univariable association of each covariate on overall survival (OS) was assessed using the Cox proportional hazards regression model. A multivariable Cox model was fit by a backward variable selection method with an α = 0.20 removal criterion. OS was represented in a Kaplan-Meier plot.
RESULTS
Patient and Hospital Characteristics
Between September 2013 and April 2016, 120 patients were enrolled. Two patients were excluded from the analysis: one because of refusal of transfusion support for religious reasons and a second enrolled 12 days after initiation of therapy and already with multiorgan failure at the time expert consultation was requested. This analysis includes all 118 eligible patients. Median age was 52.5 years (range, 21-84 years); 46 patients (39%) were ≥ 60 years. Sixty-eight patients (57%) were female, 23 (19.5%) were high risk,18 and 25% had an age-adjusted Charlson comorbidity index of > 4.19 Patient characteristics are listed in Table 1. Patients were treated at 32 hospitals; 16 hospitals treated only one patient during the observation period, five hospitals managed two patients, four hospitals managed three patients, and two hospitals managed four patients. The remaining five hospitals managed five, six, 10, 12, and 39 patients. Overall, 73 patients (62%) were treated in community centers and 45 (38%) in academic centers.
TABLE 1. Patient Characteristics
Induction Therapy and Supportive Care
ATRA was initiated at the time of suspicion of APL in 100% of patients. Of the 23 high-risk patients, four received ATRA alone as induction therapy. ATRA was initiated at 45 mg/m2 in two patients: one diagnosed with postmyocardial infarction with an ejection fraction of 20% and the other on the day of admission with a non–ST-elevation myocardial infarction. Cytarabine was used for reducing leukocytosis. The patients underwent consolidation therapy with ATRA/ATO postinduction and were in molecular remission at 19 and 32 months. In two patients who were > 70 years of age and had multiple comorbid conditions, ATRA was initiated at 25 mg/m2 and continued throughout their hospital stay at the same dose. Both these patients died as a result of complications from multiorgan failure and DS on days 16 and 18, respectively. In five high-risk patients, ATRA/ATO was initiated for induction in place of chemotherapy because of age or comorbid conditions precluding the use of chemotherapy (n = 4) or patient preference (n = 1). All five patients achieved hematological remission. One of these five patients (age 77 years) died as a result of recurrence of ovarian cancer 9 months after diagnosis of APL. The other four were in molecular remission at 19, 29, 38, and 40 months from diagnosis. In the remaining 14 patients, ATRA/idarubicin was the induction regimen. Two of them died during induction (days 5 and 6), both as a result of disease-related coagulopathy. Overall, 19 (82.6%) of the 23 high-risk patients achieved complete hematological remission after induction, with an induction mortality rate of 17.4%.
In the 95 non–high-risk patients, two received ATRA/chemotherapy per physician preference. One patient died on day 24 as a result of gram-negative sepsis and the other achieved complete hematological remission. In eight patients, ATRA was used as a single agent because of age and/or multiple comorbidities. One of them (age 32 years) presented with intracranial bleed and despite aggressive supportive measures, died on day 6 after initiating ATRA. Among the other seven patients receiving single-agent ATRA, one died on day 19 as a result of DS, and the other six are in molecular remission after dose-reduced ATRA/ATO consolidation. The other 85 patients received induction with ATRA/ATO. This included three patients who were pregnant with 10, 16, and 32 weeks gestation at the time of diagnosis. Two patients in their first trimester opted for termination and initiated therapy with dose-reduced ATRA at 25 mg/m2 to correct the coagulopathy, and ATO was added post-termination. The patient in her third trimester started ATRA alone but required a caesarean section for toxemia of pregnancy and then received ATO postsurgery. At 18 months of follow-up, the baby is in good health. All three patients achieved complete hematological remission after induction and molecular remission after ATRA/ATO consolidation. Thus, of the 95 low-risk patients, 89 (93.6%) achieved remission after induction, with an induction mortality rate of 6.4%. Despite adherence to transfusion guidelines, the targets could not be achieved in a few patients, especially during the initial period, because of florid coagulopathy, but there were no early deaths as a result of inadequate transfusion support.
Early Deaths
Ten patients (six non–high risk and four high risk) died, for an early death rate of 8.5%. Median age in the patients with early death was 67 years (range, 21-84 years). The cause of death was DS in five, coagulopathy in three, DS and infection in one, and infection in one. The median time to death in these 10 patients was 17 days (range, 1-36 days). In the three patients with early death as a result of coagulopathy, two (ages 32 and 40 years) died as a result of intracranial bleeding on days 1 and 6. One patient (age 21 years) presented with brain infarcts and died on day 5. All patients who died as a result of DS and/or infection were older, with a median age of 67 years (range, 61-84 years). Two patients (ages 76 and 72 years) died as a result of gram-negative sepsis (one also had DS) on days 16 and 24.
Consolidation Therapy
At the end of induction therapy, recommendations were given to the treating physicians on the best choice of consolidation therapy. Patients were managed per published regimens.1,6
Relapse and Late Deaths
Of the 108 patients who achieved a remission, seven (6.4%) experienced a relapsed (three of whom were high risk). The three high-risk patients experienced relapse at 12, 29, and 32 months while on maintenance therapy per established protocol1 at the time of relapse. Two of them died at the time of relapse, one as a result of intracranial bleed on day 4 of re-induction and the other after refusal of therapy. The patient who experienced relapse at 32 months underwent re-induction followed by an autologous hematopoietic stem-cell transplantation (HSCT) but had a molecular relapse 4 months after HSCT. ATO was given for disease control followed by a haploidentical HSCT, and the patient was in remission at 4 months after HSCT.
Three of the four non–high-risk patients who experienced relapse received inadequate consolidation with ATO because of social issues and nonadherence to therapy. All four patients received re-induction therapy with ATRA/ATO/chemotherapy and achieved a second remission. Two underwent autologous HSCT and are in remission at 6 and 7 months after transplantation. The other two patients refused HSCT and are in remission after consolidation with ATRA/ATO 4 and 30 months after achieving remission. The causes of late deaths were APL relapse (n = 2), relapse of ovarian cancer (n = 1), relapsed bladder cancer (n = 1), and complications from preexisting chronic medical problems and unrelated to APL or therapy (n = 4).
Survival
The 1-year survival probability for the entire cohort was 87.3%. After 18 months from last patient first visit and a median follow-up of 27.3 months, the OS rate was 84.5%, with an early death rate of 8.5% (Fig 2). In addition to the risk classification at diagnosis (by WBC count), age-adjusted comorbidity index and the presence of moderate to severe DS during induction were statistically significant independent predictors of OS on multivariable analysis (Table 2).
FIG 2. Kaplan-Meier graph of overall survival (OS), with 118 patients included in the survival analysis. The 1-month mortality rate was 7.6%. There were eight late deaths as a result of relapse (n = 2), ovarian cancer (n = 1), relapsed bladder cancer (n = 1), and other chronic medical conditions (n = 4). Data in parentheses are the rate (CI, %).
TABLE 2. Univariable and Multivariable Analyses
Outcomes in Community Versus Academic Centers
Seventy-three patients (61.8%) were managed at the community centers. Patients were registered under an academic center if they were transferred for management at the time of diagnosis. The median age (52 v 52.5 years) and comorbidity index (3 v 3) were similar at the academic and community centers, respectively. There was no difference in induction mortality, irrespective of where the patient was managed. Of the 73 managed at community centers, there were six deaths (three in low-risk patients and three in high-risk patients), with an induction mortality rate of 8.2%. This was similar to the 8.8% (four of 45 patients, with one high-risk patient) mortality rate seen in the academic centers. Similarly, there was no difference in survival at 1 year depending on location of therapy.
DISCUSSION
Our study shows that a high proportion of patients with APL are managed in the community similar to what is observed with other cancers. Recent population-based studies have shown that outcomes in acute myeloid leukemia were worse when managed in community centers compared with academic centers.20 In this study, we show that it is possible to improve 1-year survival in patients treated in community clinics when comanaged by an APL expert and the local treating physician. The outcomes in 29 community centers were similar to the three academic centers both at the end of induction (early death rate, 8.2% v 8.8%, respectively) and at 1 year. Overall, the 1-year survival rate in this study of 87.3% is superior to the US SEER data that showed a relative survival rate of 70.7%.8 The overall long-term survival of 84.5% with a median follow-up of 27.3 months is higher than what is seen in published population-based studies.8,9,12
APL is an uncommon disease, with approximately 3,000 cases diagnosed annually in the United States.21 The high incidence of complications, such as bleeding, thrombosis, and DS, has resulted in a recommendation that patients with APL should be referred to specialized centers. During the course of this study, 16 hospitals managed only one patient each over 3 years. Published data suggest that most large cancer centers may only see three to four patients per year.22,23 The Swedish and Canadian registry data showed that the outcomes were superior in academic centers.11,24 With our approach, using a simple algorithm along with frequent expert advice, revealed an excellent outcome overall and with no difference between community centers and academic institutions. The early death rate was similar at 8.8% in academic institutions and 8.2% in nonacademic community centers.
Elderly patients and patients with comorbidities are generally excluded from clinical trials. These patients have a significantly higher risk and early mortality than those eligible for clinical trials. In a review of patients not enrolled in trials from Germany, the early death rate in noneligible patients was 48%.14 Similarly, population-based data have shown that older age is a high-risk factor.7,9,18 These patients frequently have to be managed differently because this is a vulnerable population. The superiority of ATO-containing regimens over chemotherapy6 offers the chance of cure if early death can be reduced in most patients, including those ineligible for chemotherapy and who are elderly. In our study, there was no age- or comorbidity-based exclusion criteria. In fact, while the median age of patients in most clinical trials is in the low- to mid-40s,1,6 the median age in our study was 52.5 years, which is similar to the Swedish registry data (54 years). Forty-six patients (39%) were > 60 years of age with a median age-adjusted Charlson comorbidity index19 score of 5 in this group. There were 24 patients age > 70 years, including six who were age ≥ 80 years.
Our study does have limitations. Our comparator arm being SEER is a limitation. Our study primary end point was to compare our outcomes to SEER data. The data from SEER cover only 27% of the US population. In addition, patient and treatment data are not clearly available. Despite these issues, we wanted to include all patients who we were called about and attempted to improve outcomes in this heterogeneous group. SEER data provided us the only source of outcomes in such a heterogeneous group of patients. We did exclude two patients in our analysis: one for not being involved in the care from the diagnosis and the other who refused treatment for religious reasons. Even with including these two patients, our results are comparable to that of selected populations of clinical trials, which was our main aim of the study. Another major limitation is the lack of data on the total number of patients diagnosed with APL in the same hospitals during the study period. The majority of the patients enrolled came from Georgia and South Carolina. SEER data themselves are not accurate, and review of SEER data in the same years actually shows that the total number of patients with APL diagnosed was less than what we enrolled. Our accrual did go up in the last part of the study as many referring physicians called us with patients. This also means that we were not called for patients with APL in the earlier part of the trial.
Our algorithm by itself would not be expected to completely eliminate early deaths. Consultation with an APL expert is equally important. Accrual was lower in the first year, but with increased awareness, recruitment improved (two or fewer patients v four patients per month in the first 6 months v last 6 months). This suggests that ongoing communication and education were essential. The significance of networking and its effects on improving APL outcomes was shown by Rego et al25 in Latin America. Across six countries, patients were enrolled up to age 75 years and treated with a standard protocol, with weekly discussion by a centralized group of experts. The early death rate of 32% was decreased to 15% with this approach.
In the present era of targeted therapies in the management of diseases, a decentralized approach might offer better care over a large area and reduce disparities on the basis of geographical location. A similar approach showed remarkable improvements in the management of hepatitis C by primary care physicians under guidance from experts at the University of New Mexico.26 In our opinion, a similar approach to comanaging patients will be valuable in many other oncological conditions. Multiple targeted therapies have been approved in the past decade for various oncology indications, each with peculiar adverse effects. We are exploring the same concept in myeloma and chronic myeloid leukemia.
In summary, we show that a simplified algorithm and partnership between experts and treating community oncologists can significantly decrease early death as a result of APL in both academic and community centers. Our model is presently being implemented as an ECOG-ACRIN study (ClinicalTrials.gov identifier: NCT03253848) across the country. This model also paves the way for use in other conditions where education and academic-community partnerships could lead to better care for patients, even outside a clinical trial.
PRIOR PRESENTATION
SUPPORT
CLINICAL TRIAL INFORMATION
AUTHOR CONTRIBUTIONS
Conception and design: Anand P. Jillella, Martha L. Arellano, Amy A. Langston, Morgan L. McLemore, Chao Zhang, Asad Bashey, Robert K. Stuart, Vamsi K. Kota
Administrative support: Prachi Karkhanis, Shruthi H. Krishnamurthy, Sheldon L. Bolds
Provision of study material or patients: Anand P. Jillella, Martha L. Arellano, Manila Gaddh, Amy A. Langston, Leonard T. Heffner, Elliott F. Winton, Morgan L. McLemore, Chao Zhang, Jose Tongol, Mohamed M. El Geneidy, Asim Pati, Jonathan M. Gerber,Michael R. Grunwald, Jorge Cortes, Asad Bashey, Robert K. Stuart, Vamsi K. Kota
Collection and assembly of data: Manila Gaddh, Sheldon L. Bolds, Stephanie DeBragga, Prachi Karkhanis, Shruthi H. Krishnamurthy, Jose Tongol, Vamsi K. Kota
Data analysis and interpretation: Anand P. Jillella, Martha L. Arellano, Manila Gaddh, Amy A. Langston, Morgan L. McLemore, Chao Zhang, Kathryn S. Simon, Sheldon L. Bolds, Prachi Karkhanis, Jose Tongol, Jonathan M. Gerber, Michael R. Grunwald, Jorge Cortes, Asad Bashey, Robert K. Stuart
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Comanagement Strategy Between Academic Institutions and Community Practices to Reduce Induction Mortality in Acute Promyelocytic Leukemia
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Presented at the 62nd American Society of Hematology Annual Meeting, December 5-8, 2020.
Supported in part by a grant from the Leukemia and Lymphoma Society.
NCT02309333
Conflicts of Interest Statement: Accepted on September 22, 2020.
Martha L. Arellano
Consulting or Advisory Role: Gilead Sciences
Research Funding: Cephalon (Inst)
Manila Gaddh
Consulting or Advisory Role: Agios, Pfizer
Research Funding: MedImmune (Inst), Apellis Pharmaceuticals (Inst), Celgene (Inst), Janssen Pharmaceuticals (Inst), Daiichi Sankyo (Inst)
Travel, Accommodations, Expenses: Agios, Pfizer
Amy A. Langston
Research Funding: Chimerix (Inst), Astellas Pharma (Inst), Incyte (Inst), Takeda Pharmaceuticals (Inst), Jazz Pharmaceuticals (Inst), Kadmon (Inst), Novartis (Inst)
Leonard T. Heffner
Speakers’ Bureau: Kite Pharma
Research Funding: Pharmacyclics (Inst), Genentech (Inst), Kite Pharma (Inst), ADC Therapeutics (Inst), Astex Pharmaceuticals (Inst)
Elliott F. Winton
Research Funding: Incyte, Sierra Oncology, Samus Therapeutics, Blueprint Medicines
Asim Pati
Honoraria: Aptitude Health, ITA Group, AstraZeneca, Bristol Myers Squibb, BeiGene
Michael R. Grunwald
Stock and Other Ownership Interests: Medtronic
Honoraria: OncLive, Med Learning Group, Physicians’ Education Resource
Consulting or Advisory Role: Incyte, Cardinal Health, Pfizer, Agios, AbbVie, Trovagene, Daiichi Sankyo, Bristol-Myers Squibb, Premier, Astellas Pharma
Research Funding: Janssen Pharmaceuticals (Inst), FORMA Therapeutics (Inst), Incyte (Inst), Genentech (Inst), Roche (Inst)
Travel, Accommodations, Expenses: Amgen, Incyte
Jonathan M. Gerber
Patents, Royalties, Other Intellectual Property: US Patent No. 9,012,215, US Patent No. 10,222,376
Jorge Cortes
Consulting or Advisory Role: Bristol Myers Squibb, BioLineRx, Novartis, Pfizer, Amphivena Therapeutics, Daiichi Sankyo, Bio-Path Holdings, Astellas Pharma, Takeda Pharmaceuticals, Jazz Pharmaceuticals
Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Immunogen (Inst), Sun Pharma (Inst), Takeda Pharmaceuticals (Inst), Merus (Inst), Daiichi Sankyo (Inst), Tolero Pharmaceuticals (Inst), Trovagene (Inst), Jazz Pharmaceuticals (Inst)
Robert K. Stuart
Consulting or Advisory Role: Ono Pharmaceutical
Research Funding: Ono Pharmaceutical, Agios, Astellas Pharma
Vamsi K. Kota
Consulting or Advisory Role: Pfizer, Novartis, AbbVie
No other potential conflicts of interest were reported.
Martha L. Arellano
Consulting or Advisory Role: Gilead Sciences
Research Funding: Cephalon (Inst)
Manila Gaddh
Consulting or Advisory Role: Agios, Pfizer
Research Funding: MedImmune (Inst), Apellis Pharmaceuticals (Inst), Celgene (Inst), Janssen Pharmaceuticals (Inst), Daiichi Sankyo (Inst)
Travel, Accommodations, Expenses: Agios, Pfizer
Amy A. Langston
Research Funding: Chimerix (Inst), Astellas Pharma (Inst), Incyte (Inst), Takeda Pharmaceuticals (Inst), Jazz Pharmaceuticals (Inst), Kadmon (Inst), Novartis (Inst)
Leonard T. Heffner
Speakers’ Bureau: Kite Pharma
Research Funding: Pharmacyclics (Inst), Genentech (Inst), Kite Pharma (Inst), ADC Therapeutics (Inst), Astex Pharmaceuticals (Inst)
Elliott F. Winton
Research Funding: Incyte, Sierra Oncology, Samus Therapeutics, Blueprint Medicines
Asim Pati
Honoraria: Aptitude Health, ITA Group, AstraZeneca, Bristol Myers Squibb, BeiGene
Michael R. Grunwald
Stock and Other Ownership Interests: Medtronic
Honoraria: OncLive, Med Learning Group, Physicians’ Education Resource
Consulting or Advisory Role: Incyte, Cardinal Health, Pfizer, Agios, AbbVie, Trovagene, Daiichi Sankyo, Bristol-Myers Squibb, Premier, Astellas Pharma
Research Funding: Janssen Pharmaceuticals (Inst), FORMA Therapeutics (Inst), Incyte (Inst), Genentech (Inst), Roche (Inst)
Travel, Accommodations, Expenses: Amgen, Incyte
Jonathan M. Gerber
Patents, Royalties, Other Intellectual Property: US Patent No. 9,012,215, US Patent No. 10,222,376
Jorge Cortes
Consulting or Advisory Role: Bristol Myers Squibb, BioLineRx, Novartis, Pfizer, Amphivena Therapeutics, Daiichi Sankyo, Bio-Path Holdings, Astellas Pharma, Takeda Pharmaceuticals, Jazz Pharmaceuticals
Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Immunogen (Inst), Sun Pharma (Inst), Takeda Pharmaceuticals (Inst), Merus (Inst), Daiichi Sankyo (Inst), Tolero Pharmaceuticals (Inst), Trovagene (Inst), Jazz Pharmaceuticals (Inst)
Robert K. Stuart
Consulting or Advisory Role: Ono Pharmaceutical
Research Funding: Ono Pharmaceutical, Agios, Astellas Pharma
Vamsi K. Kota
Consulting or Advisory Role: Pfizer, Novartis, AbbVie
No other potential conflicts of interest were reported.
|
Recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33125295
| 20,350,168
|
2021-04
|
What was the outcome of reaction 'Normal newborn'?
|
Comanagement Strategy Between Academic Institutions and Community Practices to Reduce Induction Mortality in Acute Promyelocytic Leukemia.
Acute promyelocytic leukemia (APL) is a curable leukemia with > 90% survival in clinical trials. Population-based studies from Sweden and US SEER data have shown long-term survival rates of 62% and 65.7%, with the lower rate being from a higher percentage of early deaths.
In this prospective, multicenter trial, we developed a simplified algorithm that focused on prevention and early treatment of the three main causes of death: bleeding, differentiation syndrome, and infection. All patients with a diagnosis of APL were included. The initial 6 months were spent educating oncologists about early deaths in APL. At the time of suspicion of an APL, an expert was contacted. The algorithm was made available followed by discussion of the treatment plan. Communication between expert and treating physician was frequent in the first 2 weeks, during which time most deaths take place.
Between September 2013 and April 2016, 120 patients enrolled in the study from 32 hospitals. The median age was 52.5 years, with 39% > 60 years and 25% with an age-adjusted Charlson comorbidity index > 4. Sixty-three percent of patients were managed at community centers. Two patients did not meet the criteria for analysis, and of 118 evaluable patients, 10 died, with an early mortality rate of 8.5%. With a median follow-up of 27.3 months, the overall survival was 84.5%.
Induction mortality can be decreased and population-wide survival improved in APL with the use of standardized treatment guidelines. Support from experts who have more experience with induction therapy is crucial and helps to improve the outcomes.
pmcINTRODUCTION
Large multicenter trials in the United States and around the world using combinations of anthracyclines, arsenic trioxide (ATO), and all-trans retinoic acid (ATRA) have reported cure rates for patients with acute promyelocytic leukemia (APL) > 85%.1-6 Early deaths during induction in clinical trials have been reported to occur in 5%-10% of patients. Contrary to this excellent outcome in trials, reports from single institutions, pooled data from multiple institutions, and large population-based registries have reported induction mortality rates (ie, during the first 30 days after the start of therapy) of 17.3%-40%.7-14 In this study, we report the implementation of a standardized treatment algorithm for standard treatment in a network of leukemia treatment centers and comanagement by community oncologists and APL experts.
METHODS
Trial Design
This study was designed to comanage patients with APL at their local/regional practices between the community oncologists and an APL expert in an academic institution. Patients age > 18 years with a confirmed diagnosis of APL and receiving standard therapy were eligible; there were no exclusion criteria. Confirmation of promyelocytic leukemia/retinoic acid receptor-α by fluorescence in situ hybridization was required before enrolling the patient. Patients were consented to collect treatment data, which were stored at Emory University. At the lead sites, an institutional review board (IRB)–approved consent was used, and at community sites, an Emory IRB-approved consent was signed after discussing the study over the phone. Patients diagnosed at the community centers were treated at their local hospitals; no patient was transferred to an academic center. Patients managed at the larger academic centers did not initiate therapy before transfer (Fig 1).
FIG 1. CONSORT diagram showing 120 patients accrued from 32 hospitals. APL, acute promyelocytic leukemia.
Study Treatments and Supportive Care
The available guidelines15 for the management of APL and its complications were simplified into a two-page treatment algorithm. Emphasis was on prevention and early identification of disease complications and APL-directed therapy. Standard-of-care APL therapy was recommended but not directed by the study. Adherence to standard APL therapy as recommended by established guidelines was encouraged, with modifications allowed to account for age or comorbid conditions at the discretion of the treating physician in consultation with the APL expert. Suggested regimens were ATRA and ATO for non–high-risk patients and ATRA and idarubicin for high-risk patients.15 After five instances of early death occurred in elderly patients who had received ATRA 45 mg/m2 and developed severe differentiation syndrome (DS), it was recommended that all patients > 60 years of age and/or with significant comorbidities receive dose-reduced ATRA at 25 mg/m2,16 with ATO added after 10-14 days of therapy.
Prednisone at 0.5 mg/kg was recommended at diagnosis in non–high-risk patients, and dexamethasone at 10 mg twice a day was started in high-risk patients per previously published protocols.17 At the first sign of DS, the corticosteroid dose was increased, and ATRA, ATO, or both were held. Hyperleukocytosis was managed with hydroxyurea and rarely with chemotherapy per published studies.6 Patients were weighed at admission on a standing bedside scale, and aggressive diuresis was used to maintain patients at baseline weight. (Treatment guidelines are provided in the Data Supplement, online only.)
Network
The trial included a 6-month period of education of health care providers in Georgia and South Carolina to increase awareness of causes of early death in APL and the strategies being implemented to reduce mortality by a collaborative approach. Because of increased referrals from other neighboring states (predominantly Florida and North Carolina) after growing awareness of the trial, the trial was expanded to these regions. This involved sending e-mail communications and physically visiting and presenting the strategy in 15 community centers. Four large leukemia centers were identified as lead sites, and experts from the four expert sites were engaged in identifying and establishing communication with leukemia treatment centers in the four states. Cell phone numbers of APL experts were made available 24/7 during the entire study period for all necessary communications. Patients with APL who presented to the lead centers were managed with supervision by an APL expert at the site or with discussions among APL experts. Patients who presented to community leukemia centers were enrolled if an APL expert was contacted at the time of diagnosis. After the initial contact, the patient’s presentation and comorbid conditions were discussed by the treating physician with A.P.J., V.K.K., or both. Patient progress was discussed by phone, e-mail, or text messaging on a daily basis in the first 2 weeks and then every 2-3 days until discharge. In all patients, a consolidation plan and follow-up plan were also recommended at the time of completion of the induction period.
Statistical Methods
We defined early death as mortality from the time of diagnosis until the end of induction. Deaths after 30 days as a result of complications from induction were also included as early deaths for the purpose of this analysis. We estimated that a sample size of 120 patients would have 98% power to detect a difference of 15% at the end of 30 days with an α of 0.05 compared with a control group identified through the SEER database. This control group consisted of patients from the SEER database in the 3 years from 2010 to 2012. Secondary end points were survival at 1 year and relapse rates at 12 months.
Statistical analysis was conducted using SAS 9.4 software (SAS Institute, Cary, NC). Descriptive statistics for each variable were reported. For numeric covariates, the mean and standard deviation were calculated and presented. Frequency and percentage were shown for categorical variables. The univariable association of each covariate on overall survival (OS) was assessed using the Cox proportional hazards regression model. A multivariable Cox model was fit by a backward variable selection method with an α = 0.20 removal criterion. OS was represented in a Kaplan-Meier plot.
RESULTS
Patient and Hospital Characteristics
Between September 2013 and April 2016, 120 patients were enrolled. Two patients were excluded from the analysis: one because of refusal of transfusion support for religious reasons and a second enrolled 12 days after initiation of therapy and already with multiorgan failure at the time expert consultation was requested. This analysis includes all 118 eligible patients. Median age was 52.5 years (range, 21-84 years); 46 patients (39%) were ≥ 60 years. Sixty-eight patients (57%) were female, 23 (19.5%) were high risk,18 and 25% had an age-adjusted Charlson comorbidity index of > 4.19 Patient characteristics are listed in Table 1. Patients were treated at 32 hospitals; 16 hospitals treated only one patient during the observation period, five hospitals managed two patients, four hospitals managed three patients, and two hospitals managed four patients. The remaining five hospitals managed five, six, 10, 12, and 39 patients. Overall, 73 patients (62%) were treated in community centers and 45 (38%) in academic centers.
TABLE 1. Patient Characteristics
Induction Therapy and Supportive Care
ATRA was initiated at the time of suspicion of APL in 100% of patients. Of the 23 high-risk patients, four received ATRA alone as induction therapy. ATRA was initiated at 45 mg/m2 in two patients: one diagnosed with postmyocardial infarction with an ejection fraction of 20% and the other on the day of admission with a non–ST-elevation myocardial infarction. Cytarabine was used for reducing leukocytosis. The patients underwent consolidation therapy with ATRA/ATO postinduction and were in molecular remission at 19 and 32 months. In two patients who were > 70 years of age and had multiple comorbid conditions, ATRA was initiated at 25 mg/m2 and continued throughout their hospital stay at the same dose. Both these patients died as a result of complications from multiorgan failure and DS on days 16 and 18, respectively. In five high-risk patients, ATRA/ATO was initiated for induction in place of chemotherapy because of age or comorbid conditions precluding the use of chemotherapy (n = 4) or patient preference (n = 1). All five patients achieved hematological remission. One of these five patients (age 77 years) died as a result of recurrence of ovarian cancer 9 months after diagnosis of APL. The other four were in molecular remission at 19, 29, 38, and 40 months from diagnosis. In the remaining 14 patients, ATRA/idarubicin was the induction regimen. Two of them died during induction (days 5 and 6), both as a result of disease-related coagulopathy. Overall, 19 (82.6%) of the 23 high-risk patients achieved complete hematological remission after induction, with an induction mortality rate of 17.4%.
In the 95 non–high-risk patients, two received ATRA/chemotherapy per physician preference. One patient died on day 24 as a result of gram-negative sepsis and the other achieved complete hematological remission. In eight patients, ATRA was used as a single agent because of age and/or multiple comorbidities. One of them (age 32 years) presented with intracranial bleed and despite aggressive supportive measures, died on day 6 after initiating ATRA. Among the other seven patients receiving single-agent ATRA, one died on day 19 as a result of DS, and the other six are in molecular remission after dose-reduced ATRA/ATO consolidation. The other 85 patients received induction with ATRA/ATO. This included three patients who were pregnant with 10, 16, and 32 weeks gestation at the time of diagnosis. Two patients in their first trimester opted for termination and initiated therapy with dose-reduced ATRA at 25 mg/m2 to correct the coagulopathy, and ATO was added post-termination. The patient in her third trimester started ATRA alone but required a caesarean section for toxemia of pregnancy and then received ATO postsurgery. At 18 months of follow-up, the baby is in good health. All three patients achieved complete hematological remission after induction and molecular remission after ATRA/ATO consolidation. Thus, of the 95 low-risk patients, 89 (93.6%) achieved remission after induction, with an induction mortality rate of 6.4%. Despite adherence to transfusion guidelines, the targets could not be achieved in a few patients, especially during the initial period, because of florid coagulopathy, but there were no early deaths as a result of inadequate transfusion support.
Early Deaths
Ten patients (six non–high risk and four high risk) died, for an early death rate of 8.5%. Median age in the patients with early death was 67 years (range, 21-84 years). The cause of death was DS in five, coagulopathy in three, DS and infection in one, and infection in one. The median time to death in these 10 patients was 17 days (range, 1-36 days). In the three patients with early death as a result of coagulopathy, two (ages 32 and 40 years) died as a result of intracranial bleeding on days 1 and 6. One patient (age 21 years) presented with brain infarcts and died on day 5. All patients who died as a result of DS and/or infection were older, with a median age of 67 years (range, 61-84 years). Two patients (ages 76 and 72 years) died as a result of gram-negative sepsis (one also had DS) on days 16 and 24.
Consolidation Therapy
At the end of induction therapy, recommendations were given to the treating physicians on the best choice of consolidation therapy. Patients were managed per published regimens.1,6
Relapse and Late Deaths
Of the 108 patients who achieved a remission, seven (6.4%) experienced a relapsed (three of whom were high risk). The three high-risk patients experienced relapse at 12, 29, and 32 months while on maintenance therapy per established protocol1 at the time of relapse. Two of them died at the time of relapse, one as a result of intracranial bleed on day 4 of re-induction and the other after refusal of therapy. The patient who experienced relapse at 32 months underwent re-induction followed by an autologous hematopoietic stem-cell transplantation (HSCT) but had a molecular relapse 4 months after HSCT. ATO was given for disease control followed by a haploidentical HSCT, and the patient was in remission at 4 months after HSCT.
Three of the four non–high-risk patients who experienced relapse received inadequate consolidation with ATO because of social issues and nonadherence to therapy. All four patients received re-induction therapy with ATRA/ATO/chemotherapy and achieved a second remission. Two underwent autologous HSCT and are in remission at 6 and 7 months after transplantation. The other two patients refused HSCT and are in remission after consolidation with ATRA/ATO 4 and 30 months after achieving remission. The causes of late deaths were APL relapse (n = 2), relapse of ovarian cancer (n = 1), relapsed bladder cancer (n = 1), and complications from preexisting chronic medical problems and unrelated to APL or therapy (n = 4).
Survival
The 1-year survival probability for the entire cohort was 87.3%. After 18 months from last patient first visit and a median follow-up of 27.3 months, the OS rate was 84.5%, with an early death rate of 8.5% (Fig 2). In addition to the risk classification at diagnosis (by WBC count), age-adjusted comorbidity index and the presence of moderate to severe DS during induction were statistically significant independent predictors of OS on multivariable analysis (Table 2).
FIG 2. Kaplan-Meier graph of overall survival (OS), with 118 patients included in the survival analysis. The 1-month mortality rate was 7.6%. There were eight late deaths as a result of relapse (n = 2), ovarian cancer (n = 1), relapsed bladder cancer (n = 1), and other chronic medical conditions (n = 4). Data in parentheses are the rate (CI, %).
TABLE 2. Univariable and Multivariable Analyses
Outcomes in Community Versus Academic Centers
Seventy-three patients (61.8%) were managed at the community centers. Patients were registered under an academic center if they were transferred for management at the time of diagnosis. The median age (52 v 52.5 years) and comorbidity index (3 v 3) were similar at the academic and community centers, respectively. There was no difference in induction mortality, irrespective of where the patient was managed. Of the 73 managed at community centers, there were six deaths (three in low-risk patients and three in high-risk patients), with an induction mortality rate of 8.2%. This was similar to the 8.8% (four of 45 patients, with one high-risk patient) mortality rate seen in the academic centers. Similarly, there was no difference in survival at 1 year depending on location of therapy.
DISCUSSION
Our study shows that a high proportion of patients with APL are managed in the community similar to what is observed with other cancers. Recent population-based studies have shown that outcomes in acute myeloid leukemia were worse when managed in community centers compared with academic centers.20 In this study, we show that it is possible to improve 1-year survival in patients treated in community clinics when comanaged by an APL expert and the local treating physician. The outcomes in 29 community centers were similar to the three academic centers both at the end of induction (early death rate, 8.2% v 8.8%, respectively) and at 1 year. Overall, the 1-year survival rate in this study of 87.3% is superior to the US SEER data that showed a relative survival rate of 70.7%.8 The overall long-term survival of 84.5% with a median follow-up of 27.3 months is higher than what is seen in published population-based studies.8,9,12
APL is an uncommon disease, with approximately 3,000 cases diagnosed annually in the United States.21 The high incidence of complications, such as bleeding, thrombosis, and DS, has resulted in a recommendation that patients with APL should be referred to specialized centers. During the course of this study, 16 hospitals managed only one patient each over 3 years. Published data suggest that most large cancer centers may only see three to four patients per year.22,23 The Swedish and Canadian registry data showed that the outcomes were superior in academic centers.11,24 With our approach, using a simple algorithm along with frequent expert advice, revealed an excellent outcome overall and with no difference between community centers and academic institutions. The early death rate was similar at 8.8% in academic institutions and 8.2% in nonacademic community centers.
Elderly patients and patients with comorbidities are generally excluded from clinical trials. These patients have a significantly higher risk and early mortality than those eligible for clinical trials. In a review of patients not enrolled in trials from Germany, the early death rate in noneligible patients was 48%.14 Similarly, population-based data have shown that older age is a high-risk factor.7,9,18 These patients frequently have to be managed differently because this is a vulnerable population. The superiority of ATO-containing regimens over chemotherapy6 offers the chance of cure if early death can be reduced in most patients, including those ineligible for chemotherapy and who are elderly. In our study, there was no age- or comorbidity-based exclusion criteria. In fact, while the median age of patients in most clinical trials is in the low- to mid-40s,1,6 the median age in our study was 52.5 years, which is similar to the Swedish registry data (54 years). Forty-six patients (39%) were > 60 years of age with a median age-adjusted Charlson comorbidity index19 score of 5 in this group. There were 24 patients age > 70 years, including six who were age ≥ 80 years.
Our study does have limitations. Our comparator arm being SEER is a limitation. Our study primary end point was to compare our outcomes to SEER data. The data from SEER cover only 27% of the US population. In addition, patient and treatment data are not clearly available. Despite these issues, we wanted to include all patients who we were called about and attempted to improve outcomes in this heterogeneous group. SEER data provided us the only source of outcomes in such a heterogeneous group of patients. We did exclude two patients in our analysis: one for not being involved in the care from the diagnosis and the other who refused treatment for religious reasons. Even with including these two patients, our results are comparable to that of selected populations of clinical trials, which was our main aim of the study. Another major limitation is the lack of data on the total number of patients diagnosed with APL in the same hospitals during the study period. The majority of the patients enrolled came from Georgia and South Carolina. SEER data themselves are not accurate, and review of SEER data in the same years actually shows that the total number of patients with APL diagnosed was less than what we enrolled. Our accrual did go up in the last part of the study as many referring physicians called us with patients. This also means that we were not called for patients with APL in the earlier part of the trial.
Our algorithm by itself would not be expected to completely eliminate early deaths. Consultation with an APL expert is equally important. Accrual was lower in the first year, but with increased awareness, recruitment improved (two or fewer patients v four patients per month in the first 6 months v last 6 months). This suggests that ongoing communication and education were essential. The significance of networking and its effects on improving APL outcomes was shown by Rego et al25 in Latin America. Across six countries, patients were enrolled up to age 75 years and treated with a standard protocol, with weekly discussion by a centralized group of experts. The early death rate of 32% was decreased to 15% with this approach.
In the present era of targeted therapies in the management of diseases, a decentralized approach might offer better care over a large area and reduce disparities on the basis of geographical location. A similar approach showed remarkable improvements in the management of hepatitis C by primary care physicians under guidance from experts at the University of New Mexico.26 In our opinion, a similar approach to comanaging patients will be valuable in many other oncological conditions. Multiple targeted therapies have been approved in the past decade for various oncology indications, each with peculiar adverse effects. We are exploring the same concept in myeloma and chronic myeloid leukemia.
In summary, we show that a simplified algorithm and partnership between experts and treating community oncologists can significantly decrease early death as a result of APL in both academic and community centers. Our model is presently being implemented as an ECOG-ACRIN study (ClinicalTrials.gov identifier: NCT03253848) across the country. This model also paves the way for use in other conditions where education and academic-community partnerships could lead to better care for patients, even outside a clinical trial.
PRIOR PRESENTATION
SUPPORT
CLINICAL TRIAL INFORMATION
AUTHOR CONTRIBUTIONS
Conception and design: Anand P. Jillella, Martha L. Arellano, Amy A. Langston, Morgan L. McLemore, Chao Zhang, Asad Bashey, Robert K. Stuart, Vamsi K. Kota
Administrative support: Prachi Karkhanis, Shruthi H. Krishnamurthy, Sheldon L. Bolds
Provision of study material or patients: Anand P. Jillella, Martha L. Arellano, Manila Gaddh, Amy A. Langston, Leonard T. Heffner, Elliott F. Winton, Morgan L. McLemore, Chao Zhang, Jose Tongol, Mohamed M. El Geneidy, Asim Pati, Jonathan M. Gerber,Michael R. Grunwald, Jorge Cortes, Asad Bashey, Robert K. Stuart, Vamsi K. Kota
Collection and assembly of data: Manila Gaddh, Sheldon L. Bolds, Stephanie DeBragga, Prachi Karkhanis, Shruthi H. Krishnamurthy, Jose Tongol, Vamsi K. Kota
Data analysis and interpretation: Anand P. Jillella, Martha L. Arellano, Manila Gaddh, Amy A. Langston, Morgan L. McLemore, Chao Zhang, Kathryn S. Simon, Sheldon L. Bolds, Prachi Karkhanis, Jose Tongol, Jonathan M. Gerber, Michael R. Grunwald, Jorge Cortes, Asad Bashey, Robert K. Stuart
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Comanagement Strategy Between Academic Institutions and Community Practices to Reduce Induction Mortality in Acute Promyelocytic Leukemia
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Presented at the 62nd American Society of Hematology Annual Meeting, December 5-8, 2020.
Supported in part by a grant from the Leukemia and Lymphoma Society.
NCT02309333
Conflicts of Interest Statement: Accepted on September 22, 2020.
Martha L. Arellano
Consulting or Advisory Role: Gilead Sciences
Research Funding: Cephalon (Inst)
Manila Gaddh
Consulting or Advisory Role: Agios, Pfizer
Research Funding: MedImmune (Inst), Apellis Pharmaceuticals (Inst), Celgene (Inst), Janssen Pharmaceuticals (Inst), Daiichi Sankyo (Inst)
Travel, Accommodations, Expenses: Agios, Pfizer
Amy A. Langston
Research Funding: Chimerix (Inst), Astellas Pharma (Inst), Incyte (Inst), Takeda Pharmaceuticals (Inst), Jazz Pharmaceuticals (Inst), Kadmon (Inst), Novartis (Inst)
Leonard T. Heffner
Speakers’ Bureau: Kite Pharma
Research Funding: Pharmacyclics (Inst), Genentech (Inst), Kite Pharma (Inst), ADC Therapeutics (Inst), Astex Pharmaceuticals (Inst)
Elliott F. Winton
Research Funding: Incyte, Sierra Oncology, Samus Therapeutics, Blueprint Medicines
Asim Pati
Honoraria: Aptitude Health, ITA Group, AstraZeneca, Bristol Myers Squibb, BeiGene
Michael R. Grunwald
Stock and Other Ownership Interests: Medtronic
Honoraria: OncLive, Med Learning Group, Physicians’ Education Resource
Consulting or Advisory Role: Incyte, Cardinal Health, Pfizer, Agios, AbbVie, Trovagene, Daiichi Sankyo, Bristol-Myers Squibb, Premier, Astellas Pharma
Research Funding: Janssen Pharmaceuticals (Inst), FORMA Therapeutics (Inst), Incyte (Inst), Genentech (Inst), Roche (Inst)
Travel, Accommodations, Expenses: Amgen, Incyte
Jonathan M. Gerber
Patents, Royalties, Other Intellectual Property: US Patent No. 9,012,215, US Patent No. 10,222,376
Jorge Cortes
Consulting or Advisory Role: Bristol Myers Squibb, BioLineRx, Novartis, Pfizer, Amphivena Therapeutics, Daiichi Sankyo, Bio-Path Holdings, Astellas Pharma, Takeda Pharmaceuticals, Jazz Pharmaceuticals
Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Immunogen (Inst), Sun Pharma (Inst), Takeda Pharmaceuticals (Inst), Merus (Inst), Daiichi Sankyo (Inst), Tolero Pharmaceuticals (Inst), Trovagene (Inst), Jazz Pharmaceuticals (Inst)
Robert K. Stuart
Consulting or Advisory Role: Ono Pharmaceutical
Research Funding: Ono Pharmaceutical, Agios, Astellas Pharma
Vamsi K. Kota
Consulting or Advisory Role: Pfizer, Novartis, AbbVie
No other potential conflicts of interest were reported.
Martha L. Arellano
Consulting or Advisory Role: Gilead Sciences
Research Funding: Cephalon (Inst)
Manila Gaddh
Consulting or Advisory Role: Agios, Pfizer
Research Funding: MedImmune (Inst), Apellis Pharmaceuticals (Inst), Celgene (Inst), Janssen Pharmaceuticals (Inst), Daiichi Sankyo (Inst)
Travel, Accommodations, Expenses: Agios, Pfizer
Amy A. Langston
Research Funding: Chimerix (Inst), Astellas Pharma (Inst), Incyte (Inst), Takeda Pharmaceuticals (Inst), Jazz Pharmaceuticals (Inst), Kadmon (Inst), Novartis (Inst)
Leonard T. Heffner
Speakers’ Bureau: Kite Pharma
Research Funding: Pharmacyclics (Inst), Genentech (Inst), Kite Pharma (Inst), ADC Therapeutics (Inst), Astex Pharmaceuticals (Inst)
Elliott F. Winton
Research Funding: Incyte, Sierra Oncology, Samus Therapeutics, Blueprint Medicines
Asim Pati
Honoraria: Aptitude Health, ITA Group, AstraZeneca, Bristol Myers Squibb, BeiGene
Michael R. Grunwald
Stock and Other Ownership Interests: Medtronic
Honoraria: OncLive, Med Learning Group, Physicians’ Education Resource
Consulting or Advisory Role: Incyte, Cardinal Health, Pfizer, Agios, AbbVie, Trovagene, Daiichi Sankyo, Bristol-Myers Squibb, Premier, Astellas Pharma
Research Funding: Janssen Pharmaceuticals (Inst), FORMA Therapeutics (Inst), Incyte (Inst), Genentech (Inst), Roche (Inst)
Travel, Accommodations, Expenses: Amgen, Incyte
Jonathan M. Gerber
Patents, Royalties, Other Intellectual Property: US Patent No. 9,012,215, US Patent No. 10,222,376
Jorge Cortes
Consulting or Advisory Role: Bristol Myers Squibb, BioLineRx, Novartis, Pfizer, Amphivena Therapeutics, Daiichi Sankyo, Bio-Path Holdings, Astellas Pharma, Takeda Pharmaceuticals, Jazz Pharmaceuticals
Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Immunogen (Inst), Sun Pharma (Inst), Takeda Pharmaceuticals (Inst), Merus (Inst), Daiichi Sankyo (Inst), Tolero Pharmaceuticals (Inst), Trovagene (Inst), Jazz Pharmaceuticals (Inst)
Robert K. Stuart
Consulting or Advisory Role: Ono Pharmaceutical
Research Funding: Ono Pharmaceutical, Agios, Astellas Pharma
Vamsi K. Kota
Consulting or Advisory Role: Pfizer, Novartis, AbbVie
No other potential conflicts of interest were reported.
|
Recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33125295
| 20,350,168
|
2021-04
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chronic kidney disease'.
|
Emphysematous prostatitis: A case report.
We report the case of a 48-year-old man with ischemic stroke, diabetes and chronic renal failure admitted for fever with LUTS associated with nausea and vomiting.The physical examination showed a depressible abdomen, painful prostate on digital rectal examination.A biological inflammatory syndrome with diabetic ketoacidosis.The abdominopelvic CT scan confirmed the diagnosis by the presence of gas in the prostate,and the CBUE was positive for Enterobacter cloacae.The patient was treated with appropriate antibiotic therapy with transrectal aspiration of the prostate collection,but the evolution was marked by the worsening of the patient's condition leading to his death after two weeks of treatment.
Introduction
Emphysematous prostatitisis a rare inflammatory condition, characterized by gas collection and purulent exudates within the prostate. It is seen in diabetic patients with bladder outlet obstruction or bladder catheterization.
It typically presents with fever, irritative LUTS and pelvic or perineal pain.
Mortality rate varies between 1% and 16%.1 while the reported etiologic pathogens in this infection include Escherichia coli, Klebsiella pneumoniae.2Proteus mirabilis, Citrobacter, enterobacter cloacae, and yeasts.
Case report
A 48-year-old man with a history of chronic renal failure, ischemic stroke and insulin-dependent diabetes, presented with complaints of fever, malaise, oliguria, haematuria, nausea, vomiting lasting for 4 days. On physical examination he was febrile (38 °C),his blood pressure was normal (110/80 mmHg),his abdomen was depressible.Digital rectal examination demonstrated a painful prostate.
Investigations revealed leukocytosis: 12 900, renal failure with creatinine at 399μmol/l,high C-reactive protein:137mg/l, urea at 30mg/l, hyperglycemia, acidosis,and positive acetonuria. An initial clinical diagnosis of male urinary tract infection with diabetic ketoacidosis was suspected.
An abdominopelvic CT scan without contrast injection showed emphysematous lesions in the prostate (Fig. 1, Fig. 2) and seminal vesicles, both kidneys were normal, with no dilatation of the excretory cavities.Fig. 1 Abdominopelvic CT scan revealed a gas accumulation in the prostate gland.
Fig. 1Fig. 2 Coronal abdominopelvic CT revealed a gas accumulation in the prostate gland.
Fig. 2
Cytobacteriological examination of urine and blood culture were done
Empirical intravenous antibiotics were initially administered(cefotaxime and ciprofloxacine),then changed to imipeneme and ciprofloxacine in accordance to the culture reports which isolated Enterobacter cloacae, and a suprapubic catheterization was performed (Fig. 3).Fig. 3 Sagittal section of the abdomino-pelvic scanner which shows the presence of gas in the prostatic parenchyma and which shows the suprapubic catheter.
Fig. 3
On day 3, the patient became apyretic but an aggravation of the biological inflammatory syndrome with increase of the white blood cells to 20000, CRP to 200mg/l and a severe metabolic acidosis led to an emergency hemodialysis.
An abdominopelvic control scan showed prostatic hydroaeric collections. A trans-rectal aspiration was carried out under ultrasound guidance bringing back 50ml of purulent liquid, the bacteriological examination isolated the same germ isolated in the urine.
On day 4, the patient presented a generalized convulsive seizures, he was apyretic, laboratory data demonstrated regression of the biological inflammatory syndrome, with white bloodcells at 16 000 and CRP at 123mg/l, and a correct metabolic balance apart from chronic renal failure.A head CT scan performed was normal. Therefore the origin of the seizures was attributed to the antibiotics.The decision was to change them by piperacillin and flagyl which were not tested.
After 2 weeks of antibiotic adaptation, the evolution was marked by the worsening of the patient's state of consciousness with septic shock, requiring his transfer to the intensive care department where an orotracheal intubation was performed and he was put on norepinephrine in high dose.The patient died in a multi-organ failure table.
Discussion
Prostatic abscess is an uncommon condition but potentially serious disorder, characterized by gas and purulent exudate.Mortality rate is 6–30% before the advent of effective antibiotics therapy. The current reported mortality rate is 3–18%.3 The presenting signs and symptoms of emphysematous prostatic abscess are highly variable. Fever, abdominal pain, dysuria, perineal discomfort and even rectal tenesmus have been reported, Rectal examination typically reveals increased prostate size and prostatic fluctuance.
The diagnosis of emphysematous prostatic abscess is based on clinical history, rectal examination and imaging modalities.PelvicCT scan confirms diagnosis by the presence of gas in the prostatic parenchyma and possibly the extraprostatic extension of the inflammation.3
Transrectal ultrasound is used in the diagnosis of prostaticabscess, in the guidance of aspiration and drainage.3
Often the bacteria responsible for the empysematous prostatitis are Gram-positive(N. gonorrhae), but lately became rather Gram-negative which are often associated with bladder emptying disorders, with enterobacteria being the most common pathogens.3
Patients with diabetes mellitus are prone to urinary tract infections. Elevated tissue glucose levels in diabetes provide a good environment for gas-forming microbes. However, bacterial gas production does not fully explain the pathologic and clinical manifestations of emphysematous urinary tract infections.
Infections by gas-forming organisms like E. coli, Klebsiella, Proteus and Citrobacter species occur with increased frequency in patients with diabetes.4
However, cases of emphysematous prostatitis caused by Enterobacter cloacae are extremely rare, and are hardly mentioned in contemporary literature.
The treatment of empysematous prostatitis is based on antibiotics associated with collection drainage and this can be done by the transrectal route as in our case, or by the transperineal or transurethral route.
The transrectal and transperineal approaches are recommended in older patients in emergent conditions such as septic shock and with increased anesthetic risk. Transurethral resection of prostate (TURP) or transurethral incision of prostate (TUIP) is indicated if patient's condition can tolerate the procedure and general anesthesia.4
As a general rule, in patients with complicated prostatitis of acute urine retention, as in the case of our patient, the urine must be drained by a suspubian catheter, because urethral instrumentation can worsen sepsis. However, in some cases where cystostomy is contraindicated, a transuretral catheter could be used carefully.5
For antibiotic therapy the use of third-generation cephalosporin or quinolone alone, or in combination with metronidazole or gentamicin, have been reported. Prolonged administration of antibiotics for 4–6 weeks is essential to completely eradicate the pathogens.5
Conclusion
Emphysematous prostatic abscess is an uncommon but relatively serious infectious disease that may cause complications if not diagnosed at an early stage and treated appropriately. The mortality rate is more than 30% according to the reported literature.In patients with DM and other associated risk factors, we should maintain a high degree of suspicion when they do not respond well to medical management, CT scan and transrectal ultrasound may help in making this difficult diagnosis.
|
CILASTATIN SODIUM\IMIPENEM, CIPROFLOXACIN
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33134086
| 18,715,495
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'.
|
Emphysematous prostatitis: A case report.
We report the case of a 48-year-old man with ischemic stroke, diabetes and chronic renal failure admitted for fever with LUTS associated with nausea and vomiting.The physical examination showed a depressible abdomen, painful prostate on digital rectal examination.A biological inflammatory syndrome with diabetic ketoacidosis.The abdominopelvic CT scan confirmed the diagnosis by the presence of gas in the prostate,and the CBUE was positive for Enterobacter cloacae.The patient was treated with appropriate antibiotic therapy with transrectal aspiration of the prostate collection,but the evolution was marked by the worsening of the patient's condition leading to his death after two weeks of treatment.
Introduction
Emphysematous prostatitisis a rare inflammatory condition, characterized by gas collection and purulent exudates within the prostate. It is seen in diabetic patients with bladder outlet obstruction or bladder catheterization.
It typically presents with fever, irritative LUTS and pelvic or perineal pain.
Mortality rate varies between 1% and 16%.1 while the reported etiologic pathogens in this infection include Escherichia coli, Klebsiella pneumoniae.2Proteus mirabilis, Citrobacter, enterobacter cloacae, and yeasts.
Case report
A 48-year-old man with a history of chronic renal failure, ischemic stroke and insulin-dependent diabetes, presented with complaints of fever, malaise, oliguria, haematuria, nausea, vomiting lasting for 4 days. On physical examination he was febrile (38 °C),his blood pressure was normal (110/80 mmHg),his abdomen was depressible.Digital rectal examination demonstrated a painful prostate.
Investigations revealed leukocytosis: 12 900, renal failure with creatinine at 399μmol/l,high C-reactive protein:137mg/l, urea at 30mg/l, hyperglycemia, acidosis,and positive acetonuria. An initial clinical diagnosis of male urinary tract infection with diabetic ketoacidosis was suspected.
An abdominopelvic CT scan without contrast injection showed emphysematous lesions in the prostate (Fig. 1, Fig. 2) and seminal vesicles, both kidneys were normal, with no dilatation of the excretory cavities.Fig. 1 Abdominopelvic CT scan revealed a gas accumulation in the prostate gland.
Fig. 1Fig. 2 Coronal abdominopelvic CT revealed a gas accumulation in the prostate gland.
Fig. 2
Cytobacteriological examination of urine and blood culture were done
Empirical intravenous antibiotics were initially administered(cefotaxime and ciprofloxacine),then changed to imipeneme and ciprofloxacine in accordance to the culture reports which isolated Enterobacter cloacae, and a suprapubic catheterization was performed (Fig. 3).Fig. 3 Sagittal section of the abdomino-pelvic scanner which shows the presence of gas in the prostatic parenchyma and which shows the suprapubic catheter.
Fig. 3
On day 3, the patient became apyretic but an aggravation of the biological inflammatory syndrome with increase of the white blood cells to 20000, CRP to 200mg/l and a severe metabolic acidosis led to an emergency hemodialysis.
An abdominopelvic control scan showed prostatic hydroaeric collections. A trans-rectal aspiration was carried out under ultrasound guidance bringing back 50ml of purulent liquid, the bacteriological examination isolated the same germ isolated in the urine.
On day 4, the patient presented a generalized convulsive seizures, he was apyretic, laboratory data demonstrated regression of the biological inflammatory syndrome, with white bloodcells at 16 000 and CRP at 123mg/l, and a correct metabolic balance apart from chronic renal failure.A head CT scan performed was normal. Therefore the origin of the seizures was attributed to the antibiotics.The decision was to change them by piperacillin and flagyl which were not tested.
After 2 weeks of antibiotic adaptation, the evolution was marked by the worsening of the patient's state of consciousness with septic shock, requiring his transfer to the intensive care department where an orotracheal intubation was performed and he was put on norepinephrine in high dose.The patient died in a multi-organ failure table.
Discussion
Prostatic abscess is an uncommon condition but potentially serious disorder, characterized by gas and purulent exudate.Mortality rate is 6–30% before the advent of effective antibiotics therapy. The current reported mortality rate is 3–18%.3 The presenting signs and symptoms of emphysematous prostatic abscess are highly variable. Fever, abdominal pain, dysuria, perineal discomfort and even rectal tenesmus have been reported, Rectal examination typically reveals increased prostate size and prostatic fluctuance.
The diagnosis of emphysematous prostatic abscess is based on clinical history, rectal examination and imaging modalities.PelvicCT scan confirms diagnosis by the presence of gas in the prostatic parenchyma and possibly the extraprostatic extension of the inflammation.3
Transrectal ultrasound is used in the diagnosis of prostaticabscess, in the guidance of aspiration and drainage.3
Often the bacteria responsible for the empysematous prostatitis are Gram-positive(N. gonorrhae), but lately became rather Gram-negative which are often associated with bladder emptying disorders, with enterobacteria being the most common pathogens.3
Patients with diabetes mellitus are prone to urinary tract infections. Elevated tissue glucose levels in diabetes provide a good environment for gas-forming microbes. However, bacterial gas production does not fully explain the pathologic and clinical manifestations of emphysematous urinary tract infections.
Infections by gas-forming organisms like E. coli, Klebsiella, Proteus and Citrobacter species occur with increased frequency in patients with diabetes.4
However, cases of emphysematous prostatitis caused by Enterobacter cloacae are extremely rare, and are hardly mentioned in contemporary literature.
The treatment of empysematous prostatitis is based on antibiotics associated with collection drainage and this can be done by the transrectal route as in our case, or by the transperineal or transurethral route.
The transrectal and transperineal approaches are recommended in older patients in emergent conditions such as septic shock and with increased anesthetic risk. Transurethral resection of prostate (TURP) or transurethral incision of prostate (TUIP) is indicated if patient's condition can tolerate the procedure and general anesthesia.4
As a general rule, in patients with complicated prostatitis of acute urine retention, as in the case of our patient, the urine must be drained by a suspubian catheter, because urethral instrumentation can worsen sepsis. However, in some cases where cystostomy is contraindicated, a transuretral catheter could be used carefully.5
For antibiotic therapy the use of third-generation cephalosporin or quinolone alone, or in combination with metronidazole or gentamicin, have been reported. Prolonged administration of antibiotics for 4–6 weeks is essential to completely eradicate the pathogens.5
Conclusion
Emphysematous prostatic abscess is an uncommon but relatively serious infectious disease that may cause complications if not diagnosed at an early stage and treated appropriately. The mortality rate is more than 30% according to the reported literature.In patients with DM and other associated risk factors, we should maintain a high degree of suspicion when they do not respond well to medical management, CT scan and transrectal ultrasound may help in making this difficult diagnosis.
|
CILASTATIN SODIUM\IMIPENEM, CIPROFLOXACIN
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33134086
| 18,715,495
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'.
|
Emphysematous prostatitis: A case report.
We report the case of a 48-year-old man with ischemic stroke, diabetes and chronic renal failure admitted for fever with LUTS associated with nausea and vomiting.The physical examination showed a depressible abdomen, painful prostate on digital rectal examination.A biological inflammatory syndrome with diabetic ketoacidosis.The abdominopelvic CT scan confirmed the diagnosis by the presence of gas in the prostate,and the CBUE was positive for Enterobacter cloacae.The patient was treated with appropriate antibiotic therapy with transrectal aspiration of the prostate collection,but the evolution was marked by the worsening of the patient's condition leading to his death after two weeks of treatment.
Introduction
Emphysematous prostatitisis a rare inflammatory condition, characterized by gas collection and purulent exudates within the prostate. It is seen in diabetic patients with bladder outlet obstruction or bladder catheterization.
It typically presents with fever, irritative LUTS and pelvic or perineal pain.
Mortality rate varies between 1% and 16%.1 while the reported etiologic pathogens in this infection include Escherichia coli, Klebsiella pneumoniae.2Proteus mirabilis, Citrobacter, enterobacter cloacae, and yeasts.
Case report
A 48-year-old man with a history of chronic renal failure, ischemic stroke and insulin-dependent diabetes, presented with complaints of fever, malaise, oliguria, haematuria, nausea, vomiting lasting for 4 days. On physical examination he was febrile (38 °C),his blood pressure was normal (110/80 mmHg),his abdomen was depressible.Digital rectal examination demonstrated a painful prostate.
Investigations revealed leukocytosis: 12 900, renal failure with creatinine at 399μmol/l,high C-reactive protein:137mg/l, urea at 30mg/l, hyperglycemia, acidosis,and positive acetonuria. An initial clinical diagnosis of male urinary tract infection with diabetic ketoacidosis was suspected.
An abdominopelvic CT scan without contrast injection showed emphysematous lesions in the prostate (Fig. 1, Fig. 2) and seminal vesicles, both kidneys were normal, with no dilatation of the excretory cavities.Fig. 1 Abdominopelvic CT scan revealed a gas accumulation in the prostate gland.
Fig. 1Fig. 2 Coronal abdominopelvic CT revealed a gas accumulation in the prostate gland.
Fig. 2
Cytobacteriological examination of urine and blood culture were done
Empirical intravenous antibiotics were initially administered(cefotaxime and ciprofloxacine),then changed to imipeneme and ciprofloxacine in accordance to the culture reports which isolated Enterobacter cloacae, and a suprapubic catheterization was performed (Fig. 3).Fig. 3 Sagittal section of the abdomino-pelvic scanner which shows the presence of gas in the prostatic parenchyma and which shows the suprapubic catheter.
Fig. 3
On day 3, the patient became apyretic but an aggravation of the biological inflammatory syndrome with increase of the white blood cells to 20000, CRP to 200mg/l and a severe metabolic acidosis led to an emergency hemodialysis.
An abdominopelvic control scan showed prostatic hydroaeric collections. A trans-rectal aspiration was carried out under ultrasound guidance bringing back 50ml of purulent liquid, the bacteriological examination isolated the same germ isolated in the urine.
On day 4, the patient presented a generalized convulsive seizures, he was apyretic, laboratory data demonstrated regression of the biological inflammatory syndrome, with white bloodcells at 16 000 and CRP at 123mg/l, and a correct metabolic balance apart from chronic renal failure.A head CT scan performed was normal. Therefore the origin of the seizures was attributed to the antibiotics.The decision was to change them by piperacillin and flagyl which were not tested.
After 2 weeks of antibiotic adaptation, the evolution was marked by the worsening of the patient's state of consciousness with septic shock, requiring his transfer to the intensive care department where an orotracheal intubation was performed and he was put on norepinephrine in high dose.The patient died in a multi-organ failure table.
Discussion
Prostatic abscess is an uncommon condition but potentially serious disorder, characterized by gas and purulent exudate.Mortality rate is 6–30% before the advent of effective antibiotics therapy. The current reported mortality rate is 3–18%.3 The presenting signs and symptoms of emphysematous prostatic abscess are highly variable. Fever, abdominal pain, dysuria, perineal discomfort and even rectal tenesmus have been reported, Rectal examination typically reveals increased prostate size and prostatic fluctuance.
The diagnosis of emphysematous prostatic abscess is based on clinical history, rectal examination and imaging modalities.PelvicCT scan confirms diagnosis by the presence of gas in the prostatic parenchyma and possibly the extraprostatic extension of the inflammation.3
Transrectal ultrasound is used in the diagnosis of prostaticabscess, in the guidance of aspiration and drainage.3
Often the bacteria responsible for the empysematous prostatitis are Gram-positive(N. gonorrhae), but lately became rather Gram-negative which are often associated with bladder emptying disorders, with enterobacteria being the most common pathogens.3
Patients with diabetes mellitus are prone to urinary tract infections. Elevated tissue glucose levels in diabetes provide a good environment for gas-forming microbes. However, bacterial gas production does not fully explain the pathologic and clinical manifestations of emphysematous urinary tract infections.
Infections by gas-forming organisms like E. coli, Klebsiella, Proteus and Citrobacter species occur with increased frequency in patients with diabetes.4
However, cases of emphysematous prostatitis caused by Enterobacter cloacae are extremely rare, and are hardly mentioned in contemporary literature.
The treatment of empysematous prostatitis is based on antibiotics associated with collection drainage and this can be done by the transrectal route as in our case, or by the transperineal or transurethral route.
The transrectal and transperineal approaches are recommended in older patients in emergent conditions such as septic shock and with increased anesthetic risk. Transurethral resection of prostate (TURP) or transurethral incision of prostate (TUIP) is indicated if patient's condition can tolerate the procedure and general anesthesia.4
As a general rule, in patients with complicated prostatitis of acute urine retention, as in the case of our patient, the urine must be drained by a suspubian catheter, because urethral instrumentation can worsen sepsis. However, in some cases where cystostomy is contraindicated, a transuretral catheter could be used carefully.5
For antibiotic therapy the use of third-generation cephalosporin or quinolone alone, or in combination with metronidazole or gentamicin, have been reported. Prolonged administration of antibiotics for 4–6 weeks is essential to completely eradicate the pathogens.5
Conclusion
Emphysematous prostatic abscess is an uncommon but relatively serious infectious disease that may cause complications if not diagnosed at an early stage and treated appropriately. The mortality rate is more than 30% according to the reported literature.In patients with DM and other associated risk factors, we should maintain a high degree of suspicion when they do not respond well to medical management, CT scan and transrectal ultrasound may help in making this difficult diagnosis.
|
NOREPINEPHRINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33134086
| 18,694,508
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metabolic acidosis'.
|
Emphysematous prostatitis: A case report.
We report the case of a 48-year-old man with ischemic stroke, diabetes and chronic renal failure admitted for fever with LUTS associated with nausea and vomiting.The physical examination showed a depressible abdomen, painful prostate on digital rectal examination.A biological inflammatory syndrome with diabetic ketoacidosis.The abdominopelvic CT scan confirmed the diagnosis by the presence of gas in the prostate,and the CBUE was positive for Enterobacter cloacae.The patient was treated with appropriate antibiotic therapy with transrectal aspiration of the prostate collection,but the evolution was marked by the worsening of the patient's condition leading to his death after two weeks of treatment.
Introduction
Emphysematous prostatitisis a rare inflammatory condition, characterized by gas collection and purulent exudates within the prostate. It is seen in diabetic patients with bladder outlet obstruction or bladder catheterization.
It typically presents with fever, irritative LUTS and pelvic or perineal pain.
Mortality rate varies between 1% and 16%.1 while the reported etiologic pathogens in this infection include Escherichia coli, Klebsiella pneumoniae.2Proteus mirabilis, Citrobacter, enterobacter cloacae, and yeasts.
Case report
A 48-year-old man with a history of chronic renal failure, ischemic stroke and insulin-dependent diabetes, presented with complaints of fever, malaise, oliguria, haematuria, nausea, vomiting lasting for 4 days. On physical examination he was febrile (38 °C),his blood pressure was normal (110/80 mmHg),his abdomen was depressible.Digital rectal examination demonstrated a painful prostate.
Investigations revealed leukocytosis: 12 900, renal failure with creatinine at 399μmol/l,high C-reactive protein:137mg/l, urea at 30mg/l, hyperglycemia, acidosis,and positive acetonuria. An initial clinical diagnosis of male urinary tract infection with diabetic ketoacidosis was suspected.
An abdominopelvic CT scan without contrast injection showed emphysematous lesions in the prostate (Fig. 1, Fig. 2) and seminal vesicles, both kidneys were normal, with no dilatation of the excretory cavities.Fig. 1 Abdominopelvic CT scan revealed a gas accumulation in the prostate gland.
Fig. 1Fig. 2 Coronal abdominopelvic CT revealed a gas accumulation in the prostate gland.
Fig. 2
Cytobacteriological examination of urine and blood culture were done
Empirical intravenous antibiotics were initially administered(cefotaxime and ciprofloxacine),then changed to imipeneme and ciprofloxacine in accordance to the culture reports which isolated Enterobacter cloacae, and a suprapubic catheterization was performed (Fig. 3).Fig. 3 Sagittal section of the abdomino-pelvic scanner which shows the presence of gas in the prostatic parenchyma and which shows the suprapubic catheter.
Fig. 3
On day 3, the patient became apyretic but an aggravation of the biological inflammatory syndrome with increase of the white blood cells to 20000, CRP to 200mg/l and a severe metabolic acidosis led to an emergency hemodialysis.
An abdominopelvic control scan showed prostatic hydroaeric collections. A trans-rectal aspiration was carried out under ultrasound guidance bringing back 50ml of purulent liquid, the bacteriological examination isolated the same germ isolated in the urine.
On day 4, the patient presented a generalized convulsive seizures, he was apyretic, laboratory data demonstrated regression of the biological inflammatory syndrome, with white bloodcells at 16 000 and CRP at 123mg/l, and a correct metabolic balance apart from chronic renal failure.A head CT scan performed was normal. Therefore the origin of the seizures was attributed to the antibiotics.The decision was to change them by piperacillin and flagyl which were not tested.
After 2 weeks of antibiotic adaptation, the evolution was marked by the worsening of the patient's state of consciousness with septic shock, requiring his transfer to the intensive care department where an orotracheal intubation was performed and he was put on norepinephrine in high dose.The patient died in a multi-organ failure table.
Discussion
Prostatic abscess is an uncommon condition but potentially serious disorder, characterized by gas and purulent exudate.Mortality rate is 6–30% before the advent of effective antibiotics therapy. The current reported mortality rate is 3–18%.3 The presenting signs and symptoms of emphysematous prostatic abscess are highly variable. Fever, abdominal pain, dysuria, perineal discomfort and even rectal tenesmus have been reported, Rectal examination typically reveals increased prostate size and prostatic fluctuance.
The diagnosis of emphysematous prostatic abscess is based on clinical history, rectal examination and imaging modalities.PelvicCT scan confirms diagnosis by the presence of gas in the prostatic parenchyma and possibly the extraprostatic extension of the inflammation.3
Transrectal ultrasound is used in the diagnosis of prostaticabscess, in the guidance of aspiration and drainage.3
Often the bacteria responsible for the empysematous prostatitis are Gram-positive(N. gonorrhae), but lately became rather Gram-negative which are often associated with bladder emptying disorders, with enterobacteria being the most common pathogens.3
Patients with diabetes mellitus are prone to urinary tract infections. Elevated tissue glucose levels in diabetes provide a good environment for gas-forming microbes. However, bacterial gas production does not fully explain the pathologic and clinical manifestations of emphysematous urinary tract infections.
Infections by gas-forming organisms like E. coli, Klebsiella, Proteus and Citrobacter species occur with increased frequency in patients with diabetes.4
However, cases of emphysematous prostatitis caused by Enterobacter cloacae are extremely rare, and are hardly mentioned in contemporary literature.
The treatment of empysematous prostatitis is based on antibiotics associated with collection drainage and this can be done by the transrectal route as in our case, or by the transperineal or transurethral route.
The transrectal and transperineal approaches are recommended in older patients in emergent conditions such as septic shock and with increased anesthetic risk. Transurethral resection of prostate (TURP) or transurethral incision of prostate (TUIP) is indicated if patient's condition can tolerate the procedure and general anesthesia.4
As a general rule, in patients with complicated prostatitis of acute urine retention, as in the case of our patient, the urine must be drained by a suspubian catheter, because urethral instrumentation can worsen sepsis. However, in some cases where cystostomy is contraindicated, a transuretral catheter could be used carefully.5
For antibiotic therapy the use of third-generation cephalosporin or quinolone alone, or in combination with metronidazole or gentamicin, have been reported. Prolonged administration of antibiotics for 4–6 weeks is essential to completely eradicate the pathogens.5
Conclusion
Emphysematous prostatic abscess is an uncommon but relatively serious infectious disease that may cause complications if not diagnosed at an early stage and treated appropriately. The mortality rate is more than 30% according to the reported literature.In patients with DM and other associated risk factors, we should maintain a high degree of suspicion when they do not respond well to medical management, CT scan and transrectal ultrasound may help in making this difficult diagnosis.
|
CILASTATIN SODIUM\IMIPENEM, CIPROFLOXACIN
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33134086
| 18,715,495
|
2021-01
|
What was the administration route of drug 'CIPROFLOXACIN'?
|
Emphysematous prostatitis: A case report.
We report the case of a 48-year-old man with ischemic stroke, diabetes and chronic renal failure admitted for fever with LUTS associated with nausea and vomiting.The physical examination showed a depressible abdomen, painful prostate on digital rectal examination.A biological inflammatory syndrome with diabetic ketoacidosis.The abdominopelvic CT scan confirmed the diagnosis by the presence of gas in the prostate,and the CBUE was positive for Enterobacter cloacae.The patient was treated with appropriate antibiotic therapy with transrectal aspiration of the prostate collection,but the evolution was marked by the worsening of the patient's condition leading to his death after two weeks of treatment.
Introduction
Emphysematous prostatitisis a rare inflammatory condition, characterized by gas collection and purulent exudates within the prostate. It is seen in diabetic patients with bladder outlet obstruction or bladder catheterization.
It typically presents with fever, irritative LUTS and pelvic or perineal pain.
Mortality rate varies between 1% and 16%.1 while the reported etiologic pathogens in this infection include Escherichia coli, Klebsiella pneumoniae.2Proteus mirabilis, Citrobacter, enterobacter cloacae, and yeasts.
Case report
A 48-year-old man with a history of chronic renal failure, ischemic stroke and insulin-dependent diabetes, presented with complaints of fever, malaise, oliguria, haematuria, nausea, vomiting lasting for 4 days. On physical examination he was febrile (38 °C),his blood pressure was normal (110/80 mmHg),his abdomen was depressible.Digital rectal examination demonstrated a painful prostate.
Investigations revealed leukocytosis: 12 900, renal failure with creatinine at 399μmol/l,high C-reactive protein:137mg/l, urea at 30mg/l, hyperglycemia, acidosis,and positive acetonuria. An initial clinical diagnosis of male urinary tract infection with diabetic ketoacidosis was suspected.
An abdominopelvic CT scan without contrast injection showed emphysematous lesions in the prostate (Fig. 1, Fig. 2) and seminal vesicles, both kidneys were normal, with no dilatation of the excretory cavities.Fig. 1 Abdominopelvic CT scan revealed a gas accumulation in the prostate gland.
Fig. 1Fig. 2 Coronal abdominopelvic CT revealed a gas accumulation in the prostate gland.
Fig. 2
Cytobacteriological examination of urine and blood culture were done
Empirical intravenous antibiotics were initially administered(cefotaxime and ciprofloxacine),then changed to imipeneme and ciprofloxacine in accordance to the culture reports which isolated Enterobacter cloacae, and a suprapubic catheterization was performed (Fig. 3).Fig. 3 Sagittal section of the abdomino-pelvic scanner which shows the presence of gas in the prostatic parenchyma and which shows the suprapubic catheter.
Fig. 3
On day 3, the patient became apyretic but an aggravation of the biological inflammatory syndrome with increase of the white blood cells to 20000, CRP to 200mg/l and a severe metabolic acidosis led to an emergency hemodialysis.
An abdominopelvic control scan showed prostatic hydroaeric collections. A trans-rectal aspiration was carried out under ultrasound guidance bringing back 50ml of purulent liquid, the bacteriological examination isolated the same germ isolated in the urine.
On day 4, the patient presented a generalized convulsive seizures, he was apyretic, laboratory data demonstrated regression of the biological inflammatory syndrome, with white bloodcells at 16 000 and CRP at 123mg/l, and a correct metabolic balance apart from chronic renal failure.A head CT scan performed was normal. Therefore the origin of the seizures was attributed to the antibiotics.The decision was to change them by piperacillin and flagyl which were not tested.
After 2 weeks of antibiotic adaptation, the evolution was marked by the worsening of the patient's state of consciousness with septic shock, requiring his transfer to the intensive care department where an orotracheal intubation was performed and he was put on norepinephrine in high dose.The patient died in a multi-organ failure table.
Discussion
Prostatic abscess is an uncommon condition but potentially serious disorder, characterized by gas and purulent exudate.Mortality rate is 6–30% before the advent of effective antibiotics therapy. The current reported mortality rate is 3–18%.3 The presenting signs and symptoms of emphysematous prostatic abscess are highly variable. Fever, abdominal pain, dysuria, perineal discomfort and even rectal tenesmus have been reported, Rectal examination typically reveals increased prostate size and prostatic fluctuance.
The diagnosis of emphysematous prostatic abscess is based on clinical history, rectal examination and imaging modalities.PelvicCT scan confirms diagnosis by the presence of gas in the prostatic parenchyma and possibly the extraprostatic extension of the inflammation.3
Transrectal ultrasound is used in the diagnosis of prostaticabscess, in the guidance of aspiration and drainage.3
Often the bacteria responsible for the empysematous prostatitis are Gram-positive(N. gonorrhae), but lately became rather Gram-negative which are often associated with bladder emptying disorders, with enterobacteria being the most common pathogens.3
Patients with diabetes mellitus are prone to urinary tract infections. Elevated tissue glucose levels in diabetes provide a good environment for gas-forming microbes. However, bacterial gas production does not fully explain the pathologic and clinical manifestations of emphysematous urinary tract infections.
Infections by gas-forming organisms like E. coli, Klebsiella, Proteus and Citrobacter species occur with increased frequency in patients with diabetes.4
However, cases of emphysematous prostatitis caused by Enterobacter cloacae are extremely rare, and are hardly mentioned in contemporary literature.
The treatment of empysematous prostatitis is based on antibiotics associated with collection drainage and this can be done by the transrectal route as in our case, or by the transperineal or transurethral route.
The transrectal and transperineal approaches are recommended in older patients in emergent conditions such as septic shock and with increased anesthetic risk. Transurethral resection of prostate (TURP) or transurethral incision of prostate (TUIP) is indicated if patient's condition can tolerate the procedure and general anesthesia.4
As a general rule, in patients with complicated prostatitis of acute urine retention, as in the case of our patient, the urine must be drained by a suspubian catheter, because urethral instrumentation can worsen sepsis. However, in some cases where cystostomy is contraindicated, a transuretral catheter could be used carefully.5
For antibiotic therapy the use of third-generation cephalosporin or quinolone alone, or in combination with metronidazole or gentamicin, have been reported. Prolonged administration of antibiotics for 4–6 weeks is essential to completely eradicate the pathogens.5
Conclusion
Emphysematous prostatic abscess is an uncommon but relatively serious infectious disease that may cause complications if not diagnosed at an early stage and treated appropriately. The mortality rate is more than 30% according to the reported literature.In patients with DM and other associated risk factors, we should maintain a high degree of suspicion when they do not respond well to medical management, CT scan and transrectal ultrasound may help in making this difficult diagnosis.
|
Intravenous (not otherwise specified)
|
DrugAdministrationRoute
|
CC BY-NC-ND
|
33134086
| 18,776,365
|
2021-01
|
What was the administration route of drug 'IMIPENEM'?
|
Emphysematous prostatitis: A case report.
We report the case of a 48-year-old man with ischemic stroke, diabetes and chronic renal failure admitted for fever with LUTS associated with nausea and vomiting.The physical examination showed a depressible abdomen, painful prostate on digital rectal examination.A biological inflammatory syndrome with diabetic ketoacidosis.The abdominopelvic CT scan confirmed the diagnosis by the presence of gas in the prostate,and the CBUE was positive for Enterobacter cloacae.The patient was treated with appropriate antibiotic therapy with transrectal aspiration of the prostate collection,but the evolution was marked by the worsening of the patient's condition leading to his death after two weeks of treatment.
Introduction
Emphysematous prostatitisis a rare inflammatory condition, characterized by gas collection and purulent exudates within the prostate. It is seen in diabetic patients with bladder outlet obstruction or bladder catheterization.
It typically presents with fever, irritative LUTS and pelvic or perineal pain.
Mortality rate varies between 1% and 16%.1 while the reported etiologic pathogens in this infection include Escherichia coli, Klebsiella pneumoniae.2Proteus mirabilis, Citrobacter, enterobacter cloacae, and yeasts.
Case report
A 48-year-old man with a history of chronic renal failure, ischemic stroke and insulin-dependent diabetes, presented with complaints of fever, malaise, oliguria, haematuria, nausea, vomiting lasting for 4 days. On physical examination he was febrile (38 °C),his blood pressure was normal (110/80 mmHg),his abdomen was depressible.Digital rectal examination demonstrated a painful prostate.
Investigations revealed leukocytosis: 12 900, renal failure with creatinine at 399μmol/l,high C-reactive protein:137mg/l, urea at 30mg/l, hyperglycemia, acidosis,and positive acetonuria. An initial clinical diagnosis of male urinary tract infection with diabetic ketoacidosis was suspected.
An abdominopelvic CT scan without contrast injection showed emphysematous lesions in the prostate (Fig. 1, Fig. 2) and seminal vesicles, both kidneys were normal, with no dilatation of the excretory cavities.Fig. 1 Abdominopelvic CT scan revealed a gas accumulation in the prostate gland.
Fig. 1Fig. 2 Coronal abdominopelvic CT revealed a gas accumulation in the prostate gland.
Fig. 2
Cytobacteriological examination of urine and blood culture were done
Empirical intravenous antibiotics were initially administered(cefotaxime and ciprofloxacine),then changed to imipeneme and ciprofloxacine in accordance to the culture reports which isolated Enterobacter cloacae, and a suprapubic catheterization was performed (Fig. 3).Fig. 3 Sagittal section of the abdomino-pelvic scanner which shows the presence of gas in the prostatic parenchyma and which shows the suprapubic catheter.
Fig. 3
On day 3, the patient became apyretic but an aggravation of the biological inflammatory syndrome with increase of the white blood cells to 20000, CRP to 200mg/l and a severe metabolic acidosis led to an emergency hemodialysis.
An abdominopelvic control scan showed prostatic hydroaeric collections. A trans-rectal aspiration was carried out under ultrasound guidance bringing back 50ml of purulent liquid, the bacteriological examination isolated the same germ isolated in the urine.
On day 4, the patient presented a generalized convulsive seizures, he was apyretic, laboratory data demonstrated regression of the biological inflammatory syndrome, with white bloodcells at 16 000 and CRP at 123mg/l, and a correct metabolic balance apart from chronic renal failure.A head CT scan performed was normal. Therefore the origin of the seizures was attributed to the antibiotics.The decision was to change them by piperacillin and flagyl which were not tested.
After 2 weeks of antibiotic adaptation, the evolution was marked by the worsening of the patient's state of consciousness with septic shock, requiring his transfer to the intensive care department where an orotracheal intubation was performed and he was put on norepinephrine in high dose.The patient died in a multi-organ failure table.
Discussion
Prostatic abscess is an uncommon condition but potentially serious disorder, characterized by gas and purulent exudate.Mortality rate is 6–30% before the advent of effective antibiotics therapy. The current reported mortality rate is 3–18%.3 The presenting signs and symptoms of emphysematous prostatic abscess are highly variable. Fever, abdominal pain, dysuria, perineal discomfort and even rectal tenesmus have been reported, Rectal examination typically reveals increased prostate size and prostatic fluctuance.
The diagnosis of emphysematous prostatic abscess is based on clinical history, rectal examination and imaging modalities.PelvicCT scan confirms diagnosis by the presence of gas in the prostatic parenchyma and possibly the extraprostatic extension of the inflammation.3
Transrectal ultrasound is used in the diagnosis of prostaticabscess, in the guidance of aspiration and drainage.3
Often the bacteria responsible for the empysematous prostatitis are Gram-positive(N. gonorrhae), but lately became rather Gram-negative which are often associated with bladder emptying disorders, with enterobacteria being the most common pathogens.3
Patients with diabetes mellitus are prone to urinary tract infections. Elevated tissue glucose levels in diabetes provide a good environment for gas-forming microbes. However, bacterial gas production does not fully explain the pathologic and clinical manifestations of emphysematous urinary tract infections.
Infections by gas-forming organisms like E. coli, Klebsiella, Proteus and Citrobacter species occur with increased frequency in patients with diabetes.4
However, cases of emphysematous prostatitis caused by Enterobacter cloacae are extremely rare, and are hardly mentioned in contemporary literature.
The treatment of empysematous prostatitis is based on antibiotics associated with collection drainage and this can be done by the transrectal route as in our case, or by the transperineal or transurethral route.
The transrectal and transperineal approaches are recommended in older patients in emergent conditions such as septic shock and with increased anesthetic risk. Transurethral resection of prostate (TURP) or transurethral incision of prostate (TUIP) is indicated if patient's condition can tolerate the procedure and general anesthesia.4
As a general rule, in patients with complicated prostatitis of acute urine retention, as in the case of our patient, the urine must be drained by a suspubian catheter, because urethral instrumentation can worsen sepsis. However, in some cases where cystostomy is contraindicated, a transuretral catheter could be used carefully.5
For antibiotic therapy the use of third-generation cephalosporin or quinolone alone, or in combination with metronidazole or gentamicin, have been reported. Prolonged administration of antibiotics for 4–6 weeks is essential to completely eradicate the pathogens.5
Conclusion
Emphysematous prostatic abscess is an uncommon but relatively serious infectious disease that may cause complications if not diagnosed at an early stage and treated appropriately. The mortality rate is more than 30% according to the reported literature.In patients with DM and other associated risk factors, we should maintain a high degree of suspicion when they do not respond well to medical management, CT scan and transrectal ultrasound may help in making this difficult diagnosis.
|
Intravenous (not otherwise specified)
|
DrugAdministrationRoute
|
CC BY-NC-ND
|
33134086
| 18,776,365
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myelosuppression'.
|
Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children under the Age of 3 Years.
OBJECTIVE
Atypical teratoid/rhabdoid tumor (ATRT) is a highly aggressive malignancy with peak incidence in children aged less than 3 years. Standard treatment for central nervous system ATRT in children under the age of 3 years have not been established yet. The objective of this study was to analyze characteristics and clinical outcomes of ATRT in children aged less than 3 years.
A search of medical records from seven centers was performed between January 2005 and December 2016.
RESULTS
Forty-three patients were enrolled. With a median follow-up of 90 months, 27 patients (64.3%) showed at least one episode of disease progression (PD). The first date of PD was at 160 days after diagnosis. The 1- and 3-year progression-free survivals (PFS) were 51.2% and 28.5%, respectively. The 1- and 3-year overall survivals were 61.9% and 38.1%, respectively. The 3-year PFS was improved from 0% in pre-2011 to 47.4% in post-2011. Excluding one patient who did not receive any further therapy after surgery, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown cause (n=1). In univariate analysis, factors associated with higher 3-year PFS were no metastases, diagnosis after 2011, early adjuvant radiotherapy, and high-dose chemotherapy (HDCT). In multivariate analysis, the use of HDCT and adjuvant radiotherapy remained significant prognostic factors for PFS (both p < 0.01).
CONCLUSIONS
Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years.
Introduction
Atypical teratoid/rhabdoid tumor (ATRT) of the central nervous system (CNS) is a highly aggressive malignancy, accounting for 1%–2% of all pediatric CNS tumors [1,2]. Among children under the age of 3 years, ATRT constitutes the most common malignant tumor of CNS (17.3%), followed by medulloblastoma (16%) [3].
Since standard therapeutic strategies for ATRT have not been established yet, treatment approaches for ATRT vary among institutions and countries. Conventional chemotherapy in addition to high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASR) is usually utilized in pati-ents under 3 years of age to substitute for or delay the use of radiotherapy (RT) in attempt to improve outcomes and minimize long-term neurocognitive impairment [4]. However, most patients with ATRT suffer rapid disease progression (PD), although treatment regimens designed for CNS neoplasms have been used [5,6]. Outcome for patients with ATRT is generally dismal, particularly in the presence of residual tumor or metastasis. ATRT is a devastating brain neoplasm with a median survival time ranging from 6 to 13 months. This is caused not only by the disease’s aggressive characteristics, but also by a lower tolerance of young patients to treatment. This is exacerbated by the hesitancy to use RT in younger patients due to risks of functional impairment of the developing brain [7]. It has been shown that aggressive therapy can prolong survival in a subset of children with CNS ATRT [1,2,8]. Some clinical trials have incorporated early administration of RT to the primary site together with intrathecal (IT) chemotherapy, resulting in improved outcomes [9,10].
In 2005, the Korean Society for Pediatric Neuro-Oncology (KSPNO) suggested the following a protocol for ATRT patients aged less than 3 years (KSPNO-S052): six cycles of conventional chemotherapy and tandem HDCT/ASR are performed initially and RT is deferred until the patient reaches 3 years of age. In 2008, a minor revision of the protocol including a dose modification of conventional chemotherapy was made (KSPNO-S082). In 2011, the protocol was revised (KSPNO-S1102) to recommended early local RT with concurrent chemotherapy within four weeks after surgery. In addition, IT chemotherapy was incorporated.
Given the rarity of this tumor and the even lower number of very young infants affected by ATRT, no detailed clinical analyses have been directed toward patients under 3 years of age. Thus, the objective of this study was to describe patients diagnosed with ATRT in this age group and determine potential specific characteristics or prognostic factors. Their therapeutic management is also suggested.
Materials and Methods
1. Data collection
Children younger than 3 years of age at diagnosis who were newly diagnosed with CNS ATRT were eligible for this study. A search of medical records from seven centers was performed to identify patients aged 3 years or less who were diagnosed between January 2005 and December 2016. In cases with multiple intracranial and extracranial rhabdoid tumors, only patients with clear descriptions of a primary tumor within the CNS were included in this analysis. All participating centers received Institutional Review Board approval to contribute data for this study.
2. Staging
Proper staging for metastases included brain and spinal magnetic resonance imaging (MRI) and cytology of the cerebrospinal fluid (CSF). Modified Chang status for metastatic stage was recorded whenever available. It was defined as follows: M0, absence of metastases; M1, presence of metastases confined to CSF; M2, presence of metastases in the brain; M3, presence of metastases in the spinal subarachnoidal space; and M4, spread outside of the CNS [11]. M+ included M1, M2, M3, M4, and any metastasis not further described.
3. Treatment
All patients underwent maximal possible surgical resection of the primary lesion to preserve neurologic function. The extent of surgical resection defined as gross total resection (GTR), subtotal resection, or biopsy was determined based on a review of postoperative MRI and the surgeon’s intraoperative assessment. Multimodal therapies including surgery, RT, chemotherapy and HDCT/ASR were performed. Treatment was mainly performed according to KSPNO recommendations. However, some physicians modified the treatment protocol depending on clinical situation. Treatment scheme of the KSPNO regimen is shown in Fig. 1. Major differences between KSPNO-S052/-S082 (pre-2011) and KSPNO-S1101 (post-2011) were the timing of RT (delayed RT pre-2011 vs. early adjuvant RT post-2011) and IT chemotherapy for patients post-2011. Detailed chemotherapy schedules are described in Table 1.
KSPNO-S052/S082 (pre-2011) suggested the following: Induction treatment was initiated within 4 weeks of surgery. Six cycles of chemotherapy using alternating CECV (cisplatin, etoposide, cyclophosphamide, and vincristine) and CEIV (carboplatin, etoposide, ifosfamide, and vincristine) regimens were administered. Additionally, tandem HDCT/ASR was performed. The first course included carboplatin, thiotepa and etoposide (CTE), and the second course included cyclophosphamide and melphalan (CM). A 12- to 16-week interval between the first and second HDCT/ASR was allowed to minimize treatment-related mortality (TRM). RT was deferred until after 3 years of age unless the tumor showed progression or relapse. For patients with M0 disease at diagnosis and for patients those without residual tumor after HDCT, RT was omitted.
KSPNO-S1102 (post-2011) suggested the following: RT was recommended to be administered within 4 weeks of surgery with concurrent chemotherapy. IT chemotherapy including cytarabine, hydrocortisone, and methotrexate (MTX) was administered on day 0 of every chemotherapy cycle. For M+ patients, weekly IT chemotherapy was administered until clearance of CSF cytology. After six cycles of alternating CECV and CEIV regimens, tandem HDCT/ASR using CTE-CM was performed. For M+ patients at diagnosis, craniospinal irradiation (CSI) was deferred at 3 years of age.
4. Response and toxicity criteria
Disease response was evaluated by MRI and CSF cytology. Evaluations were repeated every two or three chemotherapy cycles prior to the first HDCT/ASR, between the first and second HDCT/ASR, every 3 months for the first year after completion of tandem HDCT/ASR, every 4 months for the second year, and every 6 months thereafter. Disease response was categorized as follows: complete response (CR) for complete disappearance of all tumors, partial response (PR) for decrease in tumor size by more than 50%, stable disease for less than 25% change in tumor size, PD for greater than 25% increase in tumor size or the appearance of new tumors. Toxicities were graded using the National Cancer Institute’s Common Terminology Criteria ver. 4.0.
5. Statistical analysis
The cutoff point for data analyses was March 2019. For descriptive statistics, data were compared using the Fisher exact test for categorical factors and Wilcoxon Mann-Whitney U test for continuous factors. The time to progression was calculated from the date of diagnosis until the date of PD. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of PD or relapse. Overall survival (OS) was calculated from the date of initial diagnosis to the date of last follow-up or death from any cause. PFS and OS were estimated using the Kaplan-Meier method. Univariate analysis of risk factors was performed by comparing PFS and OS using the log-rank test. Multivariate logistic regression was used to examine relationships between outcomes of PFS or OS as binary dependent variables and independent variables of patient age, metastases, extent of resection, early adjuvant RT, HDCT, and years of diagnosis. p < 0.05 was considered statistically significant. All analyses were performed using IBM SPSS ver. 18.0 (SPSS Inc., Chicago, IL).
Results
1. Patient characteristics
Baseline clinical characteristics of patients are shown in Table 2. Forty-three patients were enrolled in this study. The median age at diagnosis was 13 months (range, 0 to 32 months). Twenty patients (46.5%) were younger than 1 year of age at diagnosis. One patient presented with synchronous tumors, including ATRT in brain and a rhabdoid tumor in the kidney.
Nineteen patients (44.2%) were diagnosed before 2011 (pre-2011 group) and 24 patients (55.8%) were diagnosed after 2011 (post-2011 group). There was no significant difference in age at diagnosis (p=0.55), sex (p=0.43), extent of resection (p=0.15), or metastases (p=0.46) between pre-2011 and post-2011 groups. There were 23 (53.5%) patients with M0 disease, four (9.3%) with M1 disease, 14 (32.6%) with M2 disease, and two (4.7%) with unknown metastatic status. The incidence of metastatic disease was significantly higher in patients under 6 months of age than that in patients older than 6 months (100.0% vs. 35.3%, p < 0.01). GTR of the primary tumor was achieved in 24 patients (55.8%).
2. Treatment
One patient did not receive any further therapy after surgery. All remaining 42 patients received induction chemotherapy at a median of 20 days after surgery (range, 5 to 142 days). The median number of pretransplant chemotherapy cycles was 6 (range, 1 to 12). All patients in the post-2011 group received IT therapies. Nine patients (21.4%) received a second surgery before HDCT due to PD (n=8) or for removing residual tumor (n=1).
Twenty-nine patients (69.0%) received radiation at a median age of 23 months (range, 6 to 40 months). The median interval between diagnosis and RT was 162 days (range, 21 to 745 days). Thirteen patients (31.0%) did not receive RT due to early progression (n=8), treatment-related death (n=3), or physician’s discretion (n=2). As of 2011, RT timing changed from delayed RT (pre-2011) to early adjuvant RT (post-2011). As a result, the median period between diagnosis and RT was significantly shortened from 314.9 days in the pre-2011 group to 159.0 days in the post-2011 group (p=0.04). The period between diagnosis to RT was 114.6±104.8 days in patients who received early adjuvant RT and 313.4±231.2 days in patients who received RT as salvage therapy (p < 0.01).Among 29 patients who received RT, early adjuvant RT was administered in 14 patients (2 in the pre-2011 group and 12 in the post-2011 group) (Table 3). They received local RT at a dose of 36–63 Gy after surgery. Of them, five patients received additional CSI at a dose of 23.4–30.6 Gy concurrently (n=2) or at 3 years of age (n=3) due to M+ disease at diagnosis. Thirteen patients received local RT as salvage therapy at a dose of 25.2–55.8 Gy. Of them, five patients received CSI at a dose of 19.5–23.4 Gy. Two patients received CSI at 3 years of age after completion of HDCT as scheduled.
Twenty-four patients received HDCT/ASR (15 patients received tandem HDCTs and nine patients received only 1 HDCT). Reasons not having second HDCT included physician’s discretion (n=4), PD or relapse (n=3), prolonged bone marrow suppression (n=1), and patient refusal (n=1). During the first HDCT, eight patients received conditioning regimen including topotecan, thiotepa, and carboplatin instead of CTE. During the second HDCT, two patients received conditioning regimen including busulfan, melphalan, and thiotepa instead of CM.
Significantly more patients who received early adjuvant RT proceeded to HDCT compared to patients who did not (78.6% vs. 46.4%, p=0.04). For patients not receiving HDCT (n=18), reasons included PD or relapse (n=12), treatment-related death (n=4), patient refusal (n=1), and death due to unknown cause (n=1). The median age at the time of the first HDCT was 21.0 months (range, 9.1 to 44.5 months). The median time between diagnosis and the first HDCT was 7.5 months (range, 5.3 to 16.1 months). Disease status before the first HDCT was CR in 16 and PR in eight. Among 15 patients who underwent a second HDCT, disease status before the second HDCT was CR in 10, PR in four, and PD in one. The median interval between the first and second HDCT was 91 days (range, 35 to 126 days).
3. Clinical course and survival
Excluding one patient who received palliative care only, data for 42 patients were analyzed (Table 3). With a median follow-up of 90 months (range, 27 to 172 months), 27 patients (64.3%) showed at least one episode of PD. The first date of PD was at 160 days (median; range, 13 to 585) after the diagnosis. Twenty-one of 27 patients who showed PD died due to PD at a median of 4 months (range, 0.1 to 5.4 months) from the first day of documentation of PD. Immediate salvage therapy consisted of surgery in 11, chemotherapy in four, RT in four, gamma knife surgery in one, and supportive care only in seven. PD was found within 2 months of resection surgery before initiation of chemotherapy in three, during chemotherapy in 14, during adjuvant RT in one, during HDCT in two, and after completion of HDCT in seven. Among 14 patients with PD found during induction chemotherapy, 13 did not receive adjuvant RT previously while one patient had received RT previously (p < 0.01). Of nine patients who experienced relapse during or after HDCT, seven patients died due to PD. Two patients are still alive without disease. The median time between HDCT and subsequent relapse was 3 months (range, 1 to 11 months).
The 1- and 3-year PFS is 51.2% and 28.5%, respectively. The 1- and 3-year OS is 61.9% and 38.1%, respectively (Fig. 2). Of 42 patients analyzed, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown causes (n=1).
At the last follow-up, 15 patients were alive. All surviving patients received HDCT/ASR. Patients who achieved CR before the first HDCT showed significantly higher 3-year OS compared to patients who did not (81.3% vs. 37.5%, p < 0.01). There was no significant difference in PFS or OS between patients who underwent 1 HDCT and those who underwent 2 HDCTs.
4. Risk factors
Results of univariate and multivariate analyses for PFS are shown in Table 4. In univariate analysis, factors associated with higher 3-year PFS were no metastases (p=0.03), diagnosis after 2011 (p=0.04), early adjuvant RT (p < 0.01) and HDCT/ASR (p < 0.01) (Fig. 3). Age at diagnosis (p=0.53) and extent of resection (p=0.29) failed to influence survival rate in our study. Among 14 patients who received adjuvant RT, only three patients showed PD during (n=1) or after (n=2) the planned RT, while 24 of 28 patients who did not receive adjuvant RT showed PD (p < 0.01). Among 18 patients with metastases, patients who received early adjuvant local RT showed significantly higher PFS and OS compared to those who did not (3-year PFS: 75.0% vs. 0%, p=0.04; 3-year OS: 75.0% vs. 14.3%, p=0.03).
In multivariate analyses, the use of HDCT/ASR and early adjuvant RT remained significant prognostic factors for PFS (both p < 0.01). For OS, the use of HDCT/ASR was the only significant prognostic factor (p < 0.01). Among patients who received both early adjuvant RT and HDCT/ASR, 3-year PFS and OS were 81.8% and 90.9%, respectively.
5. Toxicity
During chemotherapy, the most frequently reported significant toxicities were bone marrow suppression and febrile neutropenia followed by infection, gastrointestinal disturbances, electrolyte disturbances, and hepatic disturbances. During HDCT, infection was the most common toxicity. Bacteremia was detected during six of 39 HDCT (3 Staphylococcus epidermidis, 2 Pseudomonas aeruginosa, and 1 Bacillus species), five of which occurred during the second HDCT course. One patient experienced sinusoidal obstruction syndrome during their second HDCT. There were five toxic deaths due to sepsis: four occurred under chemotherapy and one occurred following the second HDCT. To date, second malignancies have not been reported.
Discussion
This is the most recent update of Korean ATRT patients under 3 years of age. Tumors progressed or relapsed in 27 of 42 patients at a median of 160 days from diagnosis in our study. The 3-year PFS and OS were 28.5% and 38.1%, respectively. The 3-year PFS was improved from 0.0% in pre-2011 to 47.4% in post-2011. At diagnosis, metastasis was the only characteristic among several disease characteristics known to affect survival.
Our analysis highlights several points of interest for this young age group. First, our data suggest the importance of early adjuvant RT. We found a survival benefit associated with early adjuvant RT. Traditionally, RT has been deferred or omitted because of the risk of adverse effects, especially for patients under 3 years of age [12]. However, more recent data suggest that RT might be more efficacious than chemotherapy for ATRT patients, even for very young children [2,13,14]. In a previously reported Korean study that included patients treated with tandem HDCT/ASR, all surviving patients received RT at an early stage in their treatment [15]. No patients who received induction chemotherapy and HDCT/ASR without RT survived. This suggests that HDCT/ASR cannot replace RT for local control. Similarly, we found that patients who received early adjuvant RT showed a significantly lower chance of having PD during induction chemotherapy and a higher chance to proceed to HDCT compared to patients who did not, thus leading to improved survival. For patients with M+ disease at diagnosis, adjuvant local radiation significantly improved survival in the current study. Overall, local RT should be considered earlier in therapy to improve survival.
Secondly, our data suggest that HDCT is associated with better survival. For patients who received HDCT, PFS and OS were significantly higher compared to those who did not. There has been no randomized study to evaluate the efficacy of HDCT/ASR in ATRT patients under 3 years of age. A few studies have suggested that HDCT might have a favorable effect on ATRT patients [14,16]. A recent Canadian study has reported better 5-year PFS in patients with ATRT under 1 year of age receiving HDCT group compared to those without receiving HDCT (50.1% vs. 11.3%, p < 0.001) [17]. However, due to small numbers of patients included and various treatment modalities used, no firm conclusions can be made regarding the role of HDCT/ASR in ATRT patients. In this study, all surviving patients received HDCT/ASR. However, this does not reflect the definite efficacy of HDCT/ASR. Considering that patients who achieved CR before their first HDCT showed significantly higher OS than those who did not, multimodal treatment that might lead to CR and additional HDCT might result in better outcomes. In this study, patients who achieved CR before the first HDCT showed significantly higher OS. This suggests that pre-HDCT tumor status is important for predicting outcome. Thus, careful consideration is required when selecting candidate patients for HDCT/ASR.
Importantly, we should consider the likelihood of selection bias toward “favorable cases” in patients subjected to HDCT, which could be associated with molecular distinction. Recently, Reddy et al. [18] have reported that patients with group 1/SHH-NOTCH tumors have less aggressive feature. Biological investigation of ATRT should be continued and subsets of patients who can be cured with less therapy may exist [19].
The optimal combination of regimens for tandem HDCT has not been determined. Rosenfeld et al. [12] have reported the feasibility of tandem HDCT/ASR in patients with brain tumors using CTE-CM. Although they concluded that the CTE-CM regimen was not feasible due to toxicity, tandem CTE-CM HDCT/ASR was feasible in our study. Toxicities in our present study were manageable and only one toxic death associated with HDCT occurred. This could be due to the fact that patients were given a sufficient rest period between the first and the second HDCT/ASR. Sung et al. [20] have reported that a shorter interval (< 12 weeks) between the first and second HDCT/ASR is associated with higher TRM. Another thing to be noted was that there was no significant survival difference between patients who received 1 HDCT and those who received 2 HDCTs. In addition, bacteremia occurred more frequently in the second HDCT than in the first HDCT. Randomized trials with larger cohorts are needed to determine whether the possible survival benefit of tandem HDCT/ASR over single HDCT/ASR might ultimately outweigh adverse effects associated with dose intensive tandem HDCT/ASR.
Thirdly, optimal induction chemotherapy should be explored. Efficacies of many different treatments have been explored. However, there is no consensus regarding standard chemotherapy for ATRT. Due to the desire to avoid unacceptable adverse effects of RT on the developing brain, many institutions adopt chemotherapy-based strategies designed to avoid or delay RT. Despite often impressive responses to chemotherapy, the majority of patients in many published studies developed progressive disease early, suggesting a rapid development of resistance of ATRTs [10,21,22]. Similarly, in our study, PD occurred during induction chemotherapy in about half of cases. Considering that the most common reason not having HDCT/ASR was PD during induction chemotherapy, we could consider shorten the current six cycles of induction chemotherapy. Furthermore, patients who received induction chemotherapy without early adjuvant RT showed significantly lower survival compared to patients who received early adjuvant RT. This suggests that CECV and CEIV chemotherapy regimen used in our patients might be insufficient to prevent tumor progression/relapse. Recently, ACNS0333 comprised with three cycles of chemotherapy which incorporated high dose MTX showed promising result, with 4-year OS of 43% [18]. High-dose MTX used in “Head Start II” also appears to be efficacious and well tolerated in ATRT [8]. Slavc et al. [23] have also demonstrated the efficacy of high-dose MTX in ATRT patients. Besides intensification using cytotoxic agent, there are increasing data suggesting that ATRT might be a good candidate for pathway-specific targeted therapies, some of which are currently used in clinical trials, including AURKA, EZH2, and CDK4/6 inhibitors [24,25]. Optimwal combination of cytotoxic agents and targeted inhibitors should be explored to prevent early progression of ATRT.
Lastly, we found that the post-2011 group had significantly better PFS than the pre-2011 group. The major difference between pre- and post-2011 protocols was adjuvant local radiation and IT chemotherapy in the post-2011 protocol. There was no difference in induction chemotherapy or HDCT between pre- and post-2011 protocols. We believe that the post-2011 protocol with a combination of adjuvant RT and IT chemotherapy might have prevented early progression, eventually improving the outcome as reported by Chi et al. [10]. The role of adjuvant RT has already been described above. IT therapy was incorporated as a method of providing prophylaxis and/or treatment to the CNS axis in the post-2011 protocol. Whether IT therapy could substitute for cranial irradiation for CNS treatment and/or prophylaxis was unclear because both modalities were used in the post-2011 protocol. Considering that the year of diagnosis (pre- vs. post-2011) was not a significant predictor of survival in multivariate analyses, IT therapy might not have a beneficial role in improving survival. However, in many studies, IT chemotherapy has shown potential benefit as an addition to local RT or to intensify therapy in patients who are not candidates for CSI [10,26]. IT chemotherapy shows good penetrance into the CSF. Thus, it might be efficacious in eradicating ATRT cells in CSF, allowing postponement of CSI for patients who receive focal irradiation only. A meta-analysis by Athale et al. [26] has shown that IT therapy leads to a significantly higher OS. A more detailed randomized study I needed to evaluate IT therapy in infant ATRT to define role of IT therapy in these patients.
This study has some limitations. First, this study had a non-randomized and retrospective design. Second, we did not collect data for germline mutations in SMARCB1/INI1. Therefore, we could not assess the association between germline status and outcome. No molecular profiling was included, which could be potential prognostic indicators. Third, because current multimodality treatment strategies for ATRT include brain RT, limited data on neurocognitive outcomes of survivors raise a significant concern [27]. Although data stress the importance for RT in younger age group, this treatment option comes at a cost of serious long-term sequelae such as cognitive, motor, visual, and hearing impairment [28,29]. In addition, combining multimodal treatment deserves attention. Comprehensive long-term follow-up neuropsychologic assessments are planned for our surviving cohort. Lastly, as described above, a more detailed analysis is needed in the future to identify the role of IT therapy in the prevention and treatment of metastases.
In summary, aggressive therapy including early administration of local RT and HDCT/ASR, which was adopted in KSPNO-S1102, should be considered to improve outcomes of ATRT in children below the age of 3 years. Despite the high probability of early PD in ATRT, for patients who received both early adjuvant RT and HDCT/ASR, OS exceeded 90%. Further clinical trials may be required to determine optimal adjuvant treatments such as RT field and intensity of HDCT/ASR and the role of IT chemotherapy for patients with ATRT. Future studies regarding molecular characterization of ATRT and its prognostic implication might change current treatment strategies and delineate the group of patients so that treatment intensity could be reduced.
Acknowledgments
This study was supported by the KPHOG Research Grant 2018.
Fig. 1 Treatment recommendations by the Korean Society for Pediatric Neuro-Oncology for CNS ATRT during periods of 2005–2007 (A), 2008–2010 (B), and 2011-present (C). ASR, autologous stem cell rescue; CR, complete response; CSI, craniospinal irradiation; HDCT, high-dose chemotherapy; IT, intrathecal; RT, radiotherapy. a)R0 (< 1.5 cm2)/M0, local RT 41.4 Gy; R+ (> 1.5 cm2)/M0, local RT 55.8 Gy; Rx/M+, local RT 36 Gy+CSI 19.8 Gy at 3 years of age, b)M0, day 0 of each cycle/M+, weekly until clearing (at least 6 times), then day 0 each cycle.
Fig. 2 Kaplan-Meier estimates of progression-free survival (A) and overall survival (B).
Fig. 3 Progression-free survival according to metastases (A), year of diagnosis (B), early adjuvant radiation (C), and high-dose chemotherapy (D).
Table 1 Chemotherapy regimens
Regimen Drug Dose Schedule
KSPNO-S052 induction chemotherapy
Regimen a Cisplatin 3.5 mg/kg Day 0
Etoposide 2.5 mg/kg Days 0, 1, and 2
Cyclophosphamide 60 mg/kg Days 1 and 2
Vincristine 0.05 mg/kg Days 0, 7, and 14
Regimen b Carboplatin 10 mg/kg Days 0 and 1
Etoposide 2.5 mg/kg Days 0 to 4
Ifosfamide 60 mg/kg Days 0 to 4
Vincristine 0.05 mg/kg Days 0, 7, and 14
KSPNO-S082/S1102 induction chemotherapy
Regimen A Cisplatin 3 mg/kg Day 0
Etoposide 2.5 mg/kg Days 0, 1, and 2
Cyclophosphamide 50 mg/kg Days 1 and 2
Vincristine 0.05 mg/kg Days 0 and 7
Regimen B Carboplatin 10 mg/kg Days 0 and 1
Etoposide 2.5 mg/kg Days 0 to 4
Ifosfamide 50 mg/kg Days 0 to 4
Vincristine 0.05 mg/kg Days 0 and 7
KSPNO-S052/S082/S1102 high-dose chemotherapy
First: CTE Carboplatin 500 mg/m2 Days −8 to −6
Thiotepa 300 mg/m2 Days −5 to −3
Etoposide 250 mg/m2 Days −5 to −3
Second: CM Cyclophosphamide 1,500 mg/m2 Days −8 to −5
Melphalan 60 mg/m2 Days −4 to −2
CM, cyclophosphamide and melphalan; CTE, carboplatin, thiotepa and etoposide.
Table 2 Clinical characteristics of patients
Pre-2011 (n=19) Post-2011 (n=24) Total (n=43)
Male:Female 9:10 13:11 22:21
Age at diagnosis (mo)
Median (range) 13.0 (1–31) 14.5 (0–32) 13.0 (0–32)
< 6 mo 4 (21.1) 5 (20.8) 9 (20.9)
6–12 mo 5 (26.3) 6 (25.0) 11 (25.6)
> 12 mo 10 (52.6) 13 (54.2) 23 (53.5)
Neuraxis metastasis
M0 11 (57.9) 12 (50.0) 23 (53.5)
M1 2 (10.5) 2 (8.3) 4 (9.3)
M2 5 (26.3) 9 (37.5) 14 (32.6)
Unknown 1 (5.3) 1 (4.2) 2 (4.7)
Type of resection
Gross total resection 12 (63.2) 12 (50.0) 24 (55.8)
Subtotal resection 6 (31.6) 12 (50.0) 18 (41.9)
Biopsy 1 (5.3) 0 1 (2.3)
Palliative care only after surgery 1 (5.3) 0 1 (2.3)
Values are presented as number (%) unless otherwise indicated.
Table 3 Treatment and clinical outcomes
Pre-2011 (n=18) Post-2011 (n=24) Total (n=42)
Treatment
Chemotherapy 18 (100) 24 (100) 42 (100)
RT 12 (66.7) 17 (70.8) 29 (69.0)
Early adjuvant local RT 2 (11.1) 12 (50.0) 14 (33.3)
With concurrent CSI 1 1 2
CSI at 3 years of age after completion of HDCT 0 3 3
Salvage local RT at relapse/progression 9 (50.0) 4 (16.7) 13 (31.0)
With concurrent CSI 4 1 5
CSI at 3 years of age after completion of HDCT 1 1 2
CSI at 3 year of age only 1 (5.5) 1 (4.2) 2 (4.8)
HDCT 9 (50.0) 15 (62.5) 24 (57.1)
1 HDCT 1 (5.6) 8 (33.3) 9 (21.4)
2 HDCT 8 (44.4) 7 (29.2) 15 (35.8)
Response to treatment
Continued response 3 (16.7) 12 (50.0) 15 (35.7)
Disease progression 15 (83.3) 12 (50.0) 27 (64.3)
After initial surgery 1 2 3
During induction chemotherapy 9 5 14
During RT 0 1 1
During HDCT 0 2 2
After completion of HDCT 5 2 7
Final outcome
Alive without disease 4 (22.2) 11 (45.8) 15 (35.7)
Alive with disease 0 0 0
Death due to disease progression 11 (61.1) 10 (41.7) 21 (50.0)
Treatment-related death 2 (11.1) 3 (12.5) 5 (11.9)
Death due to unknown cause 1 (5.6) 0 1 (2.4)
Values are presented as number (%). CSI, craniospinal irradiation; HDCT, high-dose chemotherapy; RT, radiotherapy.
Table 4 Univariate and multivariate analysis of the probability of progression-free survival
Univariate Multivariatea)
HR (95% CI) p-value HR (95% CI) p-value
Years of diagnosis
Pre-2011 1 0.04 1 0.57
Post-2011 0.47 (0.23–0.96) 0.81 (0.44–1.62)
Patient age (yr)
< 1 1 0.53
≥ 1 0.79 (0.39–1.59)
Metastases
Yes 1 0.03 1 0.53
No 0.46 (0.23–0.90) 0.85 (0.43–1.59)
Extent of resection
GTR 1 0.29
No GTR 1.23 (0.56–2.27)
Early adjuvant RT
Yes 1 < 0.01 1 < 0.01
No 5.68 (2.14–15.12) 6.42 (2.29–17.90)
HDCT
Yes 1 < 0.01 1 < 0.01
No 10.26 (3.81–27.66) 12.0 (3.91–37.28)
CI, confidence interval; GTR, gross total resection; HDCT, high-dose chemotherapy; HR, hazard ratio; RT, radiotherapy.
a) Includes variables significant at p < 0.1 (overall) in univariate analysis.
Ethical Statement
Ethics approval and consent to participation: All participating centers received Institutional Review Board approval to contribute data for this study (NCC 2018-0210). This study was performed in accordance with the Declaration of Helsinki.
Author Contributions
Conceived and designed the analysis: Park M, Han JW, Park HJ.
Collected the data: Park M, Han JW, Hahn SM, Lee JA, Kim JY, Shin SH, Kim DS, Yoon HI, Hong KT, Choi JY, Kang HJ, Shin HY, Phi JH, Kim SK, Lee JW, Yoo KH, Sung KW, Koo HH, Lim DH, Shin HJ, Kim H, Koh KN, Im HJ, Ahn SD, Ra YS, Baek HJ, Kook H, Jung TY, Choi HS, Kim CY, Park HJ, Lyu CJ.
Contributed data or analysis tools: Park M.
Performed the analysis: Park M.
Wrote the paper: Park M.
Review the paper: Lyu CJ, Park HJ.
Conflicts of Interest
Conflicts of interest relevant to this article was not reported.
|
CARBOPLATIN, CISPLATIN, CYCLOPHOSPHAMIDE, ETOPOSIDE, MELPHALAN, VINCRISTINE SULFATE
|
DrugsGivenReaction
|
CC BY-NC
|
33138347
| 19,979,423
|
2021-04
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Venoocclusive liver disease'.
|
Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children under the Age of 3 Years.
OBJECTIVE
Atypical teratoid/rhabdoid tumor (ATRT) is a highly aggressive malignancy with peak incidence in children aged less than 3 years. Standard treatment for central nervous system ATRT in children under the age of 3 years have not been established yet. The objective of this study was to analyze characteristics and clinical outcomes of ATRT in children aged less than 3 years.
A search of medical records from seven centers was performed between January 2005 and December 2016.
RESULTS
Forty-three patients were enrolled. With a median follow-up of 90 months, 27 patients (64.3%) showed at least one episode of disease progression (PD). The first date of PD was at 160 days after diagnosis. The 1- and 3-year progression-free survivals (PFS) were 51.2% and 28.5%, respectively. The 1- and 3-year overall survivals were 61.9% and 38.1%, respectively. The 3-year PFS was improved from 0% in pre-2011 to 47.4% in post-2011. Excluding one patient who did not receive any further therapy after surgery, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown cause (n=1). In univariate analysis, factors associated with higher 3-year PFS were no metastases, diagnosis after 2011, early adjuvant radiotherapy, and high-dose chemotherapy (HDCT). In multivariate analysis, the use of HDCT and adjuvant radiotherapy remained significant prognostic factors for PFS (both p < 0.01).
CONCLUSIONS
Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years.
Introduction
Atypical teratoid/rhabdoid tumor (ATRT) of the central nervous system (CNS) is a highly aggressive malignancy, accounting for 1%–2% of all pediatric CNS tumors [1,2]. Among children under the age of 3 years, ATRT constitutes the most common malignant tumor of CNS (17.3%), followed by medulloblastoma (16%) [3].
Since standard therapeutic strategies for ATRT have not been established yet, treatment approaches for ATRT vary among institutions and countries. Conventional chemotherapy in addition to high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASR) is usually utilized in pati-ents under 3 years of age to substitute for or delay the use of radiotherapy (RT) in attempt to improve outcomes and minimize long-term neurocognitive impairment [4]. However, most patients with ATRT suffer rapid disease progression (PD), although treatment regimens designed for CNS neoplasms have been used [5,6]. Outcome for patients with ATRT is generally dismal, particularly in the presence of residual tumor or metastasis. ATRT is a devastating brain neoplasm with a median survival time ranging from 6 to 13 months. This is caused not only by the disease’s aggressive characteristics, but also by a lower tolerance of young patients to treatment. This is exacerbated by the hesitancy to use RT in younger patients due to risks of functional impairment of the developing brain [7]. It has been shown that aggressive therapy can prolong survival in a subset of children with CNS ATRT [1,2,8]. Some clinical trials have incorporated early administration of RT to the primary site together with intrathecal (IT) chemotherapy, resulting in improved outcomes [9,10].
In 2005, the Korean Society for Pediatric Neuro-Oncology (KSPNO) suggested the following a protocol for ATRT patients aged less than 3 years (KSPNO-S052): six cycles of conventional chemotherapy and tandem HDCT/ASR are performed initially and RT is deferred until the patient reaches 3 years of age. In 2008, a minor revision of the protocol including a dose modification of conventional chemotherapy was made (KSPNO-S082). In 2011, the protocol was revised (KSPNO-S1102) to recommended early local RT with concurrent chemotherapy within four weeks after surgery. In addition, IT chemotherapy was incorporated.
Given the rarity of this tumor and the even lower number of very young infants affected by ATRT, no detailed clinical analyses have been directed toward patients under 3 years of age. Thus, the objective of this study was to describe patients diagnosed with ATRT in this age group and determine potential specific characteristics or prognostic factors. Their therapeutic management is also suggested.
Materials and Methods
1. Data collection
Children younger than 3 years of age at diagnosis who were newly diagnosed with CNS ATRT were eligible for this study. A search of medical records from seven centers was performed to identify patients aged 3 years or less who were diagnosed between January 2005 and December 2016. In cases with multiple intracranial and extracranial rhabdoid tumors, only patients with clear descriptions of a primary tumor within the CNS were included in this analysis. All participating centers received Institutional Review Board approval to contribute data for this study.
2. Staging
Proper staging for metastases included brain and spinal magnetic resonance imaging (MRI) and cytology of the cerebrospinal fluid (CSF). Modified Chang status for metastatic stage was recorded whenever available. It was defined as follows: M0, absence of metastases; M1, presence of metastases confined to CSF; M2, presence of metastases in the brain; M3, presence of metastases in the spinal subarachnoidal space; and M4, spread outside of the CNS [11]. M+ included M1, M2, M3, M4, and any metastasis not further described.
3. Treatment
All patients underwent maximal possible surgical resection of the primary lesion to preserve neurologic function. The extent of surgical resection defined as gross total resection (GTR), subtotal resection, or biopsy was determined based on a review of postoperative MRI and the surgeon’s intraoperative assessment. Multimodal therapies including surgery, RT, chemotherapy and HDCT/ASR were performed. Treatment was mainly performed according to KSPNO recommendations. However, some physicians modified the treatment protocol depending on clinical situation. Treatment scheme of the KSPNO regimen is shown in Fig. 1. Major differences between KSPNO-S052/-S082 (pre-2011) and KSPNO-S1101 (post-2011) were the timing of RT (delayed RT pre-2011 vs. early adjuvant RT post-2011) and IT chemotherapy for patients post-2011. Detailed chemotherapy schedules are described in Table 1.
KSPNO-S052/S082 (pre-2011) suggested the following: Induction treatment was initiated within 4 weeks of surgery. Six cycles of chemotherapy using alternating CECV (cisplatin, etoposide, cyclophosphamide, and vincristine) and CEIV (carboplatin, etoposide, ifosfamide, and vincristine) regimens were administered. Additionally, tandem HDCT/ASR was performed. The first course included carboplatin, thiotepa and etoposide (CTE), and the second course included cyclophosphamide and melphalan (CM). A 12- to 16-week interval between the first and second HDCT/ASR was allowed to minimize treatment-related mortality (TRM). RT was deferred until after 3 years of age unless the tumor showed progression or relapse. For patients with M0 disease at diagnosis and for patients those without residual tumor after HDCT, RT was omitted.
KSPNO-S1102 (post-2011) suggested the following: RT was recommended to be administered within 4 weeks of surgery with concurrent chemotherapy. IT chemotherapy including cytarabine, hydrocortisone, and methotrexate (MTX) was administered on day 0 of every chemotherapy cycle. For M+ patients, weekly IT chemotherapy was administered until clearance of CSF cytology. After six cycles of alternating CECV and CEIV regimens, tandem HDCT/ASR using CTE-CM was performed. For M+ patients at diagnosis, craniospinal irradiation (CSI) was deferred at 3 years of age.
4. Response and toxicity criteria
Disease response was evaluated by MRI and CSF cytology. Evaluations were repeated every two or three chemotherapy cycles prior to the first HDCT/ASR, between the first and second HDCT/ASR, every 3 months for the first year after completion of tandem HDCT/ASR, every 4 months for the second year, and every 6 months thereafter. Disease response was categorized as follows: complete response (CR) for complete disappearance of all tumors, partial response (PR) for decrease in tumor size by more than 50%, stable disease for less than 25% change in tumor size, PD for greater than 25% increase in tumor size or the appearance of new tumors. Toxicities were graded using the National Cancer Institute’s Common Terminology Criteria ver. 4.0.
5. Statistical analysis
The cutoff point for data analyses was March 2019. For descriptive statistics, data were compared using the Fisher exact test for categorical factors and Wilcoxon Mann-Whitney U test for continuous factors. The time to progression was calculated from the date of diagnosis until the date of PD. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of PD or relapse. Overall survival (OS) was calculated from the date of initial diagnosis to the date of last follow-up or death from any cause. PFS and OS were estimated using the Kaplan-Meier method. Univariate analysis of risk factors was performed by comparing PFS and OS using the log-rank test. Multivariate logistic regression was used to examine relationships between outcomes of PFS or OS as binary dependent variables and independent variables of patient age, metastases, extent of resection, early adjuvant RT, HDCT, and years of diagnosis. p < 0.05 was considered statistically significant. All analyses were performed using IBM SPSS ver. 18.0 (SPSS Inc., Chicago, IL).
Results
1. Patient characteristics
Baseline clinical characteristics of patients are shown in Table 2. Forty-three patients were enrolled in this study. The median age at diagnosis was 13 months (range, 0 to 32 months). Twenty patients (46.5%) were younger than 1 year of age at diagnosis. One patient presented with synchronous tumors, including ATRT in brain and a rhabdoid tumor in the kidney.
Nineteen patients (44.2%) were diagnosed before 2011 (pre-2011 group) and 24 patients (55.8%) were diagnosed after 2011 (post-2011 group). There was no significant difference in age at diagnosis (p=0.55), sex (p=0.43), extent of resection (p=0.15), or metastases (p=0.46) between pre-2011 and post-2011 groups. There were 23 (53.5%) patients with M0 disease, four (9.3%) with M1 disease, 14 (32.6%) with M2 disease, and two (4.7%) with unknown metastatic status. The incidence of metastatic disease was significantly higher in patients under 6 months of age than that in patients older than 6 months (100.0% vs. 35.3%, p < 0.01). GTR of the primary tumor was achieved in 24 patients (55.8%).
2. Treatment
One patient did not receive any further therapy after surgery. All remaining 42 patients received induction chemotherapy at a median of 20 days after surgery (range, 5 to 142 days). The median number of pretransplant chemotherapy cycles was 6 (range, 1 to 12). All patients in the post-2011 group received IT therapies. Nine patients (21.4%) received a second surgery before HDCT due to PD (n=8) or for removing residual tumor (n=1).
Twenty-nine patients (69.0%) received radiation at a median age of 23 months (range, 6 to 40 months). The median interval between diagnosis and RT was 162 days (range, 21 to 745 days). Thirteen patients (31.0%) did not receive RT due to early progression (n=8), treatment-related death (n=3), or physician’s discretion (n=2). As of 2011, RT timing changed from delayed RT (pre-2011) to early adjuvant RT (post-2011). As a result, the median period between diagnosis and RT was significantly shortened from 314.9 days in the pre-2011 group to 159.0 days in the post-2011 group (p=0.04). The period between diagnosis to RT was 114.6±104.8 days in patients who received early adjuvant RT and 313.4±231.2 days in patients who received RT as salvage therapy (p < 0.01).Among 29 patients who received RT, early adjuvant RT was administered in 14 patients (2 in the pre-2011 group and 12 in the post-2011 group) (Table 3). They received local RT at a dose of 36–63 Gy after surgery. Of them, five patients received additional CSI at a dose of 23.4–30.6 Gy concurrently (n=2) or at 3 years of age (n=3) due to M+ disease at diagnosis. Thirteen patients received local RT as salvage therapy at a dose of 25.2–55.8 Gy. Of them, five patients received CSI at a dose of 19.5–23.4 Gy. Two patients received CSI at 3 years of age after completion of HDCT as scheduled.
Twenty-four patients received HDCT/ASR (15 patients received tandem HDCTs and nine patients received only 1 HDCT). Reasons not having second HDCT included physician’s discretion (n=4), PD or relapse (n=3), prolonged bone marrow suppression (n=1), and patient refusal (n=1). During the first HDCT, eight patients received conditioning regimen including topotecan, thiotepa, and carboplatin instead of CTE. During the second HDCT, two patients received conditioning regimen including busulfan, melphalan, and thiotepa instead of CM.
Significantly more patients who received early adjuvant RT proceeded to HDCT compared to patients who did not (78.6% vs. 46.4%, p=0.04). For patients not receiving HDCT (n=18), reasons included PD or relapse (n=12), treatment-related death (n=4), patient refusal (n=1), and death due to unknown cause (n=1). The median age at the time of the first HDCT was 21.0 months (range, 9.1 to 44.5 months). The median time between diagnosis and the first HDCT was 7.5 months (range, 5.3 to 16.1 months). Disease status before the first HDCT was CR in 16 and PR in eight. Among 15 patients who underwent a second HDCT, disease status before the second HDCT was CR in 10, PR in four, and PD in one. The median interval between the first and second HDCT was 91 days (range, 35 to 126 days).
3. Clinical course and survival
Excluding one patient who received palliative care only, data for 42 patients were analyzed (Table 3). With a median follow-up of 90 months (range, 27 to 172 months), 27 patients (64.3%) showed at least one episode of PD. The first date of PD was at 160 days (median; range, 13 to 585) after the diagnosis. Twenty-one of 27 patients who showed PD died due to PD at a median of 4 months (range, 0.1 to 5.4 months) from the first day of documentation of PD. Immediate salvage therapy consisted of surgery in 11, chemotherapy in four, RT in four, gamma knife surgery in one, and supportive care only in seven. PD was found within 2 months of resection surgery before initiation of chemotherapy in three, during chemotherapy in 14, during adjuvant RT in one, during HDCT in two, and after completion of HDCT in seven. Among 14 patients with PD found during induction chemotherapy, 13 did not receive adjuvant RT previously while one patient had received RT previously (p < 0.01). Of nine patients who experienced relapse during or after HDCT, seven patients died due to PD. Two patients are still alive without disease. The median time between HDCT and subsequent relapse was 3 months (range, 1 to 11 months).
The 1- and 3-year PFS is 51.2% and 28.5%, respectively. The 1- and 3-year OS is 61.9% and 38.1%, respectively (Fig. 2). Of 42 patients analyzed, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown causes (n=1).
At the last follow-up, 15 patients were alive. All surviving patients received HDCT/ASR. Patients who achieved CR before the first HDCT showed significantly higher 3-year OS compared to patients who did not (81.3% vs. 37.5%, p < 0.01). There was no significant difference in PFS or OS between patients who underwent 1 HDCT and those who underwent 2 HDCTs.
4. Risk factors
Results of univariate and multivariate analyses for PFS are shown in Table 4. In univariate analysis, factors associated with higher 3-year PFS were no metastases (p=0.03), diagnosis after 2011 (p=0.04), early adjuvant RT (p < 0.01) and HDCT/ASR (p < 0.01) (Fig. 3). Age at diagnosis (p=0.53) and extent of resection (p=0.29) failed to influence survival rate in our study. Among 14 patients who received adjuvant RT, only three patients showed PD during (n=1) or after (n=2) the planned RT, while 24 of 28 patients who did not receive adjuvant RT showed PD (p < 0.01). Among 18 patients with metastases, patients who received early adjuvant local RT showed significantly higher PFS and OS compared to those who did not (3-year PFS: 75.0% vs. 0%, p=0.04; 3-year OS: 75.0% vs. 14.3%, p=0.03).
In multivariate analyses, the use of HDCT/ASR and early adjuvant RT remained significant prognostic factors for PFS (both p < 0.01). For OS, the use of HDCT/ASR was the only significant prognostic factor (p < 0.01). Among patients who received both early adjuvant RT and HDCT/ASR, 3-year PFS and OS were 81.8% and 90.9%, respectively.
5. Toxicity
During chemotherapy, the most frequently reported significant toxicities were bone marrow suppression and febrile neutropenia followed by infection, gastrointestinal disturbances, electrolyte disturbances, and hepatic disturbances. During HDCT, infection was the most common toxicity. Bacteremia was detected during six of 39 HDCT (3 Staphylococcus epidermidis, 2 Pseudomonas aeruginosa, and 1 Bacillus species), five of which occurred during the second HDCT course. One patient experienced sinusoidal obstruction syndrome during their second HDCT. There were five toxic deaths due to sepsis: four occurred under chemotherapy and one occurred following the second HDCT. To date, second malignancies have not been reported.
Discussion
This is the most recent update of Korean ATRT patients under 3 years of age. Tumors progressed or relapsed in 27 of 42 patients at a median of 160 days from diagnosis in our study. The 3-year PFS and OS were 28.5% and 38.1%, respectively. The 3-year PFS was improved from 0.0% in pre-2011 to 47.4% in post-2011. At diagnosis, metastasis was the only characteristic among several disease characteristics known to affect survival.
Our analysis highlights several points of interest for this young age group. First, our data suggest the importance of early adjuvant RT. We found a survival benefit associated with early adjuvant RT. Traditionally, RT has been deferred or omitted because of the risk of adverse effects, especially for patients under 3 years of age [12]. However, more recent data suggest that RT might be more efficacious than chemotherapy for ATRT patients, even for very young children [2,13,14]. In a previously reported Korean study that included patients treated with tandem HDCT/ASR, all surviving patients received RT at an early stage in their treatment [15]. No patients who received induction chemotherapy and HDCT/ASR without RT survived. This suggests that HDCT/ASR cannot replace RT for local control. Similarly, we found that patients who received early adjuvant RT showed a significantly lower chance of having PD during induction chemotherapy and a higher chance to proceed to HDCT compared to patients who did not, thus leading to improved survival. For patients with M+ disease at diagnosis, adjuvant local radiation significantly improved survival in the current study. Overall, local RT should be considered earlier in therapy to improve survival.
Secondly, our data suggest that HDCT is associated with better survival. For patients who received HDCT, PFS and OS were significantly higher compared to those who did not. There has been no randomized study to evaluate the efficacy of HDCT/ASR in ATRT patients under 3 years of age. A few studies have suggested that HDCT might have a favorable effect on ATRT patients [14,16]. A recent Canadian study has reported better 5-year PFS in patients with ATRT under 1 year of age receiving HDCT group compared to those without receiving HDCT (50.1% vs. 11.3%, p < 0.001) [17]. However, due to small numbers of patients included and various treatment modalities used, no firm conclusions can be made regarding the role of HDCT/ASR in ATRT patients. In this study, all surviving patients received HDCT/ASR. However, this does not reflect the definite efficacy of HDCT/ASR. Considering that patients who achieved CR before their first HDCT showed significantly higher OS than those who did not, multimodal treatment that might lead to CR and additional HDCT might result in better outcomes. In this study, patients who achieved CR before the first HDCT showed significantly higher OS. This suggests that pre-HDCT tumor status is important for predicting outcome. Thus, careful consideration is required when selecting candidate patients for HDCT/ASR.
Importantly, we should consider the likelihood of selection bias toward “favorable cases” in patients subjected to HDCT, which could be associated with molecular distinction. Recently, Reddy et al. [18] have reported that patients with group 1/SHH-NOTCH tumors have less aggressive feature. Biological investigation of ATRT should be continued and subsets of patients who can be cured with less therapy may exist [19].
The optimal combination of regimens for tandem HDCT has not been determined. Rosenfeld et al. [12] have reported the feasibility of tandem HDCT/ASR in patients with brain tumors using CTE-CM. Although they concluded that the CTE-CM regimen was not feasible due to toxicity, tandem CTE-CM HDCT/ASR was feasible in our study. Toxicities in our present study were manageable and only one toxic death associated with HDCT occurred. This could be due to the fact that patients were given a sufficient rest period between the first and the second HDCT/ASR. Sung et al. [20] have reported that a shorter interval (< 12 weeks) between the first and second HDCT/ASR is associated with higher TRM. Another thing to be noted was that there was no significant survival difference between patients who received 1 HDCT and those who received 2 HDCTs. In addition, bacteremia occurred more frequently in the second HDCT than in the first HDCT. Randomized trials with larger cohorts are needed to determine whether the possible survival benefit of tandem HDCT/ASR over single HDCT/ASR might ultimately outweigh adverse effects associated with dose intensive tandem HDCT/ASR.
Thirdly, optimal induction chemotherapy should be explored. Efficacies of many different treatments have been explored. However, there is no consensus regarding standard chemotherapy for ATRT. Due to the desire to avoid unacceptable adverse effects of RT on the developing brain, many institutions adopt chemotherapy-based strategies designed to avoid or delay RT. Despite often impressive responses to chemotherapy, the majority of patients in many published studies developed progressive disease early, suggesting a rapid development of resistance of ATRTs [10,21,22]. Similarly, in our study, PD occurred during induction chemotherapy in about half of cases. Considering that the most common reason not having HDCT/ASR was PD during induction chemotherapy, we could consider shorten the current six cycles of induction chemotherapy. Furthermore, patients who received induction chemotherapy without early adjuvant RT showed significantly lower survival compared to patients who received early adjuvant RT. This suggests that CECV and CEIV chemotherapy regimen used in our patients might be insufficient to prevent tumor progression/relapse. Recently, ACNS0333 comprised with three cycles of chemotherapy which incorporated high dose MTX showed promising result, with 4-year OS of 43% [18]. High-dose MTX used in “Head Start II” also appears to be efficacious and well tolerated in ATRT [8]. Slavc et al. [23] have also demonstrated the efficacy of high-dose MTX in ATRT patients. Besides intensification using cytotoxic agent, there are increasing data suggesting that ATRT might be a good candidate for pathway-specific targeted therapies, some of which are currently used in clinical trials, including AURKA, EZH2, and CDK4/6 inhibitors [24,25]. Optimwal combination of cytotoxic agents and targeted inhibitors should be explored to prevent early progression of ATRT.
Lastly, we found that the post-2011 group had significantly better PFS than the pre-2011 group. The major difference between pre- and post-2011 protocols was adjuvant local radiation and IT chemotherapy in the post-2011 protocol. There was no difference in induction chemotherapy or HDCT between pre- and post-2011 protocols. We believe that the post-2011 protocol with a combination of adjuvant RT and IT chemotherapy might have prevented early progression, eventually improving the outcome as reported by Chi et al. [10]. The role of adjuvant RT has already been described above. IT therapy was incorporated as a method of providing prophylaxis and/or treatment to the CNS axis in the post-2011 protocol. Whether IT therapy could substitute for cranial irradiation for CNS treatment and/or prophylaxis was unclear because both modalities were used in the post-2011 protocol. Considering that the year of diagnosis (pre- vs. post-2011) was not a significant predictor of survival in multivariate analyses, IT therapy might not have a beneficial role in improving survival. However, in many studies, IT chemotherapy has shown potential benefit as an addition to local RT or to intensify therapy in patients who are not candidates for CSI [10,26]. IT chemotherapy shows good penetrance into the CSF. Thus, it might be efficacious in eradicating ATRT cells in CSF, allowing postponement of CSI for patients who receive focal irradiation only. A meta-analysis by Athale et al. [26] has shown that IT therapy leads to a significantly higher OS. A more detailed randomized study I needed to evaluate IT therapy in infant ATRT to define role of IT therapy in these patients.
This study has some limitations. First, this study had a non-randomized and retrospective design. Second, we did not collect data for germline mutations in SMARCB1/INI1. Therefore, we could not assess the association between germline status and outcome. No molecular profiling was included, which could be potential prognostic indicators. Third, because current multimodality treatment strategies for ATRT include brain RT, limited data on neurocognitive outcomes of survivors raise a significant concern [27]. Although data stress the importance for RT in younger age group, this treatment option comes at a cost of serious long-term sequelae such as cognitive, motor, visual, and hearing impairment [28,29]. In addition, combining multimodal treatment deserves attention. Comprehensive long-term follow-up neuropsychologic assessments are planned for our surviving cohort. Lastly, as described above, a more detailed analysis is needed in the future to identify the role of IT therapy in the prevention and treatment of metastases.
In summary, aggressive therapy including early administration of local RT and HDCT/ASR, which was adopted in KSPNO-S1102, should be considered to improve outcomes of ATRT in children below the age of 3 years. Despite the high probability of early PD in ATRT, for patients who received both early adjuvant RT and HDCT/ASR, OS exceeded 90%. Further clinical trials may be required to determine optimal adjuvant treatments such as RT field and intensity of HDCT/ASR and the role of IT chemotherapy for patients with ATRT. Future studies regarding molecular characterization of ATRT and its prognostic implication might change current treatment strategies and delineate the group of patients so that treatment intensity could be reduced.
Acknowledgments
This study was supported by the KPHOG Research Grant 2018.
Fig. 1 Treatment recommendations by the Korean Society for Pediatric Neuro-Oncology for CNS ATRT during periods of 2005–2007 (A), 2008–2010 (B), and 2011-present (C). ASR, autologous stem cell rescue; CR, complete response; CSI, craniospinal irradiation; HDCT, high-dose chemotherapy; IT, intrathecal; RT, radiotherapy. a)R0 (< 1.5 cm2)/M0, local RT 41.4 Gy; R+ (> 1.5 cm2)/M0, local RT 55.8 Gy; Rx/M+, local RT 36 Gy+CSI 19.8 Gy at 3 years of age, b)M0, day 0 of each cycle/M+, weekly until clearing (at least 6 times), then day 0 each cycle.
Fig. 2 Kaplan-Meier estimates of progression-free survival (A) and overall survival (B).
Fig. 3 Progression-free survival according to metastases (A), year of diagnosis (B), early adjuvant radiation (C), and high-dose chemotherapy (D).
Table 1 Chemotherapy regimens
Regimen Drug Dose Schedule
KSPNO-S052 induction chemotherapy
Regimen a Cisplatin 3.5 mg/kg Day 0
Etoposide 2.5 mg/kg Days 0, 1, and 2
Cyclophosphamide 60 mg/kg Days 1 and 2
Vincristine 0.05 mg/kg Days 0, 7, and 14
Regimen b Carboplatin 10 mg/kg Days 0 and 1
Etoposide 2.5 mg/kg Days 0 to 4
Ifosfamide 60 mg/kg Days 0 to 4
Vincristine 0.05 mg/kg Days 0, 7, and 14
KSPNO-S082/S1102 induction chemotherapy
Regimen A Cisplatin 3 mg/kg Day 0
Etoposide 2.5 mg/kg Days 0, 1, and 2
Cyclophosphamide 50 mg/kg Days 1 and 2
Vincristine 0.05 mg/kg Days 0 and 7
Regimen B Carboplatin 10 mg/kg Days 0 and 1
Etoposide 2.5 mg/kg Days 0 to 4
Ifosfamide 50 mg/kg Days 0 to 4
Vincristine 0.05 mg/kg Days 0 and 7
KSPNO-S052/S082/S1102 high-dose chemotherapy
First: CTE Carboplatin 500 mg/m2 Days −8 to −6
Thiotepa 300 mg/m2 Days −5 to −3
Etoposide 250 mg/m2 Days −5 to −3
Second: CM Cyclophosphamide 1,500 mg/m2 Days −8 to −5
Melphalan 60 mg/m2 Days −4 to −2
CM, cyclophosphamide and melphalan; CTE, carboplatin, thiotepa and etoposide.
Table 2 Clinical characteristics of patients
Pre-2011 (n=19) Post-2011 (n=24) Total (n=43)
Male:Female 9:10 13:11 22:21
Age at diagnosis (mo)
Median (range) 13.0 (1–31) 14.5 (0–32) 13.0 (0–32)
< 6 mo 4 (21.1) 5 (20.8) 9 (20.9)
6–12 mo 5 (26.3) 6 (25.0) 11 (25.6)
> 12 mo 10 (52.6) 13 (54.2) 23 (53.5)
Neuraxis metastasis
M0 11 (57.9) 12 (50.0) 23 (53.5)
M1 2 (10.5) 2 (8.3) 4 (9.3)
M2 5 (26.3) 9 (37.5) 14 (32.6)
Unknown 1 (5.3) 1 (4.2) 2 (4.7)
Type of resection
Gross total resection 12 (63.2) 12 (50.0) 24 (55.8)
Subtotal resection 6 (31.6) 12 (50.0) 18 (41.9)
Biopsy 1 (5.3) 0 1 (2.3)
Palliative care only after surgery 1 (5.3) 0 1 (2.3)
Values are presented as number (%) unless otherwise indicated.
Table 3 Treatment and clinical outcomes
Pre-2011 (n=18) Post-2011 (n=24) Total (n=42)
Treatment
Chemotherapy 18 (100) 24 (100) 42 (100)
RT 12 (66.7) 17 (70.8) 29 (69.0)
Early adjuvant local RT 2 (11.1) 12 (50.0) 14 (33.3)
With concurrent CSI 1 1 2
CSI at 3 years of age after completion of HDCT 0 3 3
Salvage local RT at relapse/progression 9 (50.0) 4 (16.7) 13 (31.0)
With concurrent CSI 4 1 5
CSI at 3 years of age after completion of HDCT 1 1 2
CSI at 3 year of age only 1 (5.5) 1 (4.2) 2 (4.8)
HDCT 9 (50.0) 15 (62.5) 24 (57.1)
1 HDCT 1 (5.6) 8 (33.3) 9 (21.4)
2 HDCT 8 (44.4) 7 (29.2) 15 (35.8)
Response to treatment
Continued response 3 (16.7) 12 (50.0) 15 (35.7)
Disease progression 15 (83.3) 12 (50.0) 27 (64.3)
After initial surgery 1 2 3
During induction chemotherapy 9 5 14
During RT 0 1 1
During HDCT 0 2 2
After completion of HDCT 5 2 7
Final outcome
Alive without disease 4 (22.2) 11 (45.8) 15 (35.7)
Alive with disease 0 0 0
Death due to disease progression 11 (61.1) 10 (41.7) 21 (50.0)
Treatment-related death 2 (11.1) 3 (12.5) 5 (11.9)
Death due to unknown cause 1 (5.6) 0 1 (2.4)
Values are presented as number (%). CSI, craniospinal irradiation; HDCT, high-dose chemotherapy; RT, radiotherapy.
Table 4 Univariate and multivariate analysis of the probability of progression-free survival
Univariate Multivariatea)
HR (95% CI) p-value HR (95% CI) p-value
Years of diagnosis
Pre-2011 1 0.04 1 0.57
Post-2011 0.47 (0.23–0.96) 0.81 (0.44–1.62)
Patient age (yr)
< 1 1 0.53
≥ 1 0.79 (0.39–1.59)
Metastases
Yes 1 0.03 1 0.53
No 0.46 (0.23–0.90) 0.85 (0.43–1.59)
Extent of resection
GTR 1 0.29
No GTR 1.23 (0.56–2.27)
Early adjuvant RT
Yes 1 < 0.01 1 < 0.01
No 5.68 (2.14–15.12) 6.42 (2.29–17.90)
HDCT
Yes 1 < 0.01 1 < 0.01
No 10.26 (3.81–27.66) 12.0 (3.91–37.28)
CI, confidence interval; GTR, gross total resection; HDCT, high-dose chemotherapy; HR, hazard ratio; RT, radiotherapy.
a) Includes variables significant at p < 0.1 (overall) in univariate analysis.
Ethical Statement
Ethics approval and consent to participation: All participating centers received Institutional Review Board approval to contribute data for this study (NCC 2018-0210). This study was performed in accordance with the Declaration of Helsinki.
Author Contributions
Conceived and designed the analysis: Park M, Han JW, Park HJ.
Collected the data: Park M, Han JW, Hahn SM, Lee JA, Kim JY, Shin SH, Kim DS, Yoon HI, Hong KT, Choi JY, Kang HJ, Shin HY, Phi JH, Kim SK, Lee JW, Yoo KH, Sung KW, Koo HH, Lim DH, Shin HJ, Kim H, Koh KN, Im HJ, Ahn SD, Ra YS, Baek HJ, Kook H, Jung TY, Choi HS, Kim CY, Park HJ, Lyu CJ.
Contributed data or analysis tools: Park M.
Performed the analysis: Park M.
Wrote the paper: Park M.
Review the paper: Lyu CJ, Park HJ.
Conflicts of Interest
Conflicts of interest relevant to this article was not reported.
|
CARBOPLATIN, CISPLATIN, CYCLOPHOSPHAMIDE, ETOPOSIDE, IFOSFAMIDE, MELPHALAN, THIOTEPA, VINCRISTINE
|
DrugsGivenReaction
|
CC BY-NC
|
33138347
| 19,992,879
|
2021-04
|
What was the administration route of drug 'CYTARABINE'?
|
Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children under the Age of 3 Years.
OBJECTIVE
Atypical teratoid/rhabdoid tumor (ATRT) is a highly aggressive malignancy with peak incidence in children aged less than 3 years. Standard treatment for central nervous system ATRT in children under the age of 3 years have not been established yet. The objective of this study was to analyze characteristics and clinical outcomes of ATRT in children aged less than 3 years.
A search of medical records from seven centers was performed between January 2005 and December 2016.
RESULTS
Forty-three patients were enrolled. With a median follow-up of 90 months, 27 patients (64.3%) showed at least one episode of disease progression (PD). The first date of PD was at 160 days after diagnosis. The 1- and 3-year progression-free survivals (PFS) were 51.2% and 28.5%, respectively. The 1- and 3-year overall survivals were 61.9% and 38.1%, respectively. The 3-year PFS was improved from 0% in pre-2011 to 47.4% in post-2011. Excluding one patient who did not receive any further therapy after surgery, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown cause (n=1). In univariate analysis, factors associated with higher 3-year PFS were no metastases, diagnosis after 2011, early adjuvant radiotherapy, and high-dose chemotherapy (HDCT). In multivariate analysis, the use of HDCT and adjuvant radiotherapy remained significant prognostic factors for PFS (both p < 0.01).
CONCLUSIONS
Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years.
Introduction
Atypical teratoid/rhabdoid tumor (ATRT) of the central nervous system (CNS) is a highly aggressive malignancy, accounting for 1%–2% of all pediatric CNS tumors [1,2]. Among children under the age of 3 years, ATRT constitutes the most common malignant tumor of CNS (17.3%), followed by medulloblastoma (16%) [3].
Since standard therapeutic strategies for ATRT have not been established yet, treatment approaches for ATRT vary among institutions and countries. Conventional chemotherapy in addition to high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASR) is usually utilized in pati-ents under 3 years of age to substitute for or delay the use of radiotherapy (RT) in attempt to improve outcomes and minimize long-term neurocognitive impairment [4]. However, most patients with ATRT suffer rapid disease progression (PD), although treatment regimens designed for CNS neoplasms have been used [5,6]. Outcome for patients with ATRT is generally dismal, particularly in the presence of residual tumor or metastasis. ATRT is a devastating brain neoplasm with a median survival time ranging from 6 to 13 months. This is caused not only by the disease’s aggressive characteristics, but also by a lower tolerance of young patients to treatment. This is exacerbated by the hesitancy to use RT in younger patients due to risks of functional impairment of the developing brain [7]. It has been shown that aggressive therapy can prolong survival in a subset of children with CNS ATRT [1,2,8]. Some clinical trials have incorporated early administration of RT to the primary site together with intrathecal (IT) chemotherapy, resulting in improved outcomes [9,10].
In 2005, the Korean Society for Pediatric Neuro-Oncology (KSPNO) suggested the following a protocol for ATRT patients aged less than 3 years (KSPNO-S052): six cycles of conventional chemotherapy and tandem HDCT/ASR are performed initially and RT is deferred until the patient reaches 3 years of age. In 2008, a minor revision of the protocol including a dose modification of conventional chemotherapy was made (KSPNO-S082). In 2011, the protocol was revised (KSPNO-S1102) to recommended early local RT with concurrent chemotherapy within four weeks after surgery. In addition, IT chemotherapy was incorporated.
Given the rarity of this tumor and the even lower number of very young infants affected by ATRT, no detailed clinical analyses have been directed toward patients under 3 years of age. Thus, the objective of this study was to describe patients diagnosed with ATRT in this age group and determine potential specific characteristics or prognostic factors. Their therapeutic management is also suggested.
Materials and Methods
1. Data collection
Children younger than 3 years of age at diagnosis who were newly diagnosed with CNS ATRT were eligible for this study. A search of medical records from seven centers was performed to identify patients aged 3 years or less who were diagnosed between January 2005 and December 2016. In cases with multiple intracranial and extracranial rhabdoid tumors, only patients with clear descriptions of a primary tumor within the CNS were included in this analysis. All participating centers received Institutional Review Board approval to contribute data for this study.
2. Staging
Proper staging for metastases included brain and spinal magnetic resonance imaging (MRI) and cytology of the cerebrospinal fluid (CSF). Modified Chang status for metastatic stage was recorded whenever available. It was defined as follows: M0, absence of metastases; M1, presence of metastases confined to CSF; M2, presence of metastases in the brain; M3, presence of metastases in the spinal subarachnoidal space; and M4, spread outside of the CNS [11]. M+ included M1, M2, M3, M4, and any metastasis not further described.
3. Treatment
All patients underwent maximal possible surgical resection of the primary lesion to preserve neurologic function. The extent of surgical resection defined as gross total resection (GTR), subtotal resection, or biopsy was determined based on a review of postoperative MRI and the surgeon’s intraoperative assessment. Multimodal therapies including surgery, RT, chemotherapy and HDCT/ASR were performed. Treatment was mainly performed according to KSPNO recommendations. However, some physicians modified the treatment protocol depending on clinical situation. Treatment scheme of the KSPNO regimen is shown in Fig. 1. Major differences between KSPNO-S052/-S082 (pre-2011) and KSPNO-S1101 (post-2011) were the timing of RT (delayed RT pre-2011 vs. early adjuvant RT post-2011) and IT chemotherapy for patients post-2011. Detailed chemotherapy schedules are described in Table 1.
KSPNO-S052/S082 (pre-2011) suggested the following: Induction treatment was initiated within 4 weeks of surgery. Six cycles of chemotherapy using alternating CECV (cisplatin, etoposide, cyclophosphamide, and vincristine) and CEIV (carboplatin, etoposide, ifosfamide, and vincristine) regimens were administered. Additionally, tandem HDCT/ASR was performed. The first course included carboplatin, thiotepa and etoposide (CTE), and the second course included cyclophosphamide and melphalan (CM). A 12- to 16-week interval between the first and second HDCT/ASR was allowed to minimize treatment-related mortality (TRM). RT was deferred until after 3 years of age unless the tumor showed progression or relapse. For patients with M0 disease at diagnosis and for patients those without residual tumor after HDCT, RT was omitted.
KSPNO-S1102 (post-2011) suggested the following: RT was recommended to be administered within 4 weeks of surgery with concurrent chemotherapy. IT chemotherapy including cytarabine, hydrocortisone, and methotrexate (MTX) was administered on day 0 of every chemotherapy cycle. For M+ patients, weekly IT chemotherapy was administered until clearance of CSF cytology. After six cycles of alternating CECV and CEIV regimens, tandem HDCT/ASR using CTE-CM was performed. For M+ patients at diagnosis, craniospinal irradiation (CSI) was deferred at 3 years of age.
4. Response and toxicity criteria
Disease response was evaluated by MRI and CSF cytology. Evaluations were repeated every two or three chemotherapy cycles prior to the first HDCT/ASR, between the first and second HDCT/ASR, every 3 months for the first year after completion of tandem HDCT/ASR, every 4 months for the second year, and every 6 months thereafter. Disease response was categorized as follows: complete response (CR) for complete disappearance of all tumors, partial response (PR) for decrease in tumor size by more than 50%, stable disease for less than 25% change in tumor size, PD for greater than 25% increase in tumor size or the appearance of new tumors. Toxicities were graded using the National Cancer Institute’s Common Terminology Criteria ver. 4.0.
5. Statistical analysis
The cutoff point for data analyses was March 2019. For descriptive statistics, data were compared using the Fisher exact test for categorical factors and Wilcoxon Mann-Whitney U test for continuous factors. The time to progression was calculated from the date of diagnosis until the date of PD. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of PD or relapse. Overall survival (OS) was calculated from the date of initial diagnosis to the date of last follow-up or death from any cause. PFS and OS were estimated using the Kaplan-Meier method. Univariate analysis of risk factors was performed by comparing PFS and OS using the log-rank test. Multivariate logistic regression was used to examine relationships between outcomes of PFS or OS as binary dependent variables and independent variables of patient age, metastases, extent of resection, early adjuvant RT, HDCT, and years of diagnosis. p < 0.05 was considered statistically significant. All analyses were performed using IBM SPSS ver. 18.0 (SPSS Inc., Chicago, IL).
Results
1. Patient characteristics
Baseline clinical characteristics of patients are shown in Table 2. Forty-three patients were enrolled in this study. The median age at diagnosis was 13 months (range, 0 to 32 months). Twenty patients (46.5%) were younger than 1 year of age at diagnosis. One patient presented with synchronous tumors, including ATRT in brain and a rhabdoid tumor in the kidney.
Nineteen patients (44.2%) were diagnosed before 2011 (pre-2011 group) and 24 patients (55.8%) were diagnosed after 2011 (post-2011 group). There was no significant difference in age at diagnosis (p=0.55), sex (p=0.43), extent of resection (p=0.15), or metastases (p=0.46) between pre-2011 and post-2011 groups. There were 23 (53.5%) patients with M0 disease, four (9.3%) with M1 disease, 14 (32.6%) with M2 disease, and two (4.7%) with unknown metastatic status. The incidence of metastatic disease was significantly higher in patients under 6 months of age than that in patients older than 6 months (100.0% vs. 35.3%, p < 0.01). GTR of the primary tumor was achieved in 24 patients (55.8%).
2. Treatment
One patient did not receive any further therapy after surgery. All remaining 42 patients received induction chemotherapy at a median of 20 days after surgery (range, 5 to 142 days). The median number of pretransplant chemotherapy cycles was 6 (range, 1 to 12). All patients in the post-2011 group received IT therapies. Nine patients (21.4%) received a second surgery before HDCT due to PD (n=8) or for removing residual tumor (n=1).
Twenty-nine patients (69.0%) received radiation at a median age of 23 months (range, 6 to 40 months). The median interval between diagnosis and RT was 162 days (range, 21 to 745 days). Thirteen patients (31.0%) did not receive RT due to early progression (n=8), treatment-related death (n=3), or physician’s discretion (n=2). As of 2011, RT timing changed from delayed RT (pre-2011) to early adjuvant RT (post-2011). As a result, the median period between diagnosis and RT was significantly shortened from 314.9 days in the pre-2011 group to 159.0 days in the post-2011 group (p=0.04). The period between diagnosis to RT was 114.6±104.8 days in patients who received early adjuvant RT and 313.4±231.2 days in patients who received RT as salvage therapy (p < 0.01).Among 29 patients who received RT, early adjuvant RT was administered in 14 patients (2 in the pre-2011 group and 12 in the post-2011 group) (Table 3). They received local RT at a dose of 36–63 Gy after surgery. Of them, five patients received additional CSI at a dose of 23.4–30.6 Gy concurrently (n=2) or at 3 years of age (n=3) due to M+ disease at diagnosis. Thirteen patients received local RT as salvage therapy at a dose of 25.2–55.8 Gy. Of them, five patients received CSI at a dose of 19.5–23.4 Gy. Two patients received CSI at 3 years of age after completion of HDCT as scheduled.
Twenty-four patients received HDCT/ASR (15 patients received tandem HDCTs and nine patients received only 1 HDCT). Reasons not having second HDCT included physician’s discretion (n=4), PD or relapse (n=3), prolonged bone marrow suppression (n=1), and patient refusal (n=1). During the first HDCT, eight patients received conditioning regimen including topotecan, thiotepa, and carboplatin instead of CTE. During the second HDCT, two patients received conditioning regimen including busulfan, melphalan, and thiotepa instead of CM.
Significantly more patients who received early adjuvant RT proceeded to HDCT compared to patients who did not (78.6% vs. 46.4%, p=0.04). For patients not receiving HDCT (n=18), reasons included PD or relapse (n=12), treatment-related death (n=4), patient refusal (n=1), and death due to unknown cause (n=1). The median age at the time of the first HDCT was 21.0 months (range, 9.1 to 44.5 months). The median time between diagnosis and the first HDCT was 7.5 months (range, 5.3 to 16.1 months). Disease status before the first HDCT was CR in 16 and PR in eight. Among 15 patients who underwent a second HDCT, disease status before the second HDCT was CR in 10, PR in four, and PD in one. The median interval between the first and second HDCT was 91 days (range, 35 to 126 days).
3. Clinical course and survival
Excluding one patient who received palliative care only, data for 42 patients were analyzed (Table 3). With a median follow-up of 90 months (range, 27 to 172 months), 27 patients (64.3%) showed at least one episode of PD. The first date of PD was at 160 days (median; range, 13 to 585) after the diagnosis. Twenty-one of 27 patients who showed PD died due to PD at a median of 4 months (range, 0.1 to 5.4 months) from the first day of documentation of PD. Immediate salvage therapy consisted of surgery in 11, chemotherapy in four, RT in four, gamma knife surgery in one, and supportive care only in seven. PD was found within 2 months of resection surgery before initiation of chemotherapy in three, during chemotherapy in 14, during adjuvant RT in one, during HDCT in two, and after completion of HDCT in seven. Among 14 patients with PD found during induction chemotherapy, 13 did not receive adjuvant RT previously while one patient had received RT previously (p < 0.01). Of nine patients who experienced relapse during or after HDCT, seven patients died due to PD. Two patients are still alive without disease. The median time between HDCT and subsequent relapse was 3 months (range, 1 to 11 months).
The 1- and 3-year PFS is 51.2% and 28.5%, respectively. The 1- and 3-year OS is 61.9% and 38.1%, respectively (Fig. 2). Of 42 patients analyzed, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown causes (n=1).
At the last follow-up, 15 patients were alive. All surviving patients received HDCT/ASR. Patients who achieved CR before the first HDCT showed significantly higher 3-year OS compared to patients who did not (81.3% vs. 37.5%, p < 0.01). There was no significant difference in PFS or OS between patients who underwent 1 HDCT and those who underwent 2 HDCTs.
4. Risk factors
Results of univariate and multivariate analyses for PFS are shown in Table 4. In univariate analysis, factors associated with higher 3-year PFS were no metastases (p=0.03), diagnosis after 2011 (p=0.04), early adjuvant RT (p < 0.01) and HDCT/ASR (p < 0.01) (Fig. 3). Age at diagnosis (p=0.53) and extent of resection (p=0.29) failed to influence survival rate in our study. Among 14 patients who received adjuvant RT, only three patients showed PD during (n=1) or after (n=2) the planned RT, while 24 of 28 patients who did not receive adjuvant RT showed PD (p < 0.01). Among 18 patients with metastases, patients who received early adjuvant local RT showed significantly higher PFS and OS compared to those who did not (3-year PFS: 75.0% vs. 0%, p=0.04; 3-year OS: 75.0% vs. 14.3%, p=0.03).
In multivariate analyses, the use of HDCT/ASR and early adjuvant RT remained significant prognostic factors for PFS (both p < 0.01). For OS, the use of HDCT/ASR was the only significant prognostic factor (p < 0.01). Among patients who received both early adjuvant RT and HDCT/ASR, 3-year PFS and OS were 81.8% and 90.9%, respectively.
5. Toxicity
During chemotherapy, the most frequently reported significant toxicities were bone marrow suppression and febrile neutropenia followed by infection, gastrointestinal disturbances, electrolyte disturbances, and hepatic disturbances. During HDCT, infection was the most common toxicity. Bacteremia was detected during six of 39 HDCT (3 Staphylococcus epidermidis, 2 Pseudomonas aeruginosa, and 1 Bacillus species), five of which occurred during the second HDCT course. One patient experienced sinusoidal obstruction syndrome during their second HDCT. There were five toxic deaths due to sepsis: four occurred under chemotherapy and one occurred following the second HDCT. To date, second malignancies have not been reported.
Discussion
This is the most recent update of Korean ATRT patients under 3 years of age. Tumors progressed or relapsed in 27 of 42 patients at a median of 160 days from diagnosis in our study. The 3-year PFS and OS were 28.5% and 38.1%, respectively. The 3-year PFS was improved from 0.0% in pre-2011 to 47.4% in post-2011. At diagnosis, metastasis was the only characteristic among several disease characteristics known to affect survival.
Our analysis highlights several points of interest for this young age group. First, our data suggest the importance of early adjuvant RT. We found a survival benefit associated with early adjuvant RT. Traditionally, RT has been deferred or omitted because of the risk of adverse effects, especially for patients under 3 years of age [12]. However, more recent data suggest that RT might be more efficacious than chemotherapy for ATRT patients, even for very young children [2,13,14]. In a previously reported Korean study that included patients treated with tandem HDCT/ASR, all surviving patients received RT at an early stage in their treatment [15]. No patients who received induction chemotherapy and HDCT/ASR without RT survived. This suggests that HDCT/ASR cannot replace RT for local control. Similarly, we found that patients who received early adjuvant RT showed a significantly lower chance of having PD during induction chemotherapy and a higher chance to proceed to HDCT compared to patients who did not, thus leading to improved survival. For patients with M+ disease at diagnosis, adjuvant local radiation significantly improved survival in the current study. Overall, local RT should be considered earlier in therapy to improve survival.
Secondly, our data suggest that HDCT is associated with better survival. For patients who received HDCT, PFS and OS were significantly higher compared to those who did not. There has been no randomized study to evaluate the efficacy of HDCT/ASR in ATRT patients under 3 years of age. A few studies have suggested that HDCT might have a favorable effect on ATRT patients [14,16]. A recent Canadian study has reported better 5-year PFS in patients with ATRT under 1 year of age receiving HDCT group compared to those without receiving HDCT (50.1% vs. 11.3%, p < 0.001) [17]. However, due to small numbers of patients included and various treatment modalities used, no firm conclusions can be made regarding the role of HDCT/ASR in ATRT patients. In this study, all surviving patients received HDCT/ASR. However, this does not reflect the definite efficacy of HDCT/ASR. Considering that patients who achieved CR before their first HDCT showed significantly higher OS than those who did not, multimodal treatment that might lead to CR and additional HDCT might result in better outcomes. In this study, patients who achieved CR before the first HDCT showed significantly higher OS. This suggests that pre-HDCT tumor status is important for predicting outcome. Thus, careful consideration is required when selecting candidate patients for HDCT/ASR.
Importantly, we should consider the likelihood of selection bias toward “favorable cases” in patients subjected to HDCT, which could be associated with molecular distinction. Recently, Reddy et al. [18] have reported that patients with group 1/SHH-NOTCH tumors have less aggressive feature. Biological investigation of ATRT should be continued and subsets of patients who can be cured with less therapy may exist [19].
The optimal combination of regimens for tandem HDCT has not been determined. Rosenfeld et al. [12] have reported the feasibility of tandem HDCT/ASR in patients with brain tumors using CTE-CM. Although they concluded that the CTE-CM regimen was not feasible due to toxicity, tandem CTE-CM HDCT/ASR was feasible in our study. Toxicities in our present study were manageable and only one toxic death associated with HDCT occurred. This could be due to the fact that patients were given a sufficient rest period between the first and the second HDCT/ASR. Sung et al. [20] have reported that a shorter interval (< 12 weeks) between the first and second HDCT/ASR is associated with higher TRM. Another thing to be noted was that there was no significant survival difference between patients who received 1 HDCT and those who received 2 HDCTs. In addition, bacteremia occurred more frequently in the second HDCT than in the first HDCT. Randomized trials with larger cohorts are needed to determine whether the possible survival benefit of tandem HDCT/ASR over single HDCT/ASR might ultimately outweigh adverse effects associated with dose intensive tandem HDCT/ASR.
Thirdly, optimal induction chemotherapy should be explored. Efficacies of many different treatments have been explored. However, there is no consensus regarding standard chemotherapy for ATRT. Due to the desire to avoid unacceptable adverse effects of RT on the developing brain, many institutions adopt chemotherapy-based strategies designed to avoid or delay RT. Despite often impressive responses to chemotherapy, the majority of patients in many published studies developed progressive disease early, suggesting a rapid development of resistance of ATRTs [10,21,22]. Similarly, in our study, PD occurred during induction chemotherapy in about half of cases. Considering that the most common reason not having HDCT/ASR was PD during induction chemotherapy, we could consider shorten the current six cycles of induction chemotherapy. Furthermore, patients who received induction chemotherapy without early adjuvant RT showed significantly lower survival compared to patients who received early adjuvant RT. This suggests that CECV and CEIV chemotherapy regimen used in our patients might be insufficient to prevent tumor progression/relapse. Recently, ACNS0333 comprised with three cycles of chemotherapy which incorporated high dose MTX showed promising result, with 4-year OS of 43% [18]. High-dose MTX used in “Head Start II” also appears to be efficacious and well tolerated in ATRT [8]. Slavc et al. [23] have also demonstrated the efficacy of high-dose MTX in ATRT patients. Besides intensification using cytotoxic agent, there are increasing data suggesting that ATRT might be a good candidate for pathway-specific targeted therapies, some of which are currently used in clinical trials, including AURKA, EZH2, and CDK4/6 inhibitors [24,25]. Optimwal combination of cytotoxic agents and targeted inhibitors should be explored to prevent early progression of ATRT.
Lastly, we found that the post-2011 group had significantly better PFS than the pre-2011 group. The major difference between pre- and post-2011 protocols was adjuvant local radiation and IT chemotherapy in the post-2011 protocol. There was no difference in induction chemotherapy or HDCT between pre- and post-2011 protocols. We believe that the post-2011 protocol with a combination of adjuvant RT and IT chemotherapy might have prevented early progression, eventually improving the outcome as reported by Chi et al. [10]. The role of adjuvant RT has already been described above. IT therapy was incorporated as a method of providing prophylaxis and/or treatment to the CNS axis in the post-2011 protocol. Whether IT therapy could substitute for cranial irradiation for CNS treatment and/or prophylaxis was unclear because both modalities were used in the post-2011 protocol. Considering that the year of diagnosis (pre- vs. post-2011) was not a significant predictor of survival in multivariate analyses, IT therapy might not have a beneficial role in improving survival. However, in many studies, IT chemotherapy has shown potential benefit as an addition to local RT or to intensify therapy in patients who are not candidates for CSI [10,26]. IT chemotherapy shows good penetrance into the CSF. Thus, it might be efficacious in eradicating ATRT cells in CSF, allowing postponement of CSI for patients who receive focal irradiation only. A meta-analysis by Athale et al. [26] has shown that IT therapy leads to a significantly higher OS. A more detailed randomized study I needed to evaluate IT therapy in infant ATRT to define role of IT therapy in these patients.
This study has some limitations. First, this study had a non-randomized and retrospective design. Second, we did not collect data for germline mutations in SMARCB1/INI1. Therefore, we could not assess the association between germline status and outcome. No molecular profiling was included, which could be potential prognostic indicators. Third, because current multimodality treatment strategies for ATRT include brain RT, limited data on neurocognitive outcomes of survivors raise a significant concern [27]. Although data stress the importance for RT in younger age group, this treatment option comes at a cost of serious long-term sequelae such as cognitive, motor, visual, and hearing impairment [28,29]. In addition, combining multimodal treatment deserves attention. Comprehensive long-term follow-up neuropsychologic assessments are planned for our surviving cohort. Lastly, as described above, a more detailed analysis is needed in the future to identify the role of IT therapy in the prevention and treatment of metastases.
In summary, aggressive therapy including early administration of local RT and HDCT/ASR, which was adopted in KSPNO-S1102, should be considered to improve outcomes of ATRT in children below the age of 3 years. Despite the high probability of early PD in ATRT, for patients who received both early adjuvant RT and HDCT/ASR, OS exceeded 90%. Further clinical trials may be required to determine optimal adjuvant treatments such as RT field and intensity of HDCT/ASR and the role of IT chemotherapy for patients with ATRT. Future studies regarding molecular characterization of ATRT and its prognostic implication might change current treatment strategies and delineate the group of patients so that treatment intensity could be reduced.
Acknowledgments
This study was supported by the KPHOG Research Grant 2018.
Fig. 1 Treatment recommendations by the Korean Society for Pediatric Neuro-Oncology for CNS ATRT during periods of 2005–2007 (A), 2008–2010 (B), and 2011-present (C). ASR, autologous stem cell rescue; CR, complete response; CSI, craniospinal irradiation; HDCT, high-dose chemotherapy; IT, intrathecal; RT, radiotherapy. a)R0 (< 1.5 cm2)/M0, local RT 41.4 Gy; R+ (> 1.5 cm2)/M0, local RT 55.8 Gy; Rx/M+, local RT 36 Gy+CSI 19.8 Gy at 3 years of age, b)M0, day 0 of each cycle/M+, weekly until clearing (at least 6 times), then day 0 each cycle.
Fig. 2 Kaplan-Meier estimates of progression-free survival (A) and overall survival (B).
Fig. 3 Progression-free survival according to metastases (A), year of diagnosis (B), early adjuvant radiation (C), and high-dose chemotherapy (D).
Table 1 Chemotherapy regimens
Regimen Drug Dose Schedule
KSPNO-S052 induction chemotherapy
Regimen a Cisplatin 3.5 mg/kg Day 0
Etoposide 2.5 mg/kg Days 0, 1, and 2
Cyclophosphamide 60 mg/kg Days 1 and 2
Vincristine 0.05 mg/kg Days 0, 7, and 14
Regimen b Carboplatin 10 mg/kg Days 0 and 1
Etoposide 2.5 mg/kg Days 0 to 4
Ifosfamide 60 mg/kg Days 0 to 4
Vincristine 0.05 mg/kg Days 0, 7, and 14
KSPNO-S082/S1102 induction chemotherapy
Regimen A Cisplatin 3 mg/kg Day 0
Etoposide 2.5 mg/kg Days 0, 1, and 2
Cyclophosphamide 50 mg/kg Days 1 and 2
Vincristine 0.05 mg/kg Days 0 and 7
Regimen B Carboplatin 10 mg/kg Days 0 and 1
Etoposide 2.5 mg/kg Days 0 to 4
Ifosfamide 50 mg/kg Days 0 to 4
Vincristine 0.05 mg/kg Days 0 and 7
KSPNO-S052/S082/S1102 high-dose chemotherapy
First: CTE Carboplatin 500 mg/m2 Days −8 to −6
Thiotepa 300 mg/m2 Days −5 to −3
Etoposide 250 mg/m2 Days −5 to −3
Second: CM Cyclophosphamide 1,500 mg/m2 Days −8 to −5
Melphalan 60 mg/m2 Days −4 to −2
CM, cyclophosphamide and melphalan; CTE, carboplatin, thiotepa and etoposide.
Table 2 Clinical characteristics of patients
Pre-2011 (n=19) Post-2011 (n=24) Total (n=43)
Male:Female 9:10 13:11 22:21
Age at diagnosis (mo)
Median (range) 13.0 (1–31) 14.5 (0–32) 13.0 (0–32)
< 6 mo 4 (21.1) 5 (20.8) 9 (20.9)
6–12 mo 5 (26.3) 6 (25.0) 11 (25.6)
> 12 mo 10 (52.6) 13 (54.2) 23 (53.5)
Neuraxis metastasis
M0 11 (57.9) 12 (50.0) 23 (53.5)
M1 2 (10.5) 2 (8.3) 4 (9.3)
M2 5 (26.3) 9 (37.5) 14 (32.6)
Unknown 1 (5.3) 1 (4.2) 2 (4.7)
Type of resection
Gross total resection 12 (63.2) 12 (50.0) 24 (55.8)
Subtotal resection 6 (31.6) 12 (50.0) 18 (41.9)
Biopsy 1 (5.3) 0 1 (2.3)
Palliative care only after surgery 1 (5.3) 0 1 (2.3)
Values are presented as number (%) unless otherwise indicated.
Table 3 Treatment and clinical outcomes
Pre-2011 (n=18) Post-2011 (n=24) Total (n=42)
Treatment
Chemotherapy 18 (100) 24 (100) 42 (100)
RT 12 (66.7) 17 (70.8) 29 (69.0)
Early adjuvant local RT 2 (11.1) 12 (50.0) 14 (33.3)
With concurrent CSI 1 1 2
CSI at 3 years of age after completion of HDCT 0 3 3
Salvage local RT at relapse/progression 9 (50.0) 4 (16.7) 13 (31.0)
With concurrent CSI 4 1 5
CSI at 3 years of age after completion of HDCT 1 1 2
CSI at 3 year of age only 1 (5.5) 1 (4.2) 2 (4.8)
HDCT 9 (50.0) 15 (62.5) 24 (57.1)
1 HDCT 1 (5.6) 8 (33.3) 9 (21.4)
2 HDCT 8 (44.4) 7 (29.2) 15 (35.8)
Response to treatment
Continued response 3 (16.7) 12 (50.0) 15 (35.7)
Disease progression 15 (83.3) 12 (50.0) 27 (64.3)
After initial surgery 1 2 3
During induction chemotherapy 9 5 14
During RT 0 1 1
During HDCT 0 2 2
After completion of HDCT 5 2 7
Final outcome
Alive without disease 4 (22.2) 11 (45.8) 15 (35.7)
Alive with disease 0 0 0
Death due to disease progression 11 (61.1) 10 (41.7) 21 (50.0)
Treatment-related death 2 (11.1) 3 (12.5) 5 (11.9)
Death due to unknown cause 1 (5.6) 0 1 (2.4)
Values are presented as number (%). CSI, craniospinal irradiation; HDCT, high-dose chemotherapy; RT, radiotherapy.
Table 4 Univariate and multivariate analysis of the probability of progression-free survival
Univariate Multivariatea)
HR (95% CI) p-value HR (95% CI) p-value
Years of diagnosis
Pre-2011 1 0.04 1 0.57
Post-2011 0.47 (0.23–0.96) 0.81 (0.44–1.62)
Patient age (yr)
< 1 1 0.53
≥ 1 0.79 (0.39–1.59)
Metastases
Yes 1 0.03 1 0.53
No 0.46 (0.23–0.90) 0.85 (0.43–1.59)
Extent of resection
GTR 1 0.29
No GTR 1.23 (0.56–2.27)
Early adjuvant RT
Yes 1 < 0.01 1 < 0.01
No 5.68 (2.14–15.12) 6.42 (2.29–17.90)
HDCT
Yes 1 < 0.01 1 < 0.01
No 10.26 (3.81–27.66) 12.0 (3.91–37.28)
CI, confidence interval; GTR, gross total resection; HDCT, high-dose chemotherapy; HR, hazard ratio; RT, radiotherapy.
a) Includes variables significant at p < 0.1 (overall) in univariate analysis.
Ethical Statement
Ethics approval and consent to participation: All participating centers received Institutional Review Board approval to contribute data for this study (NCC 2018-0210). This study was performed in accordance with the Declaration of Helsinki.
Author Contributions
Conceived and designed the analysis: Park M, Han JW, Park HJ.
Collected the data: Park M, Han JW, Hahn SM, Lee JA, Kim JY, Shin SH, Kim DS, Yoon HI, Hong KT, Choi JY, Kang HJ, Shin HY, Phi JH, Kim SK, Lee JW, Yoo KH, Sung KW, Koo HH, Lim DH, Shin HJ, Kim H, Koh KN, Im HJ, Ahn SD, Ra YS, Baek HJ, Kook H, Jung TY, Choi HS, Kim CY, Park HJ, Lyu CJ.
Contributed data or analysis tools: Park M.
Performed the analysis: Park M.
Wrote the paper: Park M.
Review the paper: Lyu CJ, Park HJ.
Conflicts of Interest
Conflicts of interest relevant to this article was not reported.
|
Intrathecal
|
DrugAdministrationRoute
|
CC BY-NC
|
33138347
| 19,651,900
|
2021-04
|
What was the administration route of drug 'HYDROCORTISONE'?
|
Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children under the Age of 3 Years.
OBJECTIVE
Atypical teratoid/rhabdoid tumor (ATRT) is a highly aggressive malignancy with peak incidence in children aged less than 3 years. Standard treatment for central nervous system ATRT in children under the age of 3 years have not been established yet. The objective of this study was to analyze characteristics and clinical outcomes of ATRT in children aged less than 3 years.
A search of medical records from seven centers was performed between January 2005 and December 2016.
RESULTS
Forty-three patients were enrolled. With a median follow-up of 90 months, 27 patients (64.3%) showed at least one episode of disease progression (PD). The first date of PD was at 160 days after diagnosis. The 1- and 3-year progression-free survivals (PFS) were 51.2% and 28.5%, respectively. The 1- and 3-year overall survivals were 61.9% and 38.1%, respectively. The 3-year PFS was improved from 0% in pre-2011 to 47.4% in post-2011. Excluding one patient who did not receive any further therapy after surgery, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown cause (n=1). In univariate analysis, factors associated with higher 3-year PFS were no metastases, diagnosis after 2011, early adjuvant radiotherapy, and high-dose chemotherapy (HDCT). In multivariate analysis, the use of HDCT and adjuvant radiotherapy remained significant prognostic factors for PFS (both p < 0.01).
CONCLUSIONS
Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years.
Introduction
Atypical teratoid/rhabdoid tumor (ATRT) of the central nervous system (CNS) is a highly aggressive malignancy, accounting for 1%–2% of all pediatric CNS tumors [1,2]. Among children under the age of 3 years, ATRT constitutes the most common malignant tumor of CNS (17.3%), followed by medulloblastoma (16%) [3].
Since standard therapeutic strategies for ATRT have not been established yet, treatment approaches for ATRT vary among institutions and countries. Conventional chemotherapy in addition to high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASR) is usually utilized in pati-ents under 3 years of age to substitute for or delay the use of radiotherapy (RT) in attempt to improve outcomes and minimize long-term neurocognitive impairment [4]. However, most patients with ATRT suffer rapid disease progression (PD), although treatment regimens designed for CNS neoplasms have been used [5,6]. Outcome for patients with ATRT is generally dismal, particularly in the presence of residual tumor or metastasis. ATRT is a devastating brain neoplasm with a median survival time ranging from 6 to 13 months. This is caused not only by the disease’s aggressive characteristics, but also by a lower tolerance of young patients to treatment. This is exacerbated by the hesitancy to use RT in younger patients due to risks of functional impairment of the developing brain [7]. It has been shown that aggressive therapy can prolong survival in a subset of children with CNS ATRT [1,2,8]. Some clinical trials have incorporated early administration of RT to the primary site together with intrathecal (IT) chemotherapy, resulting in improved outcomes [9,10].
In 2005, the Korean Society for Pediatric Neuro-Oncology (KSPNO) suggested the following a protocol for ATRT patients aged less than 3 years (KSPNO-S052): six cycles of conventional chemotherapy and tandem HDCT/ASR are performed initially and RT is deferred until the patient reaches 3 years of age. In 2008, a minor revision of the protocol including a dose modification of conventional chemotherapy was made (KSPNO-S082). In 2011, the protocol was revised (KSPNO-S1102) to recommended early local RT with concurrent chemotherapy within four weeks after surgery. In addition, IT chemotherapy was incorporated.
Given the rarity of this tumor and the even lower number of very young infants affected by ATRT, no detailed clinical analyses have been directed toward patients under 3 years of age. Thus, the objective of this study was to describe patients diagnosed with ATRT in this age group and determine potential specific characteristics or prognostic factors. Their therapeutic management is also suggested.
Materials and Methods
1. Data collection
Children younger than 3 years of age at diagnosis who were newly diagnosed with CNS ATRT were eligible for this study. A search of medical records from seven centers was performed to identify patients aged 3 years or less who were diagnosed between January 2005 and December 2016. In cases with multiple intracranial and extracranial rhabdoid tumors, only patients with clear descriptions of a primary tumor within the CNS were included in this analysis. All participating centers received Institutional Review Board approval to contribute data for this study.
2. Staging
Proper staging for metastases included brain and spinal magnetic resonance imaging (MRI) and cytology of the cerebrospinal fluid (CSF). Modified Chang status for metastatic stage was recorded whenever available. It was defined as follows: M0, absence of metastases; M1, presence of metastases confined to CSF; M2, presence of metastases in the brain; M3, presence of metastases in the spinal subarachnoidal space; and M4, spread outside of the CNS [11]. M+ included M1, M2, M3, M4, and any metastasis not further described.
3. Treatment
All patients underwent maximal possible surgical resection of the primary lesion to preserve neurologic function. The extent of surgical resection defined as gross total resection (GTR), subtotal resection, or biopsy was determined based on a review of postoperative MRI and the surgeon’s intraoperative assessment. Multimodal therapies including surgery, RT, chemotherapy and HDCT/ASR were performed. Treatment was mainly performed according to KSPNO recommendations. However, some physicians modified the treatment protocol depending on clinical situation. Treatment scheme of the KSPNO regimen is shown in Fig. 1. Major differences between KSPNO-S052/-S082 (pre-2011) and KSPNO-S1101 (post-2011) were the timing of RT (delayed RT pre-2011 vs. early adjuvant RT post-2011) and IT chemotherapy for patients post-2011. Detailed chemotherapy schedules are described in Table 1.
KSPNO-S052/S082 (pre-2011) suggested the following: Induction treatment was initiated within 4 weeks of surgery. Six cycles of chemotherapy using alternating CECV (cisplatin, etoposide, cyclophosphamide, and vincristine) and CEIV (carboplatin, etoposide, ifosfamide, and vincristine) regimens were administered. Additionally, tandem HDCT/ASR was performed. The first course included carboplatin, thiotepa and etoposide (CTE), and the second course included cyclophosphamide and melphalan (CM). A 12- to 16-week interval between the first and second HDCT/ASR was allowed to minimize treatment-related mortality (TRM). RT was deferred until after 3 years of age unless the tumor showed progression or relapse. For patients with M0 disease at diagnosis and for patients those without residual tumor after HDCT, RT was omitted.
KSPNO-S1102 (post-2011) suggested the following: RT was recommended to be administered within 4 weeks of surgery with concurrent chemotherapy. IT chemotherapy including cytarabine, hydrocortisone, and methotrexate (MTX) was administered on day 0 of every chemotherapy cycle. For M+ patients, weekly IT chemotherapy was administered until clearance of CSF cytology. After six cycles of alternating CECV and CEIV regimens, tandem HDCT/ASR using CTE-CM was performed. For M+ patients at diagnosis, craniospinal irradiation (CSI) was deferred at 3 years of age.
4. Response and toxicity criteria
Disease response was evaluated by MRI and CSF cytology. Evaluations were repeated every two or three chemotherapy cycles prior to the first HDCT/ASR, between the first and second HDCT/ASR, every 3 months for the first year after completion of tandem HDCT/ASR, every 4 months for the second year, and every 6 months thereafter. Disease response was categorized as follows: complete response (CR) for complete disappearance of all tumors, partial response (PR) for decrease in tumor size by more than 50%, stable disease for less than 25% change in tumor size, PD for greater than 25% increase in tumor size or the appearance of new tumors. Toxicities were graded using the National Cancer Institute’s Common Terminology Criteria ver. 4.0.
5. Statistical analysis
The cutoff point for data analyses was March 2019. For descriptive statistics, data were compared using the Fisher exact test for categorical factors and Wilcoxon Mann-Whitney U test for continuous factors. The time to progression was calculated from the date of diagnosis until the date of PD. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of PD or relapse. Overall survival (OS) was calculated from the date of initial diagnosis to the date of last follow-up or death from any cause. PFS and OS were estimated using the Kaplan-Meier method. Univariate analysis of risk factors was performed by comparing PFS and OS using the log-rank test. Multivariate logistic regression was used to examine relationships between outcomes of PFS or OS as binary dependent variables and independent variables of patient age, metastases, extent of resection, early adjuvant RT, HDCT, and years of diagnosis. p < 0.05 was considered statistically significant. All analyses were performed using IBM SPSS ver. 18.0 (SPSS Inc., Chicago, IL).
Results
1. Patient characteristics
Baseline clinical characteristics of patients are shown in Table 2. Forty-three patients were enrolled in this study. The median age at diagnosis was 13 months (range, 0 to 32 months). Twenty patients (46.5%) were younger than 1 year of age at diagnosis. One patient presented with synchronous tumors, including ATRT in brain and a rhabdoid tumor in the kidney.
Nineteen patients (44.2%) were diagnosed before 2011 (pre-2011 group) and 24 patients (55.8%) were diagnosed after 2011 (post-2011 group). There was no significant difference in age at diagnosis (p=0.55), sex (p=0.43), extent of resection (p=0.15), or metastases (p=0.46) between pre-2011 and post-2011 groups. There were 23 (53.5%) patients with M0 disease, four (9.3%) with M1 disease, 14 (32.6%) with M2 disease, and two (4.7%) with unknown metastatic status. The incidence of metastatic disease was significantly higher in patients under 6 months of age than that in patients older than 6 months (100.0% vs. 35.3%, p < 0.01). GTR of the primary tumor was achieved in 24 patients (55.8%).
2. Treatment
One patient did not receive any further therapy after surgery. All remaining 42 patients received induction chemotherapy at a median of 20 days after surgery (range, 5 to 142 days). The median number of pretransplant chemotherapy cycles was 6 (range, 1 to 12). All patients in the post-2011 group received IT therapies. Nine patients (21.4%) received a second surgery before HDCT due to PD (n=8) or for removing residual tumor (n=1).
Twenty-nine patients (69.0%) received radiation at a median age of 23 months (range, 6 to 40 months). The median interval between diagnosis and RT was 162 days (range, 21 to 745 days). Thirteen patients (31.0%) did not receive RT due to early progression (n=8), treatment-related death (n=3), or physician’s discretion (n=2). As of 2011, RT timing changed from delayed RT (pre-2011) to early adjuvant RT (post-2011). As a result, the median period between diagnosis and RT was significantly shortened from 314.9 days in the pre-2011 group to 159.0 days in the post-2011 group (p=0.04). The period between diagnosis to RT was 114.6±104.8 days in patients who received early adjuvant RT and 313.4±231.2 days in patients who received RT as salvage therapy (p < 0.01).Among 29 patients who received RT, early adjuvant RT was administered in 14 patients (2 in the pre-2011 group and 12 in the post-2011 group) (Table 3). They received local RT at a dose of 36–63 Gy after surgery. Of them, five patients received additional CSI at a dose of 23.4–30.6 Gy concurrently (n=2) or at 3 years of age (n=3) due to M+ disease at diagnosis. Thirteen patients received local RT as salvage therapy at a dose of 25.2–55.8 Gy. Of them, five patients received CSI at a dose of 19.5–23.4 Gy. Two patients received CSI at 3 years of age after completion of HDCT as scheduled.
Twenty-four patients received HDCT/ASR (15 patients received tandem HDCTs and nine patients received only 1 HDCT). Reasons not having second HDCT included physician’s discretion (n=4), PD or relapse (n=3), prolonged bone marrow suppression (n=1), and patient refusal (n=1). During the first HDCT, eight patients received conditioning regimen including topotecan, thiotepa, and carboplatin instead of CTE. During the second HDCT, two patients received conditioning regimen including busulfan, melphalan, and thiotepa instead of CM.
Significantly more patients who received early adjuvant RT proceeded to HDCT compared to patients who did not (78.6% vs. 46.4%, p=0.04). For patients not receiving HDCT (n=18), reasons included PD or relapse (n=12), treatment-related death (n=4), patient refusal (n=1), and death due to unknown cause (n=1). The median age at the time of the first HDCT was 21.0 months (range, 9.1 to 44.5 months). The median time between diagnosis and the first HDCT was 7.5 months (range, 5.3 to 16.1 months). Disease status before the first HDCT was CR in 16 and PR in eight. Among 15 patients who underwent a second HDCT, disease status before the second HDCT was CR in 10, PR in four, and PD in one. The median interval between the first and second HDCT was 91 days (range, 35 to 126 days).
3. Clinical course and survival
Excluding one patient who received palliative care only, data for 42 patients were analyzed (Table 3). With a median follow-up of 90 months (range, 27 to 172 months), 27 patients (64.3%) showed at least one episode of PD. The first date of PD was at 160 days (median; range, 13 to 585) after the diagnosis. Twenty-one of 27 patients who showed PD died due to PD at a median of 4 months (range, 0.1 to 5.4 months) from the first day of documentation of PD. Immediate salvage therapy consisted of surgery in 11, chemotherapy in four, RT in four, gamma knife surgery in one, and supportive care only in seven. PD was found within 2 months of resection surgery before initiation of chemotherapy in three, during chemotherapy in 14, during adjuvant RT in one, during HDCT in two, and after completion of HDCT in seven. Among 14 patients with PD found during induction chemotherapy, 13 did not receive adjuvant RT previously while one patient had received RT previously (p < 0.01). Of nine patients who experienced relapse during or after HDCT, seven patients died due to PD. Two patients are still alive without disease. The median time between HDCT and subsequent relapse was 3 months (range, 1 to 11 months).
The 1- and 3-year PFS is 51.2% and 28.5%, respectively. The 1- and 3-year OS is 61.9% and 38.1%, respectively (Fig. 2). Of 42 patients analyzed, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown causes (n=1).
At the last follow-up, 15 patients were alive. All surviving patients received HDCT/ASR. Patients who achieved CR before the first HDCT showed significantly higher 3-year OS compared to patients who did not (81.3% vs. 37.5%, p < 0.01). There was no significant difference in PFS or OS between patients who underwent 1 HDCT and those who underwent 2 HDCTs.
4. Risk factors
Results of univariate and multivariate analyses for PFS are shown in Table 4. In univariate analysis, factors associated with higher 3-year PFS were no metastases (p=0.03), diagnosis after 2011 (p=0.04), early adjuvant RT (p < 0.01) and HDCT/ASR (p < 0.01) (Fig. 3). Age at diagnosis (p=0.53) and extent of resection (p=0.29) failed to influence survival rate in our study. Among 14 patients who received adjuvant RT, only three patients showed PD during (n=1) or after (n=2) the planned RT, while 24 of 28 patients who did not receive adjuvant RT showed PD (p < 0.01). Among 18 patients with metastases, patients who received early adjuvant local RT showed significantly higher PFS and OS compared to those who did not (3-year PFS: 75.0% vs. 0%, p=0.04; 3-year OS: 75.0% vs. 14.3%, p=0.03).
In multivariate analyses, the use of HDCT/ASR and early adjuvant RT remained significant prognostic factors for PFS (both p < 0.01). For OS, the use of HDCT/ASR was the only significant prognostic factor (p < 0.01). Among patients who received both early adjuvant RT and HDCT/ASR, 3-year PFS and OS were 81.8% and 90.9%, respectively.
5. Toxicity
During chemotherapy, the most frequently reported significant toxicities were bone marrow suppression and febrile neutropenia followed by infection, gastrointestinal disturbances, electrolyte disturbances, and hepatic disturbances. During HDCT, infection was the most common toxicity. Bacteremia was detected during six of 39 HDCT (3 Staphylococcus epidermidis, 2 Pseudomonas aeruginosa, and 1 Bacillus species), five of which occurred during the second HDCT course. One patient experienced sinusoidal obstruction syndrome during their second HDCT. There were five toxic deaths due to sepsis: four occurred under chemotherapy and one occurred following the second HDCT. To date, second malignancies have not been reported.
Discussion
This is the most recent update of Korean ATRT patients under 3 years of age. Tumors progressed or relapsed in 27 of 42 patients at a median of 160 days from diagnosis in our study. The 3-year PFS and OS were 28.5% and 38.1%, respectively. The 3-year PFS was improved from 0.0% in pre-2011 to 47.4% in post-2011. At diagnosis, metastasis was the only characteristic among several disease characteristics known to affect survival.
Our analysis highlights several points of interest for this young age group. First, our data suggest the importance of early adjuvant RT. We found a survival benefit associated with early adjuvant RT. Traditionally, RT has been deferred or omitted because of the risk of adverse effects, especially for patients under 3 years of age [12]. However, more recent data suggest that RT might be more efficacious than chemotherapy for ATRT patients, even for very young children [2,13,14]. In a previously reported Korean study that included patients treated with tandem HDCT/ASR, all surviving patients received RT at an early stage in their treatment [15]. No patients who received induction chemotherapy and HDCT/ASR without RT survived. This suggests that HDCT/ASR cannot replace RT for local control. Similarly, we found that patients who received early adjuvant RT showed a significantly lower chance of having PD during induction chemotherapy and a higher chance to proceed to HDCT compared to patients who did not, thus leading to improved survival. For patients with M+ disease at diagnosis, adjuvant local radiation significantly improved survival in the current study. Overall, local RT should be considered earlier in therapy to improve survival.
Secondly, our data suggest that HDCT is associated with better survival. For patients who received HDCT, PFS and OS were significantly higher compared to those who did not. There has been no randomized study to evaluate the efficacy of HDCT/ASR in ATRT patients under 3 years of age. A few studies have suggested that HDCT might have a favorable effect on ATRT patients [14,16]. A recent Canadian study has reported better 5-year PFS in patients with ATRT under 1 year of age receiving HDCT group compared to those without receiving HDCT (50.1% vs. 11.3%, p < 0.001) [17]. However, due to small numbers of patients included and various treatment modalities used, no firm conclusions can be made regarding the role of HDCT/ASR in ATRT patients. In this study, all surviving patients received HDCT/ASR. However, this does not reflect the definite efficacy of HDCT/ASR. Considering that patients who achieved CR before their first HDCT showed significantly higher OS than those who did not, multimodal treatment that might lead to CR and additional HDCT might result in better outcomes. In this study, patients who achieved CR before the first HDCT showed significantly higher OS. This suggests that pre-HDCT tumor status is important for predicting outcome. Thus, careful consideration is required when selecting candidate patients for HDCT/ASR.
Importantly, we should consider the likelihood of selection bias toward “favorable cases” in patients subjected to HDCT, which could be associated with molecular distinction. Recently, Reddy et al. [18] have reported that patients with group 1/SHH-NOTCH tumors have less aggressive feature. Biological investigation of ATRT should be continued and subsets of patients who can be cured with less therapy may exist [19].
The optimal combination of regimens for tandem HDCT has not been determined. Rosenfeld et al. [12] have reported the feasibility of tandem HDCT/ASR in patients with brain tumors using CTE-CM. Although they concluded that the CTE-CM regimen was not feasible due to toxicity, tandem CTE-CM HDCT/ASR was feasible in our study. Toxicities in our present study were manageable and only one toxic death associated with HDCT occurred. This could be due to the fact that patients were given a sufficient rest period between the first and the second HDCT/ASR. Sung et al. [20] have reported that a shorter interval (< 12 weeks) between the first and second HDCT/ASR is associated with higher TRM. Another thing to be noted was that there was no significant survival difference between patients who received 1 HDCT and those who received 2 HDCTs. In addition, bacteremia occurred more frequently in the second HDCT than in the first HDCT. Randomized trials with larger cohorts are needed to determine whether the possible survival benefit of tandem HDCT/ASR over single HDCT/ASR might ultimately outweigh adverse effects associated with dose intensive tandem HDCT/ASR.
Thirdly, optimal induction chemotherapy should be explored. Efficacies of many different treatments have been explored. However, there is no consensus regarding standard chemotherapy for ATRT. Due to the desire to avoid unacceptable adverse effects of RT on the developing brain, many institutions adopt chemotherapy-based strategies designed to avoid or delay RT. Despite often impressive responses to chemotherapy, the majority of patients in many published studies developed progressive disease early, suggesting a rapid development of resistance of ATRTs [10,21,22]. Similarly, in our study, PD occurred during induction chemotherapy in about half of cases. Considering that the most common reason not having HDCT/ASR was PD during induction chemotherapy, we could consider shorten the current six cycles of induction chemotherapy. Furthermore, patients who received induction chemotherapy without early adjuvant RT showed significantly lower survival compared to patients who received early adjuvant RT. This suggests that CECV and CEIV chemotherapy regimen used in our patients might be insufficient to prevent tumor progression/relapse. Recently, ACNS0333 comprised with three cycles of chemotherapy which incorporated high dose MTX showed promising result, with 4-year OS of 43% [18]. High-dose MTX used in “Head Start II” also appears to be efficacious and well tolerated in ATRT [8]. Slavc et al. [23] have also demonstrated the efficacy of high-dose MTX in ATRT patients. Besides intensification using cytotoxic agent, there are increasing data suggesting that ATRT might be a good candidate for pathway-specific targeted therapies, some of which are currently used in clinical trials, including AURKA, EZH2, and CDK4/6 inhibitors [24,25]. Optimwal combination of cytotoxic agents and targeted inhibitors should be explored to prevent early progression of ATRT.
Lastly, we found that the post-2011 group had significantly better PFS than the pre-2011 group. The major difference between pre- and post-2011 protocols was adjuvant local radiation and IT chemotherapy in the post-2011 protocol. There was no difference in induction chemotherapy or HDCT between pre- and post-2011 protocols. We believe that the post-2011 protocol with a combination of adjuvant RT and IT chemotherapy might have prevented early progression, eventually improving the outcome as reported by Chi et al. [10]. The role of adjuvant RT has already been described above. IT therapy was incorporated as a method of providing prophylaxis and/or treatment to the CNS axis in the post-2011 protocol. Whether IT therapy could substitute for cranial irradiation for CNS treatment and/or prophylaxis was unclear because both modalities were used in the post-2011 protocol. Considering that the year of diagnosis (pre- vs. post-2011) was not a significant predictor of survival in multivariate analyses, IT therapy might not have a beneficial role in improving survival. However, in many studies, IT chemotherapy has shown potential benefit as an addition to local RT or to intensify therapy in patients who are not candidates for CSI [10,26]. IT chemotherapy shows good penetrance into the CSF. Thus, it might be efficacious in eradicating ATRT cells in CSF, allowing postponement of CSI for patients who receive focal irradiation only. A meta-analysis by Athale et al. [26] has shown that IT therapy leads to a significantly higher OS. A more detailed randomized study I needed to evaluate IT therapy in infant ATRT to define role of IT therapy in these patients.
This study has some limitations. First, this study had a non-randomized and retrospective design. Second, we did not collect data for germline mutations in SMARCB1/INI1. Therefore, we could not assess the association between germline status and outcome. No molecular profiling was included, which could be potential prognostic indicators. Third, because current multimodality treatment strategies for ATRT include brain RT, limited data on neurocognitive outcomes of survivors raise a significant concern [27]. Although data stress the importance for RT in younger age group, this treatment option comes at a cost of serious long-term sequelae such as cognitive, motor, visual, and hearing impairment [28,29]. In addition, combining multimodal treatment deserves attention. Comprehensive long-term follow-up neuropsychologic assessments are planned for our surviving cohort. Lastly, as described above, a more detailed analysis is needed in the future to identify the role of IT therapy in the prevention and treatment of metastases.
In summary, aggressive therapy including early administration of local RT and HDCT/ASR, which was adopted in KSPNO-S1102, should be considered to improve outcomes of ATRT in children below the age of 3 years. Despite the high probability of early PD in ATRT, for patients who received both early adjuvant RT and HDCT/ASR, OS exceeded 90%. Further clinical trials may be required to determine optimal adjuvant treatments such as RT field and intensity of HDCT/ASR and the role of IT chemotherapy for patients with ATRT. Future studies regarding molecular characterization of ATRT and its prognostic implication might change current treatment strategies and delineate the group of patients so that treatment intensity could be reduced.
Acknowledgments
This study was supported by the KPHOG Research Grant 2018.
Fig. 1 Treatment recommendations by the Korean Society for Pediatric Neuro-Oncology for CNS ATRT during periods of 2005–2007 (A), 2008–2010 (B), and 2011-present (C). ASR, autologous stem cell rescue; CR, complete response; CSI, craniospinal irradiation; HDCT, high-dose chemotherapy; IT, intrathecal; RT, radiotherapy. a)R0 (< 1.5 cm2)/M0, local RT 41.4 Gy; R+ (> 1.5 cm2)/M0, local RT 55.8 Gy; Rx/M+, local RT 36 Gy+CSI 19.8 Gy at 3 years of age, b)M0, day 0 of each cycle/M+, weekly until clearing (at least 6 times), then day 0 each cycle.
Fig. 2 Kaplan-Meier estimates of progression-free survival (A) and overall survival (B).
Fig. 3 Progression-free survival according to metastases (A), year of diagnosis (B), early adjuvant radiation (C), and high-dose chemotherapy (D).
Table 1 Chemotherapy regimens
Regimen Drug Dose Schedule
KSPNO-S052 induction chemotherapy
Regimen a Cisplatin 3.5 mg/kg Day 0
Etoposide 2.5 mg/kg Days 0, 1, and 2
Cyclophosphamide 60 mg/kg Days 1 and 2
Vincristine 0.05 mg/kg Days 0, 7, and 14
Regimen b Carboplatin 10 mg/kg Days 0 and 1
Etoposide 2.5 mg/kg Days 0 to 4
Ifosfamide 60 mg/kg Days 0 to 4
Vincristine 0.05 mg/kg Days 0, 7, and 14
KSPNO-S082/S1102 induction chemotherapy
Regimen A Cisplatin 3 mg/kg Day 0
Etoposide 2.5 mg/kg Days 0, 1, and 2
Cyclophosphamide 50 mg/kg Days 1 and 2
Vincristine 0.05 mg/kg Days 0 and 7
Regimen B Carboplatin 10 mg/kg Days 0 and 1
Etoposide 2.5 mg/kg Days 0 to 4
Ifosfamide 50 mg/kg Days 0 to 4
Vincristine 0.05 mg/kg Days 0 and 7
KSPNO-S052/S082/S1102 high-dose chemotherapy
First: CTE Carboplatin 500 mg/m2 Days −8 to −6
Thiotepa 300 mg/m2 Days −5 to −3
Etoposide 250 mg/m2 Days −5 to −3
Second: CM Cyclophosphamide 1,500 mg/m2 Days −8 to −5
Melphalan 60 mg/m2 Days −4 to −2
CM, cyclophosphamide and melphalan; CTE, carboplatin, thiotepa and etoposide.
Table 2 Clinical characteristics of patients
Pre-2011 (n=19) Post-2011 (n=24) Total (n=43)
Male:Female 9:10 13:11 22:21
Age at diagnosis (mo)
Median (range) 13.0 (1–31) 14.5 (0–32) 13.0 (0–32)
< 6 mo 4 (21.1) 5 (20.8) 9 (20.9)
6–12 mo 5 (26.3) 6 (25.0) 11 (25.6)
> 12 mo 10 (52.6) 13 (54.2) 23 (53.5)
Neuraxis metastasis
M0 11 (57.9) 12 (50.0) 23 (53.5)
M1 2 (10.5) 2 (8.3) 4 (9.3)
M2 5 (26.3) 9 (37.5) 14 (32.6)
Unknown 1 (5.3) 1 (4.2) 2 (4.7)
Type of resection
Gross total resection 12 (63.2) 12 (50.0) 24 (55.8)
Subtotal resection 6 (31.6) 12 (50.0) 18 (41.9)
Biopsy 1 (5.3) 0 1 (2.3)
Palliative care only after surgery 1 (5.3) 0 1 (2.3)
Values are presented as number (%) unless otherwise indicated.
Table 3 Treatment and clinical outcomes
Pre-2011 (n=18) Post-2011 (n=24) Total (n=42)
Treatment
Chemotherapy 18 (100) 24 (100) 42 (100)
RT 12 (66.7) 17 (70.8) 29 (69.0)
Early adjuvant local RT 2 (11.1) 12 (50.0) 14 (33.3)
With concurrent CSI 1 1 2
CSI at 3 years of age after completion of HDCT 0 3 3
Salvage local RT at relapse/progression 9 (50.0) 4 (16.7) 13 (31.0)
With concurrent CSI 4 1 5
CSI at 3 years of age after completion of HDCT 1 1 2
CSI at 3 year of age only 1 (5.5) 1 (4.2) 2 (4.8)
HDCT 9 (50.0) 15 (62.5) 24 (57.1)
1 HDCT 1 (5.6) 8 (33.3) 9 (21.4)
2 HDCT 8 (44.4) 7 (29.2) 15 (35.8)
Response to treatment
Continued response 3 (16.7) 12 (50.0) 15 (35.7)
Disease progression 15 (83.3) 12 (50.0) 27 (64.3)
After initial surgery 1 2 3
During induction chemotherapy 9 5 14
During RT 0 1 1
During HDCT 0 2 2
After completion of HDCT 5 2 7
Final outcome
Alive without disease 4 (22.2) 11 (45.8) 15 (35.7)
Alive with disease 0 0 0
Death due to disease progression 11 (61.1) 10 (41.7) 21 (50.0)
Treatment-related death 2 (11.1) 3 (12.5) 5 (11.9)
Death due to unknown cause 1 (5.6) 0 1 (2.4)
Values are presented as number (%). CSI, craniospinal irradiation; HDCT, high-dose chemotherapy; RT, radiotherapy.
Table 4 Univariate and multivariate analysis of the probability of progression-free survival
Univariate Multivariatea)
HR (95% CI) p-value HR (95% CI) p-value
Years of diagnosis
Pre-2011 1 0.04 1 0.57
Post-2011 0.47 (0.23–0.96) 0.81 (0.44–1.62)
Patient age (yr)
< 1 1 0.53
≥ 1 0.79 (0.39–1.59)
Metastases
Yes 1 0.03 1 0.53
No 0.46 (0.23–0.90) 0.85 (0.43–1.59)
Extent of resection
GTR 1 0.29
No GTR 1.23 (0.56–2.27)
Early adjuvant RT
Yes 1 < 0.01 1 < 0.01
No 5.68 (2.14–15.12) 6.42 (2.29–17.90)
HDCT
Yes 1 < 0.01 1 < 0.01
No 10.26 (3.81–27.66) 12.0 (3.91–37.28)
CI, confidence interval; GTR, gross total resection; HDCT, high-dose chemotherapy; HR, hazard ratio; RT, radiotherapy.
a) Includes variables significant at p < 0.1 (overall) in univariate analysis.
Ethical Statement
Ethics approval and consent to participation: All participating centers received Institutional Review Board approval to contribute data for this study (NCC 2018-0210). This study was performed in accordance with the Declaration of Helsinki.
Author Contributions
Conceived and designed the analysis: Park M, Han JW, Park HJ.
Collected the data: Park M, Han JW, Hahn SM, Lee JA, Kim JY, Shin SH, Kim DS, Yoon HI, Hong KT, Choi JY, Kang HJ, Shin HY, Phi JH, Kim SK, Lee JW, Yoo KH, Sung KW, Koo HH, Lim DH, Shin HJ, Kim H, Koh KN, Im HJ, Ahn SD, Ra YS, Baek HJ, Kook H, Jung TY, Choi HS, Kim CY, Park HJ, Lyu CJ.
Contributed data or analysis tools: Park M.
Performed the analysis: Park M.
Wrote the paper: Park M.
Review the paper: Lyu CJ, Park HJ.
Conflicts of Interest
Conflicts of interest relevant to this article was not reported.
|
Intrathecal
|
DrugAdministrationRoute
|
CC BY-NC
|
33138347
| 19,651,900
|
2021-04
|
What was the administration route of drug 'METHOTREXATE SODIUM'?
|
Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children under the Age of 3 Years.
OBJECTIVE
Atypical teratoid/rhabdoid tumor (ATRT) is a highly aggressive malignancy with peak incidence in children aged less than 3 years. Standard treatment for central nervous system ATRT in children under the age of 3 years have not been established yet. The objective of this study was to analyze characteristics and clinical outcomes of ATRT in children aged less than 3 years.
A search of medical records from seven centers was performed between January 2005 and December 2016.
RESULTS
Forty-three patients were enrolled. With a median follow-up of 90 months, 27 patients (64.3%) showed at least one episode of disease progression (PD). The first date of PD was at 160 days after diagnosis. The 1- and 3-year progression-free survivals (PFS) were 51.2% and 28.5%, respectively. The 1- and 3-year overall survivals were 61.9% and 38.1%, respectively. The 3-year PFS was improved from 0% in pre-2011 to 47.4% in post-2011. Excluding one patient who did not receive any further therapy after surgery, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown cause (n=1). In univariate analysis, factors associated with higher 3-year PFS were no metastases, diagnosis after 2011, early adjuvant radiotherapy, and high-dose chemotherapy (HDCT). In multivariate analysis, the use of HDCT and adjuvant radiotherapy remained significant prognostic factors for PFS (both p < 0.01).
CONCLUSIONS
Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years.
Introduction
Atypical teratoid/rhabdoid tumor (ATRT) of the central nervous system (CNS) is a highly aggressive malignancy, accounting for 1%–2% of all pediatric CNS tumors [1,2]. Among children under the age of 3 years, ATRT constitutes the most common malignant tumor of CNS (17.3%), followed by medulloblastoma (16%) [3].
Since standard therapeutic strategies for ATRT have not been established yet, treatment approaches for ATRT vary among institutions and countries. Conventional chemotherapy in addition to high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASR) is usually utilized in pati-ents under 3 years of age to substitute for or delay the use of radiotherapy (RT) in attempt to improve outcomes and minimize long-term neurocognitive impairment [4]. However, most patients with ATRT suffer rapid disease progression (PD), although treatment regimens designed for CNS neoplasms have been used [5,6]. Outcome for patients with ATRT is generally dismal, particularly in the presence of residual tumor or metastasis. ATRT is a devastating brain neoplasm with a median survival time ranging from 6 to 13 months. This is caused not only by the disease’s aggressive characteristics, but also by a lower tolerance of young patients to treatment. This is exacerbated by the hesitancy to use RT in younger patients due to risks of functional impairment of the developing brain [7]. It has been shown that aggressive therapy can prolong survival in a subset of children with CNS ATRT [1,2,8]. Some clinical trials have incorporated early administration of RT to the primary site together with intrathecal (IT) chemotherapy, resulting in improved outcomes [9,10].
In 2005, the Korean Society for Pediatric Neuro-Oncology (KSPNO) suggested the following a protocol for ATRT patients aged less than 3 years (KSPNO-S052): six cycles of conventional chemotherapy and tandem HDCT/ASR are performed initially and RT is deferred until the patient reaches 3 years of age. In 2008, a minor revision of the protocol including a dose modification of conventional chemotherapy was made (KSPNO-S082). In 2011, the protocol was revised (KSPNO-S1102) to recommended early local RT with concurrent chemotherapy within four weeks after surgery. In addition, IT chemotherapy was incorporated.
Given the rarity of this tumor and the even lower number of very young infants affected by ATRT, no detailed clinical analyses have been directed toward patients under 3 years of age. Thus, the objective of this study was to describe patients diagnosed with ATRT in this age group and determine potential specific characteristics or prognostic factors. Their therapeutic management is also suggested.
Materials and Methods
1. Data collection
Children younger than 3 years of age at diagnosis who were newly diagnosed with CNS ATRT were eligible for this study. A search of medical records from seven centers was performed to identify patients aged 3 years or less who were diagnosed between January 2005 and December 2016. In cases with multiple intracranial and extracranial rhabdoid tumors, only patients with clear descriptions of a primary tumor within the CNS were included in this analysis. All participating centers received Institutional Review Board approval to contribute data for this study.
2. Staging
Proper staging for metastases included brain and spinal magnetic resonance imaging (MRI) and cytology of the cerebrospinal fluid (CSF). Modified Chang status for metastatic stage was recorded whenever available. It was defined as follows: M0, absence of metastases; M1, presence of metastases confined to CSF; M2, presence of metastases in the brain; M3, presence of metastases in the spinal subarachnoidal space; and M4, spread outside of the CNS [11]. M+ included M1, M2, M3, M4, and any metastasis not further described.
3. Treatment
All patients underwent maximal possible surgical resection of the primary lesion to preserve neurologic function. The extent of surgical resection defined as gross total resection (GTR), subtotal resection, or biopsy was determined based on a review of postoperative MRI and the surgeon’s intraoperative assessment. Multimodal therapies including surgery, RT, chemotherapy and HDCT/ASR were performed. Treatment was mainly performed according to KSPNO recommendations. However, some physicians modified the treatment protocol depending on clinical situation. Treatment scheme of the KSPNO regimen is shown in Fig. 1. Major differences between KSPNO-S052/-S082 (pre-2011) and KSPNO-S1101 (post-2011) were the timing of RT (delayed RT pre-2011 vs. early adjuvant RT post-2011) and IT chemotherapy for patients post-2011. Detailed chemotherapy schedules are described in Table 1.
KSPNO-S052/S082 (pre-2011) suggested the following: Induction treatment was initiated within 4 weeks of surgery. Six cycles of chemotherapy using alternating CECV (cisplatin, etoposide, cyclophosphamide, and vincristine) and CEIV (carboplatin, etoposide, ifosfamide, and vincristine) regimens were administered. Additionally, tandem HDCT/ASR was performed. The first course included carboplatin, thiotepa and etoposide (CTE), and the second course included cyclophosphamide and melphalan (CM). A 12- to 16-week interval between the first and second HDCT/ASR was allowed to minimize treatment-related mortality (TRM). RT was deferred until after 3 years of age unless the tumor showed progression or relapse. For patients with M0 disease at diagnosis and for patients those without residual tumor after HDCT, RT was omitted.
KSPNO-S1102 (post-2011) suggested the following: RT was recommended to be administered within 4 weeks of surgery with concurrent chemotherapy. IT chemotherapy including cytarabine, hydrocortisone, and methotrexate (MTX) was administered on day 0 of every chemotherapy cycle. For M+ patients, weekly IT chemotherapy was administered until clearance of CSF cytology. After six cycles of alternating CECV and CEIV regimens, tandem HDCT/ASR using CTE-CM was performed. For M+ patients at diagnosis, craniospinal irradiation (CSI) was deferred at 3 years of age.
4. Response and toxicity criteria
Disease response was evaluated by MRI and CSF cytology. Evaluations were repeated every two or three chemotherapy cycles prior to the first HDCT/ASR, between the first and second HDCT/ASR, every 3 months for the first year after completion of tandem HDCT/ASR, every 4 months for the second year, and every 6 months thereafter. Disease response was categorized as follows: complete response (CR) for complete disappearance of all tumors, partial response (PR) for decrease in tumor size by more than 50%, stable disease for less than 25% change in tumor size, PD for greater than 25% increase in tumor size or the appearance of new tumors. Toxicities were graded using the National Cancer Institute’s Common Terminology Criteria ver. 4.0.
5. Statistical analysis
The cutoff point for data analyses was March 2019. For descriptive statistics, data were compared using the Fisher exact test for categorical factors and Wilcoxon Mann-Whitney U test for continuous factors. The time to progression was calculated from the date of diagnosis until the date of PD. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of PD or relapse. Overall survival (OS) was calculated from the date of initial diagnosis to the date of last follow-up or death from any cause. PFS and OS were estimated using the Kaplan-Meier method. Univariate analysis of risk factors was performed by comparing PFS and OS using the log-rank test. Multivariate logistic regression was used to examine relationships between outcomes of PFS or OS as binary dependent variables and independent variables of patient age, metastases, extent of resection, early adjuvant RT, HDCT, and years of diagnosis. p < 0.05 was considered statistically significant. All analyses were performed using IBM SPSS ver. 18.0 (SPSS Inc., Chicago, IL).
Results
1. Patient characteristics
Baseline clinical characteristics of patients are shown in Table 2. Forty-three patients were enrolled in this study. The median age at diagnosis was 13 months (range, 0 to 32 months). Twenty patients (46.5%) were younger than 1 year of age at diagnosis. One patient presented with synchronous tumors, including ATRT in brain and a rhabdoid tumor in the kidney.
Nineteen patients (44.2%) were diagnosed before 2011 (pre-2011 group) and 24 patients (55.8%) were diagnosed after 2011 (post-2011 group). There was no significant difference in age at diagnosis (p=0.55), sex (p=0.43), extent of resection (p=0.15), or metastases (p=0.46) between pre-2011 and post-2011 groups. There were 23 (53.5%) patients with M0 disease, four (9.3%) with M1 disease, 14 (32.6%) with M2 disease, and two (4.7%) with unknown metastatic status. The incidence of metastatic disease was significantly higher in patients under 6 months of age than that in patients older than 6 months (100.0% vs. 35.3%, p < 0.01). GTR of the primary tumor was achieved in 24 patients (55.8%).
2. Treatment
One patient did not receive any further therapy after surgery. All remaining 42 patients received induction chemotherapy at a median of 20 days after surgery (range, 5 to 142 days). The median number of pretransplant chemotherapy cycles was 6 (range, 1 to 12). All patients in the post-2011 group received IT therapies. Nine patients (21.4%) received a second surgery before HDCT due to PD (n=8) or for removing residual tumor (n=1).
Twenty-nine patients (69.0%) received radiation at a median age of 23 months (range, 6 to 40 months). The median interval between diagnosis and RT was 162 days (range, 21 to 745 days). Thirteen patients (31.0%) did not receive RT due to early progression (n=8), treatment-related death (n=3), or physician’s discretion (n=2). As of 2011, RT timing changed from delayed RT (pre-2011) to early adjuvant RT (post-2011). As a result, the median period between diagnosis and RT was significantly shortened from 314.9 days in the pre-2011 group to 159.0 days in the post-2011 group (p=0.04). The period between diagnosis to RT was 114.6±104.8 days in patients who received early adjuvant RT and 313.4±231.2 days in patients who received RT as salvage therapy (p < 0.01).Among 29 patients who received RT, early adjuvant RT was administered in 14 patients (2 in the pre-2011 group and 12 in the post-2011 group) (Table 3). They received local RT at a dose of 36–63 Gy after surgery. Of them, five patients received additional CSI at a dose of 23.4–30.6 Gy concurrently (n=2) or at 3 years of age (n=3) due to M+ disease at diagnosis. Thirteen patients received local RT as salvage therapy at a dose of 25.2–55.8 Gy. Of them, five patients received CSI at a dose of 19.5–23.4 Gy. Two patients received CSI at 3 years of age after completion of HDCT as scheduled.
Twenty-four patients received HDCT/ASR (15 patients received tandem HDCTs and nine patients received only 1 HDCT). Reasons not having second HDCT included physician’s discretion (n=4), PD or relapse (n=3), prolonged bone marrow suppression (n=1), and patient refusal (n=1). During the first HDCT, eight patients received conditioning regimen including topotecan, thiotepa, and carboplatin instead of CTE. During the second HDCT, two patients received conditioning regimen including busulfan, melphalan, and thiotepa instead of CM.
Significantly more patients who received early adjuvant RT proceeded to HDCT compared to patients who did not (78.6% vs. 46.4%, p=0.04). For patients not receiving HDCT (n=18), reasons included PD or relapse (n=12), treatment-related death (n=4), patient refusal (n=1), and death due to unknown cause (n=1). The median age at the time of the first HDCT was 21.0 months (range, 9.1 to 44.5 months). The median time between diagnosis and the first HDCT was 7.5 months (range, 5.3 to 16.1 months). Disease status before the first HDCT was CR in 16 and PR in eight. Among 15 patients who underwent a second HDCT, disease status before the second HDCT was CR in 10, PR in four, and PD in one. The median interval between the first and second HDCT was 91 days (range, 35 to 126 days).
3. Clinical course and survival
Excluding one patient who received palliative care only, data for 42 patients were analyzed (Table 3). With a median follow-up of 90 months (range, 27 to 172 months), 27 patients (64.3%) showed at least one episode of PD. The first date of PD was at 160 days (median; range, 13 to 585) after the diagnosis. Twenty-one of 27 patients who showed PD died due to PD at a median of 4 months (range, 0.1 to 5.4 months) from the first day of documentation of PD. Immediate salvage therapy consisted of surgery in 11, chemotherapy in four, RT in four, gamma knife surgery in one, and supportive care only in seven. PD was found within 2 months of resection surgery before initiation of chemotherapy in three, during chemotherapy in 14, during adjuvant RT in one, during HDCT in two, and after completion of HDCT in seven. Among 14 patients with PD found during induction chemotherapy, 13 did not receive adjuvant RT previously while one patient had received RT previously (p < 0.01). Of nine patients who experienced relapse during or after HDCT, seven patients died due to PD. Two patients are still alive without disease. The median time between HDCT and subsequent relapse was 3 months (range, 1 to 11 months).
The 1- and 3-year PFS is 51.2% and 28.5%, respectively. The 1- and 3-year OS is 61.9% and 38.1%, respectively (Fig. 2). Of 42 patients analyzed, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown causes (n=1).
At the last follow-up, 15 patients were alive. All surviving patients received HDCT/ASR. Patients who achieved CR before the first HDCT showed significantly higher 3-year OS compared to patients who did not (81.3% vs. 37.5%, p < 0.01). There was no significant difference in PFS or OS between patients who underwent 1 HDCT and those who underwent 2 HDCTs.
4. Risk factors
Results of univariate and multivariate analyses for PFS are shown in Table 4. In univariate analysis, factors associated with higher 3-year PFS were no metastases (p=0.03), diagnosis after 2011 (p=0.04), early adjuvant RT (p < 0.01) and HDCT/ASR (p < 0.01) (Fig. 3). Age at diagnosis (p=0.53) and extent of resection (p=0.29) failed to influence survival rate in our study. Among 14 patients who received adjuvant RT, only three patients showed PD during (n=1) or after (n=2) the planned RT, while 24 of 28 patients who did not receive adjuvant RT showed PD (p < 0.01). Among 18 patients with metastases, patients who received early adjuvant local RT showed significantly higher PFS and OS compared to those who did not (3-year PFS: 75.0% vs. 0%, p=0.04; 3-year OS: 75.0% vs. 14.3%, p=0.03).
In multivariate analyses, the use of HDCT/ASR and early adjuvant RT remained significant prognostic factors for PFS (both p < 0.01). For OS, the use of HDCT/ASR was the only significant prognostic factor (p < 0.01). Among patients who received both early adjuvant RT and HDCT/ASR, 3-year PFS and OS were 81.8% and 90.9%, respectively.
5. Toxicity
During chemotherapy, the most frequently reported significant toxicities were bone marrow suppression and febrile neutropenia followed by infection, gastrointestinal disturbances, electrolyte disturbances, and hepatic disturbances. During HDCT, infection was the most common toxicity. Bacteremia was detected during six of 39 HDCT (3 Staphylococcus epidermidis, 2 Pseudomonas aeruginosa, and 1 Bacillus species), five of which occurred during the second HDCT course. One patient experienced sinusoidal obstruction syndrome during their second HDCT. There were five toxic deaths due to sepsis: four occurred under chemotherapy and one occurred following the second HDCT. To date, second malignancies have not been reported.
Discussion
This is the most recent update of Korean ATRT patients under 3 years of age. Tumors progressed or relapsed in 27 of 42 patients at a median of 160 days from diagnosis in our study. The 3-year PFS and OS were 28.5% and 38.1%, respectively. The 3-year PFS was improved from 0.0% in pre-2011 to 47.4% in post-2011. At diagnosis, metastasis was the only characteristic among several disease characteristics known to affect survival.
Our analysis highlights several points of interest for this young age group. First, our data suggest the importance of early adjuvant RT. We found a survival benefit associated with early adjuvant RT. Traditionally, RT has been deferred or omitted because of the risk of adverse effects, especially for patients under 3 years of age [12]. However, more recent data suggest that RT might be more efficacious than chemotherapy for ATRT patients, even for very young children [2,13,14]. In a previously reported Korean study that included patients treated with tandem HDCT/ASR, all surviving patients received RT at an early stage in their treatment [15]. No patients who received induction chemotherapy and HDCT/ASR without RT survived. This suggests that HDCT/ASR cannot replace RT for local control. Similarly, we found that patients who received early adjuvant RT showed a significantly lower chance of having PD during induction chemotherapy and a higher chance to proceed to HDCT compared to patients who did not, thus leading to improved survival. For patients with M+ disease at diagnosis, adjuvant local radiation significantly improved survival in the current study. Overall, local RT should be considered earlier in therapy to improve survival.
Secondly, our data suggest that HDCT is associated with better survival. For patients who received HDCT, PFS and OS were significantly higher compared to those who did not. There has been no randomized study to evaluate the efficacy of HDCT/ASR in ATRT patients under 3 years of age. A few studies have suggested that HDCT might have a favorable effect on ATRT patients [14,16]. A recent Canadian study has reported better 5-year PFS in patients with ATRT under 1 year of age receiving HDCT group compared to those without receiving HDCT (50.1% vs. 11.3%, p < 0.001) [17]. However, due to small numbers of patients included and various treatment modalities used, no firm conclusions can be made regarding the role of HDCT/ASR in ATRT patients. In this study, all surviving patients received HDCT/ASR. However, this does not reflect the definite efficacy of HDCT/ASR. Considering that patients who achieved CR before their first HDCT showed significantly higher OS than those who did not, multimodal treatment that might lead to CR and additional HDCT might result in better outcomes. In this study, patients who achieved CR before the first HDCT showed significantly higher OS. This suggests that pre-HDCT tumor status is important for predicting outcome. Thus, careful consideration is required when selecting candidate patients for HDCT/ASR.
Importantly, we should consider the likelihood of selection bias toward “favorable cases” in patients subjected to HDCT, which could be associated with molecular distinction. Recently, Reddy et al. [18] have reported that patients with group 1/SHH-NOTCH tumors have less aggressive feature. Biological investigation of ATRT should be continued and subsets of patients who can be cured with less therapy may exist [19].
The optimal combination of regimens for tandem HDCT has not been determined. Rosenfeld et al. [12] have reported the feasibility of tandem HDCT/ASR in patients with brain tumors using CTE-CM. Although they concluded that the CTE-CM regimen was not feasible due to toxicity, tandem CTE-CM HDCT/ASR was feasible in our study. Toxicities in our present study were manageable and only one toxic death associated with HDCT occurred. This could be due to the fact that patients were given a sufficient rest period between the first and the second HDCT/ASR. Sung et al. [20] have reported that a shorter interval (< 12 weeks) between the first and second HDCT/ASR is associated with higher TRM. Another thing to be noted was that there was no significant survival difference between patients who received 1 HDCT and those who received 2 HDCTs. In addition, bacteremia occurred more frequently in the second HDCT than in the first HDCT. Randomized trials with larger cohorts are needed to determine whether the possible survival benefit of tandem HDCT/ASR over single HDCT/ASR might ultimately outweigh adverse effects associated with dose intensive tandem HDCT/ASR.
Thirdly, optimal induction chemotherapy should be explored. Efficacies of many different treatments have been explored. However, there is no consensus regarding standard chemotherapy for ATRT. Due to the desire to avoid unacceptable adverse effects of RT on the developing brain, many institutions adopt chemotherapy-based strategies designed to avoid or delay RT. Despite often impressive responses to chemotherapy, the majority of patients in many published studies developed progressive disease early, suggesting a rapid development of resistance of ATRTs [10,21,22]. Similarly, in our study, PD occurred during induction chemotherapy in about half of cases. Considering that the most common reason not having HDCT/ASR was PD during induction chemotherapy, we could consider shorten the current six cycles of induction chemotherapy. Furthermore, patients who received induction chemotherapy without early adjuvant RT showed significantly lower survival compared to patients who received early adjuvant RT. This suggests that CECV and CEIV chemotherapy regimen used in our patients might be insufficient to prevent tumor progression/relapse. Recently, ACNS0333 comprised with three cycles of chemotherapy which incorporated high dose MTX showed promising result, with 4-year OS of 43% [18]. High-dose MTX used in “Head Start II” also appears to be efficacious and well tolerated in ATRT [8]. Slavc et al. [23] have also demonstrated the efficacy of high-dose MTX in ATRT patients. Besides intensification using cytotoxic agent, there are increasing data suggesting that ATRT might be a good candidate for pathway-specific targeted therapies, some of which are currently used in clinical trials, including AURKA, EZH2, and CDK4/6 inhibitors [24,25]. Optimwal combination of cytotoxic agents and targeted inhibitors should be explored to prevent early progression of ATRT.
Lastly, we found that the post-2011 group had significantly better PFS than the pre-2011 group. The major difference between pre- and post-2011 protocols was adjuvant local radiation and IT chemotherapy in the post-2011 protocol. There was no difference in induction chemotherapy or HDCT between pre- and post-2011 protocols. We believe that the post-2011 protocol with a combination of adjuvant RT and IT chemotherapy might have prevented early progression, eventually improving the outcome as reported by Chi et al. [10]. The role of adjuvant RT has already been described above. IT therapy was incorporated as a method of providing prophylaxis and/or treatment to the CNS axis in the post-2011 protocol. Whether IT therapy could substitute for cranial irradiation for CNS treatment and/or prophylaxis was unclear because both modalities were used in the post-2011 protocol. Considering that the year of diagnosis (pre- vs. post-2011) was not a significant predictor of survival in multivariate analyses, IT therapy might not have a beneficial role in improving survival. However, in many studies, IT chemotherapy has shown potential benefit as an addition to local RT or to intensify therapy in patients who are not candidates for CSI [10,26]. IT chemotherapy shows good penetrance into the CSF. Thus, it might be efficacious in eradicating ATRT cells in CSF, allowing postponement of CSI for patients who receive focal irradiation only. A meta-analysis by Athale et al. [26] has shown that IT therapy leads to a significantly higher OS. A more detailed randomized study I needed to evaluate IT therapy in infant ATRT to define role of IT therapy in these patients.
This study has some limitations. First, this study had a non-randomized and retrospective design. Second, we did not collect data for germline mutations in SMARCB1/INI1. Therefore, we could not assess the association between germline status and outcome. No molecular profiling was included, which could be potential prognostic indicators. Third, because current multimodality treatment strategies for ATRT include brain RT, limited data on neurocognitive outcomes of survivors raise a significant concern [27]. Although data stress the importance for RT in younger age group, this treatment option comes at a cost of serious long-term sequelae such as cognitive, motor, visual, and hearing impairment [28,29]. In addition, combining multimodal treatment deserves attention. Comprehensive long-term follow-up neuropsychologic assessments are planned for our surviving cohort. Lastly, as described above, a more detailed analysis is needed in the future to identify the role of IT therapy in the prevention and treatment of metastases.
In summary, aggressive therapy including early administration of local RT and HDCT/ASR, which was adopted in KSPNO-S1102, should be considered to improve outcomes of ATRT in children below the age of 3 years. Despite the high probability of early PD in ATRT, for patients who received both early adjuvant RT and HDCT/ASR, OS exceeded 90%. Further clinical trials may be required to determine optimal adjuvant treatments such as RT field and intensity of HDCT/ASR and the role of IT chemotherapy for patients with ATRT. Future studies regarding molecular characterization of ATRT and its prognostic implication might change current treatment strategies and delineate the group of patients so that treatment intensity could be reduced.
Acknowledgments
This study was supported by the KPHOG Research Grant 2018.
Fig. 1 Treatment recommendations by the Korean Society for Pediatric Neuro-Oncology for CNS ATRT during periods of 2005–2007 (A), 2008–2010 (B), and 2011-present (C). ASR, autologous stem cell rescue; CR, complete response; CSI, craniospinal irradiation; HDCT, high-dose chemotherapy; IT, intrathecal; RT, radiotherapy. a)R0 (< 1.5 cm2)/M0, local RT 41.4 Gy; R+ (> 1.5 cm2)/M0, local RT 55.8 Gy; Rx/M+, local RT 36 Gy+CSI 19.8 Gy at 3 years of age, b)M0, day 0 of each cycle/M+, weekly until clearing (at least 6 times), then day 0 each cycle.
Fig. 2 Kaplan-Meier estimates of progression-free survival (A) and overall survival (B).
Fig. 3 Progression-free survival according to metastases (A), year of diagnosis (B), early adjuvant radiation (C), and high-dose chemotherapy (D).
Table 1 Chemotherapy regimens
Regimen Drug Dose Schedule
KSPNO-S052 induction chemotherapy
Regimen a Cisplatin 3.5 mg/kg Day 0
Etoposide 2.5 mg/kg Days 0, 1, and 2
Cyclophosphamide 60 mg/kg Days 1 and 2
Vincristine 0.05 mg/kg Days 0, 7, and 14
Regimen b Carboplatin 10 mg/kg Days 0 and 1
Etoposide 2.5 mg/kg Days 0 to 4
Ifosfamide 60 mg/kg Days 0 to 4
Vincristine 0.05 mg/kg Days 0, 7, and 14
KSPNO-S082/S1102 induction chemotherapy
Regimen A Cisplatin 3 mg/kg Day 0
Etoposide 2.5 mg/kg Days 0, 1, and 2
Cyclophosphamide 50 mg/kg Days 1 and 2
Vincristine 0.05 mg/kg Days 0 and 7
Regimen B Carboplatin 10 mg/kg Days 0 and 1
Etoposide 2.5 mg/kg Days 0 to 4
Ifosfamide 50 mg/kg Days 0 to 4
Vincristine 0.05 mg/kg Days 0 and 7
KSPNO-S052/S082/S1102 high-dose chemotherapy
First: CTE Carboplatin 500 mg/m2 Days −8 to −6
Thiotepa 300 mg/m2 Days −5 to −3
Etoposide 250 mg/m2 Days −5 to −3
Second: CM Cyclophosphamide 1,500 mg/m2 Days −8 to −5
Melphalan 60 mg/m2 Days −4 to −2
CM, cyclophosphamide and melphalan; CTE, carboplatin, thiotepa and etoposide.
Table 2 Clinical characteristics of patients
Pre-2011 (n=19) Post-2011 (n=24) Total (n=43)
Male:Female 9:10 13:11 22:21
Age at diagnosis (mo)
Median (range) 13.0 (1–31) 14.5 (0–32) 13.0 (0–32)
< 6 mo 4 (21.1) 5 (20.8) 9 (20.9)
6–12 mo 5 (26.3) 6 (25.0) 11 (25.6)
> 12 mo 10 (52.6) 13 (54.2) 23 (53.5)
Neuraxis metastasis
M0 11 (57.9) 12 (50.0) 23 (53.5)
M1 2 (10.5) 2 (8.3) 4 (9.3)
M2 5 (26.3) 9 (37.5) 14 (32.6)
Unknown 1 (5.3) 1 (4.2) 2 (4.7)
Type of resection
Gross total resection 12 (63.2) 12 (50.0) 24 (55.8)
Subtotal resection 6 (31.6) 12 (50.0) 18 (41.9)
Biopsy 1 (5.3) 0 1 (2.3)
Palliative care only after surgery 1 (5.3) 0 1 (2.3)
Values are presented as number (%) unless otherwise indicated.
Table 3 Treatment and clinical outcomes
Pre-2011 (n=18) Post-2011 (n=24) Total (n=42)
Treatment
Chemotherapy 18 (100) 24 (100) 42 (100)
RT 12 (66.7) 17 (70.8) 29 (69.0)
Early adjuvant local RT 2 (11.1) 12 (50.0) 14 (33.3)
With concurrent CSI 1 1 2
CSI at 3 years of age after completion of HDCT 0 3 3
Salvage local RT at relapse/progression 9 (50.0) 4 (16.7) 13 (31.0)
With concurrent CSI 4 1 5
CSI at 3 years of age after completion of HDCT 1 1 2
CSI at 3 year of age only 1 (5.5) 1 (4.2) 2 (4.8)
HDCT 9 (50.0) 15 (62.5) 24 (57.1)
1 HDCT 1 (5.6) 8 (33.3) 9 (21.4)
2 HDCT 8 (44.4) 7 (29.2) 15 (35.8)
Response to treatment
Continued response 3 (16.7) 12 (50.0) 15 (35.7)
Disease progression 15 (83.3) 12 (50.0) 27 (64.3)
After initial surgery 1 2 3
During induction chemotherapy 9 5 14
During RT 0 1 1
During HDCT 0 2 2
After completion of HDCT 5 2 7
Final outcome
Alive without disease 4 (22.2) 11 (45.8) 15 (35.7)
Alive with disease 0 0 0
Death due to disease progression 11 (61.1) 10 (41.7) 21 (50.0)
Treatment-related death 2 (11.1) 3 (12.5) 5 (11.9)
Death due to unknown cause 1 (5.6) 0 1 (2.4)
Values are presented as number (%). CSI, craniospinal irradiation; HDCT, high-dose chemotherapy; RT, radiotherapy.
Table 4 Univariate and multivariate analysis of the probability of progression-free survival
Univariate Multivariatea)
HR (95% CI) p-value HR (95% CI) p-value
Years of diagnosis
Pre-2011 1 0.04 1 0.57
Post-2011 0.47 (0.23–0.96) 0.81 (0.44–1.62)
Patient age (yr)
< 1 1 0.53
≥ 1 0.79 (0.39–1.59)
Metastases
Yes 1 0.03 1 0.53
No 0.46 (0.23–0.90) 0.85 (0.43–1.59)
Extent of resection
GTR 1 0.29
No GTR 1.23 (0.56–2.27)
Early adjuvant RT
Yes 1 < 0.01 1 < 0.01
No 5.68 (2.14–15.12) 6.42 (2.29–17.90)
HDCT
Yes 1 < 0.01 1 < 0.01
No 10.26 (3.81–27.66) 12.0 (3.91–37.28)
CI, confidence interval; GTR, gross total resection; HDCT, high-dose chemotherapy; HR, hazard ratio; RT, radiotherapy.
a) Includes variables significant at p < 0.1 (overall) in univariate analysis.
Ethical Statement
Ethics approval and consent to participation: All participating centers received Institutional Review Board approval to contribute data for this study (NCC 2018-0210). This study was performed in accordance with the Declaration of Helsinki.
Author Contributions
Conceived and designed the analysis: Park M, Han JW, Park HJ.
Collected the data: Park M, Han JW, Hahn SM, Lee JA, Kim JY, Shin SH, Kim DS, Yoon HI, Hong KT, Choi JY, Kang HJ, Shin HY, Phi JH, Kim SK, Lee JW, Yoo KH, Sung KW, Koo HH, Lim DH, Shin HJ, Kim H, Koh KN, Im HJ, Ahn SD, Ra YS, Baek HJ, Kook H, Jung TY, Choi HS, Kim CY, Park HJ, Lyu CJ.
Contributed data or analysis tools: Park M.
Performed the analysis: Park M.
Wrote the paper: Park M.
Review the paper: Lyu CJ, Park HJ.
Conflicts of Interest
Conflicts of interest relevant to this article was not reported.
|
Intrathecal
|
DrugAdministrationRoute
|
CC BY-NC
|
33138347
| 19,651,900
|
2021-04
|
What was the dosage of drug 'HYDROCORTISONE'?
|
Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children under the Age of 3 Years.
OBJECTIVE
Atypical teratoid/rhabdoid tumor (ATRT) is a highly aggressive malignancy with peak incidence in children aged less than 3 years. Standard treatment for central nervous system ATRT in children under the age of 3 years have not been established yet. The objective of this study was to analyze characteristics and clinical outcomes of ATRT in children aged less than 3 years.
A search of medical records from seven centers was performed between January 2005 and December 2016.
RESULTS
Forty-three patients were enrolled. With a median follow-up of 90 months, 27 patients (64.3%) showed at least one episode of disease progression (PD). The first date of PD was at 160 days after diagnosis. The 1- and 3-year progression-free survivals (PFS) were 51.2% and 28.5%, respectively. The 1- and 3-year overall survivals were 61.9% and 38.1%, respectively. The 3-year PFS was improved from 0% in pre-2011 to 47.4% in post-2011. Excluding one patient who did not receive any further therapy after surgery, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown cause (n=1). In univariate analysis, factors associated with higher 3-year PFS were no metastases, diagnosis after 2011, early adjuvant radiotherapy, and high-dose chemotherapy (HDCT). In multivariate analysis, the use of HDCT and adjuvant radiotherapy remained significant prognostic factors for PFS (both p < 0.01).
CONCLUSIONS
Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years.
Introduction
Atypical teratoid/rhabdoid tumor (ATRT) of the central nervous system (CNS) is a highly aggressive malignancy, accounting for 1%–2% of all pediatric CNS tumors [1,2]. Among children under the age of 3 years, ATRT constitutes the most common malignant tumor of CNS (17.3%), followed by medulloblastoma (16%) [3].
Since standard therapeutic strategies for ATRT have not been established yet, treatment approaches for ATRT vary among institutions and countries. Conventional chemotherapy in addition to high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASR) is usually utilized in pati-ents under 3 years of age to substitute for or delay the use of radiotherapy (RT) in attempt to improve outcomes and minimize long-term neurocognitive impairment [4]. However, most patients with ATRT suffer rapid disease progression (PD), although treatment regimens designed for CNS neoplasms have been used [5,6]. Outcome for patients with ATRT is generally dismal, particularly in the presence of residual tumor or metastasis. ATRT is a devastating brain neoplasm with a median survival time ranging from 6 to 13 months. This is caused not only by the disease’s aggressive characteristics, but also by a lower tolerance of young patients to treatment. This is exacerbated by the hesitancy to use RT in younger patients due to risks of functional impairment of the developing brain [7]. It has been shown that aggressive therapy can prolong survival in a subset of children with CNS ATRT [1,2,8]. Some clinical trials have incorporated early administration of RT to the primary site together with intrathecal (IT) chemotherapy, resulting in improved outcomes [9,10].
In 2005, the Korean Society for Pediatric Neuro-Oncology (KSPNO) suggested the following a protocol for ATRT patients aged less than 3 years (KSPNO-S052): six cycles of conventional chemotherapy and tandem HDCT/ASR are performed initially and RT is deferred until the patient reaches 3 years of age. In 2008, a minor revision of the protocol including a dose modification of conventional chemotherapy was made (KSPNO-S082). In 2011, the protocol was revised (KSPNO-S1102) to recommended early local RT with concurrent chemotherapy within four weeks after surgery. In addition, IT chemotherapy was incorporated.
Given the rarity of this tumor and the even lower number of very young infants affected by ATRT, no detailed clinical analyses have been directed toward patients under 3 years of age. Thus, the objective of this study was to describe patients diagnosed with ATRT in this age group and determine potential specific characteristics or prognostic factors. Their therapeutic management is also suggested.
Materials and Methods
1. Data collection
Children younger than 3 years of age at diagnosis who were newly diagnosed with CNS ATRT were eligible for this study. A search of medical records from seven centers was performed to identify patients aged 3 years or less who were diagnosed between January 2005 and December 2016. In cases with multiple intracranial and extracranial rhabdoid tumors, only patients with clear descriptions of a primary tumor within the CNS were included in this analysis. All participating centers received Institutional Review Board approval to contribute data for this study.
2. Staging
Proper staging for metastases included brain and spinal magnetic resonance imaging (MRI) and cytology of the cerebrospinal fluid (CSF). Modified Chang status for metastatic stage was recorded whenever available. It was defined as follows: M0, absence of metastases; M1, presence of metastases confined to CSF; M2, presence of metastases in the brain; M3, presence of metastases in the spinal subarachnoidal space; and M4, spread outside of the CNS [11]. M+ included M1, M2, M3, M4, and any metastasis not further described.
3. Treatment
All patients underwent maximal possible surgical resection of the primary lesion to preserve neurologic function. The extent of surgical resection defined as gross total resection (GTR), subtotal resection, or biopsy was determined based on a review of postoperative MRI and the surgeon’s intraoperative assessment. Multimodal therapies including surgery, RT, chemotherapy and HDCT/ASR were performed. Treatment was mainly performed according to KSPNO recommendations. However, some physicians modified the treatment protocol depending on clinical situation. Treatment scheme of the KSPNO regimen is shown in Fig. 1. Major differences between KSPNO-S052/-S082 (pre-2011) and KSPNO-S1101 (post-2011) were the timing of RT (delayed RT pre-2011 vs. early adjuvant RT post-2011) and IT chemotherapy for patients post-2011. Detailed chemotherapy schedules are described in Table 1.
KSPNO-S052/S082 (pre-2011) suggested the following: Induction treatment was initiated within 4 weeks of surgery. Six cycles of chemotherapy using alternating CECV (cisplatin, etoposide, cyclophosphamide, and vincristine) and CEIV (carboplatin, etoposide, ifosfamide, and vincristine) regimens were administered. Additionally, tandem HDCT/ASR was performed. The first course included carboplatin, thiotepa and etoposide (CTE), and the second course included cyclophosphamide and melphalan (CM). A 12- to 16-week interval between the first and second HDCT/ASR was allowed to minimize treatment-related mortality (TRM). RT was deferred until after 3 years of age unless the tumor showed progression or relapse. For patients with M0 disease at diagnosis and for patients those without residual tumor after HDCT, RT was omitted.
KSPNO-S1102 (post-2011) suggested the following: RT was recommended to be administered within 4 weeks of surgery with concurrent chemotherapy. IT chemotherapy including cytarabine, hydrocortisone, and methotrexate (MTX) was administered on day 0 of every chemotherapy cycle. For M+ patients, weekly IT chemotherapy was administered until clearance of CSF cytology. After six cycles of alternating CECV and CEIV regimens, tandem HDCT/ASR using CTE-CM was performed. For M+ patients at diagnosis, craniospinal irradiation (CSI) was deferred at 3 years of age.
4. Response and toxicity criteria
Disease response was evaluated by MRI and CSF cytology. Evaluations were repeated every two or three chemotherapy cycles prior to the first HDCT/ASR, between the first and second HDCT/ASR, every 3 months for the first year after completion of tandem HDCT/ASR, every 4 months for the second year, and every 6 months thereafter. Disease response was categorized as follows: complete response (CR) for complete disappearance of all tumors, partial response (PR) for decrease in tumor size by more than 50%, stable disease for less than 25% change in tumor size, PD for greater than 25% increase in tumor size or the appearance of new tumors. Toxicities were graded using the National Cancer Institute’s Common Terminology Criteria ver. 4.0.
5. Statistical analysis
The cutoff point for data analyses was March 2019. For descriptive statistics, data were compared using the Fisher exact test for categorical factors and Wilcoxon Mann-Whitney U test for continuous factors. The time to progression was calculated from the date of diagnosis until the date of PD. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of PD or relapse. Overall survival (OS) was calculated from the date of initial diagnosis to the date of last follow-up or death from any cause. PFS and OS were estimated using the Kaplan-Meier method. Univariate analysis of risk factors was performed by comparing PFS and OS using the log-rank test. Multivariate logistic regression was used to examine relationships between outcomes of PFS or OS as binary dependent variables and independent variables of patient age, metastases, extent of resection, early adjuvant RT, HDCT, and years of diagnosis. p < 0.05 was considered statistically significant. All analyses were performed using IBM SPSS ver. 18.0 (SPSS Inc., Chicago, IL).
Results
1. Patient characteristics
Baseline clinical characteristics of patients are shown in Table 2. Forty-three patients were enrolled in this study. The median age at diagnosis was 13 months (range, 0 to 32 months). Twenty patients (46.5%) were younger than 1 year of age at diagnosis. One patient presented with synchronous tumors, including ATRT in brain and a rhabdoid tumor in the kidney.
Nineteen patients (44.2%) were diagnosed before 2011 (pre-2011 group) and 24 patients (55.8%) were diagnosed after 2011 (post-2011 group). There was no significant difference in age at diagnosis (p=0.55), sex (p=0.43), extent of resection (p=0.15), or metastases (p=0.46) between pre-2011 and post-2011 groups. There were 23 (53.5%) patients with M0 disease, four (9.3%) with M1 disease, 14 (32.6%) with M2 disease, and two (4.7%) with unknown metastatic status. The incidence of metastatic disease was significantly higher in patients under 6 months of age than that in patients older than 6 months (100.0% vs. 35.3%, p < 0.01). GTR of the primary tumor was achieved in 24 patients (55.8%).
2. Treatment
One patient did not receive any further therapy after surgery. All remaining 42 patients received induction chemotherapy at a median of 20 days after surgery (range, 5 to 142 days). The median number of pretransplant chemotherapy cycles was 6 (range, 1 to 12). All patients in the post-2011 group received IT therapies. Nine patients (21.4%) received a second surgery before HDCT due to PD (n=8) or for removing residual tumor (n=1).
Twenty-nine patients (69.0%) received radiation at a median age of 23 months (range, 6 to 40 months). The median interval between diagnosis and RT was 162 days (range, 21 to 745 days). Thirteen patients (31.0%) did not receive RT due to early progression (n=8), treatment-related death (n=3), or physician’s discretion (n=2). As of 2011, RT timing changed from delayed RT (pre-2011) to early adjuvant RT (post-2011). As a result, the median period between diagnosis and RT was significantly shortened from 314.9 days in the pre-2011 group to 159.0 days in the post-2011 group (p=0.04). The period between diagnosis to RT was 114.6±104.8 days in patients who received early adjuvant RT and 313.4±231.2 days in patients who received RT as salvage therapy (p < 0.01).Among 29 patients who received RT, early adjuvant RT was administered in 14 patients (2 in the pre-2011 group and 12 in the post-2011 group) (Table 3). They received local RT at a dose of 36–63 Gy after surgery. Of them, five patients received additional CSI at a dose of 23.4–30.6 Gy concurrently (n=2) or at 3 years of age (n=3) due to M+ disease at diagnosis. Thirteen patients received local RT as salvage therapy at a dose of 25.2–55.8 Gy. Of them, five patients received CSI at a dose of 19.5–23.4 Gy. Two patients received CSI at 3 years of age after completion of HDCT as scheduled.
Twenty-four patients received HDCT/ASR (15 patients received tandem HDCTs and nine patients received only 1 HDCT). Reasons not having second HDCT included physician’s discretion (n=4), PD or relapse (n=3), prolonged bone marrow suppression (n=1), and patient refusal (n=1). During the first HDCT, eight patients received conditioning regimen including topotecan, thiotepa, and carboplatin instead of CTE. During the second HDCT, two patients received conditioning regimen including busulfan, melphalan, and thiotepa instead of CM.
Significantly more patients who received early adjuvant RT proceeded to HDCT compared to patients who did not (78.6% vs. 46.4%, p=0.04). For patients not receiving HDCT (n=18), reasons included PD or relapse (n=12), treatment-related death (n=4), patient refusal (n=1), and death due to unknown cause (n=1). The median age at the time of the first HDCT was 21.0 months (range, 9.1 to 44.5 months). The median time between diagnosis and the first HDCT was 7.5 months (range, 5.3 to 16.1 months). Disease status before the first HDCT was CR in 16 and PR in eight. Among 15 patients who underwent a second HDCT, disease status before the second HDCT was CR in 10, PR in four, and PD in one. The median interval between the first and second HDCT was 91 days (range, 35 to 126 days).
3. Clinical course and survival
Excluding one patient who received palliative care only, data for 42 patients were analyzed (Table 3). With a median follow-up of 90 months (range, 27 to 172 months), 27 patients (64.3%) showed at least one episode of PD. The first date of PD was at 160 days (median; range, 13 to 585) after the diagnosis. Twenty-one of 27 patients who showed PD died due to PD at a median of 4 months (range, 0.1 to 5.4 months) from the first day of documentation of PD. Immediate salvage therapy consisted of surgery in 11, chemotherapy in four, RT in four, gamma knife surgery in one, and supportive care only in seven. PD was found within 2 months of resection surgery before initiation of chemotherapy in three, during chemotherapy in 14, during adjuvant RT in one, during HDCT in two, and after completion of HDCT in seven. Among 14 patients with PD found during induction chemotherapy, 13 did not receive adjuvant RT previously while one patient had received RT previously (p < 0.01). Of nine patients who experienced relapse during or after HDCT, seven patients died due to PD. Two patients are still alive without disease. The median time between HDCT and subsequent relapse was 3 months (range, 1 to 11 months).
The 1- and 3-year PFS is 51.2% and 28.5%, respectively. The 1- and 3-year OS is 61.9% and 38.1%, respectively (Fig. 2). Of 42 patients analyzed, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown causes (n=1).
At the last follow-up, 15 patients were alive. All surviving patients received HDCT/ASR. Patients who achieved CR before the first HDCT showed significantly higher 3-year OS compared to patients who did not (81.3% vs. 37.5%, p < 0.01). There was no significant difference in PFS or OS between patients who underwent 1 HDCT and those who underwent 2 HDCTs.
4. Risk factors
Results of univariate and multivariate analyses for PFS are shown in Table 4. In univariate analysis, factors associated with higher 3-year PFS were no metastases (p=0.03), diagnosis after 2011 (p=0.04), early adjuvant RT (p < 0.01) and HDCT/ASR (p < 0.01) (Fig. 3). Age at diagnosis (p=0.53) and extent of resection (p=0.29) failed to influence survival rate in our study. Among 14 patients who received adjuvant RT, only three patients showed PD during (n=1) or after (n=2) the planned RT, while 24 of 28 patients who did not receive adjuvant RT showed PD (p < 0.01). Among 18 patients with metastases, patients who received early adjuvant local RT showed significantly higher PFS and OS compared to those who did not (3-year PFS: 75.0% vs. 0%, p=0.04; 3-year OS: 75.0% vs. 14.3%, p=0.03).
In multivariate analyses, the use of HDCT/ASR and early adjuvant RT remained significant prognostic factors for PFS (both p < 0.01). For OS, the use of HDCT/ASR was the only significant prognostic factor (p < 0.01). Among patients who received both early adjuvant RT and HDCT/ASR, 3-year PFS and OS were 81.8% and 90.9%, respectively.
5. Toxicity
During chemotherapy, the most frequently reported significant toxicities were bone marrow suppression and febrile neutropenia followed by infection, gastrointestinal disturbances, electrolyte disturbances, and hepatic disturbances. During HDCT, infection was the most common toxicity. Bacteremia was detected during six of 39 HDCT (3 Staphylococcus epidermidis, 2 Pseudomonas aeruginosa, and 1 Bacillus species), five of which occurred during the second HDCT course. One patient experienced sinusoidal obstruction syndrome during their second HDCT. There were five toxic deaths due to sepsis: four occurred under chemotherapy and one occurred following the second HDCT. To date, second malignancies have not been reported.
Discussion
This is the most recent update of Korean ATRT patients under 3 years of age. Tumors progressed or relapsed in 27 of 42 patients at a median of 160 days from diagnosis in our study. The 3-year PFS and OS were 28.5% and 38.1%, respectively. The 3-year PFS was improved from 0.0% in pre-2011 to 47.4% in post-2011. At diagnosis, metastasis was the only characteristic among several disease characteristics known to affect survival.
Our analysis highlights several points of interest for this young age group. First, our data suggest the importance of early adjuvant RT. We found a survival benefit associated with early adjuvant RT. Traditionally, RT has been deferred or omitted because of the risk of adverse effects, especially for patients under 3 years of age [12]. However, more recent data suggest that RT might be more efficacious than chemotherapy for ATRT patients, even for very young children [2,13,14]. In a previously reported Korean study that included patients treated with tandem HDCT/ASR, all surviving patients received RT at an early stage in their treatment [15]. No patients who received induction chemotherapy and HDCT/ASR without RT survived. This suggests that HDCT/ASR cannot replace RT for local control. Similarly, we found that patients who received early adjuvant RT showed a significantly lower chance of having PD during induction chemotherapy and a higher chance to proceed to HDCT compared to patients who did not, thus leading to improved survival. For patients with M+ disease at diagnosis, adjuvant local radiation significantly improved survival in the current study. Overall, local RT should be considered earlier in therapy to improve survival.
Secondly, our data suggest that HDCT is associated with better survival. For patients who received HDCT, PFS and OS were significantly higher compared to those who did not. There has been no randomized study to evaluate the efficacy of HDCT/ASR in ATRT patients under 3 years of age. A few studies have suggested that HDCT might have a favorable effect on ATRT patients [14,16]. A recent Canadian study has reported better 5-year PFS in patients with ATRT under 1 year of age receiving HDCT group compared to those without receiving HDCT (50.1% vs. 11.3%, p < 0.001) [17]. However, due to small numbers of patients included and various treatment modalities used, no firm conclusions can be made regarding the role of HDCT/ASR in ATRT patients. In this study, all surviving patients received HDCT/ASR. However, this does not reflect the definite efficacy of HDCT/ASR. Considering that patients who achieved CR before their first HDCT showed significantly higher OS than those who did not, multimodal treatment that might lead to CR and additional HDCT might result in better outcomes. In this study, patients who achieved CR before the first HDCT showed significantly higher OS. This suggests that pre-HDCT tumor status is important for predicting outcome. Thus, careful consideration is required when selecting candidate patients for HDCT/ASR.
Importantly, we should consider the likelihood of selection bias toward “favorable cases” in patients subjected to HDCT, which could be associated with molecular distinction. Recently, Reddy et al. [18] have reported that patients with group 1/SHH-NOTCH tumors have less aggressive feature. Biological investigation of ATRT should be continued and subsets of patients who can be cured with less therapy may exist [19].
The optimal combination of regimens for tandem HDCT has not been determined. Rosenfeld et al. [12] have reported the feasibility of tandem HDCT/ASR in patients with brain tumors using CTE-CM. Although they concluded that the CTE-CM regimen was not feasible due to toxicity, tandem CTE-CM HDCT/ASR was feasible in our study. Toxicities in our present study were manageable and only one toxic death associated with HDCT occurred. This could be due to the fact that patients were given a sufficient rest period between the first and the second HDCT/ASR. Sung et al. [20] have reported that a shorter interval (< 12 weeks) between the first and second HDCT/ASR is associated with higher TRM. Another thing to be noted was that there was no significant survival difference between patients who received 1 HDCT and those who received 2 HDCTs. In addition, bacteremia occurred more frequently in the second HDCT than in the first HDCT. Randomized trials with larger cohorts are needed to determine whether the possible survival benefit of tandem HDCT/ASR over single HDCT/ASR might ultimately outweigh adverse effects associated with dose intensive tandem HDCT/ASR.
Thirdly, optimal induction chemotherapy should be explored. Efficacies of many different treatments have been explored. However, there is no consensus regarding standard chemotherapy for ATRT. Due to the desire to avoid unacceptable adverse effects of RT on the developing brain, many institutions adopt chemotherapy-based strategies designed to avoid or delay RT. Despite often impressive responses to chemotherapy, the majority of patients in many published studies developed progressive disease early, suggesting a rapid development of resistance of ATRTs [10,21,22]. Similarly, in our study, PD occurred during induction chemotherapy in about half of cases. Considering that the most common reason not having HDCT/ASR was PD during induction chemotherapy, we could consider shorten the current six cycles of induction chemotherapy. Furthermore, patients who received induction chemotherapy without early adjuvant RT showed significantly lower survival compared to patients who received early adjuvant RT. This suggests that CECV and CEIV chemotherapy regimen used in our patients might be insufficient to prevent tumor progression/relapse. Recently, ACNS0333 comprised with three cycles of chemotherapy which incorporated high dose MTX showed promising result, with 4-year OS of 43% [18]. High-dose MTX used in “Head Start II” also appears to be efficacious and well tolerated in ATRT [8]. Slavc et al. [23] have also demonstrated the efficacy of high-dose MTX in ATRT patients. Besides intensification using cytotoxic agent, there are increasing data suggesting that ATRT might be a good candidate for pathway-specific targeted therapies, some of which are currently used in clinical trials, including AURKA, EZH2, and CDK4/6 inhibitors [24,25]. Optimwal combination of cytotoxic agents and targeted inhibitors should be explored to prevent early progression of ATRT.
Lastly, we found that the post-2011 group had significantly better PFS than the pre-2011 group. The major difference between pre- and post-2011 protocols was adjuvant local radiation and IT chemotherapy in the post-2011 protocol. There was no difference in induction chemotherapy or HDCT between pre- and post-2011 protocols. We believe that the post-2011 protocol with a combination of adjuvant RT and IT chemotherapy might have prevented early progression, eventually improving the outcome as reported by Chi et al. [10]. The role of adjuvant RT has already been described above. IT therapy was incorporated as a method of providing prophylaxis and/or treatment to the CNS axis in the post-2011 protocol. Whether IT therapy could substitute for cranial irradiation for CNS treatment and/or prophylaxis was unclear because both modalities were used in the post-2011 protocol. Considering that the year of diagnosis (pre- vs. post-2011) was not a significant predictor of survival in multivariate analyses, IT therapy might not have a beneficial role in improving survival. However, in many studies, IT chemotherapy has shown potential benefit as an addition to local RT or to intensify therapy in patients who are not candidates for CSI [10,26]. IT chemotherapy shows good penetrance into the CSF. Thus, it might be efficacious in eradicating ATRT cells in CSF, allowing postponement of CSI for patients who receive focal irradiation only. A meta-analysis by Athale et al. [26] has shown that IT therapy leads to a significantly higher OS. A more detailed randomized study I needed to evaluate IT therapy in infant ATRT to define role of IT therapy in these patients.
This study has some limitations. First, this study had a non-randomized and retrospective design. Second, we did not collect data for germline mutations in SMARCB1/INI1. Therefore, we could not assess the association between germline status and outcome. No molecular profiling was included, which could be potential prognostic indicators. Third, because current multimodality treatment strategies for ATRT include brain RT, limited data on neurocognitive outcomes of survivors raise a significant concern [27]. Although data stress the importance for RT in younger age group, this treatment option comes at a cost of serious long-term sequelae such as cognitive, motor, visual, and hearing impairment [28,29]. In addition, combining multimodal treatment deserves attention. Comprehensive long-term follow-up neuropsychologic assessments are planned for our surviving cohort. Lastly, as described above, a more detailed analysis is needed in the future to identify the role of IT therapy in the prevention and treatment of metastases.
In summary, aggressive therapy including early administration of local RT and HDCT/ASR, which was adopted in KSPNO-S1102, should be considered to improve outcomes of ATRT in children below the age of 3 years. Despite the high probability of early PD in ATRT, for patients who received both early adjuvant RT and HDCT/ASR, OS exceeded 90%. Further clinical trials may be required to determine optimal adjuvant treatments such as RT field and intensity of HDCT/ASR and the role of IT chemotherapy for patients with ATRT. Future studies regarding molecular characterization of ATRT and its prognostic implication might change current treatment strategies and delineate the group of patients so that treatment intensity could be reduced.
Acknowledgments
This study was supported by the KPHOG Research Grant 2018.
Fig. 1 Treatment recommendations by the Korean Society for Pediatric Neuro-Oncology for CNS ATRT during periods of 2005–2007 (A), 2008–2010 (B), and 2011-present (C). ASR, autologous stem cell rescue; CR, complete response; CSI, craniospinal irradiation; HDCT, high-dose chemotherapy; IT, intrathecal; RT, radiotherapy. a)R0 (< 1.5 cm2)/M0, local RT 41.4 Gy; R+ (> 1.5 cm2)/M0, local RT 55.8 Gy; Rx/M+, local RT 36 Gy+CSI 19.8 Gy at 3 years of age, b)M0, day 0 of each cycle/M+, weekly until clearing (at least 6 times), then day 0 each cycle.
Fig. 2 Kaplan-Meier estimates of progression-free survival (A) and overall survival (B).
Fig. 3 Progression-free survival according to metastases (A), year of diagnosis (B), early adjuvant radiation (C), and high-dose chemotherapy (D).
Table 1 Chemotherapy regimens
Regimen Drug Dose Schedule
KSPNO-S052 induction chemotherapy
Regimen a Cisplatin 3.5 mg/kg Day 0
Etoposide 2.5 mg/kg Days 0, 1, and 2
Cyclophosphamide 60 mg/kg Days 1 and 2
Vincristine 0.05 mg/kg Days 0, 7, and 14
Regimen b Carboplatin 10 mg/kg Days 0 and 1
Etoposide 2.5 mg/kg Days 0 to 4
Ifosfamide 60 mg/kg Days 0 to 4
Vincristine 0.05 mg/kg Days 0, 7, and 14
KSPNO-S082/S1102 induction chemotherapy
Regimen A Cisplatin 3 mg/kg Day 0
Etoposide 2.5 mg/kg Days 0, 1, and 2
Cyclophosphamide 50 mg/kg Days 1 and 2
Vincristine 0.05 mg/kg Days 0 and 7
Regimen B Carboplatin 10 mg/kg Days 0 and 1
Etoposide 2.5 mg/kg Days 0 to 4
Ifosfamide 50 mg/kg Days 0 to 4
Vincristine 0.05 mg/kg Days 0 and 7
KSPNO-S052/S082/S1102 high-dose chemotherapy
First: CTE Carboplatin 500 mg/m2 Days −8 to −6
Thiotepa 300 mg/m2 Days −5 to −3
Etoposide 250 mg/m2 Days −5 to −3
Second: CM Cyclophosphamide 1,500 mg/m2 Days −8 to −5
Melphalan 60 mg/m2 Days −4 to −2
CM, cyclophosphamide and melphalan; CTE, carboplatin, thiotepa and etoposide.
Table 2 Clinical characteristics of patients
Pre-2011 (n=19) Post-2011 (n=24) Total (n=43)
Male:Female 9:10 13:11 22:21
Age at diagnosis (mo)
Median (range) 13.0 (1–31) 14.5 (0–32) 13.0 (0–32)
< 6 mo 4 (21.1) 5 (20.8) 9 (20.9)
6–12 mo 5 (26.3) 6 (25.0) 11 (25.6)
> 12 mo 10 (52.6) 13 (54.2) 23 (53.5)
Neuraxis metastasis
M0 11 (57.9) 12 (50.0) 23 (53.5)
M1 2 (10.5) 2 (8.3) 4 (9.3)
M2 5 (26.3) 9 (37.5) 14 (32.6)
Unknown 1 (5.3) 1 (4.2) 2 (4.7)
Type of resection
Gross total resection 12 (63.2) 12 (50.0) 24 (55.8)
Subtotal resection 6 (31.6) 12 (50.0) 18 (41.9)
Biopsy 1 (5.3) 0 1 (2.3)
Palliative care only after surgery 1 (5.3) 0 1 (2.3)
Values are presented as number (%) unless otherwise indicated.
Table 3 Treatment and clinical outcomes
Pre-2011 (n=18) Post-2011 (n=24) Total (n=42)
Treatment
Chemotherapy 18 (100) 24 (100) 42 (100)
RT 12 (66.7) 17 (70.8) 29 (69.0)
Early adjuvant local RT 2 (11.1) 12 (50.0) 14 (33.3)
With concurrent CSI 1 1 2
CSI at 3 years of age after completion of HDCT 0 3 3
Salvage local RT at relapse/progression 9 (50.0) 4 (16.7) 13 (31.0)
With concurrent CSI 4 1 5
CSI at 3 years of age after completion of HDCT 1 1 2
CSI at 3 year of age only 1 (5.5) 1 (4.2) 2 (4.8)
HDCT 9 (50.0) 15 (62.5) 24 (57.1)
1 HDCT 1 (5.6) 8 (33.3) 9 (21.4)
2 HDCT 8 (44.4) 7 (29.2) 15 (35.8)
Response to treatment
Continued response 3 (16.7) 12 (50.0) 15 (35.7)
Disease progression 15 (83.3) 12 (50.0) 27 (64.3)
After initial surgery 1 2 3
During induction chemotherapy 9 5 14
During RT 0 1 1
During HDCT 0 2 2
After completion of HDCT 5 2 7
Final outcome
Alive without disease 4 (22.2) 11 (45.8) 15 (35.7)
Alive with disease 0 0 0
Death due to disease progression 11 (61.1) 10 (41.7) 21 (50.0)
Treatment-related death 2 (11.1) 3 (12.5) 5 (11.9)
Death due to unknown cause 1 (5.6) 0 1 (2.4)
Values are presented as number (%). CSI, craniospinal irradiation; HDCT, high-dose chemotherapy; RT, radiotherapy.
Table 4 Univariate and multivariate analysis of the probability of progression-free survival
Univariate Multivariatea)
HR (95% CI) p-value HR (95% CI) p-value
Years of diagnosis
Pre-2011 1 0.04 1 0.57
Post-2011 0.47 (0.23–0.96) 0.81 (0.44–1.62)
Patient age (yr)
< 1 1 0.53
≥ 1 0.79 (0.39–1.59)
Metastases
Yes 1 0.03 1 0.53
No 0.46 (0.23–0.90) 0.85 (0.43–1.59)
Extent of resection
GTR 1 0.29
No GTR 1.23 (0.56–2.27)
Early adjuvant RT
Yes 1 < 0.01 1 < 0.01
No 5.68 (2.14–15.12) 6.42 (2.29–17.90)
HDCT
Yes 1 < 0.01 1 < 0.01
No 10.26 (3.81–27.66) 12.0 (3.91–37.28)
CI, confidence interval; GTR, gross total resection; HDCT, high-dose chemotherapy; HR, hazard ratio; RT, radiotherapy.
a) Includes variables significant at p < 0.1 (overall) in univariate analysis.
Ethical Statement
Ethics approval and consent to participation: All participating centers received Institutional Review Board approval to contribute data for this study (NCC 2018-0210). This study was performed in accordance with the Declaration of Helsinki.
Author Contributions
Conceived and designed the analysis: Park M, Han JW, Park HJ.
Collected the data: Park M, Han JW, Hahn SM, Lee JA, Kim JY, Shin SH, Kim DS, Yoon HI, Hong KT, Choi JY, Kang HJ, Shin HY, Phi JH, Kim SK, Lee JW, Yoo KH, Sung KW, Koo HH, Lim DH, Shin HJ, Kim H, Koh KN, Im HJ, Ahn SD, Ra YS, Baek HJ, Kook H, Jung TY, Choi HS, Kim CY, Park HJ, Lyu CJ.
Contributed data or analysis tools: Park M.
Performed the analysis: Park M.
Wrote the paper: Park M.
Review the paper: Lyu CJ, Park HJ.
Conflicts of Interest
Conflicts of interest relevant to this article was not reported.
|
UNK, CYCLIC, ADMINISTERED ON DAY 0 OF EVERY CHEMOTHERAPY CYCLE
|
DrugDosageText
|
CC BY-NC
|
33138347
| 19,651,900
|
2021-04
|
What was the outcome of reaction 'Sepsis'?
|
Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children under the Age of 3 Years.
OBJECTIVE
Atypical teratoid/rhabdoid tumor (ATRT) is a highly aggressive malignancy with peak incidence in children aged less than 3 years. Standard treatment for central nervous system ATRT in children under the age of 3 years have not been established yet. The objective of this study was to analyze characteristics and clinical outcomes of ATRT in children aged less than 3 years.
A search of medical records from seven centers was performed between January 2005 and December 2016.
RESULTS
Forty-three patients were enrolled. With a median follow-up of 90 months, 27 patients (64.3%) showed at least one episode of disease progression (PD). The first date of PD was at 160 days after diagnosis. The 1- and 3-year progression-free survivals (PFS) were 51.2% and 28.5%, respectively. The 1- and 3-year overall survivals were 61.9% and 38.1%, respectively. The 3-year PFS was improved from 0% in pre-2011 to 47.4% in post-2011. Excluding one patient who did not receive any further therapy after surgery, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown cause (n=1). In univariate analysis, factors associated with higher 3-year PFS were no metastases, diagnosis after 2011, early adjuvant radiotherapy, and high-dose chemotherapy (HDCT). In multivariate analysis, the use of HDCT and adjuvant radiotherapy remained significant prognostic factors for PFS (both p < 0.01).
CONCLUSIONS
Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years.
Introduction
Atypical teratoid/rhabdoid tumor (ATRT) of the central nervous system (CNS) is a highly aggressive malignancy, accounting for 1%–2% of all pediatric CNS tumors [1,2]. Among children under the age of 3 years, ATRT constitutes the most common malignant tumor of CNS (17.3%), followed by medulloblastoma (16%) [3].
Since standard therapeutic strategies for ATRT have not been established yet, treatment approaches for ATRT vary among institutions and countries. Conventional chemotherapy in addition to high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASR) is usually utilized in pati-ents under 3 years of age to substitute for or delay the use of radiotherapy (RT) in attempt to improve outcomes and minimize long-term neurocognitive impairment [4]. However, most patients with ATRT suffer rapid disease progression (PD), although treatment regimens designed for CNS neoplasms have been used [5,6]. Outcome for patients with ATRT is generally dismal, particularly in the presence of residual tumor or metastasis. ATRT is a devastating brain neoplasm with a median survival time ranging from 6 to 13 months. This is caused not only by the disease’s aggressive characteristics, but also by a lower tolerance of young patients to treatment. This is exacerbated by the hesitancy to use RT in younger patients due to risks of functional impairment of the developing brain [7]. It has been shown that aggressive therapy can prolong survival in a subset of children with CNS ATRT [1,2,8]. Some clinical trials have incorporated early administration of RT to the primary site together with intrathecal (IT) chemotherapy, resulting in improved outcomes [9,10].
In 2005, the Korean Society for Pediatric Neuro-Oncology (KSPNO) suggested the following a protocol for ATRT patients aged less than 3 years (KSPNO-S052): six cycles of conventional chemotherapy and tandem HDCT/ASR are performed initially and RT is deferred until the patient reaches 3 years of age. In 2008, a minor revision of the protocol including a dose modification of conventional chemotherapy was made (KSPNO-S082). In 2011, the protocol was revised (KSPNO-S1102) to recommended early local RT with concurrent chemotherapy within four weeks after surgery. In addition, IT chemotherapy was incorporated.
Given the rarity of this tumor and the even lower number of very young infants affected by ATRT, no detailed clinical analyses have been directed toward patients under 3 years of age. Thus, the objective of this study was to describe patients diagnosed with ATRT in this age group and determine potential specific characteristics or prognostic factors. Their therapeutic management is also suggested.
Materials and Methods
1. Data collection
Children younger than 3 years of age at diagnosis who were newly diagnosed with CNS ATRT were eligible for this study. A search of medical records from seven centers was performed to identify patients aged 3 years or less who were diagnosed between January 2005 and December 2016. In cases with multiple intracranial and extracranial rhabdoid tumors, only patients with clear descriptions of a primary tumor within the CNS were included in this analysis. All participating centers received Institutional Review Board approval to contribute data for this study.
2. Staging
Proper staging for metastases included brain and spinal magnetic resonance imaging (MRI) and cytology of the cerebrospinal fluid (CSF). Modified Chang status for metastatic stage was recorded whenever available. It was defined as follows: M0, absence of metastases; M1, presence of metastases confined to CSF; M2, presence of metastases in the brain; M3, presence of metastases in the spinal subarachnoidal space; and M4, spread outside of the CNS [11]. M+ included M1, M2, M3, M4, and any metastasis not further described.
3. Treatment
All patients underwent maximal possible surgical resection of the primary lesion to preserve neurologic function. The extent of surgical resection defined as gross total resection (GTR), subtotal resection, or biopsy was determined based on a review of postoperative MRI and the surgeon’s intraoperative assessment. Multimodal therapies including surgery, RT, chemotherapy and HDCT/ASR were performed. Treatment was mainly performed according to KSPNO recommendations. However, some physicians modified the treatment protocol depending on clinical situation. Treatment scheme of the KSPNO regimen is shown in Fig. 1. Major differences between KSPNO-S052/-S082 (pre-2011) and KSPNO-S1101 (post-2011) were the timing of RT (delayed RT pre-2011 vs. early adjuvant RT post-2011) and IT chemotherapy for patients post-2011. Detailed chemotherapy schedules are described in Table 1.
KSPNO-S052/S082 (pre-2011) suggested the following: Induction treatment was initiated within 4 weeks of surgery. Six cycles of chemotherapy using alternating CECV (cisplatin, etoposide, cyclophosphamide, and vincristine) and CEIV (carboplatin, etoposide, ifosfamide, and vincristine) regimens were administered. Additionally, tandem HDCT/ASR was performed. The first course included carboplatin, thiotepa and etoposide (CTE), and the second course included cyclophosphamide and melphalan (CM). A 12- to 16-week interval between the first and second HDCT/ASR was allowed to minimize treatment-related mortality (TRM). RT was deferred until after 3 years of age unless the tumor showed progression or relapse. For patients with M0 disease at diagnosis and for patients those without residual tumor after HDCT, RT was omitted.
KSPNO-S1102 (post-2011) suggested the following: RT was recommended to be administered within 4 weeks of surgery with concurrent chemotherapy. IT chemotherapy including cytarabine, hydrocortisone, and methotrexate (MTX) was administered on day 0 of every chemotherapy cycle. For M+ patients, weekly IT chemotherapy was administered until clearance of CSF cytology. After six cycles of alternating CECV and CEIV regimens, tandem HDCT/ASR using CTE-CM was performed. For M+ patients at diagnosis, craniospinal irradiation (CSI) was deferred at 3 years of age.
4. Response and toxicity criteria
Disease response was evaluated by MRI and CSF cytology. Evaluations were repeated every two or three chemotherapy cycles prior to the first HDCT/ASR, between the first and second HDCT/ASR, every 3 months for the first year after completion of tandem HDCT/ASR, every 4 months for the second year, and every 6 months thereafter. Disease response was categorized as follows: complete response (CR) for complete disappearance of all tumors, partial response (PR) for decrease in tumor size by more than 50%, stable disease for less than 25% change in tumor size, PD for greater than 25% increase in tumor size or the appearance of new tumors. Toxicities were graded using the National Cancer Institute’s Common Terminology Criteria ver. 4.0.
5. Statistical analysis
The cutoff point for data analyses was March 2019. For descriptive statistics, data were compared using the Fisher exact test for categorical factors and Wilcoxon Mann-Whitney U test for continuous factors. The time to progression was calculated from the date of diagnosis until the date of PD. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of PD or relapse. Overall survival (OS) was calculated from the date of initial diagnosis to the date of last follow-up or death from any cause. PFS and OS were estimated using the Kaplan-Meier method. Univariate analysis of risk factors was performed by comparing PFS and OS using the log-rank test. Multivariate logistic regression was used to examine relationships between outcomes of PFS or OS as binary dependent variables and independent variables of patient age, metastases, extent of resection, early adjuvant RT, HDCT, and years of diagnosis. p < 0.05 was considered statistically significant. All analyses were performed using IBM SPSS ver. 18.0 (SPSS Inc., Chicago, IL).
Results
1. Patient characteristics
Baseline clinical characteristics of patients are shown in Table 2. Forty-three patients were enrolled in this study. The median age at diagnosis was 13 months (range, 0 to 32 months). Twenty patients (46.5%) were younger than 1 year of age at diagnosis. One patient presented with synchronous tumors, including ATRT in brain and a rhabdoid tumor in the kidney.
Nineteen patients (44.2%) were diagnosed before 2011 (pre-2011 group) and 24 patients (55.8%) were diagnosed after 2011 (post-2011 group). There was no significant difference in age at diagnosis (p=0.55), sex (p=0.43), extent of resection (p=0.15), or metastases (p=0.46) between pre-2011 and post-2011 groups. There were 23 (53.5%) patients with M0 disease, four (9.3%) with M1 disease, 14 (32.6%) with M2 disease, and two (4.7%) with unknown metastatic status. The incidence of metastatic disease was significantly higher in patients under 6 months of age than that in patients older than 6 months (100.0% vs. 35.3%, p < 0.01). GTR of the primary tumor was achieved in 24 patients (55.8%).
2. Treatment
One patient did not receive any further therapy after surgery. All remaining 42 patients received induction chemotherapy at a median of 20 days after surgery (range, 5 to 142 days). The median number of pretransplant chemotherapy cycles was 6 (range, 1 to 12). All patients in the post-2011 group received IT therapies. Nine patients (21.4%) received a second surgery before HDCT due to PD (n=8) or for removing residual tumor (n=1).
Twenty-nine patients (69.0%) received radiation at a median age of 23 months (range, 6 to 40 months). The median interval between diagnosis and RT was 162 days (range, 21 to 745 days). Thirteen patients (31.0%) did not receive RT due to early progression (n=8), treatment-related death (n=3), or physician’s discretion (n=2). As of 2011, RT timing changed from delayed RT (pre-2011) to early adjuvant RT (post-2011). As a result, the median period between diagnosis and RT was significantly shortened from 314.9 days in the pre-2011 group to 159.0 days in the post-2011 group (p=0.04). The period between diagnosis to RT was 114.6±104.8 days in patients who received early adjuvant RT and 313.4±231.2 days in patients who received RT as salvage therapy (p < 0.01).Among 29 patients who received RT, early adjuvant RT was administered in 14 patients (2 in the pre-2011 group and 12 in the post-2011 group) (Table 3). They received local RT at a dose of 36–63 Gy after surgery. Of them, five patients received additional CSI at a dose of 23.4–30.6 Gy concurrently (n=2) or at 3 years of age (n=3) due to M+ disease at diagnosis. Thirteen patients received local RT as salvage therapy at a dose of 25.2–55.8 Gy. Of them, five patients received CSI at a dose of 19.5–23.4 Gy. Two patients received CSI at 3 years of age after completion of HDCT as scheduled.
Twenty-four patients received HDCT/ASR (15 patients received tandem HDCTs and nine patients received only 1 HDCT). Reasons not having second HDCT included physician’s discretion (n=4), PD or relapse (n=3), prolonged bone marrow suppression (n=1), and patient refusal (n=1). During the first HDCT, eight patients received conditioning regimen including topotecan, thiotepa, and carboplatin instead of CTE. During the second HDCT, two patients received conditioning regimen including busulfan, melphalan, and thiotepa instead of CM.
Significantly more patients who received early adjuvant RT proceeded to HDCT compared to patients who did not (78.6% vs. 46.4%, p=0.04). For patients not receiving HDCT (n=18), reasons included PD or relapse (n=12), treatment-related death (n=4), patient refusal (n=1), and death due to unknown cause (n=1). The median age at the time of the first HDCT was 21.0 months (range, 9.1 to 44.5 months). The median time between diagnosis and the first HDCT was 7.5 months (range, 5.3 to 16.1 months). Disease status before the first HDCT was CR in 16 and PR in eight. Among 15 patients who underwent a second HDCT, disease status before the second HDCT was CR in 10, PR in four, and PD in one. The median interval between the first and second HDCT was 91 days (range, 35 to 126 days).
3. Clinical course and survival
Excluding one patient who received palliative care only, data for 42 patients were analyzed (Table 3). With a median follow-up of 90 months (range, 27 to 172 months), 27 patients (64.3%) showed at least one episode of PD. The first date of PD was at 160 days (median; range, 13 to 585) after the diagnosis. Twenty-one of 27 patients who showed PD died due to PD at a median of 4 months (range, 0.1 to 5.4 months) from the first day of documentation of PD. Immediate salvage therapy consisted of surgery in 11, chemotherapy in four, RT in four, gamma knife surgery in one, and supportive care only in seven. PD was found within 2 months of resection surgery before initiation of chemotherapy in three, during chemotherapy in 14, during adjuvant RT in one, during HDCT in two, and after completion of HDCT in seven. Among 14 patients with PD found during induction chemotherapy, 13 did not receive adjuvant RT previously while one patient had received RT previously (p < 0.01). Of nine patients who experienced relapse during or after HDCT, seven patients died due to PD. Two patients are still alive without disease. The median time between HDCT and subsequent relapse was 3 months (range, 1 to 11 months).
The 1- and 3-year PFS is 51.2% and 28.5%, respectively. The 1- and 3-year OS is 61.9% and 38.1%, respectively (Fig. 2). Of 42 patients analyzed, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown causes (n=1).
At the last follow-up, 15 patients were alive. All surviving patients received HDCT/ASR. Patients who achieved CR before the first HDCT showed significantly higher 3-year OS compared to patients who did not (81.3% vs. 37.5%, p < 0.01). There was no significant difference in PFS or OS between patients who underwent 1 HDCT and those who underwent 2 HDCTs.
4. Risk factors
Results of univariate and multivariate analyses for PFS are shown in Table 4. In univariate analysis, factors associated with higher 3-year PFS were no metastases (p=0.03), diagnosis after 2011 (p=0.04), early adjuvant RT (p < 0.01) and HDCT/ASR (p < 0.01) (Fig. 3). Age at diagnosis (p=0.53) and extent of resection (p=0.29) failed to influence survival rate in our study. Among 14 patients who received adjuvant RT, only three patients showed PD during (n=1) or after (n=2) the planned RT, while 24 of 28 patients who did not receive adjuvant RT showed PD (p < 0.01). Among 18 patients with metastases, patients who received early adjuvant local RT showed significantly higher PFS and OS compared to those who did not (3-year PFS: 75.0% vs. 0%, p=0.04; 3-year OS: 75.0% vs. 14.3%, p=0.03).
In multivariate analyses, the use of HDCT/ASR and early adjuvant RT remained significant prognostic factors for PFS (both p < 0.01). For OS, the use of HDCT/ASR was the only significant prognostic factor (p < 0.01). Among patients who received both early adjuvant RT and HDCT/ASR, 3-year PFS and OS were 81.8% and 90.9%, respectively.
5. Toxicity
During chemotherapy, the most frequently reported significant toxicities were bone marrow suppression and febrile neutropenia followed by infection, gastrointestinal disturbances, electrolyte disturbances, and hepatic disturbances. During HDCT, infection was the most common toxicity. Bacteremia was detected during six of 39 HDCT (3 Staphylococcus epidermidis, 2 Pseudomonas aeruginosa, and 1 Bacillus species), five of which occurred during the second HDCT course. One patient experienced sinusoidal obstruction syndrome during their second HDCT. There were five toxic deaths due to sepsis: four occurred under chemotherapy and one occurred following the second HDCT. To date, second malignancies have not been reported.
Discussion
This is the most recent update of Korean ATRT patients under 3 years of age. Tumors progressed or relapsed in 27 of 42 patients at a median of 160 days from diagnosis in our study. The 3-year PFS and OS were 28.5% and 38.1%, respectively. The 3-year PFS was improved from 0.0% in pre-2011 to 47.4% in post-2011. At diagnosis, metastasis was the only characteristic among several disease characteristics known to affect survival.
Our analysis highlights several points of interest for this young age group. First, our data suggest the importance of early adjuvant RT. We found a survival benefit associated with early adjuvant RT. Traditionally, RT has been deferred or omitted because of the risk of adverse effects, especially for patients under 3 years of age [12]. However, more recent data suggest that RT might be more efficacious than chemotherapy for ATRT patients, even for very young children [2,13,14]. In a previously reported Korean study that included patients treated with tandem HDCT/ASR, all surviving patients received RT at an early stage in their treatment [15]. No patients who received induction chemotherapy and HDCT/ASR without RT survived. This suggests that HDCT/ASR cannot replace RT for local control. Similarly, we found that patients who received early adjuvant RT showed a significantly lower chance of having PD during induction chemotherapy and a higher chance to proceed to HDCT compared to patients who did not, thus leading to improved survival. For patients with M+ disease at diagnosis, adjuvant local radiation significantly improved survival in the current study. Overall, local RT should be considered earlier in therapy to improve survival.
Secondly, our data suggest that HDCT is associated with better survival. For patients who received HDCT, PFS and OS were significantly higher compared to those who did not. There has been no randomized study to evaluate the efficacy of HDCT/ASR in ATRT patients under 3 years of age. A few studies have suggested that HDCT might have a favorable effect on ATRT patients [14,16]. A recent Canadian study has reported better 5-year PFS in patients with ATRT under 1 year of age receiving HDCT group compared to those without receiving HDCT (50.1% vs. 11.3%, p < 0.001) [17]. However, due to small numbers of patients included and various treatment modalities used, no firm conclusions can be made regarding the role of HDCT/ASR in ATRT patients. In this study, all surviving patients received HDCT/ASR. However, this does not reflect the definite efficacy of HDCT/ASR. Considering that patients who achieved CR before their first HDCT showed significantly higher OS than those who did not, multimodal treatment that might lead to CR and additional HDCT might result in better outcomes. In this study, patients who achieved CR before the first HDCT showed significantly higher OS. This suggests that pre-HDCT tumor status is important for predicting outcome. Thus, careful consideration is required when selecting candidate patients for HDCT/ASR.
Importantly, we should consider the likelihood of selection bias toward “favorable cases” in patients subjected to HDCT, which could be associated with molecular distinction. Recently, Reddy et al. [18] have reported that patients with group 1/SHH-NOTCH tumors have less aggressive feature. Biological investigation of ATRT should be continued and subsets of patients who can be cured with less therapy may exist [19].
The optimal combination of regimens for tandem HDCT has not been determined. Rosenfeld et al. [12] have reported the feasibility of tandem HDCT/ASR in patients with brain tumors using CTE-CM. Although they concluded that the CTE-CM regimen was not feasible due to toxicity, tandem CTE-CM HDCT/ASR was feasible in our study. Toxicities in our present study were manageable and only one toxic death associated with HDCT occurred. This could be due to the fact that patients were given a sufficient rest period between the first and the second HDCT/ASR. Sung et al. [20] have reported that a shorter interval (< 12 weeks) between the first and second HDCT/ASR is associated with higher TRM. Another thing to be noted was that there was no significant survival difference between patients who received 1 HDCT and those who received 2 HDCTs. In addition, bacteremia occurred more frequently in the second HDCT than in the first HDCT. Randomized trials with larger cohorts are needed to determine whether the possible survival benefit of tandem HDCT/ASR over single HDCT/ASR might ultimately outweigh adverse effects associated with dose intensive tandem HDCT/ASR.
Thirdly, optimal induction chemotherapy should be explored. Efficacies of many different treatments have been explored. However, there is no consensus regarding standard chemotherapy for ATRT. Due to the desire to avoid unacceptable adverse effects of RT on the developing brain, many institutions adopt chemotherapy-based strategies designed to avoid or delay RT. Despite often impressive responses to chemotherapy, the majority of patients in many published studies developed progressive disease early, suggesting a rapid development of resistance of ATRTs [10,21,22]. Similarly, in our study, PD occurred during induction chemotherapy in about half of cases. Considering that the most common reason not having HDCT/ASR was PD during induction chemotherapy, we could consider shorten the current six cycles of induction chemotherapy. Furthermore, patients who received induction chemotherapy without early adjuvant RT showed significantly lower survival compared to patients who received early adjuvant RT. This suggests that CECV and CEIV chemotherapy regimen used in our patients might be insufficient to prevent tumor progression/relapse. Recently, ACNS0333 comprised with three cycles of chemotherapy which incorporated high dose MTX showed promising result, with 4-year OS of 43% [18]. High-dose MTX used in “Head Start II” also appears to be efficacious and well tolerated in ATRT [8]. Slavc et al. [23] have also demonstrated the efficacy of high-dose MTX in ATRT patients. Besides intensification using cytotoxic agent, there are increasing data suggesting that ATRT might be a good candidate for pathway-specific targeted therapies, some of which are currently used in clinical trials, including AURKA, EZH2, and CDK4/6 inhibitors [24,25]. Optimwal combination of cytotoxic agents and targeted inhibitors should be explored to prevent early progression of ATRT.
Lastly, we found that the post-2011 group had significantly better PFS than the pre-2011 group. The major difference between pre- and post-2011 protocols was adjuvant local radiation and IT chemotherapy in the post-2011 protocol. There was no difference in induction chemotherapy or HDCT between pre- and post-2011 protocols. We believe that the post-2011 protocol with a combination of adjuvant RT and IT chemotherapy might have prevented early progression, eventually improving the outcome as reported by Chi et al. [10]. The role of adjuvant RT has already been described above. IT therapy was incorporated as a method of providing prophylaxis and/or treatment to the CNS axis in the post-2011 protocol. Whether IT therapy could substitute for cranial irradiation for CNS treatment and/or prophylaxis was unclear because both modalities were used in the post-2011 protocol. Considering that the year of diagnosis (pre- vs. post-2011) was not a significant predictor of survival in multivariate analyses, IT therapy might not have a beneficial role in improving survival. However, in many studies, IT chemotherapy has shown potential benefit as an addition to local RT or to intensify therapy in patients who are not candidates for CSI [10,26]. IT chemotherapy shows good penetrance into the CSF. Thus, it might be efficacious in eradicating ATRT cells in CSF, allowing postponement of CSI for patients who receive focal irradiation only. A meta-analysis by Athale et al. [26] has shown that IT therapy leads to a significantly higher OS. A more detailed randomized study I needed to evaluate IT therapy in infant ATRT to define role of IT therapy in these patients.
This study has some limitations. First, this study had a non-randomized and retrospective design. Second, we did not collect data for germline mutations in SMARCB1/INI1. Therefore, we could not assess the association between germline status and outcome. No molecular profiling was included, which could be potential prognostic indicators. Third, because current multimodality treatment strategies for ATRT include brain RT, limited data on neurocognitive outcomes of survivors raise a significant concern [27]. Although data stress the importance for RT in younger age group, this treatment option comes at a cost of serious long-term sequelae such as cognitive, motor, visual, and hearing impairment [28,29]. In addition, combining multimodal treatment deserves attention. Comprehensive long-term follow-up neuropsychologic assessments are planned for our surviving cohort. Lastly, as described above, a more detailed analysis is needed in the future to identify the role of IT therapy in the prevention and treatment of metastases.
In summary, aggressive therapy including early administration of local RT and HDCT/ASR, which was adopted in KSPNO-S1102, should be considered to improve outcomes of ATRT in children below the age of 3 years. Despite the high probability of early PD in ATRT, for patients who received both early adjuvant RT and HDCT/ASR, OS exceeded 90%. Further clinical trials may be required to determine optimal adjuvant treatments such as RT field and intensity of HDCT/ASR and the role of IT chemotherapy for patients with ATRT. Future studies regarding molecular characterization of ATRT and its prognostic implication might change current treatment strategies and delineate the group of patients so that treatment intensity could be reduced.
Acknowledgments
This study was supported by the KPHOG Research Grant 2018.
Fig. 1 Treatment recommendations by the Korean Society for Pediatric Neuro-Oncology for CNS ATRT during periods of 2005–2007 (A), 2008–2010 (B), and 2011-present (C). ASR, autologous stem cell rescue; CR, complete response; CSI, craniospinal irradiation; HDCT, high-dose chemotherapy; IT, intrathecal; RT, radiotherapy. a)R0 (< 1.5 cm2)/M0, local RT 41.4 Gy; R+ (> 1.5 cm2)/M0, local RT 55.8 Gy; Rx/M+, local RT 36 Gy+CSI 19.8 Gy at 3 years of age, b)M0, day 0 of each cycle/M+, weekly until clearing (at least 6 times), then day 0 each cycle.
Fig. 2 Kaplan-Meier estimates of progression-free survival (A) and overall survival (B).
Fig. 3 Progression-free survival according to metastases (A), year of diagnosis (B), early adjuvant radiation (C), and high-dose chemotherapy (D).
Table 1 Chemotherapy regimens
Regimen Drug Dose Schedule
KSPNO-S052 induction chemotherapy
Regimen a Cisplatin 3.5 mg/kg Day 0
Etoposide 2.5 mg/kg Days 0, 1, and 2
Cyclophosphamide 60 mg/kg Days 1 and 2
Vincristine 0.05 mg/kg Days 0, 7, and 14
Regimen b Carboplatin 10 mg/kg Days 0 and 1
Etoposide 2.5 mg/kg Days 0 to 4
Ifosfamide 60 mg/kg Days 0 to 4
Vincristine 0.05 mg/kg Days 0, 7, and 14
KSPNO-S082/S1102 induction chemotherapy
Regimen A Cisplatin 3 mg/kg Day 0
Etoposide 2.5 mg/kg Days 0, 1, and 2
Cyclophosphamide 50 mg/kg Days 1 and 2
Vincristine 0.05 mg/kg Days 0 and 7
Regimen B Carboplatin 10 mg/kg Days 0 and 1
Etoposide 2.5 mg/kg Days 0 to 4
Ifosfamide 50 mg/kg Days 0 to 4
Vincristine 0.05 mg/kg Days 0 and 7
KSPNO-S052/S082/S1102 high-dose chemotherapy
First: CTE Carboplatin 500 mg/m2 Days −8 to −6
Thiotepa 300 mg/m2 Days −5 to −3
Etoposide 250 mg/m2 Days −5 to −3
Second: CM Cyclophosphamide 1,500 mg/m2 Days −8 to −5
Melphalan 60 mg/m2 Days −4 to −2
CM, cyclophosphamide and melphalan; CTE, carboplatin, thiotepa and etoposide.
Table 2 Clinical characteristics of patients
Pre-2011 (n=19) Post-2011 (n=24) Total (n=43)
Male:Female 9:10 13:11 22:21
Age at diagnosis (mo)
Median (range) 13.0 (1–31) 14.5 (0–32) 13.0 (0–32)
< 6 mo 4 (21.1) 5 (20.8) 9 (20.9)
6–12 mo 5 (26.3) 6 (25.0) 11 (25.6)
> 12 mo 10 (52.6) 13 (54.2) 23 (53.5)
Neuraxis metastasis
M0 11 (57.9) 12 (50.0) 23 (53.5)
M1 2 (10.5) 2 (8.3) 4 (9.3)
M2 5 (26.3) 9 (37.5) 14 (32.6)
Unknown 1 (5.3) 1 (4.2) 2 (4.7)
Type of resection
Gross total resection 12 (63.2) 12 (50.0) 24 (55.8)
Subtotal resection 6 (31.6) 12 (50.0) 18 (41.9)
Biopsy 1 (5.3) 0 1 (2.3)
Palliative care only after surgery 1 (5.3) 0 1 (2.3)
Values are presented as number (%) unless otherwise indicated.
Table 3 Treatment and clinical outcomes
Pre-2011 (n=18) Post-2011 (n=24) Total (n=42)
Treatment
Chemotherapy 18 (100) 24 (100) 42 (100)
RT 12 (66.7) 17 (70.8) 29 (69.0)
Early adjuvant local RT 2 (11.1) 12 (50.0) 14 (33.3)
With concurrent CSI 1 1 2
CSI at 3 years of age after completion of HDCT 0 3 3
Salvage local RT at relapse/progression 9 (50.0) 4 (16.7) 13 (31.0)
With concurrent CSI 4 1 5
CSI at 3 years of age after completion of HDCT 1 1 2
CSI at 3 year of age only 1 (5.5) 1 (4.2) 2 (4.8)
HDCT 9 (50.0) 15 (62.5) 24 (57.1)
1 HDCT 1 (5.6) 8 (33.3) 9 (21.4)
2 HDCT 8 (44.4) 7 (29.2) 15 (35.8)
Response to treatment
Continued response 3 (16.7) 12 (50.0) 15 (35.7)
Disease progression 15 (83.3) 12 (50.0) 27 (64.3)
After initial surgery 1 2 3
During induction chemotherapy 9 5 14
During RT 0 1 1
During HDCT 0 2 2
After completion of HDCT 5 2 7
Final outcome
Alive without disease 4 (22.2) 11 (45.8) 15 (35.7)
Alive with disease 0 0 0
Death due to disease progression 11 (61.1) 10 (41.7) 21 (50.0)
Treatment-related death 2 (11.1) 3 (12.5) 5 (11.9)
Death due to unknown cause 1 (5.6) 0 1 (2.4)
Values are presented as number (%). CSI, craniospinal irradiation; HDCT, high-dose chemotherapy; RT, radiotherapy.
Table 4 Univariate and multivariate analysis of the probability of progression-free survival
Univariate Multivariatea)
HR (95% CI) p-value HR (95% CI) p-value
Years of diagnosis
Pre-2011 1 0.04 1 0.57
Post-2011 0.47 (0.23–0.96) 0.81 (0.44–1.62)
Patient age (yr)
< 1 1 0.53
≥ 1 0.79 (0.39–1.59)
Metastases
Yes 1 0.03 1 0.53
No 0.46 (0.23–0.90) 0.85 (0.43–1.59)
Extent of resection
GTR 1 0.29
No GTR 1.23 (0.56–2.27)
Early adjuvant RT
Yes 1 < 0.01 1 < 0.01
No 5.68 (2.14–15.12) 6.42 (2.29–17.90)
HDCT
Yes 1 < 0.01 1 < 0.01
No 10.26 (3.81–27.66) 12.0 (3.91–37.28)
CI, confidence interval; GTR, gross total resection; HDCT, high-dose chemotherapy; HR, hazard ratio; RT, radiotherapy.
a) Includes variables significant at p < 0.1 (overall) in univariate analysis.
Ethical Statement
Ethics approval and consent to participation: All participating centers received Institutional Review Board approval to contribute data for this study (NCC 2018-0210). This study was performed in accordance with the Declaration of Helsinki.
Author Contributions
Conceived and designed the analysis: Park M, Han JW, Park HJ.
Collected the data: Park M, Han JW, Hahn SM, Lee JA, Kim JY, Shin SH, Kim DS, Yoon HI, Hong KT, Choi JY, Kang HJ, Shin HY, Phi JH, Kim SK, Lee JW, Yoo KH, Sung KW, Koo HH, Lim DH, Shin HJ, Kim H, Koh KN, Im HJ, Ahn SD, Ra YS, Baek HJ, Kook H, Jung TY, Choi HS, Kim CY, Park HJ, Lyu CJ.
Contributed data or analysis tools: Park M.
Performed the analysis: Park M.
Wrote the paper: Park M.
Review the paper: Lyu CJ, Park HJ.
Conflicts of Interest
Conflicts of interest relevant to this article was not reported.
|
Fatal
|
ReactionOutcome
|
CC BY-NC
|
33138347
| 19,646,488
|
2021-04
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal distension'.
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
CAPECITABINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal pain'.
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
CAPECITABINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Alanine aminotransferase abnormal'.
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
CAPECITABINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Aspartate aminotransferase increased'.
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
CAPECITABINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Decreased appetite'.
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
CAPECITABINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'.
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
CAPECITABINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dyspnoea'.
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
CAPECITABINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Granulocytes abnormal'.
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
CAPECITABINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemoglobin abnormal'.
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
CAPECITABINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperbilirubinaemia'.
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
CAPECITABINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyponatraemia'.
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
CAPECITABINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lymphopenia'.
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
CAPECITABINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutrophil count abnormal'.
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
CAPECITABINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Platelet count abnormal'.
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
CAPECITABINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'White blood cell disorder'.
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
CAPECITABINE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
What was the administration route of drug 'CAPECITABINE'?
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
Oral
|
DrugAdministrationRoute
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
What was the dosage of drug 'CAPECITABINE'?
|
A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma.
A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies. This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.
This study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical-grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).
This study was an open-label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m2 capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1-4 and days 8-11 every 21-day cycle. The primary endpoint was 6-month survival rate, and secondary endpoints were progression-free survival, overall survival, disease control rate, and safety.
Thirty-nine subjects completed the study with a 46.2% stable disease rate. The median progression-free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6-month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha-fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.
Our data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.
Discussion
In 2007, sorafenib was approved by the U.S. Food and Drug Administration (FDA). Results from two phase III clinical trials indicated that sorafenib increased mOS from 7.9 months to 10.7 months (in the U.S. SHARP trial) and from 4.2 months to 6.5 months (in the Asia‐Pacific trial). One potential explanation for the difference between the two populations was the etiology of the underlying hepatitis, with HBV‐positive HCC more prevalent in Asian countries. Any regimens capable of increasing the therapeutic index of current therapies among HBV‐positive patients with HCC would benefit the global HCC population.
YIV‐906 (PHY906) was developed as an orphan drug for treating patients with advanced liver cancer. In March 2018, the FDA granted YIV‐906 orphan drug designation for the indication of HCC. Based on the encouraging safety profile and the median overall survival from previous U.S. and Taiwan studies of YIV‐906 and capecitabine combination therapy and a phase I YIV‐906 and sorafenib combination therapy, an ongoing phase II randomized placebo‐controlled study investigating the combination of YIV‐906 and sorafenib (Nexavar, Bayer, Leverkusen, Germany) in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted by Yiviva Inc. at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for YIV‐906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
In this study, the combination of PHY906 plus capecitabine was found to have an mOS of 6 months with a 6‐month survival rate of 51% among 39 patients assessed by intention to treat. Results indicated that patients who were systemic therapy naïve, including chemotherapy (n = 7), thalidomide, or everolimus treatments, could have better clinical outcome than those who have received multiple prior systemic therapies, with mOS of 9.2 and 5.45 months, respectively. Interestingly, patients with lower starting AFP also showed better mOS (9.2 months). In addition, 27 patients were treated with at least two cycles of study drug, whereas 12 patients had fewer than two cycles of treatment. A subgroup analysis was performed comparing these 27 evaluable patients with nonevaluable patients (fewer than two cycles of treatment, n = 12). The data indicated an mOS of 8.4 months versus 1.8 months (Fig. 1A; p = .0084).
Figure 1 Kaplan‐Meier plots: percentage survival. (A): Impact of treatment cycles on the clinical outcomes. (B): Chemotherapy‐naïve evaluable patients with hepatocellular carcinoma and hepatitis B virus benefited most with PHY906 plus capecitabine drug treatment (combination of both U.S. and Taiwan studies).Abbreviations: CI, confidence interval; HR, hazard ratio; mOS, median overall survival.
In our previous study of PHY906/capecitabine in the U.S., better clinical outcomes were reported in evaluable Asian patients (who completed at least two cycles of treatment) than in the evaluable non‐Asian patients, with mOS of 16.5 and 6.9 months, respectively. By combining HBV‐positive, evaluable, Asian patients with HCC who were naïve to systemic therapy in both the Taiwan and the U.S. trials, the mOS was 16.5 months (Fig. 1B), suggesting that the PHY906/capecitabine combination may provide a survival benefit and has a tolerable safety profile for patients with HCC and HBV infection. This effect has also been observed in colon cancer, pancreatic cancer, and chemoradiation therapy.
Based on the encouraging safety profile and the mOS from previous studies, an ongoing phase II randomized placebo‐controlled study investigating the combination of PHY906 and sorafenib in HBV‐positive patients with advanced hepatocellular carcinoma is being conducted at 22 study sites in the U.S., China, Hong Kong, and Taiwan. The goal is to seek approval in the U.S. and China for PHY906 as a prescription drug for first‐line (sorafenib), second‐line (PD‐1), or third‐line (capecitabine) therapy.
Trial Information
Disease Hepatocellular carcinoma
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy One prior regimen
Type of Study Phase II, single arm
Primary Endpoint Six‐month survival rate
Secondary Endpoints Disease control rate (complete response/partial response + stable disease), progression‐free survival, overall survival, AFP reduction, change in quality of life, safety
Investigator's Analysis Active and should be pursued further
Drug Information
Drug 1
Generic/Working Name PHY906, KD018, YIV‐906
Trade Name YIV‐906
Company Name Yiviva Inc.
Dose 800 b.i.d. milligrams (mg) per day
Route Oral (p.o.)
Schedule of Administration Patients were initially treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment, days 1 through 14, and 7 days off treatment; PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Drug 2
Generic/Working Name Xeloda
Trade Name Capecitabine
Company Name Roche
Dose 750 milligrams (mg) per squared meter (m2)
Route Oral (p.o.)
Schedule of Administration Patients were initially be treated for two 21‐day courses with PHY906 800 mg b.i.d. + capecitabine 750 mg/m2 b.i.d. according to the following schedule: capecitabine 14 days on treatment and 7 days off treatment and PHY906 days 1 through 4 and days 8 through 11 of each course. Patients might remain on study beyond their initial two courses of treatment until tumor progression or unacceptable toxicity mandated their removal.
Patient Characteristics
Number of Patients, Male 32
Number of Patients, Female 7
Stage Stage II: 1 (2.6%); stage IIIA: 14 (35.9%); stage IIIB: 3 (7.7%); stage IIIC 4 (10.3%); stage IV 17 (43.6%)
Age Median (range): 54 (32–75) years
Number of Prior Systemic Therapies Median (range): 1 (0–3)
Performance Status: ECOG 0 — 0
1 — 39
2 — 0
3 — 0
Unknown — 0
Cancer Types or Histologic Subtypes Hepatocellular carcinoma: 39
Hepatocellular carcinoma + HBV: 27
Hepatocellular carcinoma + hepatitis C virus: 7
Hepatocellular carcinoma + HBV + hepatitis C virus: 5
Primary Assessment Method
Title Response Assessment
Number of Patients Screened 45
Number of Patients Enrolled 39
Number of Patients Evaluable for Toxicity 39
Number of Patients Evaluated for Efficacy 39
Evaluation Method RECIST 1.0
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 0 (0%)
Response Assessment SD n = 18 (46.2%)
Response Assessment PD n = 20 (51.3%)
Response Assessment OTHER n = 1 (2.6%)
(Median) Duration Assessments PFS 1.50 months; confidence interval: 95%
(Median) Duration Assessments OS 6.03 months
Adverse Events
All Cycles
Name NC/NA, % Grade 1, % Grade 2, % Grade 3, % Grade 4, % Grade 5, % All grades, %
Diarrhea 49 38 10 3 0 0 51
Fatigue (asthenia, lethargy, malaise) 51 31 18 0 0 0 49
INR of prothrombin time 62 33 5 0 0 0 38
Bilirubin (hyperbilirubinemia) 56 5 26 10 3 0 44
Rash: hand‐foot skin reaction 85 10 5 0 0 0 15
Insomnia 66 26 8 0 0 0 34
Hyperpigmentation 74 26 0 0 0 0 26
Anorexia 74 10 13 3 0 0 26
Distension/bloating, abdominal 71 5 21 3 0 0 29
Nausea 71 26 3 0 0 0 29
Edema: limb 74 18 8 0 0 0 26
Alkaline phosphatase 95 5 0 0 0 0 5
ALT, SGPT 66 21 5 8 0 0 34
AST, SGOT 51 5 18 18 8 0 49
Sodium, serum‐low (hyponatremia) 76 13 0 8 3 0 24
Pain: abdomen NOS 49 23 18 10 0 0 51
Dyspnea (shortness of breath) 73 21 3 3 0 0 27
Platelets 71 21 5 0 3 0 29
Hemoglobin 46 23 28 3 0 0 54
Leukocytes (total WBC) 81 8 8 0 3 0 19
Lymphopenia 77 0 8 15 0 0 23
Neutrophils/granulocytes (ANC/AGC) 91 3 3 0 3 0 9
Abbreviations: AGC, atypical glandular cells; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; INR, international normalized ratio; NC/NA, no change from baseline/no adverse event; NOS, not otherwise specified; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell.
Assessment, Analysis, and Discussion
Completion Study completed
Investigator's Assessment Active and should be pursued further
Hepatocellular carcinoma (HCC) is a leading cause of death from cancer worldwide. The median survival time of patients with unresectable and recurrent HCC ranges from 3 to 7 months [1, 2, 3]. The etiology of the disease is multifactorial; hepatitis B virus (HBV) and C virus infections are strongly linked to its development [4, 5, 6, 7, 8]. Over the last few years, the number of cases of HCC has increased in the U.S., mainly because of hepatitis C virus infection. Worldwide, 55% of all HCC cases are reported from China, and more than 60% of HCC cases are associated with HBV infection [9, 10, 11, 12]. In most instances, HCC is associated with a background history of decompensated liver disease and cirrhosis. Usually patients with HCC present with advanced disease, whereby surgical resection and/or chemical embolism is not feasible; treatment options for such patients are limited [13, 14, 15, 16]. Inoperable HCC cases are mostly treated with sorafenib as first‐line treatment [17], and the efficacy of sorafenib has been evaluated in two large multicenter, randomized, double‐blind, placebo‐controlled phase III trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial and a phase III trial conducted in the Asia‐Pacific region [18, 19]. Both trials demonstrated that sorafenib enhanced median overall survival (mOS) and time to tumor progression when compared with placebo. A noninferior alternative to sorafenib is lenvatinib, which received FDA approval for the first‐line treatment of unresectable HCC in 2018 [20]. Capecitabine, an oral 5‐fluorouracil prodrug approved for the treatment of metastatic colorectal and breast cancer, has been used off label to treat HCC and showed modest activity before any anti‐HCC drugs were approved [21, 22, 23, 24]. Studies also showed that capecitabine plus bevacizumab, or capecitabine plus bevacizumab/oxaliplatin in advanced HCC, were also effective and tolerable [25, 26]. The most common side effects associated with capecitabine are myelosuppression and skin toxicity, and the most limiting side effect is severe gastrointestinal (GI) toxicity. In contrast, common side effects associated with sorafenib include abdominal pain, anorexia, diarrhea, fatigue, hair loss, hand or foot skin reaction, nausea, rash or superficial skin shedding, and weight loss in patients with HCC [18, 19, 27, 28]. Among all side effects caused by sorafenib, 55% of recipients report diarrhea [29, 30]. Therefore, any agent that can alleviate the toxicity caused by HCC therapeutics without compromising the antitumor efficacy will provide an additive benefit. The FDA has approved several immunotherapies for HCC, including atezolizumab plus bevacizumab as first‐line treatment and nivolumab or pembrolizumab as second‐line treatments.
Traditional Chinese medicine has been used to treat a variety of diseases for centuries, especially for GI symptoms like nausea, vomiting, diarrhea, and abdominal spasms [31, 32, 33]. One traditional Chinese medicine formulation, PHY906 or YIV‐906, comprising a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and Ziziphus jujube Mill.), has been used for approximately 1,800 years for a variety of maladies, most notably severe gastrointestinal distress, for example, nausea, vomiting, diarrhea, and abdominal spasms. It is prepared under current Good Manufacturing Practice conditions and has been well characterized by both chemical and biological fingerprints. Multiple clinical batches of PHY906 have been documented to have more than 90% consistency using integration of chemical and biological fingerprints. Stability studies indicated that PHY906 capsules remained stable for at least 6 years at room temperature.
Notably, PHY906/YIV‐906 does not exhibit toxicities with other agents used for HCC chemotherapy in preclinical and clinical studies [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In fact, in nearly all cases, the combination regimen was found to imply a better therapeutic outcome than the historical efficacy of the chemotherapeutic agent alone and did not exhibit toxicities [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. More importantly, quality of life scores did not deteriorate significantly from baseline scores. For example, the mechanism of action in reducing CPT‐11–induced diarrhea and intestinal damage involves inhibition of several inflammatory processes, such as NF‐κB, COX‐2, IL‐6, iNOs, and promoting intestinal progenitor cell repopulation [35, 36]. In addition, the mechanism of enhancing antitumor agents are due to the activation of innate and adaptive immunity in the tumor tissue microenvironment [37, 39, 46, 47].
PHY906/capecitabine combination therapy resulted in limited deleterious side effects. Previous data from a U.S.‐based phase I/II clinical trial involving PHY906/capecitabine therapy revealed beneficial effects and reduced toxicities for the Asian subpopulation with an mOS of 16.5 months and no capecitabine‐induced grade 3/4 GI toxicities in advanced nonresectable patients (with HCC) with the PHY906 plus capecitabine combination therapy from a phase I/II study of PHY906 plus capecitabine in the U.S [49]. This study sought to validate similar effects of reduced chemotherapy‐induced gastrointestinal toxicity and enhanced antitumor activity for patient populations with HCC in Taiwan.
In the present study, capecitabine/PHY906 combination therapy resulted in only a few grade 3 and 4 drug‐related toxicities. In essence, this combination was well tolerated by patients in both the current Taiwan and previous U.S. HCC studies. The incidence of nausea and emesis was lower with the PHY906/capecitabine combination than with the capecitabine treatment alone. Moreover, only two patients (5.13%) discontinued treatment in the current combination because of adverse effects from capecitabine [18, 19, 23, 24]. Similar to the earlier trial in the U.S., toxicities were manageable with minimal grade 3 or 4 toxicities [48]. As in the previous U.S. trial, quality of life scores did not deteriorate significantly from baseline scores during the combination therapy of PHY906 and capecitabine. These observations concur with previous studies involving irinotecan‐based chemotherapy in colorectal cancer, gemcitabine‐refractory pancreatic cancer, and chemoradiation therapy in rectal cancer [37, 39, 46, 47, 49].
Sorafenib has been standard for HCC treatment. Based on results of the SHARP and Asia‐Pacific phase III studies, 95% of patients were classified as Child‐Pugh A and had no previous treatment. The mOS of patients enrolled in the SHARP and Asian studies was 10.7 and 6.5 months, respectively, whereas that of placebo was 7.9 and 4.2 months, respectively [18, 19]. The patients enrolled in the current study had a poorer prognosis; 90% were previously treated with chemotherapy or targeted therapy involving chemoembolization or radiation, and > 60% had had two prior treatments. The antitumor outcome (mOS, 6‐month‐ or 12‐month survival rate) in our Taiwan study (n = 39) was not as promising as that of U.S. study (n = 42). The combination regimen of PHY906 plus capecitabine was mainly used as the first‐line treatment in the U.S. study, whereas it was mainly used as a second‐ or third‐line treatment in the Taiwan study. Patients in the present Taiwan study were heavily pretreated with various procedures or regimens, including targeted therapies, chemotherapies, transarterial chemoembolization/percutaneous ethanol injection, surgery, radiation therapy, or a combination. The starting alpha‐fetoprotein (AFP) levels were relatively higher in Taiwan, with 33.3% of patients having AFP higher than 12,000 ng/mL, compared with the counterpart U.S. study (16.7%) [48].
In the Taiwan study, the PHY906/capecitabine combination increased the median overall survival time to 6 months, whereas the average survival time was around 3 months for patients with HCC whose previous treatments had failed. Patients who did not receive prior targeted therapy or chemotherapy, or who had lower starting AFP level, had a better clinical outcome. Because some of the patients did not finish two courses of combination therapy, additional analysis was done to compare the differences between patients who had fewer than two cycles of treatment (n = 12) and patients who completed at least two cycles of treatment (n = 27). The mOS difference between these two groups of patients was 1.8 and 8.4 months, respectively (p = .0084) (Fig. 1A). Interestingly our data also indicated that HBV‐positive evaluable patients (with two or more courses of combination therapy) had an mOS of 8.4 months. In our previous PHY906/capecitabine U.S. study, Asian patients (n = 10) had an mOS of 16.5 months, relative to 6.7 months for the non‐Asian counterpart (n = 10). Notably, patients in the group infected with HBV only (n = 9) did not reach 50% overall survival, whereas a median survival of 6.7 months was estimated for others (n = 11). The results implied that combination therapy might benefit Asian patients with HBV infection. By combining Asian HBV‐infected patients (with HCC) who (a) did not receive prior systemic therapy and (b) finished two or more cycles of combination treatment from the U.S. and Taiwan trials, the mOS was 16.5 months (Fig. 1B). These results support the notion that the PHY906/capecitabine combination therapy may provide a survival benefit with a tolerable safety profile in patients with advanced HCC. Moreover, Asian patients with HBV seem to have remarkable mOS in both previous and current HCC studies. These results suggest that PHY906/capecitabine combination therapy may provide a selective clinical advantage for patients with HCC and HBV infection.
The mechanism underlying the function of PHY906 is multifactorial and could involve inhibition of multidrug‐resistant protein and CYP450, which may facilitate the uptake of chemotherapeutic drugs. Several pathways have been implicated in the mechanism of PHY906. The inhibition of tachykinin NK‐1, opiate δ receptors, and acetylcholinesterase could be reasons for the reduction of gastrointestinal toxicity [51]. Moreover, reports have shown that NF‐κB and matrix metalloproteases can be inhibited by PHY906. PHY606 may also affect the integrity of blood vessels and HIF‐α and Fos/Juk pathway. In mouse models, PHY906 was found to increase the inflammation in the tumor microenvironment through activation of M1 macrophages, resulting in tumor rejection [44]. Some or all of these mechanisms could play a critical role in PHY906 enhancement of antitumor properties when combined with other chemotherapeutic agents.
Based on previous studies, the Chinese herb medicine extract PHY906 is a formula that enhances antitumor activity and reduces chemotherapy‐induced gastrointestinal toxicity in hepatocellular cancer. Results from this study also suggest that PHY906 combination therapy could be an alternative to currently available treatment options for HCC. Further larger cohorts for phase II/III clinical studies involving PHY906 combination therapy are warranted. For future consideration, the trial design can be improved by using a double‐blind, randomized placebo control to reduce the potential bias. Moreover, the inclusion criteria can be redefined on the number of prior treatments to confirm whether PHY906 selectively benefits naïve patients with HCC or those receiving second, third, or multiple lines of treatment. The combination treatment options could also be redesigned and use FDA‐approved standard of care, such as sorafenib or lenvatinib instead of capecitabine, in the trial. Therefore, an ongoing study entitled “A Phase II Randomized Placebo‐Controlled Study Investigating the Combination of YIV‐906 and Sorafenib (Nexavar) in HBV(+) Patients with Advanced Hepatocellular Carcinoma” (ClinicalTrials.gov identifier: NCT04000737) was designed to resolve the previously mentioned issues. We plan to conduct a phase III study to combination therapy of PHY906 plus capecitabine as a third‐line therapy for Asian patients with HCC and HBV infection.
Disclosures
Shwu‐Huey Liu: Yiviva (E, OI [cofounder]), PHY906 (YIV‐906) patents (IP); Yung‐Chi Cheng: Yiviva (E, OI [cofounder], C/A, SAB, RF‐institutional), PHY906 (YIV‐906) patents (IP). 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
Acknowledgments
The authors thank National Health Research Institutes and TTY Biopharm Co., Ltd for conducting and sponsoring the study in Taiwan. The authors also thank TTY Biopharm Co., Ltd. for supporting this clinical trial in Taiwan between 2008 and 2012. Parts of this study were supported by Sino‐American Cancer Foundation. The authors wish to acknowledge An Lu for her assistance in the preparation of this manuscript.
ClinicalTrials.gov Identifier: NCT00076609
Sponsor: Yiviva Inc.
Principal Investigator: Yun Yen
IRB Approved: Yes
Click here to access other published clinical trials.
|
14 DAYS ON TREATMENT, DAYS 1 THROUGH 14, AND 7 DAYS OFF TREATMENT
|
DrugDosageText
|
CC BY-NC-ND
|
33140457
| 18,531,474
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Parkinson^s disease'.
|
Real-World Virological Efficacy and Safety of Ledipasvir and Sofosbuvir in Patients with Chronic Hepatitis C Virus Genotype 2 Infection: A Multicenter Study.
BACKGROUND
The real-world virological efficacy and safety of interferon-free direct-acting antiviral (DAA) therapy with ledipasvir (LDV) plus sofosbuvir (SOF) were assessed in patients who were chronically infected with hepatitis C virus (HCV) genotype 2.
METHODS
A total of 126 patients with chronic hepatitis C due to HCV genotype 2 infection who were treated with the LDV/SOF regimen were enrolled. The sustained virological response (SVR) rate and safety were analyzed. SVR was assessed in the intention-to-treat (ITT) population as well as in the modified intention-to-treat (mITT) population, which excluded patients with non-virological failure, including those who dropped out before the SVR assessment.
RESULTS
The overall SVR rates of the ITT and mITT populations were 87.3% (95% confidence interval [CI] 80.2-92.6) (110/126) and 97.3% (95% CI 92.4-99.4) (110/113), respectively. In the mITT population, the percentages of patients with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 92.9% (95% CI 86.5-96.9) (105/113), 99.1% (95% CI 95.2-100.0) (112/113), and 100.0% (95% CI 97.4-100.0) (113/113), respectively. Subgroup analyses of the mITT population showed no significant differences in SVR rates according to age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, or baseline estimated glomerular filtration rate. In all subpopulations, the SVR rates were > 90%. There were no severe adverse events associated with the treatment.
CONCLUSIONS
The LDV/SOF regimen showed high virological efficacy and acceptable safety in patients with HCV genotype 2 infection.
BACKGROUND
UMIN registration no. 000038604.
Key Summary Points
Why carry out this study?
In a Japanese randomized controlled trial, LDV/SOF treatment in patients with HCV genotype 2 resulted in high SVR rates (96%) that were equivalent to those of SOF plus ribavirin (95%).
Real-world clinical data on LDV/SOF treatment for patients with HCV genotype 2 are limited.
To investigate the real-world outcomes of LDV/SOF treatment for patients with HCV genotype 2 in a multicenter study conducted throughout Japan.
What was learned from the study?
The overall SVR rates of the ITT and mITT populations were 87.3% (110/126) and 97.3% (110/113), respectively.
There were no severe adverse events associated with the treatment.
The LDV/SOF regimen showed high virological efficacy and acceptable safety in patients with HCV genotype 2.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to 10.6084/m9.figshare.13118183.
Introduction
Hepatitis C virus (HCV) infection affected 71 million people globally in 2015 [1]. It is a major risk factor for cirrhosis, hepatocellular carcinoma (HCC), and liver-related death. In Japan, 1.0–1.5 million individuals are infected with HCV, and approximately 55% of HCC is associated with chronic HCV infection [2]. Anti-HCV therapy to eradicate HCV is an essential treatment for chronic HCV infection, as it reportedly prevents the progression of liver fibrosis [3–5] and the development of HCC [6–10] and also reduces all-cause mortality, including mortality due to non-liver-related diseases [11, 12].
Among the six HCV genotypes, HCV genotype 2 accounts for approximately 13% of infections globally [13]. This HCV genotype is common in Latin America, sub-Saharan Africa, and East Asia. In many countries in these regions, official approval for new direct-acting antivirals (DAAs) has been delayed because DAA treatment is costly and market access and governmental restrictions differ between certain countries. The current guidelines of the American Association for the Study of Liver Diseases [14] and the European Association for the Study of the Liver [15] recommend the following interferon-free DAA regimens for patients with HCV genotype 2 infection: sofosbuvir (SOF) plus velpatasvir for 12 weeks or glecaprevir plus pibrentasvir for 8–12 weeks.
Until recently, approximately 70% of patients with HCV infection in Japan had genotype 1b and the remainder had genotype 2 [16]. Lately, however, the proportion of HCV genotype 1b has decreased and is now < 50% in individuals born after 1970. By contrast, the percentage of HCV genotype 2 infection, especially 2b, has increased in younger generations. The current guidelines of the Japan Society of Hepatology [17] recommend the following interferon-free DAA regimens for non-decompensated cirrhotic patients with HCV genotype 2 infection: SOF plus ribavirin for 12 weeks, glecaprevir plus pibrentasvir for 8–12 weeks, or ledipasvir (LDV) plus SOF for 12 weeks. LDV is an HCV NS5A inhibitor, and SOF is a potent NS5B nucleotide polymerase inhibitor with pan-genotypic activity and a high barrier to resistance. In a Japanese randomized controlled trial, LDV/SOF treatment in patients with HCV genotype 2 infection resulted in high sustained virological response (SVR) rates (96%) that were equivalent to those of SOF plus ribavirin (95%) [18]. However, real-world clinical data on LDV/SOF treatment for patients with HCV genotype 2 infection are limited. Therefore, it is necessary to clarify the real-world clinical outcomes of LDV/SOF treatment for patients with HCV genotype 2 infection in Japan.
In this study, we analyzed the real-world outcomes of this treatment approach for patients with HCV genotype 2 infection in a multicenter study conducted throughout Japan.
Methods
Patients
This prospective cohort study was conducted to characterize the prevalence of nonhypervascular hypointense nodules (NHHNs) during the hepatobiliary phase of EOB-MRI and the incidence of hyper-vascularization among patients in whom HCV was eradicated with DAA therapy. The study was registered to the UMIN Clinical Trial Registry (UMIN000017020). The study was conducted after approval by the hospital's Institutional Review Board. It was carried out in compliance with the Helsinki Declaration. Written informed consent was obtained from all participating patients. This study was approved by the ethics committee of Ogaki Municipal Hospital (IRB #20180927-13-k). All documents approved by Ogaki Municipal Hospital (Kumada T) were sent to each institution and approved by each institution under the same IRB name and number. This study was performed in accordance with the 2013 Helsinki Declaration. All patients consented to provide their data. Written informed consent was obtained from each patient before enrollment. All patients consented to provide their data. Consent to participate and allow their data to be published was obtained from each patient before enrollment.
This was a multicenter study conducted at 18 institutions in the Hokkaido, Kanto, Hokushinnestu, Chubu, Kansai, Chugoku, Shikoku, and Kyusyu areas of Japan. A total of 126 patients with chronic hepatitis C due to HCV genotype 2 infection who underwent DAA treatment with the LDV/SOF regimen between September 2018 and September 2019 were enrolled. Persistent infection with HCV genotype 2 was proved in all patients by both positive serum HCV antibody titers (ARCHITECT Anti-HCV; Abbott Laboratories, Abbott Park, IL, USA) and the presence of serum HCV RNA determined using a real-time PCR–based method (COBAS AmpliPrep/COBAS TaqMan HCV Test version 2; Roche Molecular Systems, Pleasanton, CA, USA; lower limit of quantification, 1.6 log10 IU/ml; lower limit of detection, 1.2 log10 IU/ml). HCV genotype was evaluated by PCR with genotype-specific primers to amplify the core gene sequences [19]. In some institutions, only the HCV serotype could be determined by a serotyping assay based on the type-specific antibodies because of insurance coverage. Patients with severe chronic renal failure were excluded. Patients with decompensated cirrhosis were also excluded because this DAA regimen is contraindicated for this population in Japan.
Treatment and Follow-Up
Patients received fixed doses of LDV (90 mg) and SOF (400 mg) (Harvoni; Gilead Sciences, Tokyo, Japan) once daily on an outpatient basis. The duration of the treatment regimen was scheduled for 12 weeks. Patients were asked to visit the clinic for monitoring of treatment response every 2 weeks throughout the treatment period and every 4 weeks during follow-up, which lasted until 12 weeks after the end of treatment. Laboratory data, specifically complete blood count and serum levels of alanine aminotransferase, aspartate aminotransferase, albumin, total bilirubin, and creatinine, were measured before and every 2–4 weeks after the start of therapy. Serum HCV RNA levels were measured before treatment; at 4, 8, and 12 weeks after the start of therapy while treatment was ongoing; at the end of treatment; and at 12 weeks after the end of treatment. Viral suppression was defined as undetectable serum HCV RNA. Relapse was defined when serum HCV RNA was undetectable at the end of therapy but became detectable between the end of treatment and 12 weeks after the completion of therapy. Breakthrough was defined when HCV RNA became detectable after its initial disappearance during treatment. Non-response was defined when serum HCV RNA levels increased despite their initial decrease during treatment. SVR was defined as undetectable serum HCV RNA at 12 weeks after the end of treatment. In this study, SVR was assessed in the intention-to-treat (ITT) population as well as in the modified intention-to-treat (mITT) population, which excluded patients with non-virological failure, including those who dropped out before the SVR assessment. Potential adverse events, including laboratory value abnormalities that emerged after the start of therapy, were monitored by attending physicians at every patient visit. Treatment discontinuation was determined based on attending physicians’ evaluations.
Assessment of Advanced Liver Fibrosis and Renal Dysfunction
Liver fibrosis was assessed based on pretreatment laboratory data using the FIB-4 index, a laboratory liver fibrosis index defined by the following formula [20]: aspartate aminotransferase [IU/l] × age [years]/platelet count [109/l] × alanine aminotransferase [IU/l]1/2. Patients were defined as having advanced fibrosis (i.e., F3 or F4 by the METAVIR score [21]) when the FIB-4 index was ≥ 3.25 [22].
Renal function was assessed by the estimated glomerular filtration rate (eGFR) (ml/min/1.73 m2) based on pretreatment laboratory data using the following formula [23]: 194 × serum creatinine (mg/dl) − 1.094 × age − 0.287 × 0.739 (if female). Chronic kidney disease was classified as eGFR < 60 ml/min/1.73 m2 [24]. In addition, severe chronic renal failure was classified as eGFR < 30 ml/min/1.73 m2 [24].
Statistical Analysis
Continuous variables are expressed as medians (the first–third quartiles). For comparisons of baseline characteristics and SVR rates between patient subgroups, differences in categorical variables were analyzed using Fisher’s exact test.
All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [25]. More precisely, it is a modified version of the R commander designed to add statistical functions frequently used in biostatistics. Statistical significance was defined as p < 0.05.
Results
Patient Characteristics
Table 1 shows the characteristics of the study patients at the start of DAA therapy. There were 65 females (51.6%) and 61 males (48.4%), with a median (interquartile range) age of 60.5 (47.0–74.0) years.Table 1 Patient characteristics (n = 126)
Age (years)* 60.5 (47.0–74.0)
Sex (female/male) 65/61
History of interferon-based therapy (no/yes) 116/10
History of curatively treated HCC (no/yes) 121/5
Aspartate aminotransferase (IU/l)* 34 (26–54)
Alanine aminotransferase (IU/l)* 36 (21–69)
γ-glutamyl transpeptidase (IU/l)* 38 (20–64)
Albumin (g/dl)* 4.1 (3.8–4.4)
Total bilirubin (mg/dl)* 0.6 (0.5–0.8)
Creatinine (mg/dl)* 0.72 (0.60–0.83)
Prothrombin time (%)* 103 (91–112)
Platelet count (× 104/mm3)* 19.8 (15.2–26.1)
Hemoglobin (g/dl)* 13.7 (12.8–14.8)
Fasting plasma glucose (mg/dl)* 102 (91–113)
HCV genotype (2a/2b/2 [un-subtyped]) 80/40/6
HCV RNA (log10 IU/ml)* 6.1 (4.9–6.6)
FIB-4 index* 1.83 (0.95–3.19)
eGFR (ml/min/1.73 m2)* 62.4 (41.0–87.3)
HCV hepatitis C virus, HCC hepatocellular carcinoma, eGFR estimated glomerular filtration rate
*Values are expressed as medians (first to third quartiles)
The age was ≥ 70 years in 46 patients (36.5%), including 18 patients (14.3%) who were ≥ 80 years old. Ten patients (7.9%) had a history of interferon-based therapy, and one patient (0.8%) had a history of interferon-free DAA therapy. The FIB-4 index at baseline was > 3.25 in 31 patients (24.6%). Five patients (4.0%) had a history of curatively treated HCC. Renal dysfunction with eGFR < 60 ml/min/1.73 m2 was observed in 59 patients (46.8%). Among patients who underwent HCV subtyping, there were 80 (63.5%) and 40 (31.5%) patients with genotype 2a and 2b, respectively.
Virological Treatment Outcomes in the ITT and mITT Populations
The overall SVR rates in the ITT and mITT populations were 87.3% (95% confidence interval [CI] 80.2–92.6) (110/126) and 97.3% (95% CI 92.4–99.4) (110/113), respectively.
The percentages of the mITT population with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 92.9% (95% CI 86.5–96.9) (105/113), 99.1% (95% CI 95.2–100.0) (112/113), and 100.0% (95% CI 97.4–100.0) (113/113), respectively.
Virological Treatment Outcomes in the ITT Population Subgroups
Figure 1 shows SVR rates based on patient age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, and baseline eGFR in the ITT population. The SVR rates in patients with baseline FIB-4 index (≤ 3.25/> 3.25) were 91.6% (95% CI 84.1–96.3) (87/95)/74.2% (95% CI 55.4–88.1) (23/31). The SVR rate was significantly lower in patients with a baseline FIB-4 index ≥ 3.25 (p = 0.025), but did not differ significantly according to any of the other parameters.Fig. 1 SVR rates in ITT population subgroups. The SVR rates in the ITT population were stratified by subgroups, as follows: patient age (< 70 years/≥ 70 years), 91.2% (95% CI 82.8–96.4) (73/80)/80.4% (95% CI 66.1–90.6) (37/46) (p = 0.098); sex (female/male), 90.8% (95% CI 81.0–96.5) (59/65)/83.6% (95% CI 71.9–91.8) (51/61) (p = 0.288); HCV genotype (2a/2b), 88.8% (95% CI 79.7–94.7) (71/80)/87.5% (95% CI 73.2–95.8) (35/40) (p = 1.000); history of interferon-based therapy (yes/no), 80.0% (95% CI 44.4–97.5) (8/10)/87.9% (95% CI 80.6–93.2) (102/116) (p = 0.614); baseline FIB-4 index (≤ 3.25/> 3.25), 91.6% (95% CI 84.1–96.3) (87/95)/74.2% (95% CI 55.4–88.1) (23/31) (p = 0.025); and baseline eGFR (< 60/≥ 60 ml/min/1.73 m2), 91.5% (95% CI 81.3–97.2) (54/59)/83.6% (95% CI 72.5–91.5) (56/67) (p = 0.404), respectively. The error bars indicate the lower and upper values of the 95% CI of each SVR rate. SVR sustained virological response, ITT intention to treat, HCV hepatitis C virus, CI confidence interval
Reasons for Lack of Inclusion in the mITT Population
Thirteen patients were excluded from the ITT population. There were 1, 1, 1, 1, and 3 patients who self-discontinued their DAA administration at 1, 2, 4, 6, and 8 weeks after the start of treatment, respectively. In addition, there were 1, 1, and 3 patients who self-discontinued their visits at 0, 4, and 8 weeks after the end of treatment, respectively. One patient who discontinued DAA administration because of worsening of current disease (worsening of Parkinson’s symptoms).
Virological Treatment Outcomes in mITT Population Subgroups
Figure 2 shows SVR rates based on patient age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, and baseline eGFR in the mITT population. There were no significant differences in SVR rates according to these parameters.Fig. 2 SVR rates in mITT population subgroups. The SVR rates in the mITT population were stratified by subgroups, as follows: patient age (< 70 years/≥ 70 years), 98.6% (95% CI 92.7–100.0) (73/74)/94.9% (95% CI 82.7–99.4) (37/39) (p = 0.273); sex (female/male), 98.3% (95% CI 91.1–100.0) (59/60)/96.2% (95% CI 87.0–99.5) (51/53) (p = 0.599); HCV genotype (2a/2b), 98.6% (95% CI 92.5–100.0) (71/72)/94.6% (95% CI 81.8–99.3) (35/37) (p = 0.265); history of interferon-based therapy (yes/no), 100.0% (95% CI 68.8–100.0) (8/8)/97.1% (95% CI 91.9–99.4) (102/105) (p = 1.000); baseline FIB-4 index (≤ 3.25/> 3.25), 98.9% (95% CI 93.8–100.0) (87/88)/92.0% (95% CI 74.0–99.0) (23/25) (p = 0.123); and baseline eGFR (< 60/≥ 60 ml/min/1.73 m2), 98.2% (95% CI 90.3–100.0) (54/55)/96.6% (95% CI 88.1–99.6) (56/58) (p = 1.000), respectively. The error bars indicate the lower and upper values of the 95% CI of each SVR rate. SVR sustained virological response, mITT modified intention to treat, HCV hepatitis C virus, CI confidence interval
Table 2 lists the characteristics of three patients who failed to achieve SVR in the mITT population. All three patients relapsed after the end of therapy. Of these, two patients were infected with genotype 2b HCV and had a baseline FIB-4 index of ≥ 3.25.Table 2 Patients who failed to achieve SVR (n = 3)
No. 1 2 3
Age 83 69 71
Sex Male Female Female
History of interferon-based therapy No No No
History of curatively treated HCC No No Yes
HCV genotype 2a 2b 2b
HCV RNA (log10 IU/ml) 6.5 6.8 6.5
FIB-4 index 2.12 6.35 10.24
eGFR (ml/min/1.73 m2) 71.9 44.4 85.0
Undetectable HCV RNA after the start of therapy 8 weeks 8 weeks 4 weeks
Detectable HCV RNA after the end of therapy 4 weeks 4 weeks 12 weeks
Details of SVR Relapse Relapse Relapse
HCC hepatocellular carcinoma, HCV hepatitis C virus, eGFR estimated glomerular filtration rate
Safety
Two patients had adverse events during the DAA treatment. In one patient (84-year-old female; genotype 2a) with Parkinson’s disease, the DAA treatment was discontinued at 1 week after the start of therapy because of worsening of Parkinson’s symptoms. These symptoms improved after the DAA treatment was stopped. However, the causal relation of the treatment and this adverse effect was unclear. Another patient (50-year-old female; genotype 2a) developed oral ulcers at 2 weeks after the start of therapy, but they were mild and she was able to continue treatment. These oral ulcers were considered as an adverse event related to LDV/SOF treatment by the attending physician.
Discussion
This multicenter clinical study conducted throughout Japan enrolled a relatively large number of patients with HCV genotype 2 infection and either chronic hepatitis or non-decompensated cirrhosis and showed that LDV/SOF treatment achieved a high SVR rate of 97.3% in the mITT population. In this group, HCV RNA was undetectable in > 90% of patients at 4 weeks after the start of treatment and in almost all patients (99.1%) at 8 weeks. Furthermore, subgroup analyses of the mITT population based on patient age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, and baseline eGFR showed no significant differences in SVR rates according to these parameters. Notably, high SVR rates > 90% were obtained in the mITT population even in elderly individuals and those with advanced fibrosis or a history of interferon-based therapy. Regarding safety, only one elderly patient discontinued this DAA treatment because of exacerbation of Parkinson’s disease symptoms. As a result, there were only one dropout patient and one patient with a mild adverse event (oral ulcers), respectively, associated with this DAA treatment. Therefore, it is considered that the LDV/SOF treatment showed excellent efficacy and acceptable safety in patients with HCV genotype 2 infection.
Genotype 2 HCV has previously shown high rates of response to combination therapy with SOF plus ribavirin, a broad-spectrum antiviral. In three registered studies of SOF plus ribavirin, 12 weeks of treatment resulted in an SVR rate of 94% among patients with chronic HCV genotype 2 infection [26–28]. Compared with SOF, which has a favorable safety profile and is well tolerated [29], ribavirin has poorer tolerability, mostly because it can cause hemolytic anemia. HCV patients with ribavirin-associated anemia have significantly increased resource utilization and medical costs [30].
LDV/SOF has been investigated for the treatment of patients with HCV genotype 2 infection in phase 2 and 3 trials in the Asia-Pacific region [18, 31, 32]. Gane et al. [31] reported in their phase 2 trial that the SVR rates at 8 weeks and 12 weeks after the start of LDV/SOF treatment were 74% (20/27) and 96% (25/26), respectively, in patients with HCV genotype 2, indicating a significant difference between time points (p < 0.001). In a phase 3 trial conducted in a Japanese cohort with HCV genotype 2 infection, Asahina et al. [18] showed that SVR rates were 96% (102/106) with LDV/SOF treatment and 95% (103/108) with SOF plus ribavirin treatment, indicating that LDV/SOF was non-inferior to SOF plus ribavirin. However, limited real-world clinical data have been reported to date on treatment outcomes with LDV/SOF in patients with HCV genotype 2 infection. There were no differences in patient characteristics such as age and sex between the phase 3 trial from Japan and this study cohort. Although almost all of the patients in this phase 3 trial visited a few university hospitals in Japan, this study's patients visited not only university hospitals but also community-based general hospitals nationwide. Recently, Liu et al. [33] demonstrated good efficacy and safety in Taiwanese patients with HCV genotype 2 infection treated with SOF-based regimens, and all 39 patients who received LDV/SOF treatment achieved SVR. Additionally, in a recent multicenter study in the Kyusyu area of Japan, Ogawa et al. [34] also reported that LDV/SOF treatment of patients with HCV genotype 2 infection was effective and safe, with an SVR rate of 96.5% (55/57) in the mITT population. In their ITT population (n = 58), there were 35 (60.3%), 10 (17.2%), and 13 (22.4%) patients with HCV genotype 2a, 2b, and 2 (un-subtyped) infection, respectively. Similar to the studies of Liu et al. [33] and Ogawa et al. [34], almost all patients in our study achieved SVR and there were no serious adverse events or deaths. An advantage of our study relative to that of Ogawa et al. was that it included more patients from throughout Japan. In addition, only 4.8% (6/126) of patients with HCV genotype 2 infection were un-subtyped. Unfortunately, there was no Japanese randomized controlled trial regarding the SOF plus velpatasvir treatment for non-decompensated cirrhotic patients with HCV genotype 2 infection. Only decompensated cirrhotic patients with HCV infection were accepted to use the SOF plus velpatasvir treatment based on the results of randomized controlled trial in Japan. Conversely, the LDV/SOF treatment for non-decompensated cirrhotic patients with HCV genotype 2 infection was accepted based on the good results of Japanese randomized controlled trial [18] in the Japanese guidelines.
The main limitation of this study was that it did not assess the relationship between SVR rate and NS5A and NS5B mutations. Generally, LDV at half-maximal effective concentration is much less efficacious against HCV genotype 2 than genotype 1, especially in patients with NS5A L31 M, despite the fact that SOF demonstrates similar efficacy against genotypes 1 and 2 [35]. However, resistance-associated substitution analysis showed that almost all patients (94–97%) with subtype 2a infection and 39–89% of those with subtype 2b infection originally had NS5A L31 M at baseline [18, 36]. In addition, the SVR rate in patients with NS5A resistance-associated substitutions was extremely high (97.6%, 165/169) in clinical trials [18, 31, 32]. Therefore, it is considered that NS5A L31 M, and not NS5B, is unassociated with treatment outcome. Further studies assessing NS5A and NS5B mutations should be performed. Another limitation is that 13 patients were excluded from the mITT population, mainly because of self-discontinuation of visits during or after LDV/SOF treatment. This may be related to the social background such as a history of intravenous drug use or a history of tattooing in patients with HCV genotype 2 infection [16, 37]. Additional studies of this treatment with fewer dropouts are warranted. Third, it included a relatively small number of patients. Future studies with more patients are warranted.
Conclusion
An IFN-free DAA regimen with LDV/SOF demonstrated a very high SVR rate and acceptable safety profile in patients infected with HCV genotype 2 infection. In particular, the LDV/SOF regimen resulted in good SVR rates regardless of patient age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, and baseline eGFR. Further studies are warranted to confirm these findings in other populations.
Acknowledgements
We thank the participants of the study.
Funding
This work was supported by Gilead Sciences (commercial research funding). Gilead Sciences also funded the journal’s Rapid Service Fees.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authorship Contributions
Concept and study design: Takashi Kumada and Toshifumi Tada. Data acquisition: All authors. Analyses of the data: Takashi Kumada and Toshifumi Tada. Statistics: Toshifumi Tada. Supervise: Takashi Kumada. Preparing the manuscript: Toshifumi Tada. Review and approval: All authors.
Disclosures
Takashi Kumada served as a speaker for Gilead and AbbVie. Hidenori Toyoda has served as a speaker for Gilead, AbbVie, and MSD. Toshifumi Tada, Hiroaki Okushin, Joji Tani, Koichi Takaguchi, Akemi Tsutsui, Satoshi Yasuda, Kazufumi Dohmen, Atsushi Hiraoka, Kojiro Michitaka, Kazuhiro Nouso, Kazuya Kariyama, Soo Ryang Kim, Soo Ki Kim, Shinichi Fujioka, Shigeru Mikami, Yuto Watanabe, Tsutomu Tamai, Masanori Atsukawa, Norio Itokawa, Hironori Tanaka, Kunihiko Tsuji, Toru Ishikawa, Michitaka Imai, Ei Itobayashi, Hiroshi Shibata, and Noritomo Shimada declare that they have no competing interests.
Compliance with Ethics Guidelines
This study was approved by the ethics committee of Ogaki Municipal Hospital (IRB #20180927-13-k). All documents approved by Ogaki Municipal Hospital (Kumada T) were sent to each institution and approved by each institution under the same IRB name and number. This study was performed in accordance with the 2013 Helsinki Declaration. All patients consented to provide their data. Written informed consent was obtained from each patient before enrollment. All patients consented to provide their data. Consent to both participate and allow the data to be published was obtained from each patient before enrollment.
Data Availability
The datasets are available from the corresponding author on reasonable request.
|
LEDIPASVIR\SOFOSBUVIR
|
DrugsGivenReaction
|
CC BY-NC
|
33141401
| 18,502,592
|
2021-03
|
What was the administration route of drug 'LEDIPASVIR\SOFOSBUVIR'?
|
Real-World Virological Efficacy and Safety of Ledipasvir and Sofosbuvir in Patients with Chronic Hepatitis C Virus Genotype 2 Infection: A Multicenter Study.
BACKGROUND
The real-world virological efficacy and safety of interferon-free direct-acting antiviral (DAA) therapy with ledipasvir (LDV) plus sofosbuvir (SOF) were assessed in patients who were chronically infected with hepatitis C virus (HCV) genotype 2.
METHODS
A total of 126 patients with chronic hepatitis C due to HCV genotype 2 infection who were treated with the LDV/SOF regimen were enrolled. The sustained virological response (SVR) rate and safety were analyzed. SVR was assessed in the intention-to-treat (ITT) population as well as in the modified intention-to-treat (mITT) population, which excluded patients with non-virological failure, including those who dropped out before the SVR assessment.
RESULTS
The overall SVR rates of the ITT and mITT populations were 87.3% (95% confidence interval [CI] 80.2-92.6) (110/126) and 97.3% (95% CI 92.4-99.4) (110/113), respectively. In the mITT population, the percentages of patients with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 92.9% (95% CI 86.5-96.9) (105/113), 99.1% (95% CI 95.2-100.0) (112/113), and 100.0% (95% CI 97.4-100.0) (113/113), respectively. Subgroup analyses of the mITT population showed no significant differences in SVR rates according to age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, or baseline estimated glomerular filtration rate. In all subpopulations, the SVR rates were > 90%. There were no severe adverse events associated with the treatment.
CONCLUSIONS
The LDV/SOF regimen showed high virological efficacy and acceptable safety in patients with HCV genotype 2 infection.
BACKGROUND
UMIN registration no. 000038604.
Key Summary Points
Why carry out this study?
In a Japanese randomized controlled trial, LDV/SOF treatment in patients with HCV genotype 2 resulted in high SVR rates (96%) that were equivalent to those of SOF plus ribavirin (95%).
Real-world clinical data on LDV/SOF treatment for patients with HCV genotype 2 are limited.
To investigate the real-world outcomes of LDV/SOF treatment for patients with HCV genotype 2 in a multicenter study conducted throughout Japan.
What was learned from the study?
The overall SVR rates of the ITT and mITT populations were 87.3% (110/126) and 97.3% (110/113), respectively.
There were no severe adverse events associated with the treatment.
The LDV/SOF regimen showed high virological efficacy and acceptable safety in patients with HCV genotype 2.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to 10.6084/m9.figshare.13118183.
Introduction
Hepatitis C virus (HCV) infection affected 71 million people globally in 2015 [1]. It is a major risk factor for cirrhosis, hepatocellular carcinoma (HCC), and liver-related death. In Japan, 1.0–1.5 million individuals are infected with HCV, and approximately 55% of HCC is associated with chronic HCV infection [2]. Anti-HCV therapy to eradicate HCV is an essential treatment for chronic HCV infection, as it reportedly prevents the progression of liver fibrosis [3–5] and the development of HCC [6–10] and also reduces all-cause mortality, including mortality due to non-liver-related diseases [11, 12].
Among the six HCV genotypes, HCV genotype 2 accounts for approximately 13% of infections globally [13]. This HCV genotype is common in Latin America, sub-Saharan Africa, and East Asia. In many countries in these regions, official approval for new direct-acting antivirals (DAAs) has been delayed because DAA treatment is costly and market access and governmental restrictions differ between certain countries. The current guidelines of the American Association for the Study of Liver Diseases [14] and the European Association for the Study of the Liver [15] recommend the following interferon-free DAA regimens for patients with HCV genotype 2 infection: sofosbuvir (SOF) plus velpatasvir for 12 weeks or glecaprevir plus pibrentasvir for 8–12 weeks.
Until recently, approximately 70% of patients with HCV infection in Japan had genotype 1b and the remainder had genotype 2 [16]. Lately, however, the proportion of HCV genotype 1b has decreased and is now < 50% in individuals born after 1970. By contrast, the percentage of HCV genotype 2 infection, especially 2b, has increased in younger generations. The current guidelines of the Japan Society of Hepatology [17] recommend the following interferon-free DAA regimens for non-decompensated cirrhotic patients with HCV genotype 2 infection: SOF plus ribavirin for 12 weeks, glecaprevir plus pibrentasvir for 8–12 weeks, or ledipasvir (LDV) plus SOF for 12 weeks. LDV is an HCV NS5A inhibitor, and SOF is a potent NS5B nucleotide polymerase inhibitor with pan-genotypic activity and a high barrier to resistance. In a Japanese randomized controlled trial, LDV/SOF treatment in patients with HCV genotype 2 infection resulted in high sustained virological response (SVR) rates (96%) that were equivalent to those of SOF plus ribavirin (95%) [18]. However, real-world clinical data on LDV/SOF treatment for patients with HCV genotype 2 infection are limited. Therefore, it is necessary to clarify the real-world clinical outcomes of LDV/SOF treatment for patients with HCV genotype 2 infection in Japan.
In this study, we analyzed the real-world outcomes of this treatment approach for patients with HCV genotype 2 infection in a multicenter study conducted throughout Japan.
Methods
Patients
This prospective cohort study was conducted to characterize the prevalence of nonhypervascular hypointense nodules (NHHNs) during the hepatobiliary phase of EOB-MRI and the incidence of hyper-vascularization among patients in whom HCV was eradicated with DAA therapy. The study was registered to the UMIN Clinical Trial Registry (UMIN000017020). The study was conducted after approval by the hospital's Institutional Review Board. It was carried out in compliance with the Helsinki Declaration. Written informed consent was obtained from all participating patients. This study was approved by the ethics committee of Ogaki Municipal Hospital (IRB #20180927-13-k). All documents approved by Ogaki Municipal Hospital (Kumada T) were sent to each institution and approved by each institution under the same IRB name and number. This study was performed in accordance with the 2013 Helsinki Declaration. All patients consented to provide their data. Written informed consent was obtained from each patient before enrollment. All patients consented to provide their data. Consent to participate and allow their data to be published was obtained from each patient before enrollment.
This was a multicenter study conducted at 18 institutions in the Hokkaido, Kanto, Hokushinnestu, Chubu, Kansai, Chugoku, Shikoku, and Kyusyu areas of Japan. A total of 126 patients with chronic hepatitis C due to HCV genotype 2 infection who underwent DAA treatment with the LDV/SOF regimen between September 2018 and September 2019 were enrolled. Persistent infection with HCV genotype 2 was proved in all patients by both positive serum HCV antibody titers (ARCHITECT Anti-HCV; Abbott Laboratories, Abbott Park, IL, USA) and the presence of serum HCV RNA determined using a real-time PCR–based method (COBAS AmpliPrep/COBAS TaqMan HCV Test version 2; Roche Molecular Systems, Pleasanton, CA, USA; lower limit of quantification, 1.6 log10 IU/ml; lower limit of detection, 1.2 log10 IU/ml). HCV genotype was evaluated by PCR with genotype-specific primers to amplify the core gene sequences [19]. In some institutions, only the HCV serotype could be determined by a serotyping assay based on the type-specific antibodies because of insurance coverage. Patients with severe chronic renal failure were excluded. Patients with decompensated cirrhosis were also excluded because this DAA regimen is contraindicated for this population in Japan.
Treatment and Follow-Up
Patients received fixed doses of LDV (90 mg) and SOF (400 mg) (Harvoni; Gilead Sciences, Tokyo, Japan) once daily on an outpatient basis. The duration of the treatment regimen was scheduled for 12 weeks. Patients were asked to visit the clinic for monitoring of treatment response every 2 weeks throughout the treatment period and every 4 weeks during follow-up, which lasted until 12 weeks after the end of treatment. Laboratory data, specifically complete blood count and serum levels of alanine aminotransferase, aspartate aminotransferase, albumin, total bilirubin, and creatinine, were measured before and every 2–4 weeks after the start of therapy. Serum HCV RNA levels were measured before treatment; at 4, 8, and 12 weeks after the start of therapy while treatment was ongoing; at the end of treatment; and at 12 weeks after the end of treatment. Viral suppression was defined as undetectable serum HCV RNA. Relapse was defined when serum HCV RNA was undetectable at the end of therapy but became detectable between the end of treatment and 12 weeks after the completion of therapy. Breakthrough was defined when HCV RNA became detectable after its initial disappearance during treatment. Non-response was defined when serum HCV RNA levels increased despite their initial decrease during treatment. SVR was defined as undetectable serum HCV RNA at 12 weeks after the end of treatment. In this study, SVR was assessed in the intention-to-treat (ITT) population as well as in the modified intention-to-treat (mITT) population, which excluded patients with non-virological failure, including those who dropped out before the SVR assessment. Potential adverse events, including laboratory value abnormalities that emerged after the start of therapy, were monitored by attending physicians at every patient visit. Treatment discontinuation was determined based on attending physicians’ evaluations.
Assessment of Advanced Liver Fibrosis and Renal Dysfunction
Liver fibrosis was assessed based on pretreatment laboratory data using the FIB-4 index, a laboratory liver fibrosis index defined by the following formula [20]: aspartate aminotransferase [IU/l] × age [years]/platelet count [109/l] × alanine aminotransferase [IU/l]1/2. Patients were defined as having advanced fibrosis (i.e., F3 or F4 by the METAVIR score [21]) when the FIB-4 index was ≥ 3.25 [22].
Renal function was assessed by the estimated glomerular filtration rate (eGFR) (ml/min/1.73 m2) based on pretreatment laboratory data using the following formula [23]: 194 × serum creatinine (mg/dl) − 1.094 × age − 0.287 × 0.739 (if female). Chronic kidney disease was classified as eGFR < 60 ml/min/1.73 m2 [24]. In addition, severe chronic renal failure was classified as eGFR < 30 ml/min/1.73 m2 [24].
Statistical Analysis
Continuous variables are expressed as medians (the first–third quartiles). For comparisons of baseline characteristics and SVR rates between patient subgroups, differences in categorical variables were analyzed using Fisher’s exact test.
All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [25]. More precisely, it is a modified version of the R commander designed to add statistical functions frequently used in biostatistics. Statistical significance was defined as p < 0.05.
Results
Patient Characteristics
Table 1 shows the characteristics of the study patients at the start of DAA therapy. There were 65 females (51.6%) and 61 males (48.4%), with a median (interquartile range) age of 60.5 (47.0–74.0) years.Table 1 Patient characteristics (n = 126)
Age (years)* 60.5 (47.0–74.0)
Sex (female/male) 65/61
History of interferon-based therapy (no/yes) 116/10
History of curatively treated HCC (no/yes) 121/5
Aspartate aminotransferase (IU/l)* 34 (26–54)
Alanine aminotransferase (IU/l)* 36 (21–69)
γ-glutamyl transpeptidase (IU/l)* 38 (20–64)
Albumin (g/dl)* 4.1 (3.8–4.4)
Total bilirubin (mg/dl)* 0.6 (0.5–0.8)
Creatinine (mg/dl)* 0.72 (0.60–0.83)
Prothrombin time (%)* 103 (91–112)
Platelet count (× 104/mm3)* 19.8 (15.2–26.1)
Hemoglobin (g/dl)* 13.7 (12.8–14.8)
Fasting plasma glucose (mg/dl)* 102 (91–113)
HCV genotype (2a/2b/2 [un-subtyped]) 80/40/6
HCV RNA (log10 IU/ml)* 6.1 (4.9–6.6)
FIB-4 index* 1.83 (0.95–3.19)
eGFR (ml/min/1.73 m2)* 62.4 (41.0–87.3)
HCV hepatitis C virus, HCC hepatocellular carcinoma, eGFR estimated glomerular filtration rate
*Values are expressed as medians (first to third quartiles)
The age was ≥ 70 years in 46 patients (36.5%), including 18 patients (14.3%) who were ≥ 80 years old. Ten patients (7.9%) had a history of interferon-based therapy, and one patient (0.8%) had a history of interferon-free DAA therapy. The FIB-4 index at baseline was > 3.25 in 31 patients (24.6%). Five patients (4.0%) had a history of curatively treated HCC. Renal dysfunction with eGFR < 60 ml/min/1.73 m2 was observed in 59 patients (46.8%). Among patients who underwent HCV subtyping, there were 80 (63.5%) and 40 (31.5%) patients with genotype 2a and 2b, respectively.
Virological Treatment Outcomes in the ITT and mITT Populations
The overall SVR rates in the ITT and mITT populations were 87.3% (95% confidence interval [CI] 80.2–92.6) (110/126) and 97.3% (95% CI 92.4–99.4) (110/113), respectively.
The percentages of the mITT population with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 92.9% (95% CI 86.5–96.9) (105/113), 99.1% (95% CI 95.2–100.0) (112/113), and 100.0% (95% CI 97.4–100.0) (113/113), respectively.
Virological Treatment Outcomes in the ITT Population Subgroups
Figure 1 shows SVR rates based on patient age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, and baseline eGFR in the ITT population. The SVR rates in patients with baseline FIB-4 index (≤ 3.25/> 3.25) were 91.6% (95% CI 84.1–96.3) (87/95)/74.2% (95% CI 55.4–88.1) (23/31). The SVR rate was significantly lower in patients with a baseline FIB-4 index ≥ 3.25 (p = 0.025), but did not differ significantly according to any of the other parameters.Fig. 1 SVR rates in ITT population subgroups. The SVR rates in the ITT population were stratified by subgroups, as follows: patient age (< 70 years/≥ 70 years), 91.2% (95% CI 82.8–96.4) (73/80)/80.4% (95% CI 66.1–90.6) (37/46) (p = 0.098); sex (female/male), 90.8% (95% CI 81.0–96.5) (59/65)/83.6% (95% CI 71.9–91.8) (51/61) (p = 0.288); HCV genotype (2a/2b), 88.8% (95% CI 79.7–94.7) (71/80)/87.5% (95% CI 73.2–95.8) (35/40) (p = 1.000); history of interferon-based therapy (yes/no), 80.0% (95% CI 44.4–97.5) (8/10)/87.9% (95% CI 80.6–93.2) (102/116) (p = 0.614); baseline FIB-4 index (≤ 3.25/> 3.25), 91.6% (95% CI 84.1–96.3) (87/95)/74.2% (95% CI 55.4–88.1) (23/31) (p = 0.025); and baseline eGFR (< 60/≥ 60 ml/min/1.73 m2), 91.5% (95% CI 81.3–97.2) (54/59)/83.6% (95% CI 72.5–91.5) (56/67) (p = 0.404), respectively. The error bars indicate the lower and upper values of the 95% CI of each SVR rate. SVR sustained virological response, ITT intention to treat, HCV hepatitis C virus, CI confidence interval
Reasons for Lack of Inclusion in the mITT Population
Thirteen patients were excluded from the ITT population. There were 1, 1, 1, 1, and 3 patients who self-discontinued their DAA administration at 1, 2, 4, 6, and 8 weeks after the start of treatment, respectively. In addition, there were 1, 1, and 3 patients who self-discontinued their visits at 0, 4, and 8 weeks after the end of treatment, respectively. One patient who discontinued DAA administration because of worsening of current disease (worsening of Parkinson’s symptoms).
Virological Treatment Outcomes in mITT Population Subgroups
Figure 2 shows SVR rates based on patient age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, and baseline eGFR in the mITT population. There were no significant differences in SVR rates according to these parameters.Fig. 2 SVR rates in mITT population subgroups. The SVR rates in the mITT population were stratified by subgroups, as follows: patient age (< 70 years/≥ 70 years), 98.6% (95% CI 92.7–100.0) (73/74)/94.9% (95% CI 82.7–99.4) (37/39) (p = 0.273); sex (female/male), 98.3% (95% CI 91.1–100.0) (59/60)/96.2% (95% CI 87.0–99.5) (51/53) (p = 0.599); HCV genotype (2a/2b), 98.6% (95% CI 92.5–100.0) (71/72)/94.6% (95% CI 81.8–99.3) (35/37) (p = 0.265); history of interferon-based therapy (yes/no), 100.0% (95% CI 68.8–100.0) (8/8)/97.1% (95% CI 91.9–99.4) (102/105) (p = 1.000); baseline FIB-4 index (≤ 3.25/> 3.25), 98.9% (95% CI 93.8–100.0) (87/88)/92.0% (95% CI 74.0–99.0) (23/25) (p = 0.123); and baseline eGFR (< 60/≥ 60 ml/min/1.73 m2), 98.2% (95% CI 90.3–100.0) (54/55)/96.6% (95% CI 88.1–99.6) (56/58) (p = 1.000), respectively. The error bars indicate the lower and upper values of the 95% CI of each SVR rate. SVR sustained virological response, mITT modified intention to treat, HCV hepatitis C virus, CI confidence interval
Table 2 lists the characteristics of three patients who failed to achieve SVR in the mITT population. All three patients relapsed after the end of therapy. Of these, two patients were infected with genotype 2b HCV and had a baseline FIB-4 index of ≥ 3.25.Table 2 Patients who failed to achieve SVR (n = 3)
No. 1 2 3
Age 83 69 71
Sex Male Female Female
History of interferon-based therapy No No No
History of curatively treated HCC No No Yes
HCV genotype 2a 2b 2b
HCV RNA (log10 IU/ml) 6.5 6.8 6.5
FIB-4 index 2.12 6.35 10.24
eGFR (ml/min/1.73 m2) 71.9 44.4 85.0
Undetectable HCV RNA after the start of therapy 8 weeks 8 weeks 4 weeks
Detectable HCV RNA after the end of therapy 4 weeks 4 weeks 12 weeks
Details of SVR Relapse Relapse Relapse
HCC hepatocellular carcinoma, HCV hepatitis C virus, eGFR estimated glomerular filtration rate
Safety
Two patients had adverse events during the DAA treatment. In one patient (84-year-old female; genotype 2a) with Parkinson’s disease, the DAA treatment was discontinued at 1 week after the start of therapy because of worsening of Parkinson’s symptoms. These symptoms improved after the DAA treatment was stopped. However, the causal relation of the treatment and this adverse effect was unclear. Another patient (50-year-old female; genotype 2a) developed oral ulcers at 2 weeks after the start of therapy, but they were mild and she was able to continue treatment. These oral ulcers were considered as an adverse event related to LDV/SOF treatment by the attending physician.
Discussion
This multicenter clinical study conducted throughout Japan enrolled a relatively large number of patients with HCV genotype 2 infection and either chronic hepatitis or non-decompensated cirrhosis and showed that LDV/SOF treatment achieved a high SVR rate of 97.3% in the mITT population. In this group, HCV RNA was undetectable in > 90% of patients at 4 weeks after the start of treatment and in almost all patients (99.1%) at 8 weeks. Furthermore, subgroup analyses of the mITT population based on patient age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, and baseline eGFR showed no significant differences in SVR rates according to these parameters. Notably, high SVR rates > 90% were obtained in the mITT population even in elderly individuals and those with advanced fibrosis or a history of interferon-based therapy. Regarding safety, only one elderly patient discontinued this DAA treatment because of exacerbation of Parkinson’s disease symptoms. As a result, there were only one dropout patient and one patient with a mild adverse event (oral ulcers), respectively, associated with this DAA treatment. Therefore, it is considered that the LDV/SOF treatment showed excellent efficacy and acceptable safety in patients with HCV genotype 2 infection.
Genotype 2 HCV has previously shown high rates of response to combination therapy with SOF plus ribavirin, a broad-spectrum antiviral. In three registered studies of SOF plus ribavirin, 12 weeks of treatment resulted in an SVR rate of 94% among patients with chronic HCV genotype 2 infection [26–28]. Compared with SOF, which has a favorable safety profile and is well tolerated [29], ribavirin has poorer tolerability, mostly because it can cause hemolytic anemia. HCV patients with ribavirin-associated anemia have significantly increased resource utilization and medical costs [30].
LDV/SOF has been investigated for the treatment of patients with HCV genotype 2 infection in phase 2 and 3 trials in the Asia-Pacific region [18, 31, 32]. Gane et al. [31] reported in their phase 2 trial that the SVR rates at 8 weeks and 12 weeks after the start of LDV/SOF treatment were 74% (20/27) and 96% (25/26), respectively, in patients with HCV genotype 2, indicating a significant difference between time points (p < 0.001). In a phase 3 trial conducted in a Japanese cohort with HCV genotype 2 infection, Asahina et al. [18] showed that SVR rates were 96% (102/106) with LDV/SOF treatment and 95% (103/108) with SOF plus ribavirin treatment, indicating that LDV/SOF was non-inferior to SOF plus ribavirin. However, limited real-world clinical data have been reported to date on treatment outcomes with LDV/SOF in patients with HCV genotype 2 infection. There were no differences in patient characteristics such as age and sex between the phase 3 trial from Japan and this study cohort. Although almost all of the patients in this phase 3 trial visited a few university hospitals in Japan, this study's patients visited not only university hospitals but also community-based general hospitals nationwide. Recently, Liu et al. [33] demonstrated good efficacy and safety in Taiwanese patients with HCV genotype 2 infection treated with SOF-based regimens, and all 39 patients who received LDV/SOF treatment achieved SVR. Additionally, in a recent multicenter study in the Kyusyu area of Japan, Ogawa et al. [34] also reported that LDV/SOF treatment of patients with HCV genotype 2 infection was effective and safe, with an SVR rate of 96.5% (55/57) in the mITT population. In their ITT population (n = 58), there were 35 (60.3%), 10 (17.2%), and 13 (22.4%) patients with HCV genotype 2a, 2b, and 2 (un-subtyped) infection, respectively. Similar to the studies of Liu et al. [33] and Ogawa et al. [34], almost all patients in our study achieved SVR and there were no serious adverse events or deaths. An advantage of our study relative to that of Ogawa et al. was that it included more patients from throughout Japan. In addition, only 4.8% (6/126) of patients with HCV genotype 2 infection were un-subtyped. Unfortunately, there was no Japanese randomized controlled trial regarding the SOF plus velpatasvir treatment for non-decompensated cirrhotic patients with HCV genotype 2 infection. Only decompensated cirrhotic patients with HCV infection were accepted to use the SOF plus velpatasvir treatment based on the results of randomized controlled trial in Japan. Conversely, the LDV/SOF treatment for non-decompensated cirrhotic patients with HCV genotype 2 infection was accepted based on the good results of Japanese randomized controlled trial [18] in the Japanese guidelines.
The main limitation of this study was that it did not assess the relationship between SVR rate and NS5A and NS5B mutations. Generally, LDV at half-maximal effective concentration is much less efficacious against HCV genotype 2 than genotype 1, especially in patients with NS5A L31 M, despite the fact that SOF demonstrates similar efficacy against genotypes 1 and 2 [35]. However, resistance-associated substitution analysis showed that almost all patients (94–97%) with subtype 2a infection and 39–89% of those with subtype 2b infection originally had NS5A L31 M at baseline [18, 36]. In addition, the SVR rate in patients with NS5A resistance-associated substitutions was extremely high (97.6%, 165/169) in clinical trials [18, 31, 32]. Therefore, it is considered that NS5A L31 M, and not NS5B, is unassociated with treatment outcome. Further studies assessing NS5A and NS5B mutations should be performed. Another limitation is that 13 patients were excluded from the mITT population, mainly because of self-discontinuation of visits during or after LDV/SOF treatment. This may be related to the social background such as a history of intravenous drug use or a history of tattooing in patients with HCV genotype 2 infection [16, 37]. Additional studies of this treatment with fewer dropouts are warranted. Third, it included a relatively small number of patients. Future studies with more patients are warranted.
Conclusion
An IFN-free DAA regimen with LDV/SOF demonstrated a very high SVR rate and acceptable safety profile in patients infected with HCV genotype 2 infection. In particular, the LDV/SOF regimen resulted in good SVR rates regardless of patient age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, and baseline eGFR. Further studies are warranted to confirm these findings in other populations.
Acknowledgements
We thank the participants of the study.
Funding
This work was supported by Gilead Sciences (commercial research funding). Gilead Sciences also funded the journal’s Rapid Service Fees.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authorship Contributions
Concept and study design: Takashi Kumada and Toshifumi Tada. Data acquisition: All authors. Analyses of the data: Takashi Kumada and Toshifumi Tada. Statistics: Toshifumi Tada. Supervise: Takashi Kumada. Preparing the manuscript: Toshifumi Tada. Review and approval: All authors.
Disclosures
Takashi Kumada served as a speaker for Gilead and AbbVie. Hidenori Toyoda has served as a speaker for Gilead, AbbVie, and MSD. Toshifumi Tada, Hiroaki Okushin, Joji Tani, Koichi Takaguchi, Akemi Tsutsui, Satoshi Yasuda, Kazufumi Dohmen, Atsushi Hiraoka, Kojiro Michitaka, Kazuhiro Nouso, Kazuya Kariyama, Soo Ryang Kim, Soo Ki Kim, Shinichi Fujioka, Shigeru Mikami, Yuto Watanabe, Tsutomu Tamai, Masanori Atsukawa, Norio Itokawa, Hironori Tanaka, Kunihiko Tsuji, Toru Ishikawa, Michitaka Imai, Ei Itobayashi, Hiroshi Shibata, and Noritomo Shimada declare that they have no competing interests.
Compliance with Ethics Guidelines
This study was approved by the ethics committee of Ogaki Municipal Hospital (IRB #20180927-13-k). All documents approved by Ogaki Municipal Hospital (Kumada T) were sent to each institution and approved by each institution under the same IRB name and number. This study was performed in accordance with the 2013 Helsinki Declaration. All patients consented to provide their data. Written informed consent was obtained from each patient before enrollment. All patients consented to provide their data. Consent to both participate and allow the data to be published was obtained from each patient before enrollment.
Data Availability
The datasets are available from the corresponding author on reasonable request.
|
Oral
|
DrugAdministrationRoute
|
CC BY-NC
|
33141401
| 18,502,592
|
2021-03
|
What was the outcome of reaction 'Parkinson^s disease'?
|
Real-World Virological Efficacy and Safety of Ledipasvir and Sofosbuvir in Patients with Chronic Hepatitis C Virus Genotype 2 Infection: A Multicenter Study.
BACKGROUND
The real-world virological efficacy and safety of interferon-free direct-acting antiviral (DAA) therapy with ledipasvir (LDV) plus sofosbuvir (SOF) were assessed in patients who were chronically infected with hepatitis C virus (HCV) genotype 2.
METHODS
A total of 126 patients with chronic hepatitis C due to HCV genotype 2 infection who were treated with the LDV/SOF regimen were enrolled. The sustained virological response (SVR) rate and safety were analyzed. SVR was assessed in the intention-to-treat (ITT) population as well as in the modified intention-to-treat (mITT) population, which excluded patients with non-virological failure, including those who dropped out before the SVR assessment.
RESULTS
The overall SVR rates of the ITT and mITT populations were 87.3% (95% confidence interval [CI] 80.2-92.6) (110/126) and 97.3% (95% CI 92.4-99.4) (110/113), respectively. In the mITT population, the percentages of patients with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 92.9% (95% CI 86.5-96.9) (105/113), 99.1% (95% CI 95.2-100.0) (112/113), and 100.0% (95% CI 97.4-100.0) (113/113), respectively. Subgroup analyses of the mITT population showed no significant differences in SVR rates according to age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, or baseline estimated glomerular filtration rate. In all subpopulations, the SVR rates were > 90%. There were no severe adverse events associated with the treatment.
CONCLUSIONS
The LDV/SOF regimen showed high virological efficacy and acceptable safety in patients with HCV genotype 2 infection.
BACKGROUND
UMIN registration no. 000038604.
Key Summary Points
Why carry out this study?
In a Japanese randomized controlled trial, LDV/SOF treatment in patients with HCV genotype 2 resulted in high SVR rates (96%) that were equivalent to those of SOF plus ribavirin (95%).
Real-world clinical data on LDV/SOF treatment for patients with HCV genotype 2 are limited.
To investigate the real-world outcomes of LDV/SOF treatment for patients with HCV genotype 2 in a multicenter study conducted throughout Japan.
What was learned from the study?
The overall SVR rates of the ITT and mITT populations were 87.3% (110/126) and 97.3% (110/113), respectively.
There were no severe adverse events associated with the treatment.
The LDV/SOF regimen showed high virological efficacy and acceptable safety in patients with HCV genotype 2.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to 10.6084/m9.figshare.13118183.
Introduction
Hepatitis C virus (HCV) infection affected 71 million people globally in 2015 [1]. It is a major risk factor for cirrhosis, hepatocellular carcinoma (HCC), and liver-related death. In Japan, 1.0–1.5 million individuals are infected with HCV, and approximately 55% of HCC is associated with chronic HCV infection [2]. Anti-HCV therapy to eradicate HCV is an essential treatment for chronic HCV infection, as it reportedly prevents the progression of liver fibrosis [3–5] and the development of HCC [6–10] and also reduces all-cause mortality, including mortality due to non-liver-related diseases [11, 12].
Among the six HCV genotypes, HCV genotype 2 accounts for approximately 13% of infections globally [13]. This HCV genotype is common in Latin America, sub-Saharan Africa, and East Asia. In many countries in these regions, official approval for new direct-acting antivirals (DAAs) has been delayed because DAA treatment is costly and market access and governmental restrictions differ between certain countries. The current guidelines of the American Association for the Study of Liver Diseases [14] and the European Association for the Study of the Liver [15] recommend the following interferon-free DAA regimens for patients with HCV genotype 2 infection: sofosbuvir (SOF) plus velpatasvir for 12 weeks or glecaprevir plus pibrentasvir for 8–12 weeks.
Until recently, approximately 70% of patients with HCV infection in Japan had genotype 1b and the remainder had genotype 2 [16]. Lately, however, the proportion of HCV genotype 1b has decreased and is now < 50% in individuals born after 1970. By contrast, the percentage of HCV genotype 2 infection, especially 2b, has increased in younger generations. The current guidelines of the Japan Society of Hepatology [17] recommend the following interferon-free DAA regimens for non-decompensated cirrhotic patients with HCV genotype 2 infection: SOF plus ribavirin for 12 weeks, glecaprevir plus pibrentasvir for 8–12 weeks, or ledipasvir (LDV) plus SOF for 12 weeks. LDV is an HCV NS5A inhibitor, and SOF is a potent NS5B nucleotide polymerase inhibitor with pan-genotypic activity and a high barrier to resistance. In a Japanese randomized controlled trial, LDV/SOF treatment in patients with HCV genotype 2 infection resulted in high sustained virological response (SVR) rates (96%) that were equivalent to those of SOF plus ribavirin (95%) [18]. However, real-world clinical data on LDV/SOF treatment for patients with HCV genotype 2 infection are limited. Therefore, it is necessary to clarify the real-world clinical outcomes of LDV/SOF treatment for patients with HCV genotype 2 infection in Japan.
In this study, we analyzed the real-world outcomes of this treatment approach for patients with HCV genotype 2 infection in a multicenter study conducted throughout Japan.
Methods
Patients
This prospective cohort study was conducted to characterize the prevalence of nonhypervascular hypointense nodules (NHHNs) during the hepatobiliary phase of EOB-MRI and the incidence of hyper-vascularization among patients in whom HCV was eradicated with DAA therapy. The study was registered to the UMIN Clinical Trial Registry (UMIN000017020). The study was conducted after approval by the hospital's Institutional Review Board. It was carried out in compliance with the Helsinki Declaration. Written informed consent was obtained from all participating patients. This study was approved by the ethics committee of Ogaki Municipal Hospital (IRB #20180927-13-k). All documents approved by Ogaki Municipal Hospital (Kumada T) were sent to each institution and approved by each institution under the same IRB name and number. This study was performed in accordance with the 2013 Helsinki Declaration. All patients consented to provide their data. Written informed consent was obtained from each patient before enrollment. All patients consented to provide their data. Consent to participate and allow their data to be published was obtained from each patient before enrollment.
This was a multicenter study conducted at 18 institutions in the Hokkaido, Kanto, Hokushinnestu, Chubu, Kansai, Chugoku, Shikoku, and Kyusyu areas of Japan. A total of 126 patients with chronic hepatitis C due to HCV genotype 2 infection who underwent DAA treatment with the LDV/SOF regimen between September 2018 and September 2019 were enrolled. Persistent infection with HCV genotype 2 was proved in all patients by both positive serum HCV antibody titers (ARCHITECT Anti-HCV; Abbott Laboratories, Abbott Park, IL, USA) and the presence of serum HCV RNA determined using a real-time PCR–based method (COBAS AmpliPrep/COBAS TaqMan HCV Test version 2; Roche Molecular Systems, Pleasanton, CA, USA; lower limit of quantification, 1.6 log10 IU/ml; lower limit of detection, 1.2 log10 IU/ml). HCV genotype was evaluated by PCR with genotype-specific primers to amplify the core gene sequences [19]. In some institutions, only the HCV serotype could be determined by a serotyping assay based on the type-specific antibodies because of insurance coverage. Patients with severe chronic renal failure were excluded. Patients with decompensated cirrhosis were also excluded because this DAA regimen is contraindicated for this population in Japan.
Treatment and Follow-Up
Patients received fixed doses of LDV (90 mg) and SOF (400 mg) (Harvoni; Gilead Sciences, Tokyo, Japan) once daily on an outpatient basis. The duration of the treatment regimen was scheduled for 12 weeks. Patients were asked to visit the clinic for monitoring of treatment response every 2 weeks throughout the treatment period and every 4 weeks during follow-up, which lasted until 12 weeks after the end of treatment. Laboratory data, specifically complete blood count and serum levels of alanine aminotransferase, aspartate aminotransferase, albumin, total bilirubin, and creatinine, were measured before and every 2–4 weeks after the start of therapy. Serum HCV RNA levels were measured before treatment; at 4, 8, and 12 weeks after the start of therapy while treatment was ongoing; at the end of treatment; and at 12 weeks after the end of treatment. Viral suppression was defined as undetectable serum HCV RNA. Relapse was defined when serum HCV RNA was undetectable at the end of therapy but became detectable between the end of treatment and 12 weeks after the completion of therapy. Breakthrough was defined when HCV RNA became detectable after its initial disappearance during treatment. Non-response was defined when serum HCV RNA levels increased despite their initial decrease during treatment. SVR was defined as undetectable serum HCV RNA at 12 weeks after the end of treatment. In this study, SVR was assessed in the intention-to-treat (ITT) population as well as in the modified intention-to-treat (mITT) population, which excluded patients with non-virological failure, including those who dropped out before the SVR assessment. Potential adverse events, including laboratory value abnormalities that emerged after the start of therapy, were monitored by attending physicians at every patient visit. Treatment discontinuation was determined based on attending physicians’ evaluations.
Assessment of Advanced Liver Fibrosis and Renal Dysfunction
Liver fibrosis was assessed based on pretreatment laboratory data using the FIB-4 index, a laboratory liver fibrosis index defined by the following formula [20]: aspartate aminotransferase [IU/l] × age [years]/platelet count [109/l] × alanine aminotransferase [IU/l]1/2. Patients were defined as having advanced fibrosis (i.e., F3 or F4 by the METAVIR score [21]) when the FIB-4 index was ≥ 3.25 [22].
Renal function was assessed by the estimated glomerular filtration rate (eGFR) (ml/min/1.73 m2) based on pretreatment laboratory data using the following formula [23]: 194 × serum creatinine (mg/dl) − 1.094 × age − 0.287 × 0.739 (if female). Chronic kidney disease was classified as eGFR < 60 ml/min/1.73 m2 [24]. In addition, severe chronic renal failure was classified as eGFR < 30 ml/min/1.73 m2 [24].
Statistical Analysis
Continuous variables are expressed as medians (the first–third quartiles). For comparisons of baseline characteristics and SVR rates between patient subgroups, differences in categorical variables were analyzed using Fisher’s exact test.
All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [25]. More precisely, it is a modified version of the R commander designed to add statistical functions frequently used in biostatistics. Statistical significance was defined as p < 0.05.
Results
Patient Characteristics
Table 1 shows the characteristics of the study patients at the start of DAA therapy. There were 65 females (51.6%) and 61 males (48.4%), with a median (interquartile range) age of 60.5 (47.0–74.0) years.Table 1 Patient characteristics (n = 126)
Age (years)* 60.5 (47.0–74.0)
Sex (female/male) 65/61
History of interferon-based therapy (no/yes) 116/10
History of curatively treated HCC (no/yes) 121/5
Aspartate aminotransferase (IU/l)* 34 (26–54)
Alanine aminotransferase (IU/l)* 36 (21–69)
γ-glutamyl transpeptidase (IU/l)* 38 (20–64)
Albumin (g/dl)* 4.1 (3.8–4.4)
Total bilirubin (mg/dl)* 0.6 (0.5–0.8)
Creatinine (mg/dl)* 0.72 (0.60–0.83)
Prothrombin time (%)* 103 (91–112)
Platelet count (× 104/mm3)* 19.8 (15.2–26.1)
Hemoglobin (g/dl)* 13.7 (12.8–14.8)
Fasting plasma glucose (mg/dl)* 102 (91–113)
HCV genotype (2a/2b/2 [un-subtyped]) 80/40/6
HCV RNA (log10 IU/ml)* 6.1 (4.9–6.6)
FIB-4 index* 1.83 (0.95–3.19)
eGFR (ml/min/1.73 m2)* 62.4 (41.0–87.3)
HCV hepatitis C virus, HCC hepatocellular carcinoma, eGFR estimated glomerular filtration rate
*Values are expressed as medians (first to third quartiles)
The age was ≥ 70 years in 46 patients (36.5%), including 18 patients (14.3%) who were ≥ 80 years old. Ten patients (7.9%) had a history of interferon-based therapy, and one patient (0.8%) had a history of interferon-free DAA therapy. The FIB-4 index at baseline was > 3.25 in 31 patients (24.6%). Five patients (4.0%) had a history of curatively treated HCC. Renal dysfunction with eGFR < 60 ml/min/1.73 m2 was observed in 59 patients (46.8%). Among patients who underwent HCV subtyping, there were 80 (63.5%) and 40 (31.5%) patients with genotype 2a and 2b, respectively.
Virological Treatment Outcomes in the ITT and mITT Populations
The overall SVR rates in the ITT and mITT populations were 87.3% (95% confidence interval [CI] 80.2–92.6) (110/126) and 97.3% (95% CI 92.4–99.4) (110/113), respectively.
The percentages of the mITT population with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 92.9% (95% CI 86.5–96.9) (105/113), 99.1% (95% CI 95.2–100.0) (112/113), and 100.0% (95% CI 97.4–100.0) (113/113), respectively.
Virological Treatment Outcomes in the ITT Population Subgroups
Figure 1 shows SVR rates based on patient age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, and baseline eGFR in the ITT population. The SVR rates in patients with baseline FIB-4 index (≤ 3.25/> 3.25) were 91.6% (95% CI 84.1–96.3) (87/95)/74.2% (95% CI 55.4–88.1) (23/31). The SVR rate was significantly lower in patients with a baseline FIB-4 index ≥ 3.25 (p = 0.025), but did not differ significantly according to any of the other parameters.Fig. 1 SVR rates in ITT population subgroups. The SVR rates in the ITT population were stratified by subgroups, as follows: patient age (< 70 years/≥ 70 years), 91.2% (95% CI 82.8–96.4) (73/80)/80.4% (95% CI 66.1–90.6) (37/46) (p = 0.098); sex (female/male), 90.8% (95% CI 81.0–96.5) (59/65)/83.6% (95% CI 71.9–91.8) (51/61) (p = 0.288); HCV genotype (2a/2b), 88.8% (95% CI 79.7–94.7) (71/80)/87.5% (95% CI 73.2–95.8) (35/40) (p = 1.000); history of interferon-based therapy (yes/no), 80.0% (95% CI 44.4–97.5) (8/10)/87.9% (95% CI 80.6–93.2) (102/116) (p = 0.614); baseline FIB-4 index (≤ 3.25/> 3.25), 91.6% (95% CI 84.1–96.3) (87/95)/74.2% (95% CI 55.4–88.1) (23/31) (p = 0.025); and baseline eGFR (< 60/≥ 60 ml/min/1.73 m2), 91.5% (95% CI 81.3–97.2) (54/59)/83.6% (95% CI 72.5–91.5) (56/67) (p = 0.404), respectively. The error bars indicate the lower and upper values of the 95% CI of each SVR rate. SVR sustained virological response, ITT intention to treat, HCV hepatitis C virus, CI confidence interval
Reasons for Lack of Inclusion in the mITT Population
Thirteen patients were excluded from the ITT population. There were 1, 1, 1, 1, and 3 patients who self-discontinued their DAA administration at 1, 2, 4, 6, and 8 weeks after the start of treatment, respectively. In addition, there were 1, 1, and 3 patients who self-discontinued their visits at 0, 4, and 8 weeks after the end of treatment, respectively. One patient who discontinued DAA administration because of worsening of current disease (worsening of Parkinson’s symptoms).
Virological Treatment Outcomes in mITT Population Subgroups
Figure 2 shows SVR rates based on patient age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, and baseline eGFR in the mITT population. There were no significant differences in SVR rates according to these parameters.Fig. 2 SVR rates in mITT population subgroups. The SVR rates in the mITT population were stratified by subgroups, as follows: patient age (< 70 years/≥ 70 years), 98.6% (95% CI 92.7–100.0) (73/74)/94.9% (95% CI 82.7–99.4) (37/39) (p = 0.273); sex (female/male), 98.3% (95% CI 91.1–100.0) (59/60)/96.2% (95% CI 87.0–99.5) (51/53) (p = 0.599); HCV genotype (2a/2b), 98.6% (95% CI 92.5–100.0) (71/72)/94.6% (95% CI 81.8–99.3) (35/37) (p = 0.265); history of interferon-based therapy (yes/no), 100.0% (95% CI 68.8–100.0) (8/8)/97.1% (95% CI 91.9–99.4) (102/105) (p = 1.000); baseline FIB-4 index (≤ 3.25/> 3.25), 98.9% (95% CI 93.8–100.0) (87/88)/92.0% (95% CI 74.0–99.0) (23/25) (p = 0.123); and baseline eGFR (< 60/≥ 60 ml/min/1.73 m2), 98.2% (95% CI 90.3–100.0) (54/55)/96.6% (95% CI 88.1–99.6) (56/58) (p = 1.000), respectively. The error bars indicate the lower and upper values of the 95% CI of each SVR rate. SVR sustained virological response, mITT modified intention to treat, HCV hepatitis C virus, CI confidence interval
Table 2 lists the characteristics of three patients who failed to achieve SVR in the mITT population. All three patients relapsed after the end of therapy. Of these, two patients were infected with genotype 2b HCV and had a baseline FIB-4 index of ≥ 3.25.Table 2 Patients who failed to achieve SVR (n = 3)
No. 1 2 3
Age 83 69 71
Sex Male Female Female
History of interferon-based therapy No No No
History of curatively treated HCC No No Yes
HCV genotype 2a 2b 2b
HCV RNA (log10 IU/ml) 6.5 6.8 6.5
FIB-4 index 2.12 6.35 10.24
eGFR (ml/min/1.73 m2) 71.9 44.4 85.0
Undetectable HCV RNA after the start of therapy 8 weeks 8 weeks 4 weeks
Detectable HCV RNA after the end of therapy 4 weeks 4 weeks 12 weeks
Details of SVR Relapse Relapse Relapse
HCC hepatocellular carcinoma, HCV hepatitis C virus, eGFR estimated glomerular filtration rate
Safety
Two patients had adverse events during the DAA treatment. In one patient (84-year-old female; genotype 2a) with Parkinson’s disease, the DAA treatment was discontinued at 1 week after the start of therapy because of worsening of Parkinson’s symptoms. These symptoms improved after the DAA treatment was stopped. However, the causal relation of the treatment and this adverse effect was unclear. Another patient (50-year-old female; genotype 2a) developed oral ulcers at 2 weeks after the start of therapy, but they were mild and she was able to continue treatment. These oral ulcers were considered as an adverse event related to LDV/SOF treatment by the attending physician.
Discussion
This multicenter clinical study conducted throughout Japan enrolled a relatively large number of patients with HCV genotype 2 infection and either chronic hepatitis or non-decompensated cirrhosis and showed that LDV/SOF treatment achieved a high SVR rate of 97.3% in the mITT population. In this group, HCV RNA was undetectable in > 90% of patients at 4 weeks after the start of treatment and in almost all patients (99.1%) at 8 weeks. Furthermore, subgroup analyses of the mITT population based on patient age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, and baseline eGFR showed no significant differences in SVR rates according to these parameters. Notably, high SVR rates > 90% were obtained in the mITT population even in elderly individuals and those with advanced fibrosis or a history of interferon-based therapy. Regarding safety, only one elderly patient discontinued this DAA treatment because of exacerbation of Parkinson’s disease symptoms. As a result, there were only one dropout patient and one patient with a mild adverse event (oral ulcers), respectively, associated with this DAA treatment. Therefore, it is considered that the LDV/SOF treatment showed excellent efficacy and acceptable safety in patients with HCV genotype 2 infection.
Genotype 2 HCV has previously shown high rates of response to combination therapy with SOF plus ribavirin, a broad-spectrum antiviral. In three registered studies of SOF plus ribavirin, 12 weeks of treatment resulted in an SVR rate of 94% among patients with chronic HCV genotype 2 infection [26–28]. Compared with SOF, which has a favorable safety profile and is well tolerated [29], ribavirin has poorer tolerability, mostly because it can cause hemolytic anemia. HCV patients with ribavirin-associated anemia have significantly increased resource utilization and medical costs [30].
LDV/SOF has been investigated for the treatment of patients with HCV genotype 2 infection in phase 2 and 3 trials in the Asia-Pacific region [18, 31, 32]. Gane et al. [31] reported in their phase 2 trial that the SVR rates at 8 weeks and 12 weeks after the start of LDV/SOF treatment were 74% (20/27) and 96% (25/26), respectively, in patients with HCV genotype 2, indicating a significant difference between time points (p < 0.001). In a phase 3 trial conducted in a Japanese cohort with HCV genotype 2 infection, Asahina et al. [18] showed that SVR rates were 96% (102/106) with LDV/SOF treatment and 95% (103/108) with SOF plus ribavirin treatment, indicating that LDV/SOF was non-inferior to SOF plus ribavirin. However, limited real-world clinical data have been reported to date on treatment outcomes with LDV/SOF in patients with HCV genotype 2 infection. There were no differences in patient characteristics such as age and sex between the phase 3 trial from Japan and this study cohort. Although almost all of the patients in this phase 3 trial visited a few university hospitals in Japan, this study's patients visited not only university hospitals but also community-based general hospitals nationwide. Recently, Liu et al. [33] demonstrated good efficacy and safety in Taiwanese patients with HCV genotype 2 infection treated with SOF-based regimens, and all 39 patients who received LDV/SOF treatment achieved SVR. Additionally, in a recent multicenter study in the Kyusyu area of Japan, Ogawa et al. [34] also reported that LDV/SOF treatment of patients with HCV genotype 2 infection was effective and safe, with an SVR rate of 96.5% (55/57) in the mITT population. In their ITT population (n = 58), there were 35 (60.3%), 10 (17.2%), and 13 (22.4%) patients with HCV genotype 2a, 2b, and 2 (un-subtyped) infection, respectively. Similar to the studies of Liu et al. [33] and Ogawa et al. [34], almost all patients in our study achieved SVR and there were no serious adverse events or deaths. An advantage of our study relative to that of Ogawa et al. was that it included more patients from throughout Japan. In addition, only 4.8% (6/126) of patients with HCV genotype 2 infection were un-subtyped. Unfortunately, there was no Japanese randomized controlled trial regarding the SOF plus velpatasvir treatment for non-decompensated cirrhotic patients with HCV genotype 2 infection. Only decompensated cirrhotic patients with HCV infection were accepted to use the SOF plus velpatasvir treatment based on the results of randomized controlled trial in Japan. Conversely, the LDV/SOF treatment for non-decompensated cirrhotic patients with HCV genotype 2 infection was accepted based on the good results of Japanese randomized controlled trial [18] in the Japanese guidelines.
The main limitation of this study was that it did not assess the relationship between SVR rate and NS5A and NS5B mutations. Generally, LDV at half-maximal effective concentration is much less efficacious against HCV genotype 2 than genotype 1, especially in patients with NS5A L31 M, despite the fact that SOF demonstrates similar efficacy against genotypes 1 and 2 [35]. However, resistance-associated substitution analysis showed that almost all patients (94–97%) with subtype 2a infection and 39–89% of those with subtype 2b infection originally had NS5A L31 M at baseline [18, 36]. In addition, the SVR rate in patients with NS5A resistance-associated substitutions was extremely high (97.6%, 165/169) in clinical trials [18, 31, 32]. Therefore, it is considered that NS5A L31 M, and not NS5B, is unassociated with treatment outcome. Further studies assessing NS5A and NS5B mutations should be performed. Another limitation is that 13 patients were excluded from the mITT population, mainly because of self-discontinuation of visits during or after LDV/SOF treatment. This may be related to the social background such as a history of intravenous drug use or a history of tattooing in patients with HCV genotype 2 infection [16, 37]. Additional studies of this treatment with fewer dropouts are warranted. Third, it included a relatively small number of patients. Future studies with more patients are warranted.
Conclusion
An IFN-free DAA regimen with LDV/SOF demonstrated a very high SVR rate and acceptable safety profile in patients infected with HCV genotype 2 infection. In particular, the LDV/SOF regimen resulted in good SVR rates regardless of patient age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, and baseline eGFR. Further studies are warranted to confirm these findings in other populations.
Acknowledgements
We thank the participants of the study.
Funding
This work was supported by Gilead Sciences (commercial research funding). Gilead Sciences also funded the journal’s Rapid Service Fees.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authorship Contributions
Concept and study design: Takashi Kumada and Toshifumi Tada. Data acquisition: All authors. Analyses of the data: Takashi Kumada and Toshifumi Tada. Statistics: Toshifumi Tada. Supervise: Takashi Kumada. Preparing the manuscript: Toshifumi Tada. Review and approval: All authors.
Disclosures
Takashi Kumada served as a speaker for Gilead and AbbVie. Hidenori Toyoda has served as a speaker for Gilead, AbbVie, and MSD. Toshifumi Tada, Hiroaki Okushin, Joji Tani, Koichi Takaguchi, Akemi Tsutsui, Satoshi Yasuda, Kazufumi Dohmen, Atsushi Hiraoka, Kojiro Michitaka, Kazuhiro Nouso, Kazuya Kariyama, Soo Ryang Kim, Soo Ki Kim, Shinichi Fujioka, Shigeru Mikami, Yuto Watanabe, Tsutomu Tamai, Masanori Atsukawa, Norio Itokawa, Hironori Tanaka, Kunihiko Tsuji, Toru Ishikawa, Michitaka Imai, Ei Itobayashi, Hiroshi Shibata, and Noritomo Shimada declare that they have no competing interests.
Compliance with Ethics Guidelines
This study was approved by the ethics committee of Ogaki Municipal Hospital (IRB #20180927-13-k). All documents approved by Ogaki Municipal Hospital (Kumada T) were sent to each institution and approved by each institution under the same IRB name and number. This study was performed in accordance with the 2013 Helsinki Declaration. All patients consented to provide their data. Written informed consent was obtained from each patient before enrollment. All patients consented to provide their data. Consent to both participate and allow the data to be published was obtained from each patient before enrollment.
Data Availability
The datasets are available from the corresponding author on reasonable request.
|
Recovering
|
ReactionOutcome
|
CC BY-NC
|
33141401
| 18,502,592
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'.
|
An exceptional response to 177LuPSMA undermined by neuroendocrine transformation.
Approximately 25% of patients who have undergone extensive systemic therapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment associated neuroendocrine prostate cancer (NEPC). 177Lu-prostate specific membrane antigen (-PSMA) is an emerging alternative therapy for mCRPC patients who have exhausted other systemic therapy options; however, cells with neuroendocrine differentiation do not express PSMA and are not affected by this treatment. This case highlights an exceptional response of skeletal metastases to 177LuPSMA that is undermined by neuroendocrine transformation in the liver.
Introduction
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC).1 We present a case of a patient who has undergone extensive treatment including an emerging therapy, 177Lu-prostate specific membrane antigen (-PSMA),2 who develops rapidly progressive incurable disease.
Case presentation
A 73-year-old male patient developed nausea and lethargy following his second cycle of Lutetium 177 prostate specific membrane antigen (177LuPSMA) for metastatic castration-resistant prostate cancer (mCRPC). Seven years prior he had undergone robotic prostatectomy for Gleason 5 + 4 = 9 adenocarcinoma with extraprostatic extension. He received intermittent doses of androgen deprivation therapy (ADT) over the following years. Twelve months prior to this presentation, he was referred for consideration of docetaxel chemotherapy for metastatic hormone-sensitive prostate cancer. The patient declined this treatment option and continued with ADT. Three months thereafter his cancer became castration-resistant. He received four cycles of docetaxel chemotherapy followed by five cycles of cabazitaxel chemotherapy with no appreciable response.
The patient's PSA peaked at 150 μg/L (reference range: 0.3–6.5 μg/L). He received two cycles of 177LuPSMA therapy, six weeks apart. Fig. 1 reveals the extent of the bone disease prior to the commencement of 177LuPSMA therapy. Fig. 2 reveals extent of the bone disease after the 177LuPSMA therapy.Fig. 1 PSMA PET/CT prior to 177Lu-PSMA therapy. Anterior whole body projection, MIP revealing wide spread bone metastases.
Fig. 1Fig. 2 PMSA PET/CT six weeks following the first 177Lu-PMSA therapy. Anterior whole body projection, MIP revealing an excellent response of the bone metastases.
Fig. 2
Following the second cycle of radiologically and biochemically successful treatment, the patient complained of xerostomia, nausea and lethargy, all common side effects of 177LuPSMA.3 His PSA had decreased to 0.5 μg/L (<1% of the baseline). However, the companion diagnostic PSMA scan of his liver, performed with the second 177LuPSMA revealed multifocal hypodense changes without PSMA activity. Within a fortnight, his liver function tests started to deteriorate. A liver ultrasound confirmed marked heterogeneity with nodularity. An attempted ultrasound-guided liver biopsy was aborted owing to brisk bleeding with the placement of the coaxial needle prior to the biopsy. His serum chromogranin A level was 214 μg/L (reference range <102). Fig. 3 reveals the MRI used to confirm diffuse metastatic liver disease.Fig. 3 MRI liver T1 axial view, fat suppression. Revealing widespread replacement with metastatic disease.
Fig. 3
Based on the rapid development of widely disseminated, small homogenous metastases throughout the liver and in no other visceral organs, in the context of a very low PSA and high Chromogranin A (with Chromogranin A being a well-documented bio marker for neuroendocrine tumour), the diagnosis of neuroendocrine transformation from prostate adenocarcinoma was discussed with the patient. He proceeded to treatment with carboplatin and etoposide chemotherapy. Sadly, his cancer did not respond and he died within weeks from liver failure due to the burden of metastatic disease.
Discussion
Prostate cancer is the most common cancer diagnosed in men in developed countries. Few prostate cancers harbour neuroendocrine variants at diagnosis. The vast majority of prostate cancers are prostatic adenocarcinoma which behave as a chronic disease and can be treated with standard therapies. Treatment of metastatic prostate cancer has become progressively complex and incorporates the use of androgen deprivation therapy, systemic taxane chemotherapy, and targeted androgen therapy. These treatments can be used in varying combinations over a number of years to slow the progression of metastatic prostate cancer whilst preserving the patients’ quality of life.
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC). Common features of treatment-associated NEPC include disproportionately low PSA levels in combination with rapid disease progression and high burdens of lytic bone and visceral metastases. Serum levels of the neuroendocrine markers, chromogranin A, neurone-specific enolase and gastrin-releasing peptide, are usually elevated.4 Chromogranin A is considered to be both specific and sensitive and is the most commonly used biomarker in neuroendocrine tumour differentiation. The only factor associated with more rapid disease transformation from prostatic adenocarcinoma is an initial Gleason score ≥ 8.1,4
Tissue diagnosis via metastatic biopsy can reveal different pathological subtypes of neuroendocrine tumours which portend various rates of survival, but all are invariably fatal. Treatment is currently based on systemic platinum-based therapy which offers a rapid but unsustained response.1 This empiric treatment is based on its use in other small-cell tumours, particularly those arising from the lung, and is not as successful in treating NEPC. To date there is a lack of published clinical trial data for the successful treatment of NEPC. Some trials are currently focusing on genomic sequencing of NEPC to differentiate treatable and targetable variants.
177Lu-prostate specific membrane antigen (-PSMA) therapy is an emerging treatment for patients with mCRPC cancer after exhaustion of other systemic therapies. 177LuPSMA is a radiolabelled isotope which binds with high affinity to the PSMA, a transmembrane glycoprotein which is expressed in prostate epithelium and over-expressed, more than one hundred-fold, in prostate cancer cells. This enables targeted delivery of beta-radiation to malignant cells. Many trials of this treatment modality have included heavily pre-treated patients who have already received multiple chemotherapy and hormonal agents. Responses to 177LuPSMA treatment include a reduction of PSA of ≥50%, an improved quality of life, and decreased levels of pain.4 Adverse effects of 177LuPSMA are few and can be anticipated due the distribution of PSMA expressing cells such as in salivary glands resulting in xerostomia, and in the small intestine resulting nausea and gastrointestinal upset. Since renal tubules also express PSMA, this therapy is safe for administration to patients with mildly decreased renal function (eGFR >40mL/min) without obstruction. Patients with sufficient haematological reserve, with platelets >75 × 109/L and neutrophils >1.5 × 109/L, can also safely receive this treatment. Transient increase in pain at the sites of metastases and fatigue can be expected.3,5
Cells with neuroendocrine differentiation do not express PSMA and are not affected by 177LuPSMA.5 Based on case studies which have shown patients to have treatment-associated neuroendocrine prostate cancer some clinicians recommend FDG PET/CT imaging to further select patients for PSMA targeted therapy.
Conclusion
This case has demonstrated an exceptional response to 177LuPSMA for previously identified bone metastases with near complete resolution of these on PSMA PET/CT scan and a drop to <1% baseline of the PSA. However, this response has been undermined by the transformation of the metastases in the liver to neuroendocrine tumours that do not respond to 177LuPSMA.
Consent
The patient's wife provided proxy consent for anonymised clinical information and imaging to be included in this paper. The written consent is stored in the patient's hospital record.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
None.
|
CABAZITAXEL, CARBOPLATIN, DOCETAXEL, ETOPOSIDE, LUTETIUM CHLORIDE LU-177
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33145175
| 19,405,946
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic cancer metastatic'.
|
An exceptional response to 177LuPSMA undermined by neuroendocrine transformation.
Approximately 25% of patients who have undergone extensive systemic therapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment associated neuroendocrine prostate cancer (NEPC). 177Lu-prostate specific membrane antigen (-PSMA) is an emerging alternative therapy for mCRPC patients who have exhausted other systemic therapy options; however, cells with neuroendocrine differentiation do not express PSMA and are not affected by this treatment. This case highlights an exceptional response of skeletal metastases to 177LuPSMA that is undermined by neuroendocrine transformation in the liver.
Introduction
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC).1 We present a case of a patient who has undergone extensive treatment including an emerging therapy, 177Lu-prostate specific membrane antigen (-PSMA),2 who develops rapidly progressive incurable disease.
Case presentation
A 73-year-old male patient developed nausea and lethargy following his second cycle of Lutetium 177 prostate specific membrane antigen (177LuPSMA) for metastatic castration-resistant prostate cancer (mCRPC). Seven years prior he had undergone robotic prostatectomy for Gleason 5 + 4 = 9 adenocarcinoma with extraprostatic extension. He received intermittent doses of androgen deprivation therapy (ADT) over the following years. Twelve months prior to this presentation, he was referred for consideration of docetaxel chemotherapy for metastatic hormone-sensitive prostate cancer. The patient declined this treatment option and continued with ADT. Three months thereafter his cancer became castration-resistant. He received four cycles of docetaxel chemotherapy followed by five cycles of cabazitaxel chemotherapy with no appreciable response.
The patient's PSA peaked at 150 μg/L (reference range: 0.3–6.5 μg/L). He received two cycles of 177LuPSMA therapy, six weeks apart. Fig. 1 reveals the extent of the bone disease prior to the commencement of 177LuPSMA therapy. Fig. 2 reveals extent of the bone disease after the 177LuPSMA therapy.Fig. 1 PSMA PET/CT prior to 177Lu-PSMA therapy. Anterior whole body projection, MIP revealing wide spread bone metastases.
Fig. 1Fig. 2 PMSA PET/CT six weeks following the first 177Lu-PMSA therapy. Anterior whole body projection, MIP revealing an excellent response of the bone metastases.
Fig. 2
Following the second cycle of radiologically and biochemically successful treatment, the patient complained of xerostomia, nausea and lethargy, all common side effects of 177LuPSMA.3 His PSA had decreased to 0.5 μg/L (<1% of the baseline). However, the companion diagnostic PSMA scan of his liver, performed with the second 177LuPSMA revealed multifocal hypodense changes without PSMA activity. Within a fortnight, his liver function tests started to deteriorate. A liver ultrasound confirmed marked heterogeneity with nodularity. An attempted ultrasound-guided liver biopsy was aborted owing to brisk bleeding with the placement of the coaxial needle prior to the biopsy. His serum chromogranin A level was 214 μg/L (reference range <102). Fig. 3 reveals the MRI used to confirm diffuse metastatic liver disease.Fig. 3 MRI liver T1 axial view, fat suppression. Revealing widespread replacement with metastatic disease.
Fig. 3
Based on the rapid development of widely disseminated, small homogenous metastases throughout the liver and in no other visceral organs, in the context of a very low PSA and high Chromogranin A (with Chromogranin A being a well-documented bio marker for neuroendocrine tumour), the diagnosis of neuroendocrine transformation from prostate adenocarcinoma was discussed with the patient. He proceeded to treatment with carboplatin and etoposide chemotherapy. Sadly, his cancer did not respond and he died within weeks from liver failure due to the burden of metastatic disease.
Discussion
Prostate cancer is the most common cancer diagnosed in men in developed countries. Few prostate cancers harbour neuroendocrine variants at diagnosis. The vast majority of prostate cancers are prostatic adenocarcinoma which behave as a chronic disease and can be treated with standard therapies. Treatment of metastatic prostate cancer has become progressively complex and incorporates the use of androgen deprivation therapy, systemic taxane chemotherapy, and targeted androgen therapy. These treatments can be used in varying combinations over a number of years to slow the progression of metastatic prostate cancer whilst preserving the patients’ quality of life.
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC). Common features of treatment-associated NEPC include disproportionately low PSA levels in combination with rapid disease progression and high burdens of lytic bone and visceral metastases. Serum levels of the neuroendocrine markers, chromogranin A, neurone-specific enolase and gastrin-releasing peptide, are usually elevated.4 Chromogranin A is considered to be both specific and sensitive and is the most commonly used biomarker in neuroendocrine tumour differentiation. The only factor associated with more rapid disease transformation from prostatic adenocarcinoma is an initial Gleason score ≥ 8.1,4
Tissue diagnosis via metastatic biopsy can reveal different pathological subtypes of neuroendocrine tumours which portend various rates of survival, but all are invariably fatal. Treatment is currently based on systemic platinum-based therapy which offers a rapid but unsustained response.1 This empiric treatment is based on its use in other small-cell tumours, particularly those arising from the lung, and is not as successful in treating NEPC. To date there is a lack of published clinical trial data for the successful treatment of NEPC. Some trials are currently focusing on genomic sequencing of NEPC to differentiate treatable and targetable variants.
177Lu-prostate specific membrane antigen (-PSMA) therapy is an emerging treatment for patients with mCRPC cancer after exhaustion of other systemic therapies. 177LuPSMA is a radiolabelled isotope which binds with high affinity to the PSMA, a transmembrane glycoprotein which is expressed in prostate epithelium and over-expressed, more than one hundred-fold, in prostate cancer cells. This enables targeted delivery of beta-radiation to malignant cells. Many trials of this treatment modality have included heavily pre-treated patients who have already received multiple chemotherapy and hormonal agents. Responses to 177LuPSMA treatment include a reduction of PSA of ≥50%, an improved quality of life, and decreased levels of pain.4 Adverse effects of 177LuPSMA are few and can be anticipated due the distribution of PSMA expressing cells such as in salivary glands resulting in xerostomia, and in the small intestine resulting nausea and gastrointestinal upset. Since renal tubules also express PSMA, this therapy is safe for administration to patients with mildly decreased renal function (eGFR >40mL/min) without obstruction. Patients with sufficient haematological reserve, with platelets >75 × 109/L and neutrophils >1.5 × 109/L, can also safely receive this treatment. Transient increase in pain at the sites of metastases and fatigue can be expected.3,5
Cells with neuroendocrine differentiation do not express PSMA and are not affected by 177LuPSMA.5 Based on case studies which have shown patients to have treatment-associated neuroendocrine prostate cancer some clinicians recommend FDG PET/CT imaging to further select patients for PSMA targeted therapy.
Conclusion
This case has demonstrated an exceptional response to 177LuPSMA for previously identified bone metastases with near complete resolution of these on PSMA PET/CT scan and a drop to <1% baseline of the PSA. However, this response has been undermined by the transformation of the metastases in the liver to neuroendocrine tumours that do not respond to 177LuPSMA.
Consent
The patient's wife provided proxy consent for anonymised clinical information and imaging to be included in this paper. The written consent is stored in the patient's hospital record.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
None.
|
CABAZITAXEL, CARBOPLATIN, DOCETAXEL, ETOPOSIDE, LUTETIUM CHLORIDE LU-177
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33145175
| 19,405,946
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neuroendocrine carcinoma of prostate'.
|
An exceptional response to 177LuPSMA undermined by neuroendocrine transformation.
Approximately 25% of patients who have undergone extensive systemic therapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment associated neuroendocrine prostate cancer (NEPC). 177Lu-prostate specific membrane antigen (-PSMA) is an emerging alternative therapy for mCRPC patients who have exhausted other systemic therapy options; however, cells with neuroendocrine differentiation do not express PSMA and are not affected by this treatment. This case highlights an exceptional response of skeletal metastases to 177LuPSMA that is undermined by neuroendocrine transformation in the liver.
Introduction
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC).1 We present a case of a patient who has undergone extensive treatment including an emerging therapy, 177Lu-prostate specific membrane antigen (-PSMA),2 who develops rapidly progressive incurable disease.
Case presentation
A 73-year-old male patient developed nausea and lethargy following his second cycle of Lutetium 177 prostate specific membrane antigen (177LuPSMA) for metastatic castration-resistant prostate cancer (mCRPC). Seven years prior he had undergone robotic prostatectomy for Gleason 5 + 4 = 9 adenocarcinoma with extraprostatic extension. He received intermittent doses of androgen deprivation therapy (ADT) over the following years. Twelve months prior to this presentation, he was referred for consideration of docetaxel chemotherapy for metastatic hormone-sensitive prostate cancer. The patient declined this treatment option and continued with ADT. Three months thereafter his cancer became castration-resistant. He received four cycles of docetaxel chemotherapy followed by five cycles of cabazitaxel chemotherapy with no appreciable response.
The patient's PSA peaked at 150 μg/L (reference range: 0.3–6.5 μg/L). He received two cycles of 177LuPSMA therapy, six weeks apart. Fig. 1 reveals the extent of the bone disease prior to the commencement of 177LuPSMA therapy. Fig. 2 reveals extent of the bone disease after the 177LuPSMA therapy.Fig. 1 PSMA PET/CT prior to 177Lu-PSMA therapy. Anterior whole body projection, MIP revealing wide spread bone metastases.
Fig. 1Fig. 2 PMSA PET/CT six weeks following the first 177Lu-PMSA therapy. Anterior whole body projection, MIP revealing an excellent response of the bone metastases.
Fig. 2
Following the second cycle of radiologically and biochemically successful treatment, the patient complained of xerostomia, nausea and lethargy, all common side effects of 177LuPSMA.3 His PSA had decreased to 0.5 μg/L (<1% of the baseline). However, the companion diagnostic PSMA scan of his liver, performed with the second 177LuPSMA revealed multifocal hypodense changes without PSMA activity. Within a fortnight, his liver function tests started to deteriorate. A liver ultrasound confirmed marked heterogeneity with nodularity. An attempted ultrasound-guided liver biopsy was aborted owing to brisk bleeding with the placement of the coaxial needle prior to the biopsy. His serum chromogranin A level was 214 μg/L (reference range <102). Fig. 3 reveals the MRI used to confirm diffuse metastatic liver disease.Fig. 3 MRI liver T1 axial view, fat suppression. Revealing widespread replacement with metastatic disease.
Fig. 3
Based on the rapid development of widely disseminated, small homogenous metastases throughout the liver and in no other visceral organs, in the context of a very low PSA and high Chromogranin A (with Chromogranin A being a well-documented bio marker for neuroendocrine tumour), the diagnosis of neuroendocrine transformation from prostate adenocarcinoma was discussed with the patient. He proceeded to treatment with carboplatin and etoposide chemotherapy. Sadly, his cancer did not respond and he died within weeks from liver failure due to the burden of metastatic disease.
Discussion
Prostate cancer is the most common cancer diagnosed in men in developed countries. Few prostate cancers harbour neuroendocrine variants at diagnosis. The vast majority of prostate cancers are prostatic adenocarcinoma which behave as a chronic disease and can be treated with standard therapies. Treatment of metastatic prostate cancer has become progressively complex and incorporates the use of androgen deprivation therapy, systemic taxane chemotherapy, and targeted androgen therapy. These treatments can be used in varying combinations over a number of years to slow the progression of metastatic prostate cancer whilst preserving the patients’ quality of life.
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC). Common features of treatment-associated NEPC include disproportionately low PSA levels in combination with rapid disease progression and high burdens of lytic bone and visceral metastases. Serum levels of the neuroendocrine markers, chromogranin A, neurone-specific enolase and gastrin-releasing peptide, are usually elevated.4 Chromogranin A is considered to be both specific and sensitive and is the most commonly used biomarker in neuroendocrine tumour differentiation. The only factor associated with more rapid disease transformation from prostatic adenocarcinoma is an initial Gleason score ≥ 8.1,4
Tissue diagnosis via metastatic biopsy can reveal different pathological subtypes of neuroendocrine tumours which portend various rates of survival, but all are invariably fatal. Treatment is currently based on systemic platinum-based therapy which offers a rapid but unsustained response.1 This empiric treatment is based on its use in other small-cell tumours, particularly those arising from the lung, and is not as successful in treating NEPC. To date there is a lack of published clinical trial data for the successful treatment of NEPC. Some trials are currently focusing on genomic sequencing of NEPC to differentiate treatable and targetable variants.
177Lu-prostate specific membrane antigen (-PSMA) therapy is an emerging treatment for patients with mCRPC cancer after exhaustion of other systemic therapies. 177LuPSMA is a radiolabelled isotope which binds with high affinity to the PSMA, a transmembrane glycoprotein which is expressed in prostate epithelium and over-expressed, more than one hundred-fold, in prostate cancer cells. This enables targeted delivery of beta-radiation to malignant cells. Many trials of this treatment modality have included heavily pre-treated patients who have already received multiple chemotherapy and hormonal agents. Responses to 177LuPSMA treatment include a reduction of PSA of ≥50%, an improved quality of life, and decreased levels of pain.4 Adverse effects of 177LuPSMA are few and can be anticipated due the distribution of PSMA expressing cells such as in salivary glands resulting in xerostomia, and in the small intestine resulting nausea and gastrointestinal upset. Since renal tubules also express PSMA, this therapy is safe for administration to patients with mildly decreased renal function (eGFR >40mL/min) without obstruction. Patients with sufficient haematological reserve, with platelets >75 × 109/L and neutrophils >1.5 × 109/L, can also safely receive this treatment. Transient increase in pain at the sites of metastases and fatigue can be expected.3,5
Cells with neuroendocrine differentiation do not express PSMA and are not affected by 177LuPSMA.5 Based on case studies which have shown patients to have treatment-associated neuroendocrine prostate cancer some clinicians recommend FDG PET/CT imaging to further select patients for PSMA targeted therapy.
Conclusion
This case has demonstrated an exceptional response to 177LuPSMA for previously identified bone metastases with near complete resolution of these on PSMA PET/CT scan and a drop to <1% baseline of the PSA. However, this response has been undermined by the transformation of the metastases in the liver to neuroendocrine tumours that do not respond to 177LuPSMA.
Consent
The patient's wife provided proxy consent for anonymised clinical information and imaging to be included in this paper. The written consent is stored in the patient's hospital record.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
None.
|
CABAZITAXEL, CARBOPLATIN, DOCETAXEL, ETOPOSIDE, LUTETIUM CHLORIDE LU-177
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33145175
| 19,405,946
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy non-responder'.
|
An exceptional response to 177LuPSMA undermined by neuroendocrine transformation.
Approximately 25% of patients who have undergone extensive systemic therapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment associated neuroendocrine prostate cancer (NEPC). 177Lu-prostate specific membrane antigen (-PSMA) is an emerging alternative therapy for mCRPC patients who have exhausted other systemic therapy options; however, cells with neuroendocrine differentiation do not express PSMA and are not affected by this treatment. This case highlights an exceptional response of skeletal metastases to 177LuPSMA that is undermined by neuroendocrine transformation in the liver.
Introduction
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC).1 We present a case of a patient who has undergone extensive treatment including an emerging therapy, 177Lu-prostate specific membrane antigen (-PSMA),2 who develops rapidly progressive incurable disease.
Case presentation
A 73-year-old male patient developed nausea and lethargy following his second cycle of Lutetium 177 prostate specific membrane antigen (177LuPSMA) for metastatic castration-resistant prostate cancer (mCRPC). Seven years prior he had undergone robotic prostatectomy for Gleason 5 + 4 = 9 adenocarcinoma with extraprostatic extension. He received intermittent doses of androgen deprivation therapy (ADT) over the following years. Twelve months prior to this presentation, he was referred for consideration of docetaxel chemotherapy for metastatic hormone-sensitive prostate cancer. The patient declined this treatment option and continued with ADT. Three months thereafter his cancer became castration-resistant. He received four cycles of docetaxel chemotherapy followed by five cycles of cabazitaxel chemotherapy with no appreciable response.
The patient's PSA peaked at 150 μg/L (reference range: 0.3–6.5 μg/L). He received two cycles of 177LuPSMA therapy, six weeks apart. Fig. 1 reveals the extent of the bone disease prior to the commencement of 177LuPSMA therapy. Fig. 2 reveals extent of the bone disease after the 177LuPSMA therapy.Fig. 1 PSMA PET/CT prior to 177Lu-PSMA therapy. Anterior whole body projection, MIP revealing wide spread bone metastases.
Fig. 1Fig. 2 PMSA PET/CT six weeks following the first 177Lu-PMSA therapy. Anterior whole body projection, MIP revealing an excellent response of the bone metastases.
Fig. 2
Following the second cycle of radiologically and biochemically successful treatment, the patient complained of xerostomia, nausea and lethargy, all common side effects of 177LuPSMA.3 His PSA had decreased to 0.5 μg/L (<1% of the baseline). However, the companion diagnostic PSMA scan of his liver, performed with the second 177LuPSMA revealed multifocal hypodense changes without PSMA activity. Within a fortnight, his liver function tests started to deteriorate. A liver ultrasound confirmed marked heterogeneity with nodularity. An attempted ultrasound-guided liver biopsy was aborted owing to brisk bleeding with the placement of the coaxial needle prior to the biopsy. His serum chromogranin A level was 214 μg/L (reference range <102). Fig. 3 reveals the MRI used to confirm diffuse metastatic liver disease.Fig. 3 MRI liver T1 axial view, fat suppression. Revealing widespread replacement with metastatic disease.
Fig. 3
Based on the rapid development of widely disseminated, small homogenous metastases throughout the liver and in no other visceral organs, in the context of a very low PSA and high Chromogranin A (with Chromogranin A being a well-documented bio marker for neuroendocrine tumour), the diagnosis of neuroendocrine transformation from prostate adenocarcinoma was discussed with the patient. He proceeded to treatment with carboplatin and etoposide chemotherapy. Sadly, his cancer did not respond and he died within weeks from liver failure due to the burden of metastatic disease.
Discussion
Prostate cancer is the most common cancer diagnosed in men in developed countries. Few prostate cancers harbour neuroendocrine variants at diagnosis. The vast majority of prostate cancers are prostatic adenocarcinoma which behave as a chronic disease and can be treated with standard therapies. Treatment of metastatic prostate cancer has become progressively complex and incorporates the use of androgen deprivation therapy, systemic taxane chemotherapy, and targeted androgen therapy. These treatments can be used in varying combinations over a number of years to slow the progression of metastatic prostate cancer whilst preserving the patients’ quality of life.
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC). Common features of treatment-associated NEPC include disproportionately low PSA levels in combination with rapid disease progression and high burdens of lytic bone and visceral metastases. Serum levels of the neuroendocrine markers, chromogranin A, neurone-specific enolase and gastrin-releasing peptide, are usually elevated.4 Chromogranin A is considered to be both specific and sensitive and is the most commonly used biomarker in neuroendocrine tumour differentiation. The only factor associated with more rapid disease transformation from prostatic adenocarcinoma is an initial Gleason score ≥ 8.1,4
Tissue diagnosis via metastatic biopsy can reveal different pathological subtypes of neuroendocrine tumours which portend various rates of survival, but all are invariably fatal. Treatment is currently based on systemic platinum-based therapy which offers a rapid but unsustained response.1 This empiric treatment is based on its use in other small-cell tumours, particularly those arising from the lung, and is not as successful in treating NEPC. To date there is a lack of published clinical trial data for the successful treatment of NEPC. Some trials are currently focusing on genomic sequencing of NEPC to differentiate treatable and targetable variants.
177Lu-prostate specific membrane antigen (-PSMA) therapy is an emerging treatment for patients with mCRPC cancer after exhaustion of other systemic therapies. 177LuPSMA is a radiolabelled isotope which binds with high affinity to the PSMA, a transmembrane glycoprotein which is expressed in prostate epithelium and over-expressed, more than one hundred-fold, in prostate cancer cells. This enables targeted delivery of beta-radiation to malignant cells. Many trials of this treatment modality have included heavily pre-treated patients who have already received multiple chemotherapy and hormonal agents. Responses to 177LuPSMA treatment include a reduction of PSA of ≥50%, an improved quality of life, and decreased levels of pain.4 Adverse effects of 177LuPSMA are few and can be anticipated due the distribution of PSMA expressing cells such as in salivary glands resulting in xerostomia, and in the small intestine resulting nausea and gastrointestinal upset. Since renal tubules also express PSMA, this therapy is safe for administration to patients with mildly decreased renal function (eGFR >40mL/min) without obstruction. Patients with sufficient haematological reserve, with platelets >75 × 109/L and neutrophils >1.5 × 109/L, can also safely receive this treatment. Transient increase in pain at the sites of metastases and fatigue can be expected.3,5
Cells with neuroendocrine differentiation do not express PSMA and are not affected by 177LuPSMA.5 Based on case studies which have shown patients to have treatment-associated neuroendocrine prostate cancer some clinicians recommend FDG PET/CT imaging to further select patients for PSMA targeted therapy.
Conclusion
This case has demonstrated an exceptional response to 177LuPSMA for previously identified bone metastases with near complete resolution of these on PSMA PET/CT scan and a drop to <1% baseline of the PSA. However, this response has been undermined by the transformation of the metastases in the liver to neuroendocrine tumours that do not respond to 177LuPSMA.
Consent
The patient's wife provided proxy consent for anonymised clinical information and imaging to be included in this paper. The written consent is stored in the patient's hospital record.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
None.
|
CARBOPLATIN, ETOPOSIDE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33145175
| 19,432,357
|
2021-01
|
What was the outcome of reaction 'Hepatic cancer metastatic'?
|
An exceptional response to 177LuPSMA undermined by neuroendocrine transformation.
Approximately 25% of patients who have undergone extensive systemic therapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment associated neuroendocrine prostate cancer (NEPC). 177Lu-prostate specific membrane antigen (-PSMA) is an emerging alternative therapy for mCRPC patients who have exhausted other systemic therapy options; however, cells with neuroendocrine differentiation do not express PSMA and are not affected by this treatment. This case highlights an exceptional response of skeletal metastases to 177LuPSMA that is undermined by neuroendocrine transformation in the liver.
Introduction
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC).1 We present a case of a patient who has undergone extensive treatment including an emerging therapy, 177Lu-prostate specific membrane antigen (-PSMA),2 who develops rapidly progressive incurable disease.
Case presentation
A 73-year-old male patient developed nausea and lethargy following his second cycle of Lutetium 177 prostate specific membrane antigen (177LuPSMA) for metastatic castration-resistant prostate cancer (mCRPC). Seven years prior he had undergone robotic prostatectomy for Gleason 5 + 4 = 9 adenocarcinoma with extraprostatic extension. He received intermittent doses of androgen deprivation therapy (ADT) over the following years. Twelve months prior to this presentation, he was referred for consideration of docetaxel chemotherapy for metastatic hormone-sensitive prostate cancer. The patient declined this treatment option and continued with ADT. Three months thereafter his cancer became castration-resistant. He received four cycles of docetaxel chemotherapy followed by five cycles of cabazitaxel chemotherapy with no appreciable response.
The patient's PSA peaked at 150 μg/L (reference range: 0.3–6.5 μg/L). He received two cycles of 177LuPSMA therapy, six weeks apart. Fig. 1 reveals the extent of the bone disease prior to the commencement of 177LuPSMA therapy. Fig. 2 reveals extent of the bone disease after the 177LuPSMA therapy.Fig. 1 PSMA PET/CT prior to 177Lu-PSMA therapy. Anterior whole body projection, MIP revealing wide spread bone metastases.
Fig. 1Fig. 2 PMSA PET/CT six weeks following the first 177Lu-PMSA therapy. Anterior whole body projection, MIP revealing an excellent response of the bone metastases.
Fig. 2
Following the second cycle of radiologically and biochemically successful treatment, the patient complained of xerostomia, nausea and lethargy, all common side effects of 177LuPSMA.3 His PSA had decreased to 0.5 μg/L (<1% of the baseline). However, the companion diagnostic PSMA scan of his liver, performed with the second 177LuPSMA revealed multifocal hypodense changes without PSMA activity. Within a fortnight, his liver function tests started to deteriorate. A liver ultrasound confirmed marked heterogeneity with nodularity. An attempted ultrasound-guided liver biopsy was aborted owing to brisk bleeding with the placement of the coaxial needle prior to the biopsy. His serum chromogranin A level was 214 μg/L (reference range <102). Fig. 3 reveals the MRI used to confirm diffuse metastatic liver disease.Fig. 3 MRI liver T1 axial view, fat suppression. Revealing widespread replacement with metastatic disease.
Fig. 3
Based on the rapid development of widely disseminated, small homogenous metastases throughout the liver and in no other visceral organs, in the context of a very low PSA and high Chromogranin A (with Chromogranin A being a well-documented bio marker for neuroendocrine tumour), the diagnosis of neuroendocrine transformation from prostate adenocarcinoma was discussed with the patient. He proceeded to treatment with carboplatin and etoposide chemotherapy. Sadly, his cancer did not respond and he died within weeks from liver failure due to the burden of metastatic disease.
Discussion
Prostate cancer is the most common cancer diagnosed in men in developed countries. Few prostate cancers harbour neuroendocrine variants at diagnosis. The vast majority of prostate cancers are prostatic adenocarcinoma which behave as a chronic disease and can be treated with standard therapies. Treatment of metastatic prostate cancer has become progressively complex and incorporates the use of androgen deprivation therapy, systemic taxane chemotherapy, and targeted androgen therapy. These treatments can be used in varying combinations over a number of years to slow the progression of metastatic prostate cancer whilst preserving the patients’ quality of life.
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC). Common features of treatment-associated NEPC include disproportionately low PSA levels in combination with rapid disease progression and high burdens of lytic bone and visceral metastases. Serum levels of the neuroendocrine markers, chromogranin A, neurone-specific enolase and gastrin-releasing peptide, are usually elevated.4 Chromogranin A is considered to be both specific and sensitive and is the most commonly used biomarker in neuroendocrine tumour differentiation. The only factor associated with more rapid disease transformation from prostatic adenocarcinoma is an initial Gleason score ≥ 8.1,4
Tissue diagnosis via metastatic biopsy can reveal different pathological subtypes of neuroendocrine tumours which portend various rates of survival, but all are invariably fatal. Treatment is currently based on systemic platinum-based therapy which offers a rapid but unsustained response.1 This empiric treatment is based on its use in other small-cell tumours, particularly those arising from the lung, and is not as successful in treating NEPC. To date there is a lack of published clinical trial data for the successful treatment of NEPC. Some trials are currently focusing on genomic sequencing of NEPC to differentiate treatable and targetable variants.
177Lu-prostate specific membrane antigen (-PSMA) therapy is an emerging treatment for patients with mCRPC cancer after exhaustion of other systemic therapies. 177LuPSMA is a radiolabelled isotope which binds with high affinity to the PSMA, a transmembrane glycoprotein which is expressed in prostate epithelium and over-expressed, more than one hundred-fold, in prostate cancer cells. This enables targeted delivery of beta-radiation to malignant cells. Many trials of this treatment modality have included heavily pre-treated patients who have already received multiple chemotherapy and hormonal agents. Responses to 177LuPSMA treatment include a reduction of PSA of ≥50%, an improved quality of life, and decreased levels of pain.4 Adverse effects of 177LuPSMA are few and can be anticipated due the distribution of PSMA expressing cells such as in salivary glands resulting in xerostomia, and in the small intestine resulting nausea and gastrointestinal upset. Since renal tubules also express PSMA, this therapy is safe for administration to patients with mildly decreased renal function (eGFR >40mL/min) without obstruction. Patients with sufficient haematological reserve, with platelets >75 × 109/L and neutrophils >1.5 × 109/L, can also safely receive this treatment. Transient increase in pain at the sites of metastases and fatigue can be expected.3,5
Cells with neuroendocrine differentiation do not express PSMA and are not affected by 177LuPSMA.5 Based on case studies which have shown patients to have treatment-associated neuroendocrine prostate cancer some clinicians recommend FDG PET/CT imaging to further select patients for PSMA targeted therapy.
Conclusion
This case has demonstrated an exceptional response to 177LuPSMA for previously identified bone metastases with near complete resolution of these on PSMA PET/CT scan and a drop to <1% baseline of the PSA. However, this response has been undermined by the transformation of the metastases in the liver to neuroendocrine tumours that do not respond to 177LuPSMA.
Consent
The patient's wife provided proxy consent for anonymised clinical information and imaging to be included in this paper. The written consent is stored in the patient's hospital record.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
None.
|
Fatal
|
ReactionOutcome
|
CC BY-NC-ND
|
33145175
| 19,405,946
|
2021-01
|
What was the outcome of reaction 'Hepatic failure'?
|
An exceptional response to 177LuPSMA undermined by neuroendocrine transformation.
Approximately 25% of patients who have undergone extensive systemic therapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment associated neuroendocrine prostate cancer (NEPC). 177Lu-prostate specific membrane antigen (-PSMA) is an emerging alternative therapy for mCRPC patients who have exhausted other systemic therapy options; however, cells with neuroendocrine differentiation do not express PSMA and are not affected by this treatment. This case highlights an exceptional response of skeletal metastases to 177LuPSMA that is undermined by neuroendocrine transformation in the liver.
Introduction
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC).1 We present a case of a patient who has undergone extensive treatment including an emerging therapy, 177Lu-prostate specific membrane antigen (-PSMA),2 who develops rapidly progressive incurable disease.
Case presentation
A 73-year-old male patient developed nausea and lethargy following his second cycle of Lutetium 177 prostate specific membrane antigen (177LuPSMA) for metastatic castration-resistant prostate cancer (mCRPC). Seven years prior he had undergone robotic prostatectomy for Gleason 5 + 4 = 9 adenocarcinoma with extraprostatic extension. He received intermittent doses of androgen deprivation therapy (ADT) over the following years. Twelve months prior to this presentation, he was referred for consideration of docetaxel chemotherapy for metastatic hormone-sensitive prostate cancer. The patient declined this treatment option and continued with ADT. Three months thereafter his cancer became castration-resistant. He received four cycles of docetaxel chemotherapy followed by five cycles of cabazitaxel chemotherapy with no appreciable response.
The patient's PSA peaked at 150 μg/L (reference range: 0.3–6.5 μg/L). He received two cycles of 177LuPSMA therapy, six weeks apart. Fig. 1 reveals the extent of the bone disease prior to the commencement of 177LuPSMA therapy. Fig. 2 reveals extent of the bone disease after the 177LuPSMA therapy.Fig. 1 PSMA PET/CT prior to 177Lu-PSMA therapy. Anterior whole body projection, MIP revealing wide spread bone metastases.
Fig. 1Fig. 2 PMSA PET/CT six weeks following the first 177Lu-PMSA therapy. Anterior whole body projection, MIP revealing an excellent response of the bone metastases.
Fig. 2
Following the second cycle of radiologically and biochemically successful treatment, the patient complained of xerostomia, nausea and lethargy, all common side effects of 177LuPSMA.3 His PSA had decreased to 0.5 μg/L (<1% of the baseline). However, the companion diagnostic PSMA scan of his liver, performed with the second 177LuPSMA revealed multifocal hypodense changes without PSMA activity. Within a fortnight, his liver function tests started to deteriorate. A liver ultrasound confirmed marked heterogeneity with nodularity. An attempted ultrasound-guided liver biopsy was aborted owing to brisk bleeding with the placement of the coaxial needle prior to the biopsy. His serum chromogranin A level was 214 μg/L (reference range <102). Fig. 3 reveals the MRI used to confirm diffuse metastatic liver disease.Fig. 3 MRI liver T1 axial view, fat suppression. Revealing widespread replacement with metastatic disease.
Fig. 3
Based on the rapid development of widely disseminated, small homogenous metastases throughout the liver and in no other visceral organs, in the context of a very low PSA and high Chromogranin A (with Chromogranin A being a well-documented bio marker for neuroendocrine tumour), the diagnosis of neuroendocrine transformation from prostate adenocarcinoma was discussed with the patient. He proceeded to treatment with carboplatin and etoposide chemotherapy. Sadly, his cancer did not respond and he died within weeks from liver failure due to the burden of metastatic disease.
Discussion
Prostate cancer is the most common cancer diagnosed in men in developed countries. Few prostate cancers harbour neuroendocrine variants at diagnosis. The vast majority of prostate cancers are prostatic adenocarcinoma which behave as a chronic disease and can be treated with standard therapies. Treatment of metastatic prostate cancer has become progressively complex and incorporates the use of androgen deprivation therapy, systemic taxane chemotherapy, and targeted androgen therapy. These treatments can be used in varying combinations over a number of years to slow the progression of metastatic prostate cancer whilst preserving the patients’ quality of life.
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC). Common features of treatment-associated NEPC include disproportionately low PSA levels in combination with rapid disease progression and high burdens of lytic bone and visceral metastases. Serum levels of the neuroendocrine markers, chromogranin A, neurone-specific enolase and gastrin-releasing peptide, are usually elevated.4 Chromogranin A is considered to be both specific and sensitive and is the most commonly used biomarker in neuroendocrine tumour differentiation. The only factor associated with more rapid disease transformation from prostatic adenocarcinoma is an initial Gleason score ≥ 8.1,4
Tissue diagnosis via metastatic biopsy can reveal different pathological subtypes of neuroendocrine tumours which portend various rates of survival, but all are invariably fatal. Treatment is currently based on systemic platinum-based therapy which offers a rapid but unsustained response.1 This empiric treatment is based on its use in other small-cell tumours, particularly those arising from the lung, and is not as successful in treating NEPC. To date there is a lack of published clinical trial data for the successful treatment of NEPC. Some trials are currently focusing on genomic sequencing of NEPC to differentiate treatable and targetable variants.
177Lu-prostate specific membrane antigen (-PSMA) therapy is an emerging treatment for patients with mCRPC cancer after exhaustion of other systemic therapies. 177LuPSMA is a radiolabelled isotope which binds with high affinity to the PSMA, a transmembrane glycoprotein which is expressed in prostate epithelium and over-expressed, more than one hundred-fold, in prostate cancer cells. This enables targeted delivery of beta-radiation to malignant cells. Many trials of this treatment modality have included heavily pre-treated patients who have already received multiple chemotherapy and hormonal agents. Responses to 177LuPSMA treatment include a reduction of PSA of ≥50%, an improved quality of life, and decreased levels of pain.4 Adverse effects of 177LuPSMA are few and can be anticipated due the distribution of PSMA expressing cells such as in salivary glands resulting in xerostomia, and in the small intestine resulting nausea and gastrointestinal upset. Since renal tubules also express PSMA, this therapy is safe for administration to patients with mildly decreased renal function (eGFR >40mL/min) without obstruction. Patients with sufficient haematological reserve, with platelets >75 × 109/L and neutrophils >1.5 × 109/L, can also safely receive this treatment. Transient increase in pain at the sites of metastases and fatigue can be expected.3,5
Cells with neuroendocrine differentiation do not express PSMA and are not affected by 177LuPSMA.5 Based on case studies which have shown patients to have treatment-associated neuroendocrine prostate cancer some clinicians recommend FDG PET/CT imaging to further select patients for PSMA targeted therapy.
Conclusion
This case has demonstrated an exceptional response to 177LuPSMA for previously identified bone metastases with near complete resolution of these on PSMA PET/CT scan and a drop to <1% baseline of the PSA. However, this response has been undermined by the transformation of the metastases in the liver to neuroendocrine tumours that do not respond to 177LuPSMA.
Consent
The patient's wife provided proxy consent for anonymised clinical information and imaging to be included in this paper. The written consent is stored in the patient's hospital record.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
None.
|
Fatal
|
ReactionOutcome
|
CC BY-NC-ND
|
33145175
| 19,432,357
|
2021-01
|
What was the outcome of reaction 'Neuroendocrine carcinoma of prostate'?
|
An exceptional response to 177LuPSMA undermined by neuroendocrine transformation.
Approximately 25% of patients who have undergone extensive systemic therapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment associated neuroendocrine prostate cancer (NEPC). 177Lu-prostate specific membrane antigen (-PSMA) is an emerging alternative therapy for mCRPC patients who have exhausted other systemic therapy options; however, cells with neuroendocrine differentiation do not express PSMA and are not affected by this treatment. This case highlights an exceptional response of skeletal metastases to 177LuPSMA that is undermined by neuroendocrine transformation in the liver.
Introduction
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC).1 We present a case of a patient who has undergone extensive treatment including an emerging therapy, 177Lu-prostate specific membrane antigen (-PSMA),2 who develops rapidly progressive incurable disease.
Case presentation
A 73-year-old male patient developed nausea and lethargy following his second cycle of Lutetium 177 prostate specific membrane antigen (177LuPSMA) for metastatic castration-resistant prostate cancer (mCRPC). Seven years prior he had undergone robotic prostatectomy for Gleason 5 + 4 = 9 adenocarcinoma with extraprostatic extension. He received intermittent doses of androgen deprivation therapy (ADT) over the following years. Twelve months prior to this presentation, he was referred for consideration of docetaxel chemotherapy for metastatic hormone-sensitive prostate cancer. The patient declined this treatment option and continued with ADT. Three months thereafter his cancer became castration-resistant. He received four cycles of docetaxel chemotherapy followed by five cycles of cabazitaxel chemotherapy with no appreciable response.
The patient's PSA peaked at 150 μg/L (reference range: 0.3–6.5 μg/L). He received two cycles of 177LuPSMA therapy, six weeks apart. Fig. 1 reveals the extent of the bone disease prior to the commencement of 177LuPSMA therapy. Fig. 2 reveals extent of the bone disease after the 177LuPSMA therapy.Fig. 1 PSMA PET/CT prior to 177Lu-PSMA therapy. Anterior whole body projection, MIP revealing wide spread bone metastases.
Fig. 1Fig. 2 PMSA PET/CT six weeks following the first 177Lu-PMSA therapy. Anterior whole body projection, MIP revealing an excellent response of the bone metastases.
Fig. 2
Following the second cycle of radiologically and biochemically successful treatment, the patient complained of xerostomia, nausea and lethargy, all common side effects of 177LuPSMA.3 His PSA had decreased to 0.5 μg/L (<1% of the baseline). However, the companion diagnostic PSMA scan of his liver, performed with the second 177LuPSMA revealed multifocal hypodense changes without PSMA activity. Within a fortnight, his liver function tests started to deteriorate. A liver ultrasound confirmed marked heterogeneity with nodularity. An attempted ultrasound-guided liver biopsy was aborted owing to brisk bleeding with the placement of the coaxial needle prior to the biopsy. His serum chromogranin A level was 214 μg/L (reference range <102). Fig. 3 reveals the MRI used to confirm diffuse metastatic liver disease.Fig. 3 MRI liver T1 axial view, fat suppression. Revealing widespread replacement with metastatic disease.
Fig. 3
Based on the rapid development of widely disseminated, small homogenous metastases throughout the liver and in no other visceral organs, in the context of a very low PSA and high Chromogranin A (with Chromogranin A being a well-documented bio marker for neuroendocrine tumour), the diagnosis of neuroendocrine transformation from prostate adenocarcinoma was discussed with the patient. He proceeded to treatment with carboplatin and etoposide chemotherapy. Sadly, his cancer did not respond and he died within weeks from liver failure due to the burden of metastatic disease.
Discussion
Prostate cancer is the most common cancer diagnosed in men in developed countries. Few prostate cancers harbour neuroendocrine variants at diagnosis. The vast majority of prostate cancers are prostatic adenocarcinoma which behave as a chronic disease and can be treated with standard therapies. Treatment of metastatic prostate cancer has become progressively complex and incorporates the use of androgen deprivation therapy, systemic taxane chemotherapy, and targeted androgen therapy. These treatments can be used in varying combinations over a number of years to slow the progression of metastatic prostate cancer whilst preserving the patients’ quality of life.
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC). Common features of treatment-associated NEPC include disproportionately low PSA levels in combination with rapid disease progression and high burdens of lytic bone and visceral metastases. Serum levels of the neuroendocrine markers, chromogranin A, neurone-specific enolase and gastrin-releasing peptide, are usually elevated.4 Chromogranin A is considered to be both specific and sensitive and is the most commonly used biomarker in neuroendocrine tumour differentiation. The only factor associated with more rapid disease transformation from prostatic adenocarcinoma is an initial Gleason score ≥ 8.1,4
Tissue diagnosis via metastatic biopsy can reveal different pathological subtypes of neuroendocrine tumours which portend various rates of survival, but all are invariably fatal. Treatment is currently based on systemic platinum-based therapy which offers a rapid but unsustained response.1 This empiric treatment is based on its use in other small-cell tumours, particularly those arising from the lung, and is not as successful in treating NEPC. To date there is a lack of published clinical trial data for the successful treatment of NEPC. Some trials are currently focusing on genomic sequencing of NEPC to differentiate treatable and targetable variants.
177Lu-prostate specific membrane antigen (-PSMA) therapy is an emerging treatment for patients with mCRPC cancer after exhaustion of other systemic therapies. 177LuPSMA is a radiolabelled isotope which binds with high affinity to the PSMA, a transmembrane glycoprotein which is expressed in prostate epithelium and over-expressed, more than one hundred-fold, in prostate cancer cells. This enables targeted delivery of beta-radiation to malignant cells. Many trials of this treatment modality have included heavily pre-treated patients who have already received multiple chemotherapy and hormonal agents. Responses to 177LuPSMA treatment include a reduction of PSA of ≥50%, an improved quality of life, and decreased levels of pain.4 Adverse effects of 177LuPSMA are few and can be anticipated due the distribution of PSMA expressing cells such as in salivary glands resulting in xerostomia, and in the small intestine resulting nausea and gastrointestinal upset. Since renal tubules also express PSMA, this therapy is safe for administration to patients with mildly decreased renal function (eGFR >40mL/min) without obstruction. Patients with sufficient haematological reserve, with platelets >75 × 109/L and neutrophils >1.5 × 109/L, can also safely receive this treatment. Transient increase in pain at the sites of metastases and fatigue can be expected.3,5
Cells with neuroendocrine differentiation do not express PSMA and are not affected by 177LuPSMA.5 Based on case studies which have shown patients to have treatment-associated neuroendocrine prostate cancer some clinicians recommend FDG PET/CT imaging to further select patients for PSMA targeted therapy.
Conclusion
This case has demonstrated an exceptional response to 177LuPSMA for previously identified bone metastases with near complete resolution of these on PSMA PET/CT scan and a drop to <1% baseline of the PSA. However, this response has been undermined by the transformation of the metastases in the liver to neuroendocrine tumours that do not respond to 177LuPSMA.
Consent
The patient's wife provided proxy consent for anonymised clinical information and imaging to be included in this paper. The written consent is stored in the patient's hospital record.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
None.
|
Fatal
|
ReactionOutcome
|
CC BY-NC-ND
|
33145175
| 19,405,946
|
2021-01
|
What was the outcome of reaction 'Therapy non-responder'?
|
An exceptional response to 177LuPSMA undermined by neuroendocrine transformation.
Approximately 25% of patients who have undergone extensive systemic therapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment associated neuroendocrine prostate cancer (NEPC). 177Lu-prostate specific membrane antigen (-PSMA) is an emerging alternative therapy for mCRPC patients who have exhausted other systemic therapy options; however, cells with neuroendocrine differentiation do not express PSMA and are not affected by this treatment. This case highlights an exceptional response of skeletal metastases to 177LuPSMA that is undermined by neuroendocrine transformation in the liver.
Introduction
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC).1 We present a case of a patient who has undergone extensive treatment including an emerging therapy, 177Lu-prostate specific membrane antigen (-PSMA),2 who develops rapidly progressive incurable disease.
Case presentation
A 73-year-old male patient developed nausea and lethargy following his second cycle of Lutetium 177 prostate specific membrane antigen (177LuPSMA) for metastatic castration-resistant prostate cancer (mCRPC). Seven years prior he had undergone robotic prostatectomy for Gleason 5 + 4 = 9 adenocarcinoma with extraprostatic extension. He received intermittent doses of androgen deprivation therapy (ADT) over the following years. Twelve months prior to this presentation, he was referred for consideration of docetaxel chemotherapy for metastatic hormone-sensitive prostate cancer. The patient declined this treatment option and continued with ADT. Three months thereafter his cancer became castration-resistant. He received four cycles of docetaxel chemotherapy followed by five cycles of cabazitaxel chemotherapy with no appreciable response.
The patient's PSA peaked at 150 μg/L (reference range: 0.3–6.5 μg/L). He received two cycles of 177LuPSMA therapy, six weeks apart. Fig. 1 reveals the extent of the bone disease prior to the commencement of 177LuPSMA therapy. Fig. 2 reveals extent of the bone disease after the 177LuPSMA therapy.Fig. 1 PSMA PET/CT prior to 177Lu-PSMA therapy. Anterior whole body projection, MIP revealing wide spread bone metastases.
Fig. 1Fig. 2 PMSA PET/CT six weeks following the first 177Lu-PMSA therapy. Anterior whole body projection, MIP revealing an excellent response of the bone metastases.
Fig. 2
Following the second cycle of radiologically and biochemically successful treatment, the patient complained of xerostomia, nausea and lethargy, all common side effects of 177LuPSMA.3 His PSA had decreased to 0.5 μg/L (<1% of the baseline). However, the companion diagnostic PSMA scan of his liver, performed with the second 177LuPSMA revealed multifocal hypodense changes without PSMA activity. Within a fortnight, his liver function tests started to deteriorate. A liver ultrasound confirmed marked heterogeneity with nodularity. An attempted ultrasound-guided liver biopsy was aborted owing to brisk bleeding with the placement of the coaxial needle prior to the biopsy. His serum chromogranin A level was 214 μg/L (reference range <102). Fig. 3 reveals the MRI used to confirm diffuse metastatic liver disease.Fig. 3 MRI liver T1 axial view, fat suppression. Revealing widespread replacement with metastatic disease.
Fig. 3
Based on the rapid development of widely disseminated, small homogenous metastases throughout the liver and in no other visceral organs, in the context of a very low PSA and high Chromogranin A (with Chromogranin A being a well-documented bio marker for neuroendocrine tumour), the diagnosis of neuroendocrine transformation from prostate adenocarcinoma was discussed with the patient. He proceeded to treatment with carboplatin and etoposide chemotherapy. Sadly, his cancer did not respond and he died within weeks from liver failure due to the burden of metastatic disease.
Discussion
Prostate cancer is the most common cancer diagnosed in men in developed countries. Few prostate cancers harbour neuroendocrine variants at diagnosis. The vast majority of prostate cancers are prostatic adenocarcinoma which behave as a chronic disease and can be treated with standard therapies. Treatment of metastatic prostate cancer has become progressively complex and incorporates the use of androgen deprivation therapy, systemic taxane chemotherapy, and targeted androgen therapy. These treatments can be used in varying combinations over a number of years to slow the progression of metastatic prostate cancer whilst preserving the patients’ quality of life.
Approximately 25% of patients who have undergone extensive hormone therapy and/or chemotherapy for advanced metastatic castration-resistant prostate cancer (mCRPC) develop treatment-associated neuroendocrine prostate cancer (NEPC). Common features of treatment-associated NEPC include disproportionately low PSA levels in combination with rapid disease progression and high burdens of lytic bone and visceral metastases. Serum levels of the neuroendocrine markers, chromogranin A, neurone-specific enolase and gastrin-releasing peptide, are usually elevated.4 Chromogranin A is considered to be both specific and sensitive and is the most commonly used biomarker in neuroendocrine tumour differentiation. The only factor associated with more rapid disease transformation from prostatic adenocarcinoma is an initial Gleason score ≥ 8.1,4
Tissue diagnosis via metastatic biopsy can reveal different pathological subtypes of neuroendocrine tumours which portend various rates of survival, but all are invariably fatal. Treatment is currently based on systemic platinum-based therapy which offers a rapid but unsustained response.1 This empiric treatment is based on its use in other small-cell tumours, particularly those arising from the lung, and is not as successful in treating NEPC. To date there is a lack of published clinical trial data for the successful treatment of NEPC. Some trials are currently focusing on genomic sequencing of NEPC to differentiate treatable and targetable variants.
177Lu-prostate specific membrane antigen (-PSMA) therapy is an emerging treatment for patients with mCRPC cancer after exhaustion of other systemic therapies. 177LuPSMA is a radiolabelled isotope which binds with high affinity to the PSMA, a transmembrane glycoprotein which is expressed in prostate epithelium and over-expressed, more than one hundred-fold, in prostate cancer cells. This enables targeted delivery of beta-radiation to malignant cells. Many trials of this treatment modality have included heavily pre-treated patients who have already received multiple chemotherapy and hormonal agents. Responses to 177LuPSMA treatment include a reduction of PSA of ≥50%, an improved quality of life, and decreased levels of pain.4 Adverse effects of 177LuPSMA are few and can be anticipated due the distribution of PSMA expressing cells such as in salivary glands resulting in xerostomia, and in the small intestine resulting nausea and gastrointestinal upset. Since renal tubules also express PSMA, this therapy is safe for administration to patients with mildly decreased renal function (eGFR >40mL/min) without obstruction. Patients with sufficient haematological reserve, with platelets >75 × 109/L and neutrophils >1.5 × 109/L, can also safely receive this treatment. Transient increase in pain at the sites of metastases and fatigue can be expected.3,5
Cells with neuroendocrine differentiation do not express PSMA and are not affected by 177LuPSMA.5 Based on case studies which have shown patients to have treatment-associated neuroendocrine prostate cancer some clinicians recommend FDG PET/CT imaging to further select patients for PSMA targeted therapy.
Conclusion
This case has demonstrated an exceptional response to 177LuPSMA for previously identified bone metastases with near complete resolution of these on PSMA PET/CT scan and a drop to <1% baseline of the PSA. However, this response has been undermined by the transformation of the metastases in the liver to neuroendocrine tumours that do not respond to 177LuPSMA.
Consent
The patient's wife provided proxy consent for anonymised clinical information and imaging to be included in this paper. The written consent is stored in the patient's hospital record.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
None.
|
Fatal
|
ReactionOutcome
|
CC BY-NC-ND
|
33145175
| 19,432,357
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic enzyme increased'.
|
Successfully treated bilateral renal fungal balls with continuous Anidulafulgin irrigation.
A 73-year-old man with a history of type 2 diabetes mellitus, nephrolithiasis, and recurrent urinary tract infections caused by Candida glabrata was admitted to our hospital. Urosepsis was diagnosed and C. glabrata was isolated from urine and blood cultures. Computed tomography intravenous pyelography (CT-IVP) revealed bilateral filling defects caused by renal fungal balls. Treatment initially comprised intravenous anidulafungin coupled with continuous local anidulafungin irrigation via bilateral nephrostomy tubes, which was followed by high-dose oral fluconazole. This regimen successfully eradicated the C. glabrata in follow-up cultures.
Introduction
The incidence of urinary tract infections caused by Candida spp. is increasing as antibiotic and immunosuppressive use increases.1 Candida can enter the upper urinary tract from the bloodstream (antegrade) or by ascending from the lower urinary tract (retrograde), with renal fungal balls as a rare presentation. To date, reports have focused on infections of the bladder or a single ureter, Candida albicans as the causative pathogen, and treatment with fluconazole or amphotericin B irrigation via nephrostomy tubes. We present a case of sepsis and bilateral renal fungal balls caused by Candida glabrata, treated by irrigation with anidulafungin (an echinocandin) via nephrostomy tubes.
Case presentation
The patient was a 73-year-old man with a history of type 2 diabetes mellitus, psoriasis, nephrolithiasis, and recurrent urinary tract infection caused by C. glabrata. Renal tract examination by cystoscopy and ultrasound had previously failed to reveal the underlying cause of his candiduria. At least six courses of oral fluconazole (doses of 200–400 mg/day for 10–28 days) had failed to achieve cure.
He presented to our emergency room with fever, reduced dietary intake and dysuria one month after his last course of fluconazole. Laboratory findings showed elevated inflammatory markers (leukocyte count, 13.1 × 109/L; C-reactive protein, 141 mg/L) and acute-on-chronic renal impairment (estimated glomerular filtration rate [eGFR], 24 mL/min/1.73m2). Diagnostic testing for SARS-CoV-2 was negative and ultrasound revealed left-sided hydronephrosis.
Based on previous urine cultures growing C. glabrata, intravenous treatment was started with meropenem and anidulafungin, and we placed a transurethral catheter on the day of admission. His fever subsided the day after starting intravenous treatment, and given that blood and urine cultures subsequently confirmed C. glabrata in isolation, meropenem was discontinued. CT-IVP showed bilateral hydronephrosis with filling defects in the renal pelvises and calices caused by renal fungal balls (Fig. 1-A). Renography confirmed that drainage was impaired on both sides, so we placed bilateral percutaneous nephrostomies 7 days after hospital admission. Because of a national shortage of amphotericin B due to SARS-CoV-2 at the time of treatment, we opted to treat by continuous irrigation with anidulafungin via both nephrostomy tubes at a dosage of 5 mg/L (500 mL/24h/tube). During hospitalization, the patient's renal function gradually improved (eGFR 63 mL/min/1.73m2). Although a CT-IVP (contrast via nephrostomy) performed after 1 week of anidulafungin irrigation showed improvement, the fungal balls had not completely dissolved, so the anidulafungin irrigation and intravenous therapy were continued (Fig. 1-B).Fig. 1 Follow-up of CT-IVP throughout treatment course showing gradual decrease of renal fungal balls. A: Upon presentation showing bilateral hydronephrosis with filling defects in renal pelvises and calices. B: One week after starting anidulafungin irrigation showing improvement but some fungal balls remaining. C: Four weeks after initial irrigation treatment no fungal balls were remaining. D: Eight weeks after last CT-IVP no recurrence was seen.
Fig. 1
A transurethral resection of the prostate was performed 12 days after starting the irrigation because of persistent lower urinary tract symptoms, obstructive flow and ureteral obstruction due to bladder wall hypertrophy. Prior to surgery, the patient received prophylactic cefazolin (1 g, single dose). We discontinued anidulafungin on postoperative day 2, but the patient developed a fever the following day, for which we started intravenous ceftriaxone. However, blood and urine cultures again showed C. glabrata, so the intravenous ceftriaxone was stopped and intravenous anidulafungin was started. The surgical pathology report showed benign prostatic hyperplasia with no signs of yeast infection.
Another CT-IVP, performed 14 days after starting the irrigation therapy, showed no further evidence of either the fungal balls or the ureteric obstructions. Therefore, we stopped the irrigation, removed the nephrostomy tubes and transurethral catheter, and stopped intravenous anidulafungin. The patient was discharged on high-dose oral fluconazole (800 mg/day). A follow-up CT–IVP 2 weeks later confirmed that the fungal balls had not recurred (Fig. 1-C). Six weeks after discharge the patient was re-admitted with malaise and elevated liver enzymes, which we diagnosed as a side effect of the fluconazole. Given that urine and blood cultures showed no signs of candidiasis, we discontinued the fluconazole and arranged follow-up CT-IVP 8 weeks after the previous scan, and this showed no recurrence (Fig. 1-D).
Discussion
Candiduria is a common problem that is only rarely complicated by the formation of renal fungal balls. Moreover, when candidemia is present, the mortality rate can reach 47% irrespective of this pathology.2 Renal fungal balls are typically formed when C. albicans causes an invasive infection and forms (pseudo)hyphae that cluster, and if sufficiently large, can lead to urinary obstruction and hydronephrosis.3 Although C. glabrata cannot produce (pseudo)hyphae, it is capable of causing renal abscesses and fungal balls.3
C. albicans previously accounted for 70%–80% of all isolates from candida-infected patients. More recently, non-albicans species like C. glabrata and C. tropicalis have started to emerge. The widespread and increased use of immunosuppressives and broad-spectrum antimycotics are thought to play a part in this mycological shift.1 Infections of the urinary tract caused by C. albicans tend to be relatively easy to treat because of susceptibility to fluconazole, which can achieve high urinary concentrations. By contrast, species such as C. glabrata, which develop resistance to fluconazole, can be more difficult to treat.1,4
In cases of fluconazole-resistant C. glabrata, the Infectious Diseases Society of America recommends amphotericin B. However, when renal fungal balls are present, the guideline further recommends surgical removal or irrigation with amphotericin B via nephrostomy tubes. The guideline does not recommend treatment with systemic echinocandins (i.e. anidulafungin) because of poor urinary excretion (<1%).2 Anidulafungin (Ecalta®) is available in the European Union and 63 other countries (Table 1).Table 1 List of countries were Anidulafungin (Ecalta®) is available.
Table 1Argentina El Salvador United Kingdom
Australia European Union Oman
Azerbaijan Philippines Panama
Bahama's Ghana Paraguay
Bahrain Guatemala Peru
Bangladesh Honduras Qatar
Barbados Hong Kong Russia
Belarus India Saudi-Arabia
Bermuda Indonesia Serbia
Bolivia Israel Singapore
Bosnia and Herzegovina Jamaica South Africa
Brasil Jordan Sri Lanka
Brunei Darussalam Kazakhstan Swiss
Canada Kuwait Thailand
Cayman Islands Korea Trinidad and Tobago
Chili Lebanon Tunisia
Colombia Macau Turkey
Costa Rica Malaysia Venezuela
Curacao Mexico United Arab Emirates
Dominican Republic Nicaragua United States of America
Ecuador Norway
Egypt Ukraine
Previous case reports have indicated that successful treatment can be achieved with guidewire fragmentation, surgical removal, intravenous fluconazole plus saline irrigation, and fluconazole and amphotericin B irrigation. We did not find any case reports of successful irrigation with an echinocandin, this is probably due to the known efficacy and cost-effectiveness of amphotericin B.4,5
Finally, risk factors for candiduria include diabetes mellitus, urinary tract abnormality or obstruction, prolonged antibiotic therapy, and renal failure.1,4 Our patient was predisposed to candiduria by his history of diabetes mellitus and urinary obstruction.
Conclusion
Renal fungal balls are a rare entity, especially those caused by C. glabrata. Current management strategies consist of therapy with intravenous antifungals plus irrigation via nephrostomy tubes. In the present case, we found that irrigation with anidulafungin may be a good alternative to fluconazole or amphotericin B, particularly where those may be contraindicated or unsuitable.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author contributions
NvM and JP contributed equally and wrote the manuscript. MW and GD critically revised the manuscript.
Declaration of competing interest
None.
Acknowledgments
We thank Dr Robert Sykes (www.doctored.org.uk) for providing editorial services.
|
FLUCONAZOLE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33145176
| 19,403,378
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malaise'.
|
Successfully treated bilateral renal fungal balls with continuous Anidulafulgin irrigation.
A 73-year-old man with a history of type 2 diabetes mellitus, nephrolithiasis, and recurrent urinary tract infections caused by Candida glabrata was admitted to our hospital. Urosepsis was diagnosed and C. glabrata was isolated from urine and blood cultures. Computed tomography intravenous pyelography (CT-IVP) revealed bilateral filling defects caused by renal fungal balls. Treatment initially comprised intravenous anidulafungin coupled with continuous local anidulafungin irrigation via bilateral nephrostomy tubes, which was followed by high-dose oral fluconazole. This regimen successfully eradicated the C. glabrata in follow-up cultures.
Introduction
The incidence of urinary tract infections caused by Candida spp. is increasing as antibiotic and immunosuppressive use increases.1 Candida can enter the upper urinary tract from the bloodstream (antegrade) or by ascending from the lower urinary tract (retrograde), with renal fungal balls as a rare presentation. To date, reports have focused on infections of the bladder or a single ureter, Candida albicans as the causative pathogen, and treatment with fluconazole or amphotericin B irrigation via nephrostomy tubes. We present a case of sepsis and bilateral renal fungal balls caused by Candida glabrata, treated by irrigation with anidulafungin (an echinocandin) via nephrostomy tubes.
Case presentation
The patient was a 73-year-old man with a history of type 2 diabetes mellitus, psoriasis, nephrolithiasis, and recurrent urinary tract infection caused by C. glabrata. Renal tract examination by cystoscopy and ultrasound had previously failed to reveal the underlying cause of his candiduria. At least six courses of oral fluconazole (doses of 200–400 mg/day for 10–28 days) had failed to achieve cure.
He presented to our emergency room with fever, reduced dietary intake and dysuria one month after his last course of fluconazole. Laboratory findings showed elevated inflammatory markers (leukocyte count, 13.1 × 109/L; C-reactive protein, 141 mg/L) and acute-on-chronic renal impairment (estimated glomerular filtration rate [eGFR], 24 mL/min/1.73m2). Diagnostic testing for SARS-CoV-2 was negative and ultrasound revealed left-sided hydronephrosis.
Based on previous urine cultures growing C. glabrata, intravenous treatment was started with meropenem and anidulafungin, and we placed a transurethral catheter on the day of admission. His fever subsided the day after starting intravenous treatment, and given that blood and urine cultures subsequently confirmed C. glabrata in isolation, meropenem was discontinued. CT-IVP showed bilateral hydronephrosis with filling defects in the renal pelvises and calices caused by renal fungal balls (Fig. 1-A). Renography confirmed that drainage was impaired on both sides, so we placed bilateral percutaneous nephrostomies 7 days after hospital admission. Because of a national shortage of amphotericin B due to SARS-CoV-2 at the time of treatment, we opted to treat by continuous irrigation with anidulafungin via both nephrostomy tubes at a dosage of 5 mg/L (500 mL/24h/tube). During hospitalization, the patient's renal function gradually improved (eGFR 63 mL/min/1.73m2). Although a CT-IVP (contrast via nephrostomy) performed after 1 week of anidulafungin irrigation showed improvement, the fungal balls had not completely dissolved, so the anidulafungin irrigation and intravenous therapy were continued (Fig. 1-B).Fig. 1 Follow-up of CT-IVP throughout treatment course showing gradual decrease of renal fungal balls. A: Upon presentation showing bilateral hydronephrosis with filling defects in renal pelvises and calices. B: One week after starting anidulafungin irrigation showing improvement but some fungal balls remaining. C: Four weeks after initial irrigation treatment no fungal balls were remaining. D: Eight weeks after last CT-IVP no recurrence was seen.
Fig. 1
A transurethral resection of the prostate was performed 12 days after starting the irrigation because of persistent lower urinary tract symptoms, obstructive flow and ureteral obstruction due to bladder wall hypertrophy. Prior to surgery, the patient received prophylactic cefazolin (1 g, single dose). We discontinued anidulafungin on postoperative day 2, but the patient developed a fever the following day, for which we started intravenous ceftriaxone. However, blood and urine cultures again showed C. glabrata, so the intravenous ceftriaxone was stopped and intravenous anidulafungin was started. The surgical pathology report showed benign prostatic hyperplasia with no signs of yeast infection.
Another CT-IVP, performed 14 days after starting the irrigation therapy, showed no further evidence of either the fungal balls or the ureteric obstructions. Therefore, we stopped the irrigation, removed the nephrostomy tubes and transurethral catheter, and stopped intravenous anidulafungin. The patient was discharged on high-dose oral fluconazole (800 mg/day). A follow-up CT–IVP 2 weeks later confirmed that the fungal balls had not recurred (Fig. 1-C). Six weeks after discharge the patient was re-admitted with malaise and elevated liver enzymes, which we diagnosed as a side effect of the fluconazole. Given that urine and blood cultures showed no signs of candidiasis, we discontinued the fluconazole and arranged follow-up CT-IVP 8 weeks after the previous scan, and this showed no recurrence (Fig. 1-D).
Discussion
Candiduria is a common problem that is only rarely complicated by the formation of renal fungal balls. Moreover, when candidemia is present, the mortality rate can reach 47% irrespective of this pathology.2 Renal fungal balls are typically formed when C. albicans causes an invasive infection and forms (pseudo)hyphae that cluster, and if sufficiently large, can lead to urinary obstruction and hydronephrosis.3 Although C. glabrata cannot produce (pseudo)hyphae, it is capable of causing renal abscesses and fungal balls.3
C. albicans previously accounted for 70%–80% of all isolates from candida-infected patients. More recently, non-albicans species like C. glabrata and C. tropicalis have started to emerge. The widespread and increased use of immunosuppressives and broad-spectrum antimycotics are thought to play a part in this mycological shift.1 Infections of the urinary tract caused by C. albicans tend to be relatively easy to treat because of susceptibility to fluconazole, which can achieve high urinary concentrations. By contrast, species such as C. glabrata, which develop resistance to fluconazole, can be more difficult to treat.1,4
In cases of fluconazole-resistant C. glabrata, the Infectious Diseases Society of America recommends amphotericin B. However, when renal fungal balls are present, the guideline further recommends surgical removal or irrigation with amphotericin B via nephrostomy tubes. The guideline does not recommend treatment with systemic echinocandins (i.e. anidulafungin) because of poor urinary excretion (<1%).2 Anidulafungin (Ecalta®) is available in the European Union and 63 other countries (Table 1).Table 1 List of countries were Anidulafungin (Ecalta®) is available.
Table 1Argentina El Salvador United Kingdom
Australia European Union Oman
Azerbaijan Philippines Panama
Bahama's Ghana Paraguay
Bahrain Guatemala Peru
Bangladesh Honduras Qatar
Barbados Hong Kong Russia
Belarus India Saudi-Arabia
Bermuda Indonesia Serbia
Bolivia Israel Singapore
Bosnia and Herzegovina Jamaica South Africa
Brasil Jordan Sri Lanka
Brunei Darussalam Kazakhstan Swiss
Canada Kuwait Thailand
Cayman Islands Korea Trinidad and Tobago
Chili Lebanon Tunisia
Colombia Macau Turkey
Costa Rica Malaysia Venezuela
Curacao Mexico United Arab Emirates
Dominican Republic Nicaragua United States of America
Ecuador Norway
Egypt Ukraine
Previous case reports have indicated that successful treatment can be achieved with guidewire fragmentation, surgical removal, intravenous fluconazole plus saline irrigation, and fluconazole and amphotericin B irrigation. We did not find any case reports of successful irrigation with an echinocandin, this is probably due to the known efficacy and cost-effectiveness of amphotericin B.4,5
Finally, risk factors for candiduria include diabetes mellitus, urinary tract abnormality or obstruction, prolonged antibiotic therapy, and renal failure.1,4 Our patient was predisposed to candiduria by his history of diabetes mellitus and urinary obstruction.
Conclusion
Renal fungal balls are a rare entity, especially those caused by C. glabrata. Current management strategies consist of therapy with intravenous antifungals plus irrigation via nephrostomy tubes. In the present case, we found that irrigation with anidulafungin may be a good alternative to fluconazole or amphotericin B, particularly where those may be contraindicated or unsuitable.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author contributions
NvM and JP contributed equally and wrote the manuscript. MW and GD critically revised the manuscript.
Declaration of competing interest
None.
Acknowledgments
We thank Dr Robert Sykes (www.doctored.org.uk) for providing editorial services.
|
FLUCONAZOLE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33145176
| 19,403,378
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'.
|
Successfully treated bilateral renal fungal balls with continuous Anidulafulgin irrigation.
A 73-year-old man with a history of type 2 diabetes mellitus, nephrolithiasis, and recurrent urinary tract infections caused by Candida glabrata was admitted to our hospital. Urosepsis was diagnosed and C. glabrata was isolated from urine and blood cultures. Computed tomography intravenous pyelography (CT-IVP) revealed bilateral filling defects caused by renal fungal balls. Treatment initially comprised intravenous anidulafungin coupled with continuous local anidulafungin irrigation via bilateral nephrostomy tubes, which was followed by high-dose oral fluconazole. This regimen successfully eradicated the C. glabrata in follow-up cultures.
Introduction
The incidence of urinary tract infections caused by Candida spp. is increasing as antibiotic and immunosuppressive use increases.1 Candida can enter the upper urinary tract from the bloodstream (antegrade) or by ascending from the lower urinary tract (retrograde), with renal fungal balls as a rare presentation. To date, reports have focused on infections of the bladder or a single ureter, Candida albicans as the causative pathogen, and treatment with fluconazole or amphotericin B irrigation via nephrostomy tubes. We present a case of sepsis and bilateral renal fungal balls caused by Candida glabrata, treated by irrigation with anidulafungin (an echinocandin) via nephrostomy tubes.
Case presentation
The patient was a 73-year-old man with a history of type 2 diabetes mellitus, psoriasis, nephrolithiasis, and recurrent urinary tract infection caused by C. glabrata. Renal tract examination by cystoscopy and ultrasound had previously failed to reveal the underlying cause of his candiduria. At least six courses of oral fluconazole (doses of 200–400 mg/day for 10–28 days) had failed to achieve cure.
He presented to our emergency room with fever, reduced dietary intake and dysuria one month after his last course of fluconazole. Laboratory findings showed elevated inflammatory markers (leukocyte count, 13.1 × 109/L; C-reactive protein, 141 mg/L) and acute-on-chronic renal impairment (estimated glomerular filtration rate [eGFR], 24 mL/min/1.73m2). Diagnostic testing for SARS-CoV-2 was negative and ultrasound revealed left-sided hydronephrosis.
Based on previous urine cultures growing C. glabrata, intravenous treatment was started with meropenem and anidulafungin, and we placed a transurethral catheter on the day of admission. His fever subsided the day after starting intravenous treatment, and given that blood and urine cultures subsequently confirmed C. glabrata in isolation, meropenem was discontinued. CT-IVP showed bilateral hydronephrosis with filling defects in the renal pelvises and calices caused by renal fungal balls (Fig. 1-A). Renography confirmed that drainage was impaired on both sides, so we placed bilateral percutaneous nephrostomies 7 days after hospital admission. Because of a national shortage of amphotericin B due to SARS-CoV-2 at the time of treatment, we opted to treat by continuous irrigation with anidulafungin via both nephrostomy tubes at a dosage of 5 mg/L (500 mL/24h/tube). During hospitalization, the patient's renal function gradually improved (eGFR 63 mL/min/1.73m2). Although a CT-IVP (contrast via nephrostomy) performed after 1 week of anidulafungin irrigation showed improvement, the fungal balls had not completely dissolved, so the anidulafungin irrigation and intravenous therapy were continued (Fig. 1-B).Fig. 1 Follow-up of CT-IVP throughout treatment course showing gradual decrease of renal fungal balls. A: Upon presentation showing bilateral hydronephrosis with filling defects in renal pelvises and calices. B: One week after starting anidulafungin irrigation showing improvement but some fungal balls remaining. C: Four weeks after initial irrigation treatment no fungal balls were remaining. D: Eight weeks after last CT-IVP no recurrence was seen.
Fig. 1
A transurethral resection of the prostate was performed 12 days after starting the irrigation because of persistent lower urinary tract symptoms, obstructive flow and ureteral obstruction due to bladder wall hypertrophy. Prior to surgery, the patient received prophylactic cefazolin (1 g, single dose). We discontinued anidulafungin on postoperative day 2, but the patient developed a fever the following day, for which we started intravenous ceftriaxone. However, blood and urine cultures again showed C. glabrata, so the intravenous ceftriaxone was stopped and intravenous anidulafungin was started. The surgical pathology report showed benign prostatic hyperplasia with no signs of yeast infection.
Another CT-IVP, performed 14 days after starting the irrigation therapy, showed no further evidence of either the fungal balls or the ureteric obstructions. Therefore, we stopped the irrigation, removed the nephrostomy tubes and transurethral catheter, and stopped intravenous anidulafungin. The patient was discharged on high-dose oral fluconazole (800 mg/day). A follow-up CT–IVP 2 weeks later confirmed that the fungal balls had not recurred (Fig. 1-C). Six weeks after discharge the patient was re-admitted with malaise and elevated liver enzymes, which we diagnosed as a side effect of the fluconazole. Given that urine and blood cultures showed no signs of candidiasis, we discontinued the fluconazole and arranged follow-up CT-IVP 8 weeks after the previous scan, and this showed no recurrence (Fig. 1-D).
Discussion
Candiduria is a common problem that is only rarely complicated by the formation of renal fungal balls. Moreover, when candidemia is present, the mortality rate can reach 47% irrespective of this pathology.2 Renal fungal balls are typically formed when C. albicans causes an invasive infection and forms (pseudo)hyphae that cluster, and if sufficiently large, can lead to urinary obstruction and hydronephrosis.3 Although C. glabrata cannot produce (pseudo)hyphae, it is capable of causing renal abscesses and fungal balls.3
C. albicans previously accounted for 70%–80% of all isolates from candida-infected patients. More recently, non-albicans species like C. glabrata and C. tropicalis have started to emerge. The widespread and increased use of immunosuppressives and broad-spectrum antimycotics are thought to play a part in this mycological shift.1 Infections of the urinary tract caused by C. albicans tend to be relatively easy to treat because of susceptibility to fluconazole, which can achieve high urinary concentrations. By contrast, species such as C. glabrata, which develop resistance to fluconazole, can be more difficult to treat.1,4
In cases of fluconazole-resistant C. glabrata, the Infectious Diseases Society of America recommends amphotericin B. However, when renal fungal balls are present, the guideline further recommends surgical removal or irrigation with amphotericin B via nephrostomy tubes. The guideline does not recommend treatment with systemic echinocandins (i.e. anidulafungin) because of poor urinary excretion (<1%).2 Anidulafungin (Ecalta®) is available in the European Union and 63 other countries (Table 1).Table 1 List of countries were Anidulafungin (Ecalta®) is available.
Table 1Argentina El Salvador United Kingdom
Australia European Union Oman
Azerbaijan Philippines Panama
Bahama's Ghana Paraguay
Bahrain Guatemala Peru
Bangladesh Honduras Qatar
Barbados Hong Kong Russia
Belarus India Saudi-Arabia
Bermuda Indonesia Serbia
Bolivia Israel Singapore
Bosnia and Herzegovina Jamaica South Africa
Brasil Jordan Sri Lanka
Brunei Darussalam Kazakhstan Swiss
Canada Kuwait Thailand
Cayman Islands Korea Trinidad and Tobago
Chili Lebanon Tunisia
Colombia Macau Turkey
Costa Rica Malaysia Venezuela
Curacao Mexico United Arab Emirates
Dominican Republic Nicaragua United States of America
Ecuador Norway
Egypt Ukraine
Previous case reports have indicated that successful treatment can be achieved with guidewire fragmentation, surgical removal, intravenous fluconazole plus saline irrigation, and fluconazole and amphotericin B irrigation. We did not find any case reports of successful irrigation with an echinocandin, this is probably due to the known efficacy and cost-effectiveness of amphotericin B.4,5
Finally, risk factors for candiduria include diabetes mellitus, urinary tract abnormality or obstruction, prolonged antibiotic therapy, and renal failure.1,4 Our patient was predisposed to candiduria by his history of diabetes mellitus and urinary obstruction.
Conclusion
Renal fungal balls are a rare entity, especially those caused by C. glabrata. Current management strategies consist of therapy with intravenous antifungals plus irrigation via nephrostomy tubes. In the present case, we found that irrigation with anidulafungin may be a good alternative to fluconazole or amphotericin B, particularly where those may be contraindicated or unsuitable.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author contributions
NvM and JP contributed equally and wrote the manuscript. MW and GD critically revised the manuscript.
Declaration of competing interest
None.
Acknowledgments
We thank Dr Robert Sykes (www.doctored.org.uk) for providing editorial services.
|
FLUCONAZOLE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33145176
| 19,403,378
|
2021-01
|
What was the administration route of drug 'FLUCONAZOLE'?
|
Successfully treated bilateral renal fungal balls with continuous Anidulafulgin irrigation.
A 73-year-old man with a history of type 2 diabetes mellitus, nephrolithiasis, and recurrent urinary tract infections caused by Candida glabrata was admitted to our hospital. Urosepsis was diagnosed and C. glabrata was isolated from urine and blood cultures. Computed tomography intravenous pyelography (CT-IVP) revealed bilateral filling defects caused by renal fungal balls. Treatment initially comprised intravenous anidulafungin coupled with continuous local anidulafungin irrigation via bilateral nephrostomy tubes, which was followed by high-dose oral fluconazole. This regimen successfully eradicated the C. glabrata in follow-up cultures.
Introduction
The incidence of urinary tract infections caused by Candida spp. is increasing as antibiotic and immunosuppressive use increases.1 Candida can enter the upper urinary tract from the bloodstream (antegrade) or by ascending from the lower urinary tract (retrograde), with renal fungal balls as a rare presentation. To date, reports have focused on infections of the bladder or a single ureter, Candida albicans as the causative pathogen, and treatment with fluconazole or amphotericin B irrigation via nephrostomy tubes. We present a case of sepsis and bilateral renal fungal balls caused by Candida glabrata, treated by irrigation with anidulafungin (an echinocandin) via nephrostomy tubes.
Case presentation
The patient was a 73-year-old man with a history of type 2 diabetes mellitus, psoriasis, nephrolithiasis, and recurrent urinary tract infection caused by C. glabrata. Renal tract examination by cystoscopy and ultrasound had previously failed to reveal the underlying cause of his candiduria. At least six courses of oral fluconazole (doses of 200–400 mg/day for 10–28 days) had failed to achieve cure.
He presented to our emergency room with fever, reduced dietary intake and dysuria one month after his last course of fluconazole. Laboratory findings showed elevated inflammatory markers (leukocyte count, 13.1 × 109/L; C-reactive protein, 141 mg/L) and acute-on-chronic renal impairment (estimated glomerular filtration rate [eGFR], 24 mL/min/1.73m2). Diagnostic testing for SARS-CoV-2 was negative and ultrasound revealed left-sided hydronephrosis.
Based on previous urine cultures growing C. glabrata, intravenous treatment was started with meropenem and anidulafungin, and we placed a transurethral catheter on the day of admission. His fever subsided the day after starting intravenous treatment, and given that blood and urine cultures subsequently confirmed C. glabrata in isolation, meropenem was discontinued. CT-IVP showed bilateral hydronephrosis with filling defects in the renal pelvises and calices caused by renal fungal balls (Fig. 1-A). Renography confirmed that drainage was impaired on both sides, so we placed bilateral percutaneous nephrostomies 7 days after hospital admission. Because of a national shortage of amphotericin B due to SARS-CoV-2 at the time of treatment, we opted to treat by continuous irrigation with anidulafungin via both nephrostomy tubes at a dosage of 5 mg/L (500 mL/24h/tube). During hospitalization, the patient's renal function gradually improved (eGFR 63 mL/min/1.73m2). Although a CT-IVP (contrast via nephrostomy) performed after 1 week of anidulafungin irrigation showed improvement, the fungal balls had not completely dissolved, so the anidulafungin irrigation and intravenous therapy were continued (Fig. 1-B).Fig. 1 Follow-up of CT-IVP throughout treatment course showing gradual decrease of renal fungal balls. A: Upon presentation showing bilateral hydronephrosis with filling defects in renal pelvises and calices. B: One week after starting anidulafungin irrigation showing improvement but some fungal balls remaining. C: Four weeks after initial irrigation treatment no fungal balls were remaining. D: Eight weeks after last CT-IVP no recurrence was seen.
Fig. 1
A transurethral resection of the prostate was performed 12 days after starting the irrigation because of persistent lower urinary tract symptoms, obstructive flow and ureteral obstruction due to bladder wall hypertrophy. Prior to surgery, the patient received prophylactic cefazolin (1 g, single dose). We discontinued anidulafungin on postoperative day 2, but the patient developed a fever the following day, for which we started intravenous ceftriaxone. However, blood and urine cultures again showed C. glabrata, so the intravenous ceftriaxone was stopped and intravenous anidulafungin was started. The surgical pathology report showed benign prostatic hyperplasia with no signs of yeast infection.
Another CT-IVP, performed 14 days after starting the irrigation therapy, showed no further evidence of either the fungal balls or the ureteric obstructions. Therefore, we stopped the irrigation, removed the nephrostomy tubes and transurethral catheter, and stopped intravenous anidulafungin. The patient was discharged on high-dose oral fluconazole (800 mg/day). A follow-up CT–IVP 2 weeks later confirmed that the fungal balls had not recurred (Fig. 1-C). Six weeks after discharge the patient was re-admitted with malaise and elevated liver enzymes, which we diagnosed as a side effect of the fluconazole. Given that urine and blood cultures showed no signs of candidiasis, we discontinued the fluconazole and arranged follow-up CT-IVP 8 weeks after the previous scan, and this showed no recurrence (Fig. 1-D).
Discussion
Candiduria is a common problem that is only rarely complicated by the formation of renal fungal balls. Moreover, when candidemia is present, the mortality rate can reach 47% irrespective of this pathology.2 Renal fungal balls are typically formed when C. albicans causes an invasive infection and forms (pseudo)hyphae that cluster, and if sufficiently large, can lead to urinary obstruction and hydronephrosis.3 Although C. glabrata cannot produce (pseudo)hyphae, it is capable of causing renal abscesses and fungal balls.3
C. albicans previously accounted for 70%–80% of all isolates from candida-infected patients. More recently, non-albicans species like C. glabrata and C. tropicalis have started to emerge. The widespread and increased use of immunosuppressives and broad-spectrum antimycotics are thought to play a part in this mycological shift.1 Infections of the urinary tract caused by C. albicans tend to be relatively easy to treat because of susceptibility to fluconazole, which can achieve high urinary concentrations. By contrast, species such as C. glabrata, which develop resistance to fluconazole, can be more difficult to treat.1,4
In cases of fluconazole-resistant C. glabrata, the Infectious Diseases Society of America recommends amphotericin B. However, when renal fungal balls are present, the guideline further recommends surgical removal or irrigation with amphotericin B via nephrostomy tubes. The guideline does not recommend treatment with systemic echinocandins (i.e. anidulafungin) because of poor urinary excretion (<1%).2 Anidulafungin (Ecalta®) is available in the European Union and 63 other countries (Table 1).Table 1 List of countries were Anidulafungin (Ecalta®) is available.
Table 1Argentina El Salvador United Kingdom
Australia European Union Oman
Azerbaijan Philippines Panama
Bahama's Ghana Paraguay
Bahrain Guatemala Peru
Bangladesh Honduras Qatar
Barbados Hong Kong Russia
Belarus India Saudi-Arabia
Bermuda Indonesia Serbia
Bolivia Israel Singapore
Bosnia and Herzegovina Jamaica South Africa
Brasil Jordan Sri Lanka
Brunei Darussalam Kazakhstan Swiss
Canada Kuwait Thailand
Cayman Islands Korea Trinidad and Tobago
Chili Lebanon Tunisia
Colombia Macau Turkey
Costa Rica Malaysia Venezuela
Curacao Mexico United Arab Emirates
Dominican Republic Nicaragua United States of America
Ecuador Norway
Egypt Ukraine
Previous case reports have indicated that successful treatment can be achieved with guidewire fragmentation, surgical removal, intravenous fluconazole plus saline irrigation, and fluconazole and amphotericin B irrigation. We did not find any case reports of successful irrigation with an echinocandin, this is probably due to the known efficacy and cost-effectiveness of amphotericin B.4,5
Finally, risk factors for candiduria include diabetes mellitus, urinary tract abnormality or obstruction, prolonged antibiotic therapy, and renal failure.1,4 Our patient was predisposed to candiduria by his history of diabetes mellitus and urinary obstruction.
Conclusion
Renal fungal balls are a rare entity, especially those caused by C. glabrata. Current management strategies consist of therapy with intravenous antifungals plus irrigation via nephrostomy tubes. In the present case, we found that irrigation with anidulafungin may be a good alternative to fluconazole or amphotericin B, particularly where those may be contraindicated or unsuitable.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author contributions
NvM and JP contributed equally and wrote the manuscript. MW and GD critically revised the manuscript.
Declaration of competing interest
None.
Acknowledgments
We thank Dr Robert Sykes (www.doctored.org.uk) for providing editorial services.
|
Oral
|
DrugAdministrationRoute
|
CC BY-NC-ND
|
33145176
| 19,403,378
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'.
|
Atypical neuroimaging characteristics of hemophagocytic lymphohistiocytosis in infants: a case series of hemorrhagic brain lesions in the deep grey matter.
Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystem condition associated with uncontrolled overproduction and infiltration of lymphocytes and histiocytes predominantly in liver, lymph nodes, spleen, and central nervous system. Neuroimaging findings on MRI are fairly nonspecific and classically include periventricular white matter signal abnormalities and diffuse atrophy. Focal parenchymal lesions may demonstrate post contrast ring or nodular enhancement and calcification. However, the MR imaging characteristics can be highly variable. Here, we present two cases of HLH in infants with multiple hemorrhagic lesions mostly depicted in both thalami and basal ganglia regions. Thalamic, basal ganglia, and brain stem involvement with hemorrhagic changes in HLH are rarely described in literature. Early diagnosis of HLH may be lifesaving. Awareness of the disease is necessary to investigate its characteristic findings and avoiding a delay in diagnosis.
Introduction
Hemophagocytic lymphohistiocytosis (HLH) is an uncommon life-threatening hematologic disease more prevalent in children than in adults. The factual incidence is unknown due to difficulties in identifying the disease. An estimated prevalence of pediatric HLH cases is 1.07/100,000 [1]. The disease is characterized by uncontrolled overproduction and infiltration of lymphocytes and histiocytes. HLH typically involves multiple organ systems and predominantly affects the liver, spleen, lymph nodes, and the central nervous system (CNS) [1]. The primary form of HLH is familial (autosomal recessive or X-linked) and occurs in infants with predisposing inherited immune deficiencies. In addition, “acquired” HLH can be seen in older children secondary due to infection, autoimmune disease, immunosuppression, and malignancies [1, 2]. The diagnosis of HLH requires five out of eight defined clinical and laboratory criteria to be fulfilled as defined by the Histiocyte Society: fever, splenomegaly, cytopenia, hypertriglyceridemia, hemophagocytosis, low or absent NK-cell activity, elevated ferritin, and elevated soluble CD25 [1]. CNS involvement is frequent and is one of the major causes of mortality in HLH patients [1, 2]. Variable neurologic manifestations such as seizures, cranial nerve palsies, ataxia, nystagmus, irritability, depressed consciousness level, and hypotonia have been reported [3].
Neuroimaging findings typically are not very specific and include periventricular white matter signal abnormalities and ring or nodular enhancement of focal parenchymal lesions on MR imaging [4]. Involvement of deep gray matter and hemorrhagic lesions are rare findings in HLH disease [5].
This review presents two cases of HLH with multiple hemorrhagic lesions mostly depicted in both thalami and basal ganglia region.
Case 1
A 3-month-old girl presented with poor feeding, vomiting, altered state of consciousness, and pallor. Her mother passed away 2 weeks after (a non-complicated) delivery, because of pulmonary edema followed by multi-organ failure (no autopsy performed). Physical exam revealed small head circumference (38.5 cm (−1.6 SD)) and hepatosplenomegaly. The eyes were deviated to the left with a nystagmus, repeated protrusion of the tongue was seen, and there was axial hypotonia. Laboratory findings showed anemia, thrombocytopenia, elevated levels of ferritin, triglyceride, and soluble interleukin-2. On abdominal ultrasound, hepatosplenomegaly and nephromegaly were present. Cranial ultrasound demonstrated increased echogenicity of the basal ganglia.
Brain MRI was performed and demonstrated extensive asymmetric bilateral non-enhancing T2 hyperintense abnormalities with microbleeds in the basal ganglia and thalami and to a lesser extent in the cortical-subcortical region of both hemispheres and in the mesencephalon (Fig. 1). Two nodular enhancing lesions were present in the right caudate head and right thalamus. These neuroimaging features lead to acute hemorrhagic leukoencepalopathy (AHEM), (autosomal dominant) acute necrotizing encephalitis of childhood (ANEC), and viral encephalitis as differential diagnoses. Because of the predominant involvement of the basal ganglia and especially the thalami with multiple hemorrhagic lesions, HLH with CNS involvement was not considered as most likely diagnosis based on the imaging findings. However clinical findings could be consistent with HLH as she fulfilled 5 criteria. Despite treatment (methylprednisolone and etoposide) the girl deteriorated and developed irregular breathing pattern, a further decrease in consciousness and epilepsy. Follow-up MRI showed extensive progression of the lesions especially in the subcortical regions and brain stem (Fig. 1). The patient did not survive. Postmortem brain tissue study revealed extensive cavitating changes of both white and gray matter with influx of macrophages and histiocytes and lack of demonstrable micro-organisms in keeping with the suspected diagnosis of HLH with CNS involvement. Genetic tests including whole exome sequencing did not reveal abnormalities as a possible cause for primary HLH (Fig. 2).Fig. 1 Axial T2-weighted (a) and SWI (b) MR images of the brain at the level of the basal ganglia and thalami. Extensive signal abnormalities are shown in both the basal ganglia and thalami (a) with hemorrhagic foci mainly located in the thalami (b)
Fig. 2 Axial T2-weighted MR image (a) at the level of the deep white matter and axial SWI MR image (b) at the level of the thalami. Focal hemorrhagic lesions are shown in the deep white matter (a) and more confluent hemorrhagic foci are demonstrated in both thalami (b)
Case 2
A 2-day-old boy was born at 36 weeks of gestation. Caesarian section was performed because of placenta insufficiency and fetal distress in the context of maternal smoking. On the second day of life, the boy developed symptoms of sepsis caused by Klebsiella oxytoca grown from a central venous line. The boy developed respiratory problems, direct hyperbilirubinemia, persistent thrombocytopenia, leukopenia, anemia, acute liver failure, ascites, and subcutaneous edema. During the disease course, the patient was treated by, e.g., antibiotics, blood transfusion, and blood exchange. Increased ferritin leads to liver biopsy which was negative for neonatal hemochromatosis. Secondary HLH in the context of Klebsiella oxytoca septicemia was suspected; treatment with dexamethasone and etoposide was not effective. On the 20th day of life, the patient died due to multi-organ failure. Postmortem brain MRI demonstrated multiple hemorrhagic lesions in the deep gray matter structures and in the periventricular and deep white matter. The signal intensities of the hemorrhages were in keeping with early subacute degradation of blood. In the cerebellum blood products in a later subacute stage were seen.
Discussion
Three neuropathological stages of HLH have been described and these stages are associated with the severity of disease and increased lymphocytic and histiocytic infiltration. Stage 1 disease shows leptomeningeal infiltration. Stage 2 demonstrates additional involvement of the adjacent brain parenchyma with perivascular infiltrations (as route of spread). Stage 3 consists of massive parenchymal infiltration which leads to demyelination, parenchymal necrosis, and calcification [6]. Both of our presented cases had large parenchymal lesions with hemorrhage and necrosis compatible with stage 3 HLH disease. These neuroinflammatory processes are considered to be related to systemic inflammation in HLH in which circulating cytokines cause endothelium injury in multiple organs ultimately leading to parenchyma injury and multi-organ failure [7].
The typical neuroimaging findings reported in literature are T2 hyper- or hypointense parenchymal lesions and brain atrophy in later stages. The T2 hypo-intensity of some of the lesions is assumed to be caused by calcifications. The lesions can demonstrate ring or nodular enhancement. In addition, leptomeningeal and perivascular enhancement can be seen [4, 8, 9]. Nodular or ring enhancing lesions are likely to be associated with compromised blood-brain barrier and active demyelination [2]. This is also reflected by peripheral restricted diffusion in the non-hemorrhagic parenchymal brain lesions corresponding to the enhancing part of the HLH lesions [1, 2]. This pattern of restriction helps to differentiate the HLH brain lesions from pyogenic or fungal abscess typically demonstrating central diffusion restriction. Both parenchymal atrophy and disturbances in circulation of cerebrospinal fluid (CSF) secondary to leptomeningeal infiltration lead to ventriculomegaly and sometimes subdural effusion [8] .
In the presented cases, the diffuse hemorrhagic transformation of the brain lesions, involving both basal ganglia and thalami as well as the brainstem, is in contrast to the typical imaging findings reported in literature.
In a study evaluating 46 cases of primary HLH with CNS involvement, thalamic or brain stem lesions have not been detected in any of the patients [5]. On the contrary, the presence of lesions located in the thalami or brain stem was considered useful in differentiating acute disseminated encephalomyelitis (ADEM) from HLH [4, 5]. CNS involvement predominantly presenting with thalamic and brainstem lesions is rare in HLH disease [10]. There are a few case reports describing involvement of basal ganglia and/or thalami in HLH with CNS involvement [7, 11, 12]. Basal ganglia and thalamic lesions in the setting of HLH are considered to express the more focal imaging pattern of HLH or be a part of the mixed diffuse/focal variant [12]. Abnormalities of the thalami, basal ganglia, and brainstem on neuroimaging are reported in the setting of Griscelli’s disease [13, 14], a rare autosomal recessive disorder in which HLH can develop. In the acute stage, lymphohistiocytic infiltration is thought to cause areas of inflammation/ischemia resulting in edema and swelling. In later stages calcifications are described probably as a sequel to necrosis and atrophy [13]. The more diffuse imaging pattern of HLH shows abnormalities consistent with demyelination, edema, and gliosis [12].
In addition to thalamus and basal ganglia involvement in HLH, the hemorrhagic features of the lesions are also controversial. In a limited amount of studies evaluating neuroimaging findings of patients with HLH disease and CNS involvement, hemorrhagic transformation of the parenchymal lesions in the cerebral and cerebellar white matter have been depicted and a very few are identified in the basal ganglia, but none of these multifocal hemorrhagic changes were located in the thalami [2, 7]. The hemorrhagic transformation of the brain lesions found in HLH might be due to ischemic injury and necrosis following perivascular infiltration [2, 12–14] in the setting of systemic inflammation characterized by cytokine storm and in the end multi-organ failure [7].
The differential diagnosis of bilateral hemorrhagic lesions of the central gray matter includes acute necrotizing encephalopathy (ANE), typically involving the bilateral thalami with necrosis and hemorrhage being the predominant findings. ANE is associated with respiratory viruses as causative factor, but also genetic causes are identified [15]. Acute hemorrhagic encephalomyelitis (AHEM) is a rare and severe form of ADEM in which variable involvement of the central gray matter is seen in addition to tumefactive white matter lesions. In cases of thalamic involvement this entity mimics ANE [11, 15]. Deep cerebral venous thrombosis of both internal cerebral veins can lead to hemorrhagic thalamic lesions due to venous ischemia with variable involvement of the basal ganglia. On neuroimaging thrombosis of the occluded veins is appreciated [15]. However HLH is generally not included in the differential diagnosis of hemorrhagic lesions of the basal ganglia and thalami.
In conclusion, despite the fact that neuroimaging manifestations of HLH disease are nonspecific and may overlap with many diseases such as inflammatory, infectious or infiltrative central nervous system disorders, multifocal hemorrhagic lesions involving the periventricular white matter, basal ganglia, thalami, and brainstem should suggest the possibility of HLH disease.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Funding
No funding was received for this study.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics approval
All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent and consent to publish were obtained from the parent(s) of all individual participants included in the study.
Abbreviation
HLHHemophagocytic lymphohistiocytosis
|
DEXAMETHASONE, ETOPOSIDE
|
DrugsGivenReaction
|
CC BY
|
33156371
| 19,594,824
|
2021-02
|
What was the outcome of reaction 'Drug ineffective'?
|
Atypical neuroimaging characteristics of hemophagocytic lymphohistiocytosis in infants: a case series of hemorrhagic brain lesions in the deep grey matter.
Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystem condition associated with uncontrolled overproduction and infiltration of lymphocytes and histiocytes predominantly in liver, lymph nodes, spleen, and central nervous system. Neuroimaging findings on MRI are fairly nonspecific and classically include periventricular white matter signal abnormalities and diffuse atrophy. Focal parenchymal lesions may demonstrate post contrast ring or nodular enhancement and calcification. However, the MR imaging characteristics can be highly variable. Here, we present two cases of HLH in infants with multiple hemorrhagic lesions mostly depicted in both thalami and basal ganglia regions. Thalamic, basal ganglia, and brain stem involvement with hemorrhagic changes in HLH are rarely described in literature. Early diagnosis of HLH may be lifesaving. Awareness of the disease is necessary to investigate its characteristic findings and avoiding a delay in diagnosis.
Introduction
Hemophagocytic lymphohistiocytosis (HLH) is an uncommon life-threatening hematologic disease more prevalent in children than in adults. The factual incidence is unknown due to difficulties in identifying the disease. An estimated prevalence of pediatric HLH cases is 1.07/100,000 [1]. The disease is characterized by uncontrolled overproduction and infiltration of lymphocytes and histiocytes. HLH typically involves multiple organ systems and predominantly affects the liver, spleen, lymph nodes, and the central nervous system (CNS) [1]. The primary form of HLH is familial (autosomal recessive or X-linked) and occurs in infants with predisposing inherited immune deficiencies. In addition, “acquired” HLH can be seen in older children secondary due to infection, autoimmune disease, immunosuppression, and malignancies [1, 2]. The diagnosis of HLH requires five out of eight defined clinical and laboratory criteria to be fulfilled as defined by the Histiocyte Society: fever, splenomegaly, cytopenia, hypertriglyceridemia, hemophagocytosis, low or absent NK-cell activity, elevated ferritin, and elevated soluble CD25 [1]. CNS involvement is frequent and is one of the major causes of mortality in HLH patients [1, 2]. Variable neurologic manifestations such as seizures, cranial nerve palsies, ataxia, nystagmus, irritability, depressed consciousness level, and hypotonia have been reported [3].
Neuroimaging findings typically are not very specific and include periventricular white matter signal abnormalities and ring or nodular enhancement of focal parenchymal lesions on MR imaging [4]. Involvement of deep gray matter and hemorrhagic lesions are rare findings in HLH disease [5].
This review presents two cases of HLH with multiple hemorrhagic lesions mostly depicted in both thalami and basal ganglia region.
Case 1
A 3-month-old girl presented with poor feeding, vomiting, altered state of consciousness, and pallor. Her mother passed away 2 weeks after (a non-complicated) delivery, because of pulmonary edema followed by multi-organ failure (no autopsy performed). Physical exam revealed small head circumference (38.5 cm (−1.6 SD)) and hepatosplenomegaly. The eyes were deviated to the left with a nystagmus, repeated protrusion of the tongue was seen, and there was axial hypotonia. Laboratory findings showed anemia, thrombocytopenia, elevated levels of ferritin, triglyceride, and soluble interleukin-2. On abdominal ultrasound, hepatosplenomegaly and nephromegaly were present. Cranial ultrasound demonstrated increased echogenicity of the basal ganglia.
Brain MRI was performed and demonstrated extensive asymmetric bilateral non-enhancing T2 hyperintense abnormalities with microbleeds in the basal ganglia and thalami and to a lesser extent in the cortical-subcortical region of both hemispheres and in the mesencephalon (Fig. 1). Two nodular enhancing lesions were present in the right caudate head and right thalamus. These neuroimaging features lead to acute hemorrhagic leukoencepalopathy (AHEM), (autosomal dominant) acute necrotizing encephalitis of childhood (ANEC), and viral encephalitis as differential diagnoses. Because of the predominant involvement of the basal ganglia and especially the thalami with multiple hemorrhagic lesions, HLH with CNS involvement was not considered as most likely diagnosis based on the imaging findings. However clinical findings could be consistent with HLH as she fulfilled 5 criteria. Despite treatment (methylprednisolone and etoposide) the girl deteriorated and developed irregular breathing pattern, a further decrease in consciousness and epilepsy. Follow-up MRI showed extensive progression of the lesions especially in the subcortical regions and brain stem (Fig. 1). The patient did not survive. Postmortem brain tissue study revealed extensive cavitating changes of both white and gray matter with influx of macrophages and histiocytes and lack of demonstrable micro-organisms in keeping with the suspected diagnosis of HLH with CNS involvement. Genetic tests including whole exome sequencing did not reveal abnormalities as a possible cause for primary HLH (Fig. 2).Fig. 1 Axial T2-weighted (a) and SWI (b) MR images of the brain at the level of the basal ganglia and thalami. Extensive signal abnormalities are shown in both the basal ganglia and thalami (a) with hemorrhagic foci mainly located in the thalami (b)
Fig. 2 Axial T2-weighted MR image (a) at the level of the deep white matter and axial SWI MR image (b) at the level of the thalami. Focal hemorrhagic lesions are shown in the deep white matter (a) and more confluent hemorrhagic foci are demonstrated in both thalami (b)
Case 2
A 2-day-old boy was born at 36 weeks of gestation. Caesarian section was performed because of placenta insufficiency and fetal distress in the context of maternal smoking. On the second day of life, the boy developed symptoms of sepsis caused by Klebsiella oxytoca grown from a central venous line. The boy developed respiratory problems, direct hyperbilirubinemia, persistent thrombocytopenia, leukopenia, anemia, acute liver failure, ascites, and subcutaneous edema. During the disease course, the patient was treated by, e.g., antibiotics, blood transfusion, and blood exchange. Increased ferritin leads to liver biopsy which was negative for neonatal hemochromatosis. Secondary HLH in the context of Klebsiella oxytoca septicemia was suspected; treatment with dexamethasone and etoposide was not effective. On the 20th day of life, the patient died due to multi-organ failure. Postmortem brain MRI demonstrated multiple hemorrhagic lesions in the deep gray matter structures and in the periventricular and deep white matter. The signal intensities of the hemorrhages were in keeping with early subacute degradation of blood. In the cerebellum blood products in a later subacute stage were seen.
Discussion
Three neuropathological stages of HLH have been described and these stages are associated with the severity of disease and increased lymphocytic and histiocytic infiltration. Stage 1 disease shows leptomeningeal infiltration. Stage 2 demonstrates additional involvement of the adjacent brain parenchyma with perivascular infiltrations (as route of spread). Stage 3 consists of massive parenchymal infiltration which leads to demyelination, parenchymal necrosis, and calcification [6]. Both of our presented cases had large parenchymal lesions with hemorrhage and necrosis compatible with stage 3 HLH disease. These neuroinflammatory processes are considered to be related to systemic inflammation in HLH in which circulating cytokines cause endothelium injury in multiple organs ultimately leading to parenchyma injury and multi-organ failure [7].
The typical neuroimaging findings reported in literature are T2 hyper- or hypointense parenchymal lesions and brain atrophy in later stages. The T2 hypo-intensity of some of the lesions is assumed to be caused by calcifications. The lesions can demonstrate ring or nodular enhancement. In addition, leptomeningeal and perivascular enhancement can be seen [4, 8, 9]. Nodular or ring enhancing lesions are likely to be associated with compromised blood-brain barrier and active demyelination [2]. This is also reflected by peripheral restricted diffusion in the non-hemorrhagic parenchymal brain lesions corresponding to the enhancing part of the HLH lesions [1, 2]. This pattern of restriction helps to differentiate the HLH brain lesions from pyogenic or fungal abscess typically demonstrating central diffusion restriction. Both parenchymal atrophy and disturbances in circulation of cerebrospinal fluid (CSF) secondary to leptomeningeal infiltration lead to ventriculomegaly and sometimes subdural effusion [8] .
In the presented cases, the diffuse hemorrhagic transformation of the brain lesions, involving both basal ganglia and thalami as well as the brainstem, is in contrast to the typical imaging findings reported in literature.
In a study evaluating 46 cases of primary HLH with CNS involvement, thalamic or brain stem lesions have not been detected in any of the patients [5]. On the contrary, the presence of lesions located in the thalami or brain stem was considered useful in differentiating acute disseminated encephalomyelitis (ADEM) from HLH [4, 5]. CNS involvement predominantly presenting with thalamic and brainstem lesions is rare in HLH disease [10]. There are a few case reports describing involvement of basal ganglia and/or thalami in HLH with CNS involvement [7, 11, 12]. Basal ganglia and thalamic lesions in the setting of HLH are considered to express the more focal imaging pattern of HLH or be a part of the mixed diffuse/focal variant [12]. Abnormalities of the thalami, basal ganglia, and brainstem on neuroimaging are reported in the setting of Griscelli’s disease [13, 14], a rare autosomal recessive disorder in which HLH can develop. In the acute stage, lymphohistiocytic infiltration is thought to cause areas of inflammation/ischemia resulting in edema and swelling. In later stages calcifications are described probably as a sequel to necrosis and atrophy [13]. The more diffuse imaging pattern of HLH shows abnormalities consistent with demyelination, edema, and gliosis [12].
In addition to thalamus and basal ganglia involvement in HLH, the hemorrhagic features of the lesions are also controversial. In a limited amount of studies evaluating neuroimaging findings of patients with HLH disease and CNS involvement, hemorrhagic transformation of the parenchymal lesions in the cerebral and cerebellar white matter have been depicted and a very few are identified in the basal ganglia, but none of these multifocal hemorrhagic changes were located in the thalami [2, 7]. The hemorrhagic transformation of the brain lesions found in HLH might be due to ischemic injury and necrosis following perivascular infiltration [2, 12–14] in the setting of systemic inflammation characterized by cytokine storm and in the end multi-organ failure [7].
The differential diagnosis of bilateral hemorrhagic lesions of the central gray matter includes acute necrotizing encephalopathy (ANE), typically involving the bilateral thalami with necrosis and hemorrhage being the predominant findings. ANE is associated with respiratory viruses as causative factor, but also genetic causes are identified [15]. Acute hemorrhagic encephalomyelitis (AHEM) is a rare and severe form of ADEM in which variable involvement of the central gray matter is seen in addition to tumefactive white matter lesions. In cases of thalamic involvement this entity mimics ANE [11, 15]. Deep cerebral venous thrombosis of both internal cerebral veins can lead to hemorrhagic thalamic lesions due to venous ischemia with variable involvement of the basal ganglia. On neuroimaging thrombosis of the occluded veins is appreciated [15]. However HLH is generally not included in the differential diagnosis of hemorrhagic lesions of the basal ganglia and thalami.
In conclusion, despite the fact that neuroimaging manifestations of HLH disease are nonspecific and may overlap with many diseases such as inflammatory, infectious or infiltrative central nervous system disorders, multifocal hemorrhagic lesions involving the periventricular white matter, basal ganglia, thalami, and brainstem should suggest the possibility of HLH disease.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Funding
No funding was received for this study.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics approval
All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent and consent to publish were obtained from the parent(s) of all individual participants included in the study.
Abbreviation
HLHHemophagocytic lymphohistiocytosis
|
Fatal
|
ReactionOutcome
|
CC BY
|
33156371
| 19,594,824
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malignant neoplasm progression'.
|
Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations.
Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung cancer (NSCLC). It is critical to analyze RET mutants resistant to these drugs and unravel the molecular basis to improve patient outcomes.
Cell-free DNAs (cfDNAs) were analyzed in a RET-mutant medullary thyroid cancer (MTC) patient and a CCDC6-RET fusion NSCLC patient who had dramatic response to selpercatinib and later developed resistance. Selpercatinib-resistant RET mutants were identified and cross-profiled with pralsetinib in cell cultures. Crystal structures of RET-selpercatinib and RET-pralsetinib complexes were determined based on high-resolution diffraction data collected with synchrotron radiation.
RETG810C/S mutations at the solvent front and RETY806C/N mutation at the hinge region were found in cfDNAs of an MTC patient with RETM918T/V804M/L, who initially responded to selpercatinib and developed resistance. RETG810C mutant was detected in cfDNAs of a CCDC6-RET-fusion NSCLC patient who developed acquired resistance to selpercatinib. Five RET kinase domain mutations at three non-gatekeeper residues were identified from 39 selpercatinib-resistant cell lines. All five selpercatinib-resistant RET mutants were cross-resistant to pralsetinib. X-ray crystal structures of the RET-selpercatinib and RET-pralsetinib complexes reveal that, unlike other TKIs, these two RET TKIs anchor one end in the front cleft and wrap around the gate wall to access the back cleft.
RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations.
INTRODUCTION
Genetic alterations of the rearranged during transfection (RET) gene occur in diverse cancers.1–4 Several multi-targeted tyrosine kinase inhibitors (TKIs) with RET inhibitor activity, such as vandetanib, cabozantinib, lenvatinib, and RXDX-105, have been tested in the clinic with modest efficacy.1,5,6 In addition to dose-limiting off-target effects, these TKIs are subject to resistance by gatekeeper mutations.1,7 Structurally, this is partly because these TKIs are known or predicted to occupy both the front and back drug-binding clefts of the RET kinase domain by going through the gate that separates these two clefts.8–12
Selpercatinib13–15 and pralsetinib16 are two highly selective and potent RET TKIs. Recently, selpercatinib received the United States Food and Drug Administration (FDA) approval for treating metastatic RET fusion-positive non-small-cell lung cancer (NSCLC), advanced/metastatic RET-altered medullary thyroid cancer (MTC), and papillary thyroid carcinoma, while pralsetinib was approved by the FDA for treating RET fusion-positive NSCLC. The US FDA approved for pralsetinib was updated on December 1, 2020 to include advanced/metastatic RET-altered MTC and PTC.
Protein tyrosine kinase-targeted cancer therapies are subject to acquired resistance. Besides activation of alternative mechanisms bypassing the targeted kinase,17 a mechanism is secondary on-target mutations that interfere with drug binding.18,19 Identifying and characterizing resistance mechanisms, discovering new drugs, and translating the drugs to the clinic to overcome the resistance are critical for improving patient outcomes.
Herein, we report acquired RET mutations in a RET-mutant MTC patient and a RET fusion-positive NSCLC following treatment with selpercatinib. In preclinical experiments, we identified five selpercatinib-resistant mutants in the RET kinase domain and cross-profiling drug sensitivities of these mutants with pralsetinib. Four of the five selpercatinib-resistant RET mutations found in preclinical experiments were found as acquired RET mutations in the two patients.We also determined crystal structures of the RET-selpercatinib and RET-pralsetinib complexes with high-resolution X-ray diffraction data. These two crystal structures detail a novel kinase inhibitor binding mode not previously seen in other TKIs, and reveal the vulnerability of selpercatinib and pralsetinib to non-gatekeeper RET mutations.
PATIENTS AND METHODS
Patients
Patient 1 was a 49-year-old male who developed neck swelling and was diagnosed with sporadic MTC, harboring RET M918T mutation described previously.13 With lymph node and liver metastases, the patient was sequentially treated with six TKIs: sorafenib [best response of progressive disease (PD)], vandetanib [stable disease (SD)], cabozantinib (SD), MGCD-516 (PD), RXDX-105 [partial response (PR)], and vandetanib plus everolimus (PD). Molecular analysis of cell-free DNA (cfDNA) (Guardant360VR® [Guardant Health, Redwood City, CA]) isolated from blood taken before vandetanib plus everolimus treatment identified the founder RET M918T mutation and an acquired RET V804M gatekeeper mutation. A RET V804L gatekeeper mutant was detected subsequently. As the patient’s performance status was rapidly declining, he was initiated on selpercatinib on a single-patient protocol with rapid dose escalation to 160 mg twice daily (Figure 1A).13 The patient tolerated therapy well, had a dramatic improvement in clinical status, and confirmed PR for 24 months (Figure 1B–D). Around 25 months (30 cycles), his liver metastases increased, but he was clinically stable (Figure 1B–D). A biopsy sample was non-diagnostic and inconclusive. At 30 months (34 cycles), the patient developed hyperbilirubinemia and transaminitis, and his clinical status rapidly declined (supplementary Figure S1A, available at https://doi.org/10.1016/j.annonc.2020.10.599). The patient’s characteristics are summarized in supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.10.599.
Patient 2 was a 66-year-old male never smoker who presented with back and chest pain. A complete workup and biopsy revealed Stage IV metastatic thyroid transcription factor 1-positive lung adenocarcinoma. Immunostain for programmed cell death ligand 1 was negative. Molecular testing was negative for epidermal growth factor receptor (EGFR) or BRAF mutation, and ALK or ROS1 gene rearrangement. He was treated with eight cycles of carboplatin/pemetrexed/bevacizumab and achieved PR (Figure 2A). He was then switched to maintenance with pemetrexed and bevacizumab for four more cycles until the tumors progressed, clinical status declining with increasing pain, cough with worsening bone, and lung and liver metastases. Next-generation sequencing of plasma cfDNA revealed CCDC6-RET fusion,TP53 G244S/R181G, CDKN2A H83R, MET, and EGFR amplification (supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.10.599). The patient was enrolled in the selpercatinib trial. In a few weeks, the patient’s performance status rapidly improved, pain and cough resolved, his tumors had a deep response of 64% reduction and confirmed PR per RECIST V1.1 (Figure 2A–C). After 18 cycles of selpercatinib, his pain started to come back, his PS declined (Figure 2D, supplementary Figure S1B, available at https://doi.org/10.1016/j.annonc.2020.10.599), and his scans showed new bilobar liver metastases (Figure 2C).
Clinical methods
Patients provided written informed consent to participate in the clinical trial. Molecular tests were carried out in accordance with protocols approved by the institutional review board at UT MD Anderson Cancer Center (supplementary materials, available at https://doi.org/10.1016/j.annonc.2020.10.599).
Isolation and characterization of drug-resistant RET mutations in cell cultures
Selpercatinib-resistant RET mutations were identified by sequencing of genomic DNA from BaF3/KIF5B-RET cell lines that could grow at >10× IC50s concentrations of selpercatinib (supplementary materials, available at https://doi.org/10.1016/j.annonc.2020.10.599). The CCDC6-RETG810C, full-length RETM918T/V804M, RETM918T/V804M/G810C, and RETM918T/V804M/G810S mutants cDNA were made by site-specific mutagenesis and expressed in BaF3 for analysis. In IC50s and immunoblotting assays were as described.7,10,20
Crystal structure determination
The purified RET kinase protein contained amino acid residues 705–1013 of RET (GenPept ID: NP_066124). The atomic coordinates and structure factors of selpercatinib-bound RET and pralsetinib-bound RET have been deposited in the Protein Data Bank21 under accession numbers 7JU6 (RET-selpercatinib) (https://www.rcsb.org/structure/7JU6) and 7JU5 (RET-pralsetinib) (https://www.rcsb.org/structure/7JU5). The detailed procedures of structural studies are provided in the supplementary materials, available at https://doi.org/10.1016/j.annonc.2020.10.599.
RESULTS
Acquired RET mutations detected in cfDNA
Patient 1: plasma cfDNA analyses detected RETY806C mutation at 2 months, which corresponded to a spike of calcitonin and carcinoembryonic antigen (Figure 1C–E). The RETY806C mutation reappeared at 24.5 months. RETG810C/S mutations emerged at 22 and 24 months, respectively. The RETY806N mutation was detected in cfDNA at 29 months (Figure 1E, supplementary Table S2, available at https://doi.org/10.1016/j.annonc.2020.10.599).
We had identified G810C/S and Y806C/N as selpercatinib-resistant RET mutants in preclinical experiments using the KIF5B-RET oncogene as a model (see later). To verify that the results are applicable in the context of the RETM918T/V804M oncogene, we tested the RETG810C/S mutants in the context of RETM918T/V804M. BaF3 cell lines expressing the full-length RETM918T, RETM918T/V804M, RETM918T/V804M/G810C, and RETM918T/V804M/G810S were established, and the IC50s of selpercatinib in these cells were measured. Selpercatinib inhibited BaF3/RETM918T cells with IC50s of 23 ± 1 nM. The selpercatinib IC50s were increased 8-, 131-, and 102-fold in BaF3/RETM918T/V804M, BaF3/RETM918T/V804M/G810C, and BaF3/RETM918T/V804M/G810S cells, respectively (Figure 1F). In immunoblotting assays, while autophosphorylation of RETM918T and RETM918T/V804M mutants were inhibited by selpercatinib at the test concentrations (50–200 nM), the triple mutants were not (Figure 1G). Consistently, the BaF3/RETM918T/V804M/G810C and BaF3/RETM918T/V804M/G810S cells were resistant to selpercatinib-induced apoptosis (Figure 1G).
Patient 2: when the disease progressed during the 18th cycle of selpercatinib treatment, plasma cfDNA had CCD6-RET fusion and a novel RET NM_020975.4(RET): c.2428G>Tp.G810C Exon 14 SNV Missense RETG810C solvent-front mutation; CDKN2A NM_000077.4(CDKN2A):c.248A>Gp.H83R; TP53 NM_000546.5(TP53):c.730G>A p.G244S Exon 7 (Figure 2A, supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.10.599).
To assess whether the CCDC6-RETG810C mutant found in patient 2 was resistant to selpercatinib, BaF3/CCDC6-RET and BaF3/CCDC6-RETG810C cells were generated and analyzed. The results showed that cells expressing CCDC6-RETG810C had a 93-fold higher IC50 than cells expressing CCDC6-RET (Figure 2E). The CCDC6-RETG810C kinase was resistant to selpercatinib, and the BaF3/CCDC6-RETG810C cells were resistant to apoptosis induced by selpercatinib (Figure 2F).
Identification and characterization of selpercatinib- and pralsetinib-resistant RET mutants in cell cultures and in tumor xenografts
By screening a random mutation library of BaF3/KIF5B-RET cells, we identified four selpercatinib-resistant mutations in the RET kinase domain from 36 cell lines (Table 1). In an alternative approach, we cultured BaF3/KIF5B-RET cells with stepwise increasing concentrations of selpercatinib and established three selpercatinib-resistant cell lines that identified another RET mutation (Table 1). Thus, a total of five different selpercatinib-resistant RET mutations were identified. Cross-profiling of IC50s with pralsetinib showed that these five selpercatinib-resistant mutants were also resistant to pralsetinib (Table 1).
The five selpercatinib- and pralsetinib-resistant mutations were located at the β2 strand (RETV738A), hinge (RETY806C/N), and solvent front (RETG810C/S) sites in the RET kinase domain (see later). No gatekeeper mutation was found in resistant cell lines, consistent with the RET gatekeeper mutants being sensitive to selpercatinib. A BaF3/KIF5B-RETG810R mutation cell line was also tested. Cell lines containing these mutations had 18- to 334-fold higher IC50s for selpercatinib or pralsetinib (Table 1,Figure 3A and C). Immunoblotting assays of RET kinase activity and apoptosis showed that these mutated KIF5B-RET fusion kinases were less sensitive to inhibition by selpercatinib and pralsetinib and that the cells expressing these mutants were resistant to apoptosis induced by these drugs (Figure 3B and D).
Structural basis of resistance to selpercatinib and pralsetinib
We determined the crystal structures of the RET kinase-selpercatinib and the RET kinase-pralsetinib complexes based on the high-resolution diffraction data collected with synchrotron radiation (supplementary Table S3, available at https://doi.org/10.1016/j.annonc.2020.10.599, PDB codes 7JU6 and 7JU5, respectively). The best crystal of the RET kinase-selpercatinib complex gave diffraction data to 2.06 Å, while the best crystal of the RET kinase-pralsetinib complex gave diffraction data to 1.9 Å. Selpercatinib and pralsetinib bound the RET kinase similarly in a novel binding mode that occupied both front and back pockets in the active site clefts without passing through the gate between V804 and K758 into BP-I (Figure 4A, B, F).8 Instead, these compounds accessed the back pocket by wrapping around the gate wall K758 residue. This avoids steric clash with gatekeeper V804L/M mutations. Compared with pralsetinib, the two central rings of selpercatinib were buried deeper in the ligand-binding cleft. This placed them further from the solvent edge of the binding cleft (Figure 4G).
The nine-membered pyrazolo ring of selpercatinib occupied the adenosine pocket (AP) that is bordered by Y806 on one side (Figure 4B). The side chain of Y806 had van der Waals interactions with the pyrazolo[1,5-a]pyridine ring and the hydroxymethyl group (Figure 4C), which would be disrupted by substitution of Y806 with cysteine or asparagine that have non-hydrophobic, shorter side chains. The pyridine ring and the 6-[6-(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl group occupied FP-I and FP-II, respectively. The pyridine ring made two van der Waals interactions with the side chain of V738 located on the β2 strand (Figure 4A and D). Replacement of V738 with alanine, which has a shorter side chain, will weaken the van der Waals interactions. Selpercatinib has a hydroxymethylpropoxyl group attached to the pyrazolo[1,5-a]pyridine ring. The hydroxymethyl group projected through the solvent front at the mouth of the AP (Figure 4A, B, E). G810 is the C-lobe residue at the solvent front site. Substitution of the single hydrogen atom side chain of glycine with bulky side chains like those of cysteine, serine, and arginine would cause a steric clash with the hydroxymethylpropoxyl group.
The aminopyrimidinyl and methylaminopyrazol rings of pralsetinib occupied the AP (Figure 4F). The hydrophobic side of the side chain of Y806 made hydrophobic interactions with a face of the methylaminopyrazol ring in the AP site (Figure 4H). Mutation of Tyr-806 to Cys or Asn that contain non-hydrophobic, shorter side chains would disrupt these hydrophobic interactions. One face of the methylamino-pyrimidine ring had pi-H interactions with C-alpha carbon atoms of G810 on the C-lobe side of the solvent front, and the other face of the ring had hydrophobic interactions with both terminal methyl groups of the side chain of L730 of the β1 strand in the N-lobe side of the solvent front (Figure 4I). The methyl group of the methylpyrimidine extended into the first hydration shell at the solvent front. Substitution of G810 with an amino acid that has a larger side chain, such G810C/S/R, would introduce severe steric clashes with the methylpyrimidine ring, whereas substitution of L730 with isoleucine or valine would weaken the hydrophobic interactions and the introduced CG1 and CG2 carbon atoms would cause new steric clashes. The cyclohexane ring of pralsetinib occupied FP-I and the pyridine ring occupied FP-II (Figure 4I). The cyclohexane ring packed against the back-bone of L730 and G731 at the solvent front on the N-lobe of the active site cleft. The CG2 carbon atom of the V738 side chain formed a hydrophobic interaction with the edge of the pyridine ring (Figure 4I). These hydrophobic interactions would be lost when the V738 residue is replaced by an alanine.
DISCUSSION
While avoiding the interference of the gatekeeper mutations, selpercatinib and pralsetinib were subject to resistance caused by non-gatekeeper mutations. Four of five selpercatinib-resistant RET kinase domain mutants that we identified in the laboratory were also detected in the MTC patient and in the NSCLC patient. The fifth mutation identified in the laboratory, RETV738A, is located outside the RET coverage region of clinical cfDNA assays and thus would evade detection in these patients. Recently, the RETG810C/S solvent front mutants have also been found in the cfDNA of two patients with CCDC6-RET-positive NSCLC that acquired pralsetinib-resistance.22
The RET mutations at the C-lobe solvent front (RETG810C/S/R), hinge (RETY806C/N), and β2 strand (RETV738A) shared resistance to both selpercatinib and pralsetinib. The IC50 fold changes of RETG810C/S/R mutants were consistently higher for selpercatinib than for pralsetinib, suggesting that mutations at the C-lobe solvent front site have a higher impact on selpercatinib than on pralsetinib.
Selpercatinib and pralsetinib use a binding mode that is very different from other TKIs. Previously determined structures of complexes with TKIs show that the TKIs occupy both the front and back clefts of the drug-binding pockets by passing through the gate that separates the front and back clefts (e.g. vandetanib, PDB code 2IVU; nintedanib, PDB code 6NEC)9,10 or bind only the front cleft, such as alectinib (PDB code 3AOX),23 certinib (PDB code 4MKC),24 osimertinib (PDB code 4ZAU),25 and entrectinib (PDB code 5KVT). In contrast, selpercatinib and pralsetinib dock one end in the front cleft without inserting through the gate, and wrap around the area outside the gate wall formed by the side chain of K758 and bury the other end in the BP-II pocket of the back cleft.8 This novel binding mode allows high-affinity binding while avoiding disruption of gatekeeper mutations. Nevertheless, this novel kinase inhibitor binding mode remains liable to resistance from mutations at several non-gatekeeper residues identified in this study.
Information on acquired resistance mechanisms to RET, both on target and off target, are emerging. Previous reports have shown RETV804M and RETS904F as resistance mechanisms to vandetanib and acquired RETG810R/C/S/V mutations in RET fusion-positive NSCLC patients whose tumors developed resistance to selpercatinib.26–28 More recently, acquired RET kinase domain mutations have been found in pralsetinib-treated NSCLC patients.22 Another recent study analyzing eighteen RET fusion-positive patients who received selpercatinib or pralsetinib revealed acquired RET G810 solvent front mutations in two cases (10%), three resistant cases (15%) with acquired MET amplification, and one specimen had acquired KRAS amplification.29 Another four cases of acquired selpercatinib resistance with MET amplification were reported and, it was demonstrated that this could be overcome by combining selpercatinib with crizotinib.30 Given that >1000 patients with RET alterations were enrolled on selective RET inhibitor trials globally, these trials are still in progress, and the resistance mechanisms have been reported in just a few patients so far, the frequencies of various resistance mechanisms remain to be determined.
While the most resistant mutant G810C is the principal event in the two clinical cases here, the MTC patient who ultimately progressed harbored RET M918T/V804L/V804M/Y806C/Y806N/G810C/G810S mutations. It is envisioned that the less strong selpercatinib-resistant G810S and Y804C/N could play a significant role in patients treated with lower doses of selpercatinib. Our findings point to the need to develop next-generation RET TKIs covering both gatekeeper and non-gatekeeper mutations for on-target resistance, in addition to deciphering patterns of off-target resistance by alternative mechanisms for combination therapies.
Supplementary Material
Supplementary Material FUNDING
This work was supported by a Presbyterian Health Foundation Team Science grant (to BHMM and JW), National Institutes of Health (NIH) (grant number R01CA242845) to (BHMM, VS, and JW), the Oklahoma Tobacco Settlement Endowment Trust (to the Stephenson Cancer Center), the Cancer Prevention and Research Institute of Texas (grant number RP1100584), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (grant number 1U01 CA180964), the National Center for Advancing Translational Sciences (grant number UL1 TR000371), and the MD Anderson Cancer Center (support grant number P30 CA016672). Use of the Laboratory of the Biomolecular Structure and Function at the University of Oklahoma Health Sciences Center was supported by a grant from the National Institute of General Medical Sciences (grant number P20GM103640). Use of the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory, was supported by the U.S. Department of Energy (DOE), Office of Basic Energy Sciences under contract number DE-AC02-76SF00515. The SSRL Structural Molecular Biology (SMB) Program was supported by the DOE Office of Biological and Environmental Research, and the National Institute of General Medical Sciences (including grant number P41GM103393). We thank Drs Silvia Russi and Doukov Tzanko of the SMB program for their assistance with data collection. The shared resources at the University of Oklahoma Health Sciences Center were supported by NIH/National Institute of General Medical Sciences (grant number P20GM103639) and the NIH/National Cancer Institute (grant number P30CA225520).
DISCLOSURE
VS: research funding/grant support for clinical trials: Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, Medimmune, Altum, Dragonfly Therapeutics, Takeda and, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals; travel: Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte; consultancy/advisory board: Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, QED Pharma, Medimmune, Novartis. Other: Medscape. MH has participated in advisory boards for Blueprint Medicines Corporation, Eli Lilly and Company, and Loxo Oncology, and has served as a consultant for Veracyte. MC, receiving grant support, paid to her institution, from Eisai, Exelixis, Genentech USA, Kura Oncology, and Merck, and advisory board fees from Ignyta and Loxo Oncology. FM-B reports consulting: Aduro BioTech Inc., DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks. Advisory committee: Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals. Sponsored research: Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co. Honoraria: Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey. All remaining authors have declared no conflicts of interest.
Figure 1. Acquired resistance to selpercatinib in an MTC patient.
(A) Treatment history of an MTC patient treated with selpercatinib. (B) Axial arterial phase computed tomography images show innumerable enhancing hepatic metastases at baseline (left) before selpercatinib treatment that improved on cycle 14, day 15 (middle). A follow-up scan on cycle 30, day 22 demonstrated several new avidly enhancing lesions (right, red arrows). (C, D, E) Monitoring of calcitonin (C), carcinoembryonic antigen (CEA, D), and RET mutations in plasma cell-free DNA (cfDNA)(E). Green arrows indicate time points that the RETY806C mutation was detected. Orange arrows indicate the time point of tumor progression. (F) Comparison of IC50s of selpercatinib in BaF3 cells expressing the indicated RET mutants. (G) Immunoblotting analysis of phospho-RET (pY905), cleaved PARP, and b-actin after treatment of BaF3 cells expressing the indicated RET mutants with selpercatinib.
CEA, carcinoembryonic antigen; cPARP, cleaved poly(ADP-ribose) polymerase; MKI, multikinase inhibitor; MTC, medullary thyroid cancer; PR, partial response; pRET, phospho-RET (pY905); Rx, treatment; SPC, selpercatinib.
Figure 2. Acquired resistance to selpercatinib in a CCDC6-RET-positive NSCLC patient.
(A) Treatment history and RET alterations. (B) RECIST v 1.1 measurements. (C) Coronal reformations from contrast-enhanced abdominal computed tomography (CT) images show hepatic metastases at baseline before selpercatinib treatment (left, white arrowheads) that decreased in size and disappeared by cycle 12, day 25 (middle). Follow-up imaging on cycle 18, day 28 shows new lesions (right, black arrows). (D) Test results of lactate dehydrogenase (LDH). LDH was used as a non-specific marker of tumor burden. (E, F) Cell viability and immunoblotting analyses of BaF3/CCDC6-RET (CR) and BaF3/CCDC6-RETG810C [CR(G810C)] cells.
AVT, avastin; CBP, carboplatin; cfDNA, cell-free DNA; cPARP, cleaved poly(ADP-ribose) polymerase; NSCLC, non-small cell lung cancer; PD, progressive disease; PMT, pemetrexed; PR, partial response; pRET, phospho-RET (pY905); SPC, selpercatinib.
Figure 3. Sensitivities of RET mutants to selpercatinib and pralsetinib.
(A, C) BaF3 cells expressing KIF5B-RET (WT) or KIF5B-RET; the indicated mutations were treated with various concentrations of selpercatinib (A) or pralsetinib (C) for 3 days, and viable cells were measured. (B, D) Immunoblotting analysis of RET tyrosine phosphorylation and apoptosis after treatment of cells with selpercatinib (SPC) (B) or pralsetinib (PST) (D). Cells were treated with the drug for 4 h for analyzing RET phosphorylation or 24 h for analyzing cPARP.
cPARP, cleaved poly(ADP-ribose) polymerase; pRET, phospho-RET (pY905); WT, wildtype.
Figure 4. Crystal structures of the RET-selpercatinib and RET-pralsetinib complexes.
(A) Ribbon diagram of RET kinase-selpercatinib complex (7JU6:chain B). (B) View of the 2mFo-DFc electron density map contoured at the 1 sigma level showing the fit of selpercatinib in the 7JU6:chain B. One H-bond occurred between the drug and the protein in the adenosine pocket (AP) site. The gate is between K758 and V804. (C, D,E) Close-up views of areas of Y806, V738, and G810. Dash lines are van der Waals interactions. Distances are in angstroms (Å). (F) View of the 2mFo-DFc electron density map contoured at the 1 sigma level showing the fit of pralsetinib in 7JU5:chain A. The three left-most distances are H-bonds. The distance on the right is a van der Waals interaction. (G) Superposition of the RET kinase-pralsetinib complex (carbon atoms colored cyan) and the RET kinase-selpercatinib complex (carbon atoms colored orange). The pralsetinib and selpercatinib were not used in the least-squares fit. (H) Close-up of pralsetinib (colored magenta) in the vicinity of Y806 (colored cyan). The distances are van der Waals interactions. (I) Close-up of pralsetinib in the vicinity of V738 and G810.
Table 1. Identification of selpercatinib-resistant RET mutants and cross-profiling with pralsetinib
Method Mutant Selecting selpercatinib concentration (nM) Mutant clone count IC50 (nM) (fold: mutant/wt)
150 300 Selpercatinib Pralsetinib
Isolation from mutation library V738A 2 0 2 238.8 ± 7.2 (29) 177.5 ± 6.7 (19)
Y806C 1 0 1 174.4 ± 5.4 (21) 295.8 ± 10.7 (32)
Y806N 2 0 2 149.8 ± 6.3 (18) 292.5 ± 5.9 (32)
G810S 20 11 31 880.2 ± 25.6 (107) 390.6 ± 10.8 (42)
Cell culture with selpercatinib G810S 120 2 880.2 ± 25.6 (107) 390.6 ± 10.8 (42)
G810C 120 1 1227 ± 44.1 (150) 641.7 ± 19.1 (70)
N/A G810R N/A N/A 2744 ± 160.6 (334) 2650 ± 287.3 (288)
V804L N/A N/A 17.2 ± 0.5 (2) 1.8 ± 0.6 (2)
V804M N/A N/A 55.9 ± 1.6 (7) 16.8 ± 0.8 (2)
wt N/A N/A 8.2 ± 0.4 (1) 9.2 ± 0.4 (1)
IC50, concentration that causes 50% inhibition of growth; N/A, not applicable; wt, wildtype.
|
EVEROLIMUS, VANDETANIB
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33161056
| 19,059,427
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Medullary thyroid cancer'.
|
Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations.
Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung cancer (NSCLC). It is critical to analyze RET mutants resistant to these drugs and unravel the molecular basis to improve patient outcomes.
Cell-free DNAs (cfDNAs) were analyzed in a RET-mutant medullary thyroid cancer (MTC) patient and a CCDC6-RET fusion NSCLC patient who had dramatic response to selpercatinib and later developed resistance. Selpercatinib-resistant RET mutants were identified and cross-profiled with pralsetinib in cell cultures. Crystal structures of RET-selpercatinib and RET-pralsetinib complexes were determined based on high-resolution diffraction data collected with synchrotron radiation.
RETG810C/S mutations at the solvent front and RETY806C/N mutation at the hinge region were found in cfDNAs of an MTC patient with RETM918T/V804M/L, who initially responded to selpercatinib and developed resistance. RETG810C mutant was detected in cfDNAs of a CCDC6-RET-fusion NSCLC patient who developed acquired resistance to selpercatinib. Five RET kinase domain mutations at three non-gatekeeper residues were identified from 39 selpercatinib-resistant cell lines. All five selpercatinib-resistant RET mutants were cross-resistant to pralsetinib. X-ray crystal structures of the RET-selpercatinib and RET-pralsetinib complexes reveal that, unlike other TKIs, these two RET TKIs anchor one end in the front cleft and wrap around the gate wall to access the back cleft.
RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations.
INTRODUCTION
Genetic alterations of the rearranged during transfection (RET) gene occur in diverse cancers.1–4 Several multi-targeted tyrosine kinase inhibitors (TKIs) with RET inhibitor activity, such as vandetanib, cabozantinib, lenvatinib, and RXDX-105, have been tested in the clinic with modest efficacy.1,5,6 In addition to dose-limiting off-target effects, these TKIs are subject to resistance by gatekeeper mutations.1,7 Structurally, this is partly because these TKIs are known or predicted to occupy both the front and back drug-binding clefts of the RET kinase domain by going through the gate that separates these two clefts.8–12
Selpercatinib13–15 and pralsetinib16 are two highly selective and potent RET TKIs. Recently, selpercatinib received the United States Food and Drug Administration (FDA) approval for treating metastatic RET fusion-positive non-small-cell lung cancer (NSCLC), advanced/metastatic RET-altered medullary thyroid cancer (MTC), and papillary thyroid carcinoma, while pralsetinib was approved by the FDA for treating RET fusion-positive NSCLC. The US FDA approved for pralsetinib was updated on December 1, 2020 to include advanced/metastatic RET-altered MTC and PTC.
Protein tyrosine kinase-targeted cancer therapies are subject to acquired resistance. Besides activation of alternative mechanisms bypassing the targeted kinase,17 a mechanism is secondary on-target mutations that interfere with drug binding.18,19 Identifying and characterizing resistance mechanisms, discovering new drugs, and translating the drugs to the clinic to overcome the resistance are critical for improving patient outcomes.
Herein, we report acquired RET mutations in a RET-mutant MTC patient and a RET fusion-positive NSCLC following treatment with selpercatinib. In preclinical experiments, we identified five selpercatinib-resistant mutants in the RET kinase domain and cross-profiling drug sensitivities of these mutants with pralsetinib. Four of the five selpercatinib-resistant RET mutations found in preclinical experiments were found as acquired RET mutations in the two patients.We also determined crystal structures of the RET-selpercatinib and RET-pralsetinib complexes with high-resolution X-ray diffraction data. These two crystal structures detail a novel kinase inhibitor binding mode not previously seen in other TKIs, and reveal the vulnerability of selpercatinib and pralsetinib to non-gatekeeper RET mutations.
PATIENTS AND METHODS
Patients
Patient 1 was a 49-year-old male who developed neck swelling and was diagnosed with sporadic MTC, harboring RET M918T mutation described previously.13 With lymph node and liver metastases, the patient was sequentially treated with six TKIs: sorafenib [best response of progressive disease (PD)], vandetanib [stable disease (SD)], cabozantinib (SD), MGCD-516 (PD), RXDX-105 [partial response (PR)], and vandetanib plus everolimus (PD). Molecular analysis of cell-free DNA (cfDNA) (Guardant360VR® [Guardant Health, Redwood City, CA]) isolated from blood taken before vandetanib plus everolimus treatment identified the founder RET M918T mutation and an acquired RET V804M gatekeeper mutation. A RET V804L gatekeeper mutant was detected subsequently. As the patient’s performance status was rapidly declining, he was initiated on selpercatinib on a single-patient protocol with rapid dose escalation to 160 mg twice daily (Figure 1A).13 The patient tolerated therapy well, had a dramatic improvement in clinical status, and confirmed PR for 24 months (Figure 1B–D). Around 25 months (30 cycles), his liver metastases increased, but he was clinically stable (Figure 1B–D). A biopsy sample was non-diagnostic and inconclusive. At 30 months (34 cycles), the patient developed hyperbilirubinemia and transaminitis, and his clinical status rapidly declined (supplementary Figure S1A, available at https://doi.org/10.1016/j.annonc.2020.10.599). The patient’s characteristics are summarized in supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.10.599.
Patient 2 was a 66-year-old male never smoker who presented with back and chest pain. A complete workup and biopsy revealed Stage IV metastatic thyroid transcription factor 1-positive lung adenocarcinoma. Immunostain for programmed cell death ligand 1 was negative. Molecular testing was negative for epidermal growth factor receptor (EGFR) or BRAF mutation, and ALK or ROS1 gene rearrangement. He was treated with eight cycles of carboplatin/pemetrexed/bevacizumab and achieved PR (Figure 2A). He was then switched to maintenance with pemetrexed and bevacizumab for four more cycles until the tumors progressed, clinical status declining with increasing pain, cough with worsening bone, and lung and liver metastases. Next-generation sequencing of plasma cfDNA revealed CCDC6-RET fusion,TP53 G244S/R181G, CDKN2A H83R, MET, and EGFR amplification (supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.10.599). The patient was enrolled in the selpercatinib trial. In a few weeks, the patient’s performance status rapidly improved, pain and cough resolved, his tumors had a deep response of 64% reduction and confirmed PR per RECIST V1.1 (Figure 2A–C). After 18 cycles of selpercatinib, his pain started to come back, his PS declined (Figure 2D, supplementary Figure S1B, available at https://doi.org/10.1016/j.annonc.2020.10.599), and his scans showed new bilobar liver metastases (Figure 2C).
Clinical methods
Patients provided written informed consent to participate in the clinical trial. Molecular tests were carried out in accordance with protocols approved by the institutional review board at UT MD Anderson Cancer Center (supplementary materials, available at https://doi.org/10.1016/j.annonc.2020.10.599).
Isolation and characterization of drug-resistant RET mutations in cell cultures
Selpercatinib-resistant RET mutations were identified by sequencing of genomic DNA from BaF3/KIF5B-RET cell lines that could grow at >10× IC50s concentrations of selpercatinib (supplementary materials, available at https://doi.org/10.1016/j.annonc.2020.10.599). The CCDC6-RETG810C, full-length RETM918T/V804M, RETM918T/V804M/G810C, and RETM918T/V804M/G810S mutants cDNA were made by site-specific mutagenesis and expressed in BaF3 for analysis. In IC50s and immunoblotting assays were as described.7,10,20
Crystal structure determination
The purified RET kinase protein contained amino acid residues 705–1013 of RET (GenPept ID: NP_066124). The atomic coordinates and structure factors of selpercatinib-bound RET and pralsetinib-bound RET have been deposited in the Protein Data Bank21 under accession numbers 7JU6 (RET-selpercatinib) (https://www.rcsb.org/structure/7JU6) and 7JU5 (RET-pralsetinib) (https://www.rcsb.org/structure/7JU5). The detailed procedures of structural studies are provided in the supplementary materials, available at https://doi.org/10.1016/j.annonc.2020.10.599.
RESULTS
Acquired RET mutations detected in cfDNA
Patient 1: plasma cfDNA analyses detected RETY806C mutation at 2 months, which corresponded to a spike of calcitonin and carcinoembryonic antigen (Figure 1C–E). The RETY806C mutation reappeared at 24.5 months. RETG810C/S mutations emerged at 22 and 24 months, respectively. The RETY806N mutation was detected in cfDNA at 29 months (Figure 1E, supplementary Table S2, available at https://doi.org/10.1016/j.annonc.2020.10.599).
We had identified G810C/S and Y806C/N as selpercatinib-resistant RET mutants in preclinical experiments using the KIF5B-RET oncogene as a model (see later). To verify that the results are applicable in the context of the RETM918T/V804M oncogene, we tested the RETG810C/S mutants in the context of RETM918T/V804M. BaF3 cell lines expressing the full-length RETM918T, RETM918T/V804M, RETM918T/V804M/G810C, and RETM918T/V804M/G810S were established, and the IC50s of selpercatinib in these cells were measured. Selpercatinib inhibited BaF3/RETM918T cells with IC50s of 23 ± 1 nM. The selpercatinib IC50s were increased 8-, 131-, and 102-fold in BaF3/RETM918T/V804M, BaF3/RETM918T/V804M/G810C, and BaF3/RETM918T/V804M/G810S cells, respectively (Figure 1F). In immunoblotting assays, while autophosphorylation of RETM918T and RETM918T/V804M mutants were inhibited by selpercatinib at the test concentrations (50–200 nM), the triple mutants were not (Figure 1G). Consistently, the BaF3/RETM918T/V804M/G810C and BaF3/RETM918T/V804M/G810S cells were resistant to selpercatinib-induced apoptosis (Figure 1G).
Patient 2: when the disease progressed during the 18th cycle of selpercatinib treatment, plasma cfDNA had CCD6-RET fusion and a novel RET NM_020975.4(RET): c.2428G>Tp.G810C Exon 14 SNV Missense RETG810C solvent-front mutation; CDKN2A NM_000077.4(CDKN2A):c.248A>Gp.H83R; TP53 NM_000546.5(TP53):c.730G>A p.G244S Exon 7 (Figure 2A, supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.10.599).
To assess whether the CCDC6-RETG810C mutant found in patient 2 was resistant to selpercatinib, BaF3/CCDC6-RET and BaF3/CCDC6-RETG810C cells were generated and analyzed. The results showed that cells expressing CCDC6-RETG810C had a 93-fold higher IC50 than cells expressing CCDC6-RET (Figure 2E). The CCDC6-RETG810C kinase was resistant to selpercatinib, and the BaF3/CCDC6-RETG810C cells were resistant to apoptosis induced by selpercatinib (Figure 2F).
Identification and characterization of selpercatinib- and pralsetinib-resistant RET mutants in cell cultures and in tumor xenografts
By screening a random mutation library of BaF3/KIF5B-RET cells, we identified four selpercatinib-resistant mutations in the RET kinase domain from 36 cell lines (Table 1). In an alternative approach, we cultured BaF3/KIF5B-RET cells with stepwise increasing concentrations of selpercatinib and established three selpercatinib-resistant cell lines that identified another RET mutation (Table 1). Thus, a total of five different selpercatinib-resistant RET mutations were identified. Cross-profiling of IC50s with pralsetinib showed that these five selpercatinib-resistant mutants were also resistant to pralsetinib (Table 1).
The five selpercatinib- and pralsetinib-resistant mutations were located at the β2 strand (RETV738A), hinge (RETY806C/N), and solvent front (RETG810C/S) sites in the RET kinase domain (see later). No gatekeeper mutation was found in resistant cell lines, consistent with the RET gatekeeper mutants being sensitive to selpercatinib. A BaF3/KIF5B-RETG810R mutation cell line was also tested. Cell lines containing these mutations had 18- to 334-fold higher IC50s for selpercatinib or pralsetinib (Table 1,Figure 3A and C). Immunoblotting assays of RET kinase activity and apoptosis showed that these mutated KIF5B-RET fusion kinases were less sensitive to inhibition by selpercatinib and pralsetinib and that the cells expressing these mutants were resistant to apoptosis induced by these drugs (Figure 3B and D).
Structural basis of resistance to selpercatinib and pralsetinib
We determined the crystal structures of the RET kinase-selpercatinib and the RET kinase-pralsetinib complexes based on the high-resolution diffraction data collected with synchrotron radiation (supplementary Table S3, available at https://doi.org/10.1016/j.annonc.2020.10.599, PDB codes 7JU6 and 7JU5, respectively). The best crystal of the RET kinase-selpercatinib complex gave diffraction data to 2.06 Å, while the best crystal of the RET kinase-pralsetinib complex gave diffraction data to 1.9 Å. Selpercatinib and pralsetinib bound the RET kinase similarly in a novel binding mode that occupied both front and back pockets in the active site clefts without passing through the gate between V804 and K758 into BP-I (Figure 4A, B, F).8 Instead, these compounds accessed the back pocket by wrapping around the gate wall K758 residue. This avoids steric clash with gatekeeper V804L/M mutations. Compared with pralsetinib, the two central rings of selpercatinib were buried deeper in the ligand-binding cleft. This placed them further from the solvent edge of the binding cleft (Figure 4G).
The nine-membered pyrazolo ring of selpercatinib occupied the adenosine pocket (AP) that is bordered by Y806 on one side (Figure 4B). The side chain of Y806 had van der Waals interactions with the pyrazolo[1,5-a]pyridine ring and the hydroxymethyl group (Figure 4C), which would be disrupted by substitution of Y806 with cysteine or asparagine that have non-hydrophobic, shorter side chains. The pyridine ring and the 6-[6-(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl group occupied FP-I and FP-II, respectively. The pyridine ring made two van der Waals interactions with the side chain of V738 located on the β2 strand (Figure 4A and D). Replacement of V738 with alanine, which has a shorter side chain, will weaken the van der Waals interactions. Selpercatinib has a hydroxymethylpropoxyl group attached to the pyrazolo[1,5-a]pyridine ring. The hydroxymethyl group projected through the solvent front at the mouth of the AP (Figure 4A, B, E). G810 is the C-lobe residue at the solvent front site. Substitution of the single hydrogen atom side chain of glycine with bulky side chains like those of cysteine, serine, and arginine would cause a steric clash with the hydroxymethylpropoxyl group.
The aminopyrimidinyl and methylaminopyrazol rings of pralsetinib occupied the AP (Figure 4F). The hydrophobic side of the side chain of Y806 made hydrophobic interactions with a face of the methylaminopyrazol ring in the AP site (Figure 4H). Mutation of Tyr-806 to Cys or Asn that contain non-hydrophobic, shorter side chains would disrupt these hydrophobic interactions. One face of the methylamino-pyrimidine ring had pi-H interactions with C-alpha carbon atoms of G810 on the C-lobe side of the solvent front, and the other face of the ring had hydrophobic interactions with both terminal methyl groups of the side chain of L730 of the β1 strand in the N-lobe side of the solvent front (Figure 4I). The methyl group of the methylpyrimidine extended into the first hydration shell at the solvent front. Substitution of G810 with an amino acid that has a larger side chain, such G810C/S/R, would introduce severe steric clashes with the methylpyrimidine ring, whereas substitution of L730 with isoleucine or valine would weaken the hydrophobic interactions and the introduced CG1 and CG2 carbon atoms would cause new steric clashes. The cyclohexane ring of pralsetinib occupied FP-I and the pyridine ring occupied FP-II (Figure 4I). The cyclohexane ring packed against the back-bone of L730 and G731 at the solvent front on the N-lobe of the active site cleft. The CG2 carbon atom of the V738 side chain formed a hydrophobic interaction with the edge of the pyridine ring (Figure 4I). These hydrophobic interactions would be lost when the V738 residue is replaced by an alanine.
DISCUSSION
While avoiding the interference of the gatekeeper mutations, selpercatinib and pralsetinib were subject to resistance caused by non-gatekeeper mutations. Four of five selpercatinib-resistant RET kinase domain mutants that we identified in the laboratory were also detected in the MTC patient and in the NSCLC patient. The fifth mutation identified in the laboratory, RETV738A, is located outside the RET coverage region of clinical cfDNA assays and thus would evade detection in these patients. Recently, the RETG810C/S solvent front mutants have also been found in the cfDNA of two patients with CCDC6-RET-positive NSCLC that acquired pralsetinib-resistance.22
The RET mutations at the C-lobe solvent front (RETG810C/S/R), hinge (RETY806C/N), and β2 strand (RETV738A) shared resistance to both selpercatinib and pralsetinib. The IC50 fold changes of RETG810C/S/R mutants were consistently higher for selpercatinib than for pralsetinib, suggesting that mutations at the C-lobe solvent front site have a higher impact on selpercatinib than on pralsetinib.
Selpercatinib and pralsetinib use a binding mode that is very different from other TKIs. Previously determined structures of complexes with TKIs show that the TKIs occupy both the front and back clefts of the drug-binding pockets by passing through the gate that separates the front and back clefts (e.g. vandetanib, PDB code 2IVU; nintedanib, PDB code 6NEC)9,10 or bind only the front cleft, such as alectinib (PDB code 3AOX),23 certinib (PDB code 4MKC),24 osimertinib (PDB code 4ZAU),25 and entrectinib (PDB code 5KVT). In contrast, selpercatinib and pralsetinib dock one end in the front cleft without inserting through the gate, and wrap around the area outside the gate wall formed by the side chain of K758 and bury the other end in the BP-II pocket of the back cleft.8 This novel binding mode allows high-affinity binding while avoiding disruption of gatekeeper mutations. Nevertheless, this novel kinase inhibitor binding mode remains liable to resistance from mutations at several non-gatekeeper residues identified in this study.
Information on acquired resistance mechanisms to RET, both on target and off target, are emerging. Previous reports have shown RETV804M and RETS904F as resistance mechanisms to vandetanib and acquired RETG810R/C/S/V mutations in RET fusion-positive NSCLC patients whose tumors developed resistance to selpercatinib.26–28 More recently, acquired RET kinase domain mutations have been found in pralsetinib-treated NSCLC patients.22 Another recent study analyzing eighteen RET fusion-positive patients who received selpercatinib or pralsetinib revealed acquired RET G810 solvent front mutations in two cases (10%), three resistant cases (15%) with acquired MET amplification, and one specimen had acquired KRAS amplification.29 Another four cases of acquired selpercatinib resistance with MET amplification were reported and, it was demonstrated that this could be overcome by combining selpercatinib with crizotinib.30 Given that >1000 patients with RET alterations were enrolled on selective RET inhibitor trials globally, these trials are still in progress, and the resistance mechanisms have been reported in just a few patients so far, the frequencies of various resistance mechanisms remain to be determined.
While the most resistant mutant G810C is the principal event in the two clinical cases here, the MTC patient who ultimately progressed harbored RET M918T/V804L/V804M/Y806C/Y806N/G810C/G810S mutations. It is envisioned that the less strong selpercatinib-resistant G810S and Y804C/N could play a significant role in patients treated with lower doses of selpercatinib. Our findings point to the need to develop next-generation RET TKIs covering both gatekeeper and non-gatekeeper mutations for on-target resistance, in addition to deciphering patterns of off-target resistance by alternative mechanisms for combination therapies.
Supplementary Material
Supplementary Material FUNDING
This work was supported by a Presbyterian Health Foundation Team Science grant (to BHMM and JW), National Institutes of Health (NIH) (grant number R01CA242845) to (BHMM, VS, and JW), the Oklahoma Tobacco Settlement Endowment Trust (to the Stephenson Cancer Center), the Cancer Prevention and Research Institute of Texas (grant number RP1100584), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (grant number 1U01 CA180964), the National Center for Advancing Translational Sciences (grant number UL1 TR000371), and the MD Anderson Cancer Center (support grant number P30 CA016672). Use of the Laboratory of the Biomolecular Structure and Function at the University of Oklahoma Health Sciences Center was supported by a grant from the National Institute of General Medical Sciences (grant number P20GM103640). Use of the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory, was supported by the U.S. Department of Energy (DOE), Office of Basic Energy Sciences under contract number DE-AC02-76SF00515. The SSRL Structural Molecular Biology (SMB) Program was supported by the DOE Office of Biological and Environmental Research, and the National Institute of General Medical Sciences (including grant number P41GM103393). We thank Drs Silvia Russi and Doukov Tzanko of the SMB program for their assistance with data collection. The shared resources at the University of Oklahoma Health Sciences Center were supported by NIH/National Institute of General Medical Sciences (grant number P20GM103639) and the NIH/National Cancer Institute (grant number P30CA225520).
DISCLOSURE
VS: research funding/grant support for clinical trials: Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, Medimmune, Altum, Dragonfly Therapeutics, Takeda and, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals; travel: Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte; consultancy/advisory board: Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, QED Pharma, Medimmune, Novartis. Other: Medscape. MH has participated in advisory boards for Blueprint Medicines Corporation, Eli Lilly and Company, and Loxo Oncology, and has served as a consultant for Veracyte. MC, receiving grant support, paid to her institution, from Eisai, Exelixis, Genentech USA, Kura Oncology, and Merck, and advisory board fees from Ignyta and Loxo Oncology. FM-B reports consulting: Aduro BioTech Inc., DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks. Advisory committee: Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals. Sponsored research: Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co. Honoraria: Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey. All remaining authors have declared no conflicts of interest.
Figure 1. Acquired resistance to selpercatinib in an MTC patient.
(A) Treatment history of an MTC patient treated with selpercatinib. (B) Axial arterial phase computed tomography images show innumerable enhancing hepatic metastases at baseline (left) before selpercatinib treatment that improved on cycle 14, day 15 (middle). A follow-up scan on cycle 30, day 22 demonstrated several new avidly enhancing lesions (right, red arrows). (C, D, E) Monitoring of calcitonin (C), carcinoembryonic antigen (CEA, D), and RET mutations in plasma cell-free DNA (cfDNA)(E). Green arrows indicate time points that the RETY806C mutation was detected. Orange arrows indicate the time point of tumor progression. (F) Comparison of IC50s of selpercatinib in BaF3 cells expressing the indicated RET mutants. (G) Immunoblotting analysis of phospho-RET (pY905), cleaved PARP, and b-actin after treatment of BaF3 cells expressing the indicated RET mutants with selpercatinib.
CEA, carcinoembryonic antigen; cPARP, cleaved poly(ADP-ribose) polymerase; MKI, multikinase inhibitor; MTC, medullary thyroid cancer; PR, partial response; pRET, phospho-RET (pY905); Rx, treatment; SPC, selpercatinib.
Figure 2. Acquired resistance to selpercatinib in a CCDC6-RET-positive NSCLC patient.
(A) Treatment history and RET alterations. (B) RECIST v 1.1 measurements. (C) Coronal reformations from contrast-enhanced abdominal computed tomography (CT) images show hepatic metastases at baseline before selpercatinib treatment (left, white arrowheads) that decreased in size and disappeared by cycle 12, day 25 (middle). Follow-up imaging on cycle 18, day 28 shows new lesions (right, black arrows). (D) Test results of lactate dehydrogenase (LDH). LDH was used as a non-specific marker of tumor burden. (E, F) Cell viability and immunoblotting analyses of BaF3/CCDC6-RET (CR) and BaF3/CCDC6-RETG810C [CR(G810C)] cells.
AVT, avastin; CBP, carboplatin; cfDNA, cell-free DNA; cPARP, cleaved poly(ADP-ribose) polymerase; NSCLC, non-small cell lung cancer; PD, progressive disease; PMT, pemetrexed; PR, partial response; pRET, phospho-RET (pY905); SPC, selpercatinib.
Figure 3. Sensitivities of RET mutants to selpercatinib and pralsetinib.
(A, C) BaF3 cells expressing KIF5B-RET (WT) or KIF5B-RET; the indicated mutations were treated with various concentrations of selpercatinib (A) or pralsetinib (C) for 3 days, and viable cells were measured. (B, D) Immunoblotting analysis of RET tyrosine phosphorylation and apoptosis after treatment of cells with selpercatinib (SPC) (B) or pralsetinib (PST) (D). Cells were treated with the drug for 4 h for analyzing RET phosphorylation or 24 h for analyzing cPARP.
cPARP, cleaved poly(ADP-ribose) polymerase; pRET, phospho-RET (pY905); WT, wildtype.
Figure 4. Crystal structures of the RET-selpercatinib and RET-pralsetinib complexes.
(A) Ribbon diagram of RET kinase-selpercatinib complex (7JU6:chain B). (B) View of the 2mFo-DFc electron density map contoured at the 1 sigma level showing the fit of selpercatinib in the 7JU6:chain B. One H-bond occurred between the drug and the protein in the adenosine pocket (AP) site. The gate is between K758 and V804. (C, D,E) Close-up views of areas of Y806, V738, and G810. Dash lines are van der Waals interactions. Distances are in angstroms (Å). (F) View of the 2mFo-DFc electron density map contoured at the 1 sigma level showing the fit of pralsetinib in 7JU5:chain A. The three left-most distances are H-bonds. The distance on the right is a van der Waals interaction. (G) Superposition of the RET kinase-pralsetinib complex (carbon atoms colored cyan) and the RET kinase-selpercatinib complex (carbon atoms colored orange). The pralsetinib and selpercatinib were not used in the least-squares fit. (H) Close-up of pralsetinib (colored magenta) in the vicinity of Y806 (colored cyan). The distances are van der Waals interactions. (I) Close-up of pralsetinib in the vicinity of V738 and G810.
Table 1. Identification of selpercatinib-resistant RET mutants and cross-profiling with pralsetinib
Method Mutant Selecting selpercatinib concentration (nM) Mutant clone count IC50 (nM) (fold: mutant/wt)
150 300 Selpercatinib Pralsetinib
Isolation from mutation library V738A 2 0 2 238.8 ± 7.2 (29) 177.5 ± 6.7 (19)
Y806C 1 0 1 174.4 ± 5.4 (21) 295.8 ± 10.7 (32)
Y806N 2 0 2 149.8 ± 6.3 (18) 292.5 ± 5.9 (32)
G810S 20 11 31 880.2 ± 25.6 (107) 390.6 ± 10.8 (42)
Cell culture with selpercatinib G810S 120 2 880.2 ± 25.6 (107) 390.6 ± 10.8 (42)
G810C 120 1 1227 ± 44.1 (150) 641.7 ± 19.1 (70)
N/A G810R N/A N/A 2744 ± 160.6 (334) 2650 ± 287.3 (288)
V804L N/A N/A 17.2 ± 0.5 (2) 1.8 ± 0.6 (2)
V804M N/A N/A 55.9 ± 1.6 (7) 16.8 ± 0.8 (2)
wt N/A N/A 8.2 ± 0.4 (1) 9.2 ± 0.4 (1)
IC50, concentration that causes 50% inhibition of growth; N/A, not applicable; wt, wildtype.
|
EVEROLIMUS, VANDETANIB
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33161056
| 19,059,427
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'.
|
Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations.
Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung cancer (NSCLC). It is critical to analyze RET mutants resistant to these drugs and unravel the molecular basis to improve patient outcomes.
Cell-free DNAs (cfDNAs) were analyzed in a RET-mutant medullary thyroid cancer (MTC) patient and a CCDC6-RET fusion NSCLC patient who had dramatic response to selpercatinib and later developed resistance. Selpercatinib-resistant RET mutants were identified and cross-profiled with pralsetinib in cell cultures. Crystal structures of RET-selpercatinib and RET-pralsetinib complexes were determined based on high-resolution diffraction data collected with synchrotron radiation.
RETG810C/S mutations at the solvent front and RETY806C/N mutation at the hinge region were found in cfDNAs of an MTC patient with RETM918T/V804M/L, who initially responded to selpercatinib and developed resistance. RETG810C mutant was detected in cfDNAs of a CCDC6-RET-fusion NSCLC patient who developed acquired resistance to selpercatinib. Five RET kinase domain mutations at three non-gatekeeper residues were identified from 39 selpercatinib-resistant cell lines. All five selpercatinib-resistant RET mutants were cross-resistant to pralsetinib. X-ray crystal structures of the RET-selpercatinib and RET-pralsetinib complexes reveal that, unlike other TKIs, these two RET TKIs anchor one end in the front cleft and wrap around the gate wall to access the back cleft.
RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations.
INTRODUCTION
Genetic alterations of the rearranged during transfection (RET) gene occur in diverse cancers.1–4 Several multi-targeted tyrosine kinase inhibitors (TKIs) with RET inhibitor activity, such as vandetanib, cabozantinib, lenvatinib, and RXDX-105, have been tested in the clinic with modest efficacy.1,5,6 In addition to dose-limiting off-target effects, these TKIs are subject to resistance by gatekeeper mutations.1,7 Structurally, this is partly because these TKIs are known or predicted to occupy both the front and back drug-binding clefts of the RET kinase domain by going through the gate that separates these two clefts.8–12
Selpercatinib13–15 and pralsetinib16 are two highly selective and potent RET TKIs. Recently, selpercatinib received the United States Food and Drug Administration (FDA) approval for treating metastatic RET fusion-positive non-small-cell lung cancer (NSCLC), advanced/metastatic RET-altered medullary thyroid cancer (MTC), and papillary thyroid carcinoma, while pralsetinib was approved by the FDA for treating RET fusion-positive NSCLC. The US FDA approved for pralsetinib was updated on December 1, 2020 to include advanced/metastatic RET-altered MTC and PTC.
Protein tyrosine kinase-targeted cancer therapies are subject to acquired resistance. Besides activation of alternative mechanisms bypassing the targeted kinase,17 a mechanism is secondary on-target mutations that interfere with drug binding.18,19 Identifying and characterizing resistance mechanisms, discovering new drugs, and translating the drugs to the clinic to overcome the resistance are critical for improving patient outcomes.
Herein, we report acquired RET mutations in a RET-mutant MTC patient and a RET fusion-positive NSCLC following treatment with selpercatinib. In preclinical experiments, we identified five selpercatinib-resistant mutants in the RET kinase domain and cross-profiling drug sensitivities of these mutants with pralsetinib. Four of the five selpercatinib-resistant RET mutations found in preclinical experiments were found as acquired RET mutations in the two patients.We also determined crystal structures of the RET-selpercatinib and RET-pralsetinib complexes with high-resolution X-ray diffraction data. These two crystal structures detail a novel kinase inhibitor binding mode not previously seen in other TKIs, and reveal the vulnerability of selpercatinib and pralsetinib to non-gatekeeper RET mutations.
PATIENTS AND METHODS
Patients
Patient 1 was a 49-year-old male who developed neck swelling and was diagnosed with sporadic MTC, harboring RET M918T mutation described previously.13 With lymph node and liver metastases, the patient was sequentially treated with six TKIs: sorafenib [best response of progressive disease (PD)], vandetanib [stable disease (SD)], cabozantinib (SD), MGCD-516 (PD), RXDX-105 [partial response (PR)], and vandetanib plus everolimus (PD). Molecular analysis of cell-free DNA (cfDNA) (Guardant360VR® [Guardant Health, Redwood City, CA]) isolated from blood taken before vandetanib plus everolimus treatment identified the founder RET M918T mutation and an acquired RET V804M gatekeeper mutation. A RET V804L gatekeeper mutant was detected subsequently. As the patient’s performance status was rapidly declining, he was initiated on selpercatinib on a single-patient protocol with rapid dose escalation to 160 mg twice daily (Figure 1A).13 The patient tolerated therapy well, had a dramatic improvement in clinical status, and confirmed PR for 24 months (Figure 1B–D). Around 25 months (30 cycles), his liver metastases increased, but he was clinically stable (Figure 1B–D). A biopsy sample was non-diagnostic and inconclusive. At 30 months (34 cycles), the patient developed hyperbilirubinemia and transaminitis, and his clinical status rapidly declined (supplementary Figure S1A, available at https://doi.org/10.1016/j.annonc.2020.10.599). The patient’s characteristics are summarized in supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.10.599.
Patient 2 was a 66-year-old male never smoker who presented with back and chest pain. A complete workup and biopsy revealed Stage IV metastatic thyroid transcription factor 1-positive lung adenocarcinoma. Immunostain for programmed cell death ligand 1 was negative. Molecular testing was negative for epidermal growth factor receptor (EGFR) or BRAF mutation, and ALK or ROS1 gene rearrangement. He was treated with eight cycles of carboplatin/pemetrexed/bevacizumab and achieved PR (Figure 2A). He was then switched to maintenance with pemetrexed and bevacizumab for four more cycles until the tumors progressed, clinical status declining with increasing pain, cough with worsening bone, and lung and liver metastases. Next-generation sequencing of plasma cfDNA revealed CCDC6-RET fusion,TP53 G244S/R181G, CDKN2A H83R, MET, and EGFR amplification (supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.10.599). The patient was enrolled in the selpercatinib trial. In a few weeks, the patient’s performance status rapidly improved, pain and cough resolved, his tumors had a deep response of 64% reduction and confirmed PR per RECIST V1.1 (Figure 2A–C). After 18 cycles of selpercatinib, his pain started to come back, his PS declined (Figure 2D, supplementary Figure S1B, available at https://doi.org/10.1016/j.annonc.2020.10.599), and his scans showed new bilobar liver metastases (Figure 2C).
Clinical methods
Patients provided written informed consent to participate in the clinical trial. Molecular tests were carried out in accordance with protocols approved by the institutional review board at UT MD Anderson Cancer Center (supplementary materials, available at https://doi.org/10.1016/j.annonc.2020.10.599).
Isolation and characterization of drug-resistant RET mutations in cell cultures
Selpercatinib-resistant RET mutations were identified by sequencing of genomic DNA from BaF3/KIF5B-RET cell lines that could grow at >10× IC50s concentrations of selpercatinib (supplementary materials, available at https://doi.org/10.1016/j.annonc.2020.10.599). The CCDC6-RETG810C, full-length RETM918T/V804M, RETM918T/V804M/G810C, and RETM918T/V804M/G810S mutants cDNA were made by site-specific mutagenesis and expressed in BaF3 for analysis. In IC50s and immunoblotting assays were as described.7,10,20
Crystal structure determination
The purified RET kinase protein contained amino acid residues 705–1013 of RET (GenPept ID: NP_066124). The atomic coordinates and structure factors of selpercatinib-bound RET and pralsetinib-bound RET have been deposited in the Protein Data Bank21 under accession numbers 7JU6 (RET-selpercatinib) (https://www.rcsb.org/structure/7JU6) and 7JU5 (RET-pralsetinib) (https://www.rcsb.org/structure/7JU5). The detailed procedures of structural studies are provided in the supplementary materials, available at https://doi.org/10.1016/j.annonc.2020.10.599.
RESULTS
Acquired RET mutations detected in cfDNA
Patient 1: plasma cfDNA analyses detected RETY806C mutation at 2 months, which corresponded to a spike of calcitonin and carcinoembryonic antigen (Figure 1C–E). The RETY806C mutation reappeared at 24.5 months. RETG810C/S mutations emerged at 22 and 24 months, respectively. The RETY806N mutation was detected in cfDNA at 29 months (Figure 1E, supplementary Table S2, available at https://doi.org/10.1016/j.annonc.2020.10.599).
We had identified G810C/S and Y806C/N as selpercatinib-resistant RET mutants in preclinical experiments using the KIF5B-RET oncogene as a model (see later). To verify that the results are applicable in the context of the RETM918T/V804M oncogene, we tested the RETG810C/S mutants in the context of RETM918T/V804M. BaF3 cell lines expressing the full-length RETM918T, RETM918T/V804M, RETM918T/V804M/G810C, and RETM918T/V804M/G810S were established, and the IC50s of selpercatinib in these cells were measured. Selpercatinib inhibited BaF3/RETM918T cells with IC50s of 23 ± 1 nM. The selpercatinib IC50s were increased 8-, 131-, and 102-fold in BaF3/RETM918T/V804M, BaF3/RETM918T/V804M/G810C, and BaF3/RETM918T/V804M/G810S cells, respectively (Figure 1F). In immunoblotting assays, while autophosphorylation of RETM918T and RETM918T/V804M mutants were inhibited by selpercatinib at the test concentrations (50–200 nM), the triple mutants were not (Figure 1G). Consistently, the BaF3/RETM918T/V804M/G810C and BaF3/RETM918T/V804M/G810S cells were resistant to selpercatinib-induced apoptosis (Figure 1G).
Patient 2: when the disease progressed during the 18th cycle of selpercatinib treatment, plasma cfDNA had CCD6-RET fusion and a novel RET NM_020975.4(RET): c.2428G>Tp.G810C Exon 14 SNV Missense RETG810C solvent-front mutation; CDKN2A NM_000077.4(CDKN2A):c.248A>Gp.H83R; TP53 NM_000546.5(TP53):c.730G>A p.G244S Exon 7 (Figure 2A, supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.10.599).
To assess whether the CCDC6-RETG810C mutant found in patient 2 was resistant to selpercatinib, BaF3/CCDC6-RET and BaF3/CCDC6-RETG810C cells were generated and analyzed. The results showed that cells expressing CCDC6-RETG810C had a 93-fold higher IC50 than cells expressing CCDC6-RET (Figure 2E). The CCDC6-RETG810C kinase was resistant to selpercatinib, and the BaF3/CCDC6-RETG810C cells were resistant to apoptosis induced by selpercatinib (Figure 2F).
Identification and characterization of selpercatinib- and pralsetinib-resistant RET mutants in cell cultures and in tumor xenografts
By screening a random mutation library of BaF3/KIF5B-RET cells, we identified four selpercatinib-resistant mutations in the RET kinase domain from 36 cell lines (Table 1). In an alternative approach, we cultured BaF3/KIF5B-RET cells with stepwise increasing concentrations of selpercatinib and established three selpercatinib-resistant cell lines that identified another RET mutation (Table 1). Thus, a total of five different selpercatinib-resistant RET mutations were identified. Cross-profiling of IC50s with pralsetinib showed that these five selpercatinib-resistant mutants were also resistant to pralsetinib (Table 1).
The five selpercatinib- and pralsetinib-resistant mutations were located at the β2 strand (RETV738A), hinge (RETY806C/N), and solvent front (RETG810C/S) sites in the RET kinase domain (see later). No gatekeeper mutation was found in resistant cell lines, consistent with the RET gatekeeper mutants being sensitive to selpercatinib. A BaF3/KIF5B-RETG810R mutation cell line was also tested. Cell lines containing these mutations had 18- to 334-fold higher IC50s for selpercatinib or pralsetinib (Table 1,Figure 3A and C). Immunoblotting assays of RET kinase activity and apoptosis showed that these mutated KIF5B-RET fusion kinases were less sensitive to inhibition by selpercatinib and pralsetinib and that the cells expressing these mutants were resistant to apoptosis induced by these drugs (Figure 3B and D).
Structural basis of resistance to selpercatinib and pralsetinib
We determined the crystal structures of the RET kinase-selpercatinib and the RET kinase-pralsetinib complexes based on the high-resolution diffraction data collected with synchrotron radiation (supplementary Table S3, available at https://doi.org/10.1016/j.annonc.2020.10.599, PDB codes 7JU6 and 7JU5, respectively). The best crystal of the RET kinase-selpercatinib complex gave diffraction data to 2.06 Å, while the best crystal of the RET kinase-pralsetinib complex gave diffraction data to 1.9 Å. Selpercatinib and pralsetinib bound the RET kinase similarly in a novel binding mode that occupied both front and back pockets in the active site clefts without passing through the gate between V804 and K758 into BP-I (Figure 4A, B, F).8 Instead, these compounds accessed the back pocket by wrapping around the gate wall K758 residue. This avoids steric clash with gatekeeper V804L/M mutations. Compared with pralsetinib, the two central rings of selpercatinib were buried deeper in the ligand-binding cleft. This placed them further from the solvent edge of the binding cleft (Figure 4G).
The nine-membered pyrazolo ring of selpercatinib occupied the adenosine pocket (AP) that is bordered by Y806 on one side (Figure 4B). The side chain of Y806 had van der Waals interactions with the pyrazolo[1,5-a]pyridine ring and the hydroxymethyl group (Figure 4C), which would be disrupted by substitution of Y806 with cysteine or asparagine that have non-hydrophobic, shorter side chains. The pyridine ring and the 6-[6-(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl group occupied FP-I and FP-II, respectively. The pyridine ring made two van der Waals interactions with the side chain of V738 located on the β2 strand (Figure 4A and D). Replacement of V738 with alanine, which has a shorter side chain, will weaken the van der Waals interactions. Selpercatinib has a hydroxymethylpropoxyl group attached to the pyrazolo[1,5-a]pyridine ring. The hydroxymethyl group projected through the solvent front at the mouth of the AP (Figure 4A, B, E). G810 is the C-lobe residue at the solvent front site. Substitution of the single hydrogen atom side chain of glycine with bulky side chains like those of cysteine, serine, and arginine would cause a steric clash with the hydroxymethylpropoxyl group.
The aminopyrimidinyl and methylaminopyrazol rings of pralsetinib occupied the AP (Figure 4F). The hydrophobic side of the side chain of Y806 made hydrophobic interactions with a face of the methylaminopyrazol ring in the AP site (Figure 4H). Mutation of Tyr-806 to Cys or Asn that contain non-hydrophobic, shorter side chains would disrupt these hydrophobic interactions. One face of the methylamino-pyrimidine ring had pi-H interactions with C-alpha carbon atoms of G810 on the C-lobe side of the solvent front, and the other face of the ring had hydrophobic interactions with both terminal methyl groups of the side chain of L730 of the β1 strand in the N-lobe side of the solvent front (Figure 4I). The methyl group of the methylpyrimidine extended into the first hydration shell at the solvent front. Substitution of G810 with an amino acid that has a larger side chain, such G810C/S/R, would introduce severe steric clashes with the methylpyrimidine ring, whereas substitution of L730 with isoleucine or valine would weaken the hydrophobic interactions and the introduced CG1 and CG2 carbon atoms would cause new steric clashes. The cyclohexane ring of pralsetinib occupied FP-I and the pyridine ring occupied FP-II (Figure 4I). The cyclohexane ring packed against the back-bone of L730 and G731 at the solvent front on the N-lobe of the active site cleft. The CG2 carbon atom of the V738 side chain formed a hydrophobic interaction with the edge of the pyridine ring (Figure 4I). These hydrophobic interactions would be lost when the V738 residue is replaced by an alanine.
DISCUSSION
While avoiding the interference of the gatekeeper mutations, selpercatinib and pralsetinib were subject to resistance caused by non-gatekeeper mutations. Four of five selpercatinib-resistant RET kinase domain mutants that we identified in the laboratory were also detected in the MTC patient and in the NSCLC patient. The fifth mutation identified in the laboratory, RETV738A, is located outside the RET coverage region of clinical cfDNA assays and thus would evade detection in these patients. Recently, the RETG810C/S solvent front mutants have also been found in the cfDNA of two patients with CCDC6-RET-positive NSCLC that acquired pralsetinib-resistance.22
The RET mutations at the C-lobe solvent front (RETG810C/S/R), hinge (RETY806C/N), and β2 strand (RETV738A) shared resistance to both selpercatinib and pralsetinib. The IC50 fold changes of RETG810C/S/R mutants were consistently higher for selpercatinib than for pralsetinib, suggesting that mutations at the C-lobe solvent front site have a higher impact on selpercatinib than on pralsetinib.
Selpercatinib and pralsetinib use a binding mode that is very different from other TKIs. Previously determined structures of complexes with TKIs show that the TKIs occupy both the front and back clefts of the drug-binding pockets by passing through the gate that separates the front and back clefts (e.g. vandetanib, PDB code 2IVU; nintedanib, PDB code 6NEC)9,10 or bind only the front cleft, such as alectinib (PDB code 3AOX),23 certinib (PDB code 4MKC),24 osimertinib (PDB code 4ZAU),25 and entrectinib (PDB code 5KVT). In contrast, selpercatinib and pralsetinib dock one end in the front cleft without inserting through the gate, and wrap around the area outside the gate wall formed by the side chain of K758 and bury the other end in the BP-II pocket of the back cleft.8 This novel binding mode allows high-affinity binding while avoiding disruption of gatekeeper mutations. Nevertheless, this novel kinase inhibitor binding mode remains liable to resistance from mutations at several non-gatekeeper residues identified in this study.
Information on acquired resistance mechanisms to RET, both on target and off target, are emerging. Previous reports have shown RETV804M and RETS904F as resistance mechanisms to vandetanib and acquired RETG810R/C/S/V mutations in RET fusion-positive NSCLC patients whose tumors developed resistance to selpercatinib.26–28 More recently, acquired RET kinase domain mutations have been found in pralsetinib-treated NSCLC patients.22 Another recent study analyzing eighteen RET fusion-positive patients who received selpercatinib or pralsetinib revealed acquired RET G810 solvent front mutations in two cases (10%), three resistant cases (15%) with acquired MET amplification, and one specimen had acquired KRAS amplification.29 Another four cases of acquired selpercatinib resistance with MET amplification were reported and, it was demonstrated that this could be overcome by combining selpercatinib with crizotinib.30 Given that >1000 patients with RET alterations were enrolled on selective RET inhibitor trials globally, these trials are still in progress, and the resistance mechanisms have been reported in just a few patients so far, the frequencies of various resistance mechanisms remain to be determined.
While the most resistant mutant G810C is the principal event in the two clinical cases here, the MTC patient who ultimately progressed harbored RET M918T/V804L/V804M/Y806C/Y806N/G810C/G810S mutations. It is envisioned that the less strong selpercatinib-resistant G810S and Y804C/N could play a significant role in patients treated with lower doses of selpercatinib. Our findings point to the need to develop next-generation RET TKIs covering both gatekeeper and non-gatekeeper mutations for on-target resistance, in addition to deciphering patterns of off-target resistance by alternative mechanisms for combination therapies.
Supplementary Material
Supplementary Material FUNDING
This work was supported by a Presbyterian Health Foundation Team Science grant (to BHMM and JW), National Institutes of Health (NIH) (grant number R01CA242845) to (BHMM, VS, and JW), the Oklahoma Tobacco Settlement Endowment Trust (to the Stephenson Cancer Center), the Cancer Prevention and Research Institute of Texas (grant number RP1100584), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (grant number 1U01 CA180964), the National Center for Advancing Translational Sciences (grant number UL1 TR000371), and the MD Anderson Cancer Center (support grant number P30 CA016672). Use of the Laboratory of the Biomolecular Structure and Function at the University of Oklahoma Health Sciences Center was supported by a grant from the National Institute of General Medical Sciences (grant number P20GM103640). Use of the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory, was supported by the U.S. Department of Energy (DOE), Office of Basic Energy Sciences under contract number DE-AC02-76SF00515. The SSRL Structural Molecular Biology (SMB) Program was supported by the DOE Office of Biological and Environmental Research, and the National Institute of General Medical Sciences (including grant number P41GM103393). We thank Drs Silvia Russi and Doukov Tzanko of the SMB program for their assistance with data collection. The shared resources at the University of Oklahoma Health Sciences Center were supported by NIH/National Institute of General Medical Sciences (grant number P20GM103639) and the NIH/National Cancer Institute (grant number P30CA225520).
DISCLOSURE
VS: research funding/grant support for clinical trials: Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, Medimmune, Altum, Dragonfly Therapeutics, Takeda and, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals; travel: Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte; consultancy/advisory board: Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, QED Pharma, Medimmune, Novartis. Other: Medscape. MH has participated in advisory boards for Blueprint Medicines Corporation, Eli Lilly and Company, and Loxo Oncology, and has served as a consultant for Veracyte. MC, receiving grant support, paid to her institution, from Eisai, Exelixis, Genentech USA, Kura Oncology, and Merck, and advisory board fees from Ignyta and Loxo Oncology. FM-B reports consulting: Aduro BioTech Inc., DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks. Advisory committee: Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals. Sponsored research: Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co. Honoraria: Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey. All remaining authors have declared no conflicts of interest.
Figure 1. Acquired resistance to selpercatinib in an MTC patient.
(A) Treatment history of an MTC patient treated with selpercatinib. (B) Axial arterial phase computed tomography images show innumerable enhancing hepatic metastases at baseline (left) before selpercatinib treatment that improved on cycle 14, day 15 (middle). A follow-up scan on cycle 30, day 22 demonstrated several new avidly enhancing lesions (right, red arrows). (C, D, E) Monitoring of calcitonin (C), carcinoembryonic antigen (CEA, D), and RET mutations in plasma cell-free DNA (cfDNA)(E). Green arrows indicate time points that the RETY806C mutation was detected. Orange arrows indicate the time point of tumor progression. (F) Comparison of IC50s of selpercatinib in BaF3 cells expressing the indicated RET mutants. (G) Immunoblotting analysis of phospho-RET (pY905), cleaved PARP, and b-actin after treatment of BaF3 cells expressing the indicated RET mutants with selpercatinib.
CEA, carcinoembryonic antigen; cPARP, cleaved poly(ADP-ribose) polymerase; MKI, multikinase inhibitor; MTC, medullary thyroid cancer; PR, partial response; pRET, phospho-RET (pY905); Rx, treatment; SPC, selpercatinib.
Figure 2. Acquired resistance to selpercatinib in a CCDC6-RET-positive NSCLC patient.
(A) Treatment history and RET alterations. (B) RECIST v 1.1 measurements. (C) Coronal reformations from contrast-enhanced abdominal computed tomography (CT) images show hepatic metastases at baseline before selpercatinib treatment (left, white arrowheads) that decreased in size and disappeared by cycle 12, day 25 (middle). Follow-up imaging on cycle 18, day 28 shows new lesions (right, black arrows). (D) Test results of lactate dehydrogenase (LDH). LDH was used as a non-specific marker of tumor burden. (E, F) Cell viability and immunoblotting analyses of BaF3/CCDC6-RET (CR) and BaF3/CCDC6-RETG810C [CR(G810C)] cells.
AVT, avastin; CBP, carboplatin; cfDNA, cell-free DNA; cPARP, cleaved poly(ADP-ribose) polymerase; NSCLC, non-small cell lung cancer; PD, progressive disease; PMT, pemetrexed; PR, partial response; pRET, phospho-RET (pY905); SPC, selpercatinib.
Figure 3. Sensitivities of RET mutants to selpercatinib and pralsetinib.
(A, C) BaF3 cells expressing KIF5B-RET (WT) or KIF5B-RET; the indicated mutations were treated with various concentrations of selpercatinib (A) or pralsetinib (C) for 3 days, and viable cells were measured. (B, D) Immunoblotting analysis of RET tyrosine phosphorylation and apoptosis after treatment of cells with selpercatinib (SPC) (B) or pralsetinib (PST) (D). Cells were treated with the drug for 4 h for analyzing RET phosphorylation or 24 h for analyzing cPARP.
cPARP, cleaved poly(ADP-ribose) polymerase; pRET, phospho-RET (pY905); WT, wildtype.
Figure 4. Crystal structures of the RET-selpercatinib and RET-pralsetinib complexes.
(A) Ribbon diagram of RET kinase-selpercatinib complex (7JU6:chain B). (B) View of the 2mFo-DFc electron density map contoured at the 1 sigma level showing the fit of selpercatinib in the 7JU6:chain B. One H-bond occurred between the drug and the protein in the adenosine pocket (AP) site. The gate is between K758 and V804. (C, D,E) Close-up views of areas of Y806, V738, and G810. Dash lines are van der Waals interactions. Distances are in angstroms (Å). (F) View of the 2mFo-DFc electron density map contoured at the 1 sigma level showing the fit of pralsetinib in 7JU5:chain A. The three left-most distances are H-bonds. The distance on the right is a van der Waals interaction. (G) Superposition of the RET kinase-pralsetinib complex (carbon atoms colored cyan) and the RET kinase-selpercatinib complex (carbon atoms colored orange). The pralsetinib and selpercatinib were not used in the least-squares fit. (H) Close-up of pralsetinib (colored magenta) in the vicinity of Y806 (colored cyan). The distances are van der Waals interactions. (I) Close-up of pralsetinib in the vicinity of V738 and G810.
Table 1. Identification of selpercatinib-resistant RET mutants and cross-profiling with pralsetinib
Method Mutant Selecting selpercatinib concentration (nM) Mutant clone count IC50 (nM) (fold: mutant/wt)
150 300 Selpercatinib Pralsetinib
Isolation from mutation library V738A 2 0 2 238.8 ± 7.2 (29) 177.5 ± 6.7 (19)
Y806C 1 0 1 174.4 ± 5.4 (21) 295.8 ± 10.7 (32)
Y806N 2 0 2 149.8 ± 6.3 (18) 292.5 ± 5.9 (32)
G810S 20 11 31 880.2 ± 25.6 (107) 390.6 ± 10.8 (42)
Cell culture with selpercatinib G810S 120 2 880.2 ± 25.6 (107) 390.6 ± 10.8 (42)
G810C 120 1 1227 ± 44.1 (150) 641.7 ± 19.1 (70)
N/A G810R N/A N/A 2744 ± 160.6 (334) 2650 ± 287.3 (288)
V804L N/A N/A 17.2 ± 0.5 (2) 1.8 ± 0.6 (2)
V804M N/A N/A 55.9 ± 1.6 (7) 16.8 ± 0.8 (2)
wt N/A N/A 8.2 ± 0.4 (1) 9.2 ± 0.4 (1)
IC50, concentration that causes 50% inhibition of growth; N/A, not applicable; wt, wildtype.
|
EVEROLIMUS, VANDETANIB
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33161056
| 19,059,427
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adenocarcinoma'.
|
Impella 5.0 supported oncological surgery as bridge to LVAD.
We describe the case of a 58-year-old man presenting with myocardial infarction complicated by cardiogenic shock, treated with Impella CP which was escalated to an axillary 5.0 due to lack of cardiac recovery. Weaning from Impella 5.0 failed, and the patient was evaluated for heart transplantation (HTx) or left ventricular assist device (LVAD). HTx was excluded because of a rectal adenocarcinoma. The patient underwent colorectal surgery while on Impella. Perioperative course was uneventful. After 61 days of Impella, when the LVAD implantation was scheduled, the patient died due to K. pneumoniae infection.
Introduction
Malignancies concomitant with advanced heart failure (HF) are not rare, due to the sharing of some risk factors. The availability of new systems of mechanical circulatory support made possible the treatment of such patients, previously excluded from therapeutic perspectives.
Figure 1 (A) basal coronary angiography. (B) Chronic total occlusion of right coronary artery. (C) After left anterior descending revascularization. (D) After Impella CP implantation.
Case report
A 58‐year‐old man, current smoker and suffering from arterial hypertension, was admitted to our emergency room with an anterior ST‐elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS). The patient underwent percutaneous transluminal coronary angioplasty and drug eluting stent implantation on the proximal tract of the left anterior descending (LAD) artery and a plain old balloon angioplasty of the LAD distal tract and IABP implantation. Right and circumflex coronary arteries were chronically totally occluded Figure 1ABC. Left ventricular ejection fraction was 25%, mitral regurgitation was moderate whereas right ventricular function was normal.
Six hours later, no reversal of CS was observed, and the patient underwent Impella CP implantation from right femoral artery Figure 1D. The patient received double antiplatelet therapy (DAPT) with acetylsalicylic acid and ticagrelor associated with bivalirudin with an activated partial thromboplastin time target of 60 s.
In 1~week, the patient was weaned from inotropes and mechanical ventilation, but showed no recovery of the heart with signs of HF, prompting Impella 5.0 implantation through the right axillary artery, to ensure full hemodynamic support and extended LV unloading. End‐organ damage quickly recovered. After 15 days, no cardiac recovery was noted, and three weaning attempts failed due to acute pulmonary oedema at a still high level (P5) of support.
The patient was then evaluated for heart transplantation (HTx) or left ventricular assist device (LVAD). A colonoscopy was performed after an episode of rectal bleeding, demonstrating an ulcerating lesion with rolled and everted edges 10 cm above the anal orifice, suspected for malignancy. Endoscopic biopsy showed a well‐differentiated adenocarcinoma, ruling out HTx candidacy. Total‐body, contrast‐enhanced computed tomography (CT) scan excluded metastases.
After a multidisciplinary discussion, taking into account the risks to proceed to LVAD implantation vs. radical surgery on Impella support, the patient underwent low anterior rectal resection with total mesorectal excision with termino‐terminal anastomosis using the Knight–Griffen technique and diverting loop ileostomy.
DAPT was stopped 1 week before and bivalirudin 2 hours before surgery. Intraoperative course was uneventful, with a blood loss <1000 mL and no Impella‐related adverse events. Bivalirudin was restarted 4 hours later. Sampled nodes were free from disease. In the following weeks, diurnal spontaneous ventilation, mobilization, and oral feeding were re‐established. After 28 days, CT scan and endoscopy showed integrity of the colorectal anastomosis and the patient underwent loop ileostomy closure. LVAD implantation was delayed to allow a full weaning from mechanical ventilation (MV). Unfortunately, on the 58th day of Impella support, the patient presented with high fever, with blood cultures, and bronchoalveolar lavage positive for multi‐resistant K. pneumoniae. The patient died on the 61th day of Impella support.
Discussion
To the best of our knowledge, this is the first case of major surgery for cancer performed in a patient supported with Impella 5.0.
We faced two main clinical dilemmas, related to the timing of LVAD implantation and the need for long‐term Impella support.
LVAD before or after oncologic surgery
In patients listed for HTx, the prevalence of malignancies is up to 6%.
1
In patients with active cancer, LVAD implantation has been described in a limited number of cases.
2
International Society of Heart and Lung Transplantation (ISHLT) Guidelines recommend that in patients with active malignancy, LVAD implantation could be considered as a destination therapy after oncologic evaluation and a life expectancy >2 years.
3
In our case, CT scan documented the absence of metastases and a low probability of nodes involvement, but the risk of inadequate regional staging was still present, as pelvic nuclear magnetic resonance was not performed.
4
Moreover, the patient's clinical status played against LVAD implantation: active intestinal bleeding, which would be further worsened by the detrimental interaction with LVAD hemodynamic and coagulation milieu and the high risk of driveline infection due to the probable need for colostomy or ileostomy.
These considerations convinced us to postpone LVAD implantation, tying the definitive decision about LVAD candidacy with the feasibility of enteric anastomosis and final pathological staging.
The uncomplicated perioperative course for both surgical procedures suggests the feasibility of major surgery during Impella support, with an excellent hemodynamic stability. The perioperative management should be focused on the timing of withdrawal and restart of anticoagulation drugs. In our institution, all patients on mechanical circulatory support receive bivalirudin as anticoagulant therapy. Bivalirudin has no antagonists but a very short and predictable half‐life, if renal function is normal.
5
Length of Impella support
Impella 5.0 received CE mark for a maximum of 10 days of support, but many studies described longer runs, with a maximum of 71 days with Impella 5.0.
6
Our patient was supported for 61 days, during which all our efforts were directed towards physical rehabilitation, mobilization—promoted by the axillary arterial access—weaning from MV and restart of oral feeding.
No Impella‐related adverse events were observed. Specifically the degree of hemolysis was limited, neither pump displacement nor pump malfunctioning episodes occurred. We did not report any site complication at the axillary arterial access. Our controversial decision to stop DAPT without any bridging therapy raised from the balance between the higher bleeding risk after abdominal surgery and the risk of stent thrombosis in light of the lack of cardiac recovery after weeks of satisfactory cardiac unloading.
Our experience provides some considerations. First, coronary artery disease and many malignancies share some risk factors, making concomitant cancer a concrete possibility.
Second, strict anticoagulation management and continuous evaluation of the pump performance are essential for a safe long Impella run, allowing for thorough evaluation of comorbidities and their treatment in a de novo presentation of advanced HF; indeed, VA ECMO would not be applicable to this scenario.
Third, a high level of attention should be addressed to common causes of death in ICU. The patient presented with several risk factors for nosocomial infection, such as MV, long ICU‐stay, immunosuppression, and frailty condition, and his final cause of death was septic shock.
Fourth, IABP implantation as a first line of mechanical support could be criticized as no longer recommended. In the real world, however, the rate of IABP implantation is still high and often left to the physician's discretion, as it still represents the fastest and easiest tool in dealing with CS at its onset.
7
Our experience suggests new horizons for the use of Impella in patients requiring mechanical support during non‐cardiac surgery and the feasibility of prolonged support with Impella 5.0 as bridge to decision in STEMI patients (PROPELLA concept).
8
,
9
,
10
|
ASPIRIN, BIVALIRUDIN, THROMBOPLASTIN, TICAGRELOR
|
DrugsGivenReaction
|
CC BY-NC
|
33161652
| 19,719,802
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anal ulcer'.
|
Impella 5.0 supported oncological surgery as bridge to LVAD.
We describe the case of a 58-year-old man presenting with myocardial infarction complicated by cardiogenic shock, treated with Impella CP which was escalated to an axillary 5.0 due to lack of cardiac recovery. Weaning from Impella 5.0 failed, and the patient was evaluated for heart transplantation (HTx) or left ventricular assist device (LVAD). HTx was excluded because of a rectal adenocarcinoma. The patient underwent colorectal surgery while on Impella. Perioperative course was uneventful. After 61 days of Impella, when the LVAD implantation was scheduled, the patient died due to K. pneumoniae infection.
Introduction
Malignancies concomitant with advanced heart failure (HF) are not rare, due to the sharing of some risk factors. The availability of new systems of mechanical circulatory support made possible the treatment of such patients, previously excluded from therapeutic perspectives.
Figure 1 (A) basal coronary angiography. (B) Chronic total occlusion of right coronary artery. (C) After left anterior descending revascularization. (D) After Impella CP implantation.
Case report
A 58‐year‐old man, current smoker and suffering from arterial hypertension, was admitted to our emergency room with an anterior ST‐elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS). The patient underwent percutaneous transluminal coronary angioplasty and drug eluting stent implantation on the proximal tract of the left anterior descending (LAD) artery and a plain old balloon angioplasty of the LAD distal tract and IABP implantation. Right and circumflex coronary arteries were chronically totally occluded Figure 1ABC. Left ventricular ejection fraction was 25%, mitral regurgitation was moderate whereas right ventricular function was normal.
Six hours later, no reversal of CS was observed, and the patient underwent Impella CP implantation from right femoral artery Figure 1D. The patient received double antiplatelet therapy (DAPT) with acetylsalicylic acid and ticagrelor associated with bivalirudin with an activated partial thromboplastin time target of 60 s.
In 1~week, the patient was weaned from inotropes and mechanical ventilation, but showed no recovery of the heart with signs of HF, prompting Impella 5.0 implantation through the right axillary artery, to ensure full hemodynamic support and extended LV unloading. End‐organ damage quickly recovered. After 15 days, no cardiac recovery was noted, and three weaning attempts failed due to acute pulmonary oedema at a still high level (P5) of support.
The patient was then evaluated for heart transplantation (HTx) or left ventricular assist device (LVAD). A colonoscopy was performed after an episode of rectal bleeding, demonstrating an ulcerating lesion with rolled and everted edges 10 cm above the anal orifice, suspected for malignancy. Endoscopic biopsy showed a well‐differentiated adenocarcinoma, ruling out HTx candidacy. Total‐body, contrast‐enhanced computed tomography (CT) scan excluded metastases.
After a multidisciplinary discussion, taking into account the risks to proceed to LVAD implantation vs. radical surgery on Impella support, the patient underwent low anterior rectal resection with total mesorectal excision with termino‐terminal anastomosis using the Knight–Griffen technique and diverting loop ileostomy.
DAPT was stopped 1 week before and bivalirudin 2 hours before surgery. Intraoperative course was uneventful, with a blood loss <1000 mL and no Impella‐related adverse events. Bivalirudin was restarted 4 hours later. Sampled nodes were free from disease. In the following weeks, diurnal spontaneous ventilation, mobilization, and oral feeding were re‐established. After 28 days, CT scan and endoscopy showed integrity of the colorectal anastomosis and the patient underwent loop ileostomy closure. LVAD implantation was delayed to allow a full weaning from mechanical ventilation (MV). Unfortunately, on the 58th day of Impella support, the patient presented with high fever, with blood cultures, and bronchoalveolar lavage positive for multi‐resistant K. pneumoniae. The patient died on the 61th day of Impella support.
Discussion
To the best of our knowledge, this is the first case of major surgery for cancer performed in a patient supported with Impella 5.0.
We faced two main clinical dilemmas, related to the timing of LVAD implantation and the need for long‐term Impella support.
LVAD before or after oncologic surgery
In patients listed for HTx, the prevalence of malignancies is up to 6%.
1
In patients with active cancer, LVAD implantation has been described in a limited number of cases.
2
International Society of Heart and Lung Transplantation (ISHLT) Guidelines recommend that in patients with active malignancy, LVAD implantation could be considered as a destination therapy after oncologic evaluation and a life expectancy >2 years.
3
In our case, CT scan documented the absence of metastases and a low probability of nodes involvement, but the risk of inadequate regional staging was still present, as pelvic nuclear magnetic resonance was not performed.
4
Moreover, the patient's clinical status played against LVAD implantation: active intestinal bleeding, which would be further worsened by the detrimental interaction with LVAD hemodynamic and coagulation milieu and the high risk of driveline infection due to the probable need for colostomy or ileostomy.
These considerations convinced us to postpone LVAD implantation, tying the definitive decision about LVAD candidacy with the feasibility of enteric anastomosis and final pathological staging.
The uncomplicated perioperative course for both surgical procedures suggests the feasibility of major surgery during Impella support, with an excellent hemodynamic stability. The perioperative management should be focused on the timing of withdrawal and restart of anticoagulation drugs. In our institution, all patients on mechanical circulatory support receive bivalirudin as anticoagulant therapy. Bivalirudin has no antagonists but a very short and predictable half‐life, if renal function is normal.
5
Length of Impella support
Impella 5.0 received CE mark for a maximum of 10 days of support, but many studies described longer runs, with a maximum of 71 days with Impella 5.0.
6
Our patient was supported for 61 days, during which all our efforts were directed towards physical rehabilitation, mobilization—promoted by the axillary arterial access—weaning from MV and restart of oral feeding.
No Impella‐related adverse events were observed. Specifically the degree of hemolysis was limited, neither pump displacement nor pump malfunctioning episodes occurred. We did not report any site complication at the axillary arterial access. Our controversial decision to stop DAPT without any bridging therapy raised from the balance between the higher bleeding risk after abdominal surgery and the risk of stent thrombosis in light of the lack of cardiac recovery after weeks of satisfactory cardiac unloading.
Our experience provides some considerations. First, coronary artery disease and many malignancies share some risk factors, making concomitant cancer a concrete possibility.
Second, strict anticoagulation management and continuous evaluation of the pump performance are essential for a safe long Impella run, allowing for thorough evaluation of comorbidities and their treatment in a de novo presentation of advanced HF; indeed, VA ECMO would not be applicable to this scenario.
Third, a high level of attention should be addressed to common causes of death in ICU. The patient presented with several risk factors for nosocomial infection, such as MV, long ICU‐stay, immunosuppression, and frailty condition, and his final cause of death was septic shock.
Fourth, IABP implantation as a first line of mechanical support could be criticized as no longer recommended. In the real world, however, the rate of IABP implantation is still high and often left to the physician's discretion, as it still represents the fastest and easiest tool in dealing with CS at its onset.
7
Our experience suggests new horizons for the use of Impella in patients requiring mechanical support during non‐cardiac surgery and the feasibility of prolonged support with Impella 5.0 as bridge to decision in STEMI patients (PROPELLA concept).
8
,
9
,
10
|
ASPIRIN, BIVALIRUDIN, THROMBOPLASTIN, TICAGRELOR
|
DrugsGivenReaction
|
CC BY-NC
|
33161652
| 19,719,802
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Labelled drug-drug interaction medication error'.
|
Impella 5.0 supported oncological surgery as bridge to LVAD.
We describe the case of a 58-year-old man presenting with myocardial infarction complicated by cardiogenic shock, treated with Impella CP which was escalated to an axillary 5.0 due to lack of cardiac recovery. Weaning from Impella 5.0 failed, and the patient was evaluated for heart transplantation (HTx) or left ventricular assist device (LVAD). HTx was excluded because of a rectal adenocarcinoma. The patient underwent colorectal surgery while on Impella. Perioperative course was uneventful. After 61 days of Impella, when the LVAD implantation was scheduled, the patient died due to K. pneumoniae infection.
Introduction
Malignancies concomitant with advanced heart failure (HF) are not rare, due to the sharing of some risk factors. The availability of new systems of mechanical circulatory support made possible the treatment of such patients, previously excluded from therapeutic perspectives.
Figure 1 (A) basal coronary angiography. (B) Chronic total occlusion of right coronary artery. (C) After left anterior descending revascularization. (D) After Impella CP implantation.
Case report
A 58‐year‐old man, current smoker and suffering from arterial hypertension, was admitted to our emergency room with an anterior ST‐elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS). The patient underwent percutaneous transluminal coronary angioplasty and drug eluting stent implantation on the proximal tract of the left anterior descending (LAD) artery and a plain old balloon angioplasty of the LAD distal tract and IABP implantation. Right and circumflex coronary arteries were chronically totally occluded Figure 1ABC. Left ventricular ejection fraction was 25%, mitral regurgitation was moderate whereas right ventricular function was normal.
Six hours later, no reversal of CS was observed, and the patient underwent Impella CP implantation from right femoral artery Figure 1D. The patient received double antiplatelet therapy (DAPT) with acetylsalicylic acid and ticagrelor associated with bivalirudin with an activated partial thromboplastin time target of 60 s.
In 1~week, the patient was weaned from inotropes and mechanical ventilation, but showed no recovery of the heart with signs of HF, prompting Impella 5.0 implantation through the right axillary artery, to ensure full hemodynamic support and extended LV unloading. End‐organ damage quickly recovered. After 15 days, no cardiac recovery was noted, and three weaning attempts failed due to acute pulmonary oedema at a still high level (P5) of support.
The patient was then evaluated for heart transplantation (HTx) or left ventricular assist device (LVAD). A colonoscopy was performed after an episode of rectal bleeding, demonstrating an ulcerating lesion with rolled and everted edges 10 cm above the anal orifice, suspected for malignancy. Endoscopic biopsy showed a well‐differentiated adenocarcinoma, ruling out HTx candidacy. Total‐body, contrast‐enhanced computed tomography (CT) scan excluded metastases.
After a multidisciplinary discussion, taking into account the risks to proceed to LVAD implantation vs. radical surgery on Impella support, the patient underwent low anterior rectal resection with total mesorectal excision with termino‐terminal anastomosis using the Knight–Griffen technique and diverting loop ileostomy.
DAPT was stopped 1 week before and bivalirudin 2 hours before surgery. Intraoperative course was uneventful, with a blood loss <1000 mL and no Impella‐related adverse events. Bivalirudin was restarted 4 hours later. Sampled nodes were free from disease. In the following weeks, diurnal spontaneous ventilation, mobilization, and oral feeding were re‐established. After 28 days, CT scan and endoscopy showed integrity of the colorectal anastomosis and the patient underwent loop ileostomy closure. LVAD implantation was delayed to allow a full weaning from mechanical ventilation (MV). Unfortunately, on the 58th day of Impella support, the patient presented with high fever, with blood cultures, and bronchoalveolar lavage positive for multi‐resistant K. pneumoniae. The patient died on the 61th day of Impella support.
Discussion
To the best of our knowledge, this is the first case of major surgery for cancer performed in a patient supported with Impella 5.0.
We faced two main clinical dilemmas, related to the timing of LVAD implantation and the need for long‐term Impella support.
LVAD before or after oncologic surgery
In patients listed for HTx, the prevalence of malignancies is up to 6%.
1
In patients with active cancer, LVAD implantation has been described in a limited number of cases.
2
International Society of Heart and Lung Transplantation (ISHLT) Guidelines recommend that in patients with active malignancy, LVAD implantation could be considered as a destination therapy after oncologic evaluation and a life expectancy >2 years.
3
In our case, CT scan documented the absence of metastases and a low probability of nodes involvement, but the risk of inadequate regional staging was still present, as pelvic nuclear magnetic resonance was not performed.
4
Moreover, the patient's clinical status played against LVAD implantation: active intestinal bleeding, which would be further worsened by the detrimental interaction with LVAD hemodynamic and coagulation milieu and the high risk of driveline infection due to the probable need for colostomy or ileostomy.
These considerations convinced us to postpone LVAD implantation, tying the definitive decision about LVAD candidacy with the feasibility of enteric anastomosis and final pathological staging.
The uncomplicated perioperative course for both surgical procedures suggests the feasibility of major surgery during Impella support, with an excellent hemodynamic stability. The perioperative management should be focused on the timing of withdrawal and restart of anticoagulation drugs. In our institution, all patients on mechanical circulatory support receive bivalirudin as anticoagulant therapy. Bivalirudin has no antagonists but a very short and predictable half‐life, if renal function is normal.
5
Length of Impella support
Impella 5.0 received CE mark for a maximum of 10 days of support, but many studies described longer runs, with a maximum of 71 days with Impella 5.0.
6
Our patient was supported for 61 days, during which all our efforts were directed towards physical rehabilitation, mobilization—promoted by the axillary arterial access—weaning from MV and restart of oral feeding.
No Impella‐related adverse events were observed. Specifically the degree of hemolysis was limited, neither pump displacement nor pump malfunctioning episodes occurred. We did not report any site complication at the axillary arterial access. Our controversial decision to stop DAPT without any bridging therapy raised from the balance between the higher bleeding risk after abdominal surgery and the risk of stent thrombosis in light of the lack of cardiac recovery after weeks of satisfactory cardiac unloading.
Our experience provides some considerations. First, coronary artery disease and many malignancies share some risk factors, making concomitant cancer a concrete possibility.
Second, strict anticoagulation management and continuous evaluation of the pump performance are essential for a safe long Impella run, allowing for thorough evaluation of comorbidities and their treatment in a de novo presentation of advanced HF; indeed, VA ECMO would not be applicable to this scenario.
Third, a high level of attention should be addressed to common causes of death in ICU. The patient presented with several risk factors for nosocomial infection, such as MV, long ICU‐stay, immunosuppression, and frailty condition, and his final cause of death was septic shock.
Fourth, IABP implantation as a first line of mechanical support could be criticized as no longer recommended. In the real world, however, the rate of IABP implantation is still high and often left to the physician's discretion, as it still represents the fastest and easiest tool in dealing with CS at its onset.
7
Our experience suggests new horizons for the use of Impella in patients requiring mechanical support during non‐cardiac surgery and the feasibility of prolonged support with Impella 5.0 as bridge to decision in STEMI patients (PROPELLA concept).
8
,
9
,
10
|
ASPIRIN, BIVALIRUDIN, THROMBOPLASTIN, TICAGRELOR
|
DrugsGivenReaction
|
CC BY-NC
|
33161652
| 19,719,802
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia klebsiella'.
|
Impella 5.0 supported oncological surgery as bridge to LVAD.
We describe the case of a 58-year-old man presenting with myocardial infarction complicated by cardiogenic shock, treated with Impella CP which was escalated to an axillary 5.0 due to lack of cardiac recovery. Weaning from Impella 5.0 failed, and the patient was evaluated for heart transplantation (HTx) or left ventricular assist device (LVAD). HTx was excluded because of a rectal adenocarcinoma. The patient underwent colorectal surgery while on Impella. Perioperative course was uneventful. After 61 days of Impella, when the LVAD implantation was scheduled, the patient died due to K. pneumoniae infection.
Introduction
Malignancies concomitant with advanced heart failure (HF) are not rare, due to the sharing of some risk factors. The availability of new systems of mechanical circulatory support made possible the treatment of such patients, previously excluded from therapeutic perspectives.
Figure 1 (A) basal coronary angiography. (B) Chronic total occlusion of right coronary artery. (C) After left anterior descending revascularization. (D) After Impella CP implantation.
Case report
A 58‐year‐old man, current smoker and suffering from arterial hypertension, was admitted to our emergency room with an anterior ST‐elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS). The patient underwent percutaneous transluminal coronary angioplasty and drug eluting stent implantation on the proximal tract of the left anterior descending (LAD) artery and a plain old balloon angioplasty of the LAD distal tract and IABP implantation. Right and circumflex coronary arteries were chronically totally occluded Figure 1ABC. Left ventricular ejection fraction was 25%, mitral regurgitation was moderate whereas right ventricular function was normal.
Six hours later, no reversal of CS was observed, and the patient underwent Impella CP implantation from right femoral artery Figure 1D. The patient received double antiplatelet therapy (DAPT) with acetylsalicylic acid and ticagrelor associated with bivalirudin with an activated partial thromboplastin time target of 60 s.
In 1~week, the patient was weaned from inotropes and mechanical ventilation, but showed no recovery of the heart with signs of HF, prompting Impella 5.0 implantation through the right axillary artery, to ensure full hemodynamic support and extended LV unloading. End‐organ damage quickly recovered. After 15 days, no cardiac recovery was noted, and three weaning attempts failed due to acute pulmonary oedema at a still high level (P5) of support.
The patient was then evaluated for heart transplantation (HTx) or left ventricular assist device (LVAD). A colonoscopy was performed after an episode of rectal bleeding, demonstrating an ulcerating lesion with rolled and everted edges 10 cm above the anal orifice, suspected for malignancy. Endoscopic biopsy showed a well‐differentiated adenocarcinoma, ruling out HTx candidacy. Total‐body, contrast‐enhanced computed tomography (CT) scan excluded metastases.
After a multidisciplinary discussion, taking into account the risks to proceed to LVAD implantation vs. radical surgery on Impella support, the patient underwent low anterior rectal resection with total mesorectal excision with termino‐terminal anastomosis using the Knight–Griffen technique and diverting loop ileostomy.
DAPT was stopped 1 week before and bivalirudin 2 hours before surgery. Intraoperative course was uneventful, with a blood loss <1000 mL and no Impella‐related adverse events. Bivalirudin was restarted 4 hours later. Sampled nodes were free from disease. In the following weeks, diurnal spontaneous ventilation, mobilization, and oral feeding were re‐established. After 28 days, CT scan and endoscopy showed integrity of the colorectal anastomosis and the patient underwent loop ileostomy closure. LVAD implantation was delayed to allow a full weaning from mechanical ventilation (MV). Unfortunately, on the 58th day of Impella support, the patient presented with high fever, with blood cultures, and bronchoalveolar lavage positive for multi‐resistant K. pneumoniae. The patient died on the 61th day of Impella support.
Discussion
To the best of our knowledge, this is the first case of major surgery for cancer performed in a patient supported with Impella 5.0.
We faced two main clinical dilemmas, related to the timing of LVAD implantation and the need for long‐term Impella support.
LVAD before or after oncologic surgery
In patients listed for HTx, the prevalence of malignancies is up to 6%.
1
In patients with active cancer, LVAD implantation has been described in a limited number of cases.
2
International Society of Heart and Lung Transplantation (ISHLT) Guidelines recommend that in patients with active malignancy, LVAD implantation could be considered as a destination therapy after oncologic evaluation and a life expectancy >2 years.
3
In our case, CT scan documented the absence of metastases and a low probability of nodes involvement, but the risk of inadequate regional staging was still present, as pelvic nuclear magnetic resonance was not performed.
4
Moreover, the patient's clinical status played against LVAD implantation: active intestinal bleeding, which would be further worsened by the detrimental interaction with LVAD hemodynamic and coagulation milieu and the high risk of driveline infection due to the probable need for colostomy or ileostomy.
These considerations convinced us to postpone LVAD implantation, tying the definitive decision about LVAD candidacy with the feasibility of enteric anastomosis and final pathological staging.
The uncomplicated perioperative course for both surgical procedures suggests the feasibility of major surgery during Impella support, with an excellent hemodynamic stability. The perioperative management should be focused on the timing of withdrawal and restart of anticoagulation drugs. In our institution, all patients on mechanical circulatory support receive bivalirudin as anticoagulant therapy. Bivalirudin has no antagonists but a very short and predictable half‐life, if renal function is normal.
5
Length of Impella support
Impella 5.0 received CE mark for a maximum of 10 days of support, but many studies described longer runs, with a maximum of 71 days with Impella 5.0.
6
Our patient was supported for 61 days, during which all our efforts were directed towards physical rehabilitation, mobilization—promoted by the axillary arterial access—weaning from MV and restart of oral feeding.
No Impella‐related adverse events were observed. Specifically the degree of hemolysis was limited, neither pump displacement nor pump malfunctioning episodes occurred. We did not report any site complication at the axillary arterial access. Our controversial decision to stop DAPT without any bridging therapy raised from the balance between the higher bleeding risk after abdominal surgery and the risk of stent thrombosis in light of the lack of cardiac recovery after weeks of satisfactory cardiac unloading.
Our experience provides some considerations. First, coronary artery disease and many malignancies share some risk factors, making concomitant cancer a concrete possibility.
Second, strict anticoagulation management and continuous evaluation of the pump performance are essential for a safe long Impella run, allowing for thorough evaluation of comorbidities and their treatment in a de novo presentation of advanced HF; indeed, VA ECMO would not be applicable to this scenario.
Third, a high level of attention should be addressed to common causes of death in ICU. The patient presented with several risk factors for nosocomial infection, such as MV, long ICU‐stay, immunosuppression, and frailty condition, and his final cause of death was septic shock.
Fourth, IABP implantation as a first line of mechanical support could be criticized as no longer recommended. In the real world, however, the rate of IABP implantation is still high and often left to the physician's discretion, as it still represents the fastest and easiest tool in dealing with CS at its onset.
7
Our experience suggests new horizons for the use of Impella in patients requiring mechanical support during non‐cardiac surgery and the feasibility of prolonged support with Impella 5.0 as bridge to decision in STEMI patients (PROPELLA concept).
8
,
9
,
10
|
ASPIRIN, BIVALIRUDIN, THROMBOPLASTIN, TICAGRELOR
|
DrugsGivenReaction
|
CC BY-NC
|
33161652
| 19,719,802
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rectal haemorrhage'.
|
Impella 5.0 supported oncological surgery as bridge to LVAD.
We describe the case of a 58-year-old man presenting with myocardial infarction complicated by cardiogenic shock, treated with Impella CP which was escalated to an axillary 5.0 due to lack of cardiac recovery. Weaning from Impella 5.0 failed, and the patient was evaluated for heart transplantation (HTx) or left ventricular assist device (LVAD). HTx was excluded because of a rectal adenocarcinoma. The patient underwent colorectal surgery while on Impella. Perioperative course was uneventful. After 61 days of Impella, when the LVAD implantation was scheduled, the patient died due to K. pneumoniae infection.
Introduction
Malignancies concomitant with advanced heart failure (HF) are not rare, due to the sharing of some risk factors. The availability of new systems of mechanical circulatory support made possible the treatment of such patients, previously excluded from therapeutic perspectives.
Figure 1 (A) basal coronary angiography. (B) Chronic total occlusion of right coronary artery. (C) After left anterior descending revascularization. (D) After Impella CP implantation.
Case report
A 58‐year‐old man, current smoker and suffering from arterial hypertension, was admitted to our emergency room with an anterior ST‐elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS). The patient underwent percutaneous transluminal coronary angioplasty and drug eluting stent implantation on the proximal tract of the left anterior descending (LAD) artery and a plain old balloon angioplasty of the LAD distal tract and IABP implantation. Right and circumflex coronary arteries were chronically totally occluded Figure 1ABC. Left ventricular ejection fraction was 25%, mitral regurgitation was moderate whereas right ventricular function was normal.
Six hours later, no reversal of CS was observed, and the patient underwent Impella CP implantation from right femoral artery Figure 1D. The patient received double antiplatelet therapy (DAPT) with acetylsalicylic acid and ticagrelor associated with bivalirudin with an activated partial thromboplastin time target of 60 s.
In 1~week, the patient was weaned from inotropes and mechanical ventilation, but showed no recovery of the heart with signs of HF, prompting Impella 5.0 implantation through the right axillary artery, to ensure full hemodynamic support and extended LV unloading. End‐organ damage quickly recovered. After 15 days, no cardiac recovery was noted, and three weaning attempts failed due to acute pulmonary oedema at a still high level (P5) of support.
The patient was then evaluated for heart transplantation (HTx) or left ventricular assist device (LVAD). A colonoscopy was performed after an episode of rectal bleeding, demonstrating an ulcerating lesion with rolled and everted edges 10 cm above the anal orifice, suspected for malignancy. Endoscopic biopsy showed a well‐differentiated adenocarcinoma, ruling out HTx candidacy. Total‐body, contrast‐enhanced computed tomography (CT) scan excluded metastases.
After a multidisciplinary discussion, taking into account the risks to proceed to LVAD implantation vs. radical surgery on Impella support, the patient underwent low anterior rectal resection with total mesorectal excision with termino‐terminal anastomosis using the Knight–Griffen technique and diverting loop ileostomy.
DAPT was stopped 1 week before and bivalirudin 2 hours before surgery. Intraoperative course was uneventful, with a blood loss <1000 mL and no Impella‐related adverse events. Bivalirudin was restarted 4 hours later. Sampled nodes were free from disease. In the following weeks, diurnal spontaneous ventilation, mobilization, and oral feeding were re‐established. After 28 days, CT scan and endoscopy showed integrity of the colorectal anastomosis and the patient underwent loop ileostomy closure. LVAD implantation was delayed to allow a full weaning from mechanical ventilation (MV). Unfortunately, on the 58th day of Impella support, the patient presented with high fever, with blood cultures, and bronchoalveolar lavage positive for multi‐resistant K. pneumoniae. The patient died on the 61th day of Impella support.
Discussion
To the best of our knowledge, this is the first case of major surgery for cancer performed in a patient supported with Impella 5.0.
We faced two main clinical dilemmas, related to the timing of LVAD implantation and the need for long‐term Impella support.
LVAD before or after oncologic surgery
In patients listed for HTx, the prevalence of malignancies is up to 6%.
1
In patients with active cancer, LVAD implantation has been described in a limited number of cases.
2
International Society of Heart and Lung Transplantation (ISHLT) Guidelines recommend that in patients with active malignancy, LVAD implantation could be considered as a destination therapy after oncologic evaluation and a life expectancy >2 years.
3
In our case, CT scan documented the absence of metastases and a low probability of nodes involvement, but the risk of inadequate regional staging was still present, as pelvic nuclear magnetic resonance was not performed.
4
Moreover, the patient's clinical status played against LVAD implantation: active intestinal bleeding, which would be further worsened by the detrimental interaction with LVAD hemodynamic and coagulation milieu and the high risk of driveline infection due to the probable need for colostomy or ileostomy.
These considerations convinced us to postpone LVAD implantation, tying the definitive decision about LVAD candidacy with the feasibility of enteric anastomosis and final pathological staging.
The uncomplicated perioperative course for both surgical procedures suggests the feasibility of major surgery during Impella support, with an excellent hemodynamic stability. The perioperative management should be focused on the timing of withdrawal and restart of anticoagulation drugs. In our institution, all patients on mechanical circulatory support receive bivalirudin as anticoagulant therapy. Bivalirudin has no antagonists but a very short and predictable half‐life, if renal function is normal.
5
Length of Impella support
Impella 5.0 received CE mark for a maximum of 10 days of support, but many studies described longer runs, with a maximum of 71 days with Impella 5.0.
6
Our patient was supported for 61 days, during which all our efforts were directed towards physical rehabilitation, mobilization—promoted by the axillary arterial access—weaning from MV and restart of oral feeding.
No Impella‐related adverse events were observed. Specifically the degree of hemolysis was limited, neither pump displacement nor pump malfunctioning episodes occurred. We did not report any site complication at the axillary arterial access. Our controversial decision to stop DAPT without any bridging therapy raised from the balance between the higher bleeding risk after abdominal surgery and the risk of stent thrombosis in light of the lack of cardiac recovery after weeks of satisfactory cardiac unloading.
Our experience provides some considerations. First, coronary artery disease and many malignancies share some risk factors, making concomitant cancer a concrete possibility.
Second, strict anticoagulation management and continuous evaluation of the pump performance are essential for a safe long Impella run, allowing for thorough evaluation of comorbidities and their treatment in a de novo presentation of advanced HF; indeed, VA ECMO would not be applicable to this scenario.
Third, a high level of attention should be addressed to common causes of death in ICU. The patient presented with several risk factors for nosocomial infection, such as MV, long ICU‐stay, immunosuppression, and frailty condition, and his final cause of death was septic shock.
Fourth, IABP implantation as a first line of mechanical support could be criticized as no longer recommended. In the real world, however, the rate of IABP implantation is still high and often left to the physician's discretion, as it still represents the fastest and easiest tool in dealing with CS at its onset.
7
Our experience suggests new horizons for the use of Impella in patients requiring mechanical support during non‐cardiac surgery and the feasibility of prolonged support with Impella 5.0 as bridge to decision in STEMI patients (PROPELLA concept).
8
,
9
,
10
|
ASPIRIN, BIVALIRUDIN, THROMBOPLASTIN, TICAGRELOR
|
DrugsGivenReaction
|
CC BY-NC
|
33161652
| 19,719,802
|
2021-02
|
What was the outcome of reaction 'Pneumonia klebsiella'?
|
Impella 5.0 supported oncological surgery as bridge to LVAD.
We describe the case of a 58-year-old man presenting with myocardial infarction complicated by cardiogenic shock, treated with Impella CP which was escalated to an axillary 5.0 due to lack of cardiac recovery. Weaning from Impella 5.0 failed, and the patient was evaluated for heart transplantation (HTx) or left ventricular assist device (LVAD). HTx was excluded because of a rectal adenocarcinoma. The patient underwent colorectal surgery while on Impella. Perioperative course was uneventful. After 61 days of Impella, when the LVAD implantation was scheduled, the patient died due to K. pneumoniae infection.
Introduction
Malignancies concomitant with advanced heart failure (HF) are not rare, due to the sharing of some risk factors. The availability of new systems of mechanical circulatory support made possible the treatment of such patients, previously excluded from therapeutic perspectives.
Figure 1 (A) basal coronary angiography. (B) Chronic total occlusion of right coronary artery. (C) After left anterior descending revascularization. (D) After Impella CP implantation.
Case report
A 58‐year‐old man, current smoker and suffering from arterial hypertension, was admitted to our emergency room with an anterior ST‐elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS). The patient underwent percutaneous transluminal coronary angioplasty and drug eluting stent implantation on the proximal tract of the left anterior descending (LAD) artery and a plain old balloon angioplasty of the LAD distal tract and IABP implantation. Right and circumflex coronary arteries were chronically totally occluded Figure 1ABC. Left ventricular ejection fraction was 25%, mitral regurgitation was moderate whereas right ventricular function was normal.
Six hours later, no reversal of CS was observed, and the patient underwent Impella CP implantation from right femoral artery Figure 1D. The patient received double antiplatelet therapy (DAPT) with acetylsalicylic acid and ticagrelor associated with bivalirudin with an activated partial thromboplastin time target of 60 s.
In 1~week, the patient was weaned from inotropes and mechanical ventilation, but showed no recovery of the heart with signs of HF, prompting Impella 5.0 implantation through the right axillary artery, to ensure full hemodynamic support and extended LV unloading. End‐organ damage quickly recovered. After 15 days, no cardiac recovery was noted, and three weaning attempts failed due to acute pulmonary oedema at a still high level (P5) of support.
The patient was then evaluated for heart transplantation (HTx) or left ventricular assist device (LVAD). A colonoscopy was performed after an episode of rectal bleeding, demonstrating an ulcerating lesion with rolled and everted edges 10 cm above the anal orifice, suspected for malignancy. Endoscopic biopsy showed a well‐differentiated adenocarcinoma, ruling out HTx candidacy. Total‐body, contrast‐enhanced computed tomography (CT) scan excluded metastases.
After a multidisciplinary discussion, taking into account the risks to proceed to LVAD implantation vs. radical surgery on Impella support, the patient underwent low anterior rectal resection with total mesorectal excision with termino‐terminal anastomosis using the Knight–Griffen technique and diverting loop ileostomy.
DAPT was stopped 1 week before and bivalirudin 2 hours before surgery. Intraoperative course was uneventful, with a blood loss <1000 mL and no Impella‐related adverse events. Bivalirudin was restarted 4 hours later. Sampled nodes were free from disease. In the following weeks, diurnal spontaneous ventilation, mobilization, and oral feeding were re‐established. After 28 days, CT scan and endoscopy showed integrity of the colorectal anastomosis and the patient underwent loop ileostomy closure. LVAD implantation was delayed to allow a full weaning from mechanical ventilation (MV). Unfortunately, on the 58th day of Impella support, the patient presented with high fever, with blood cultures, and bronchoalveolar lavage positive for multi‐resistant K. pneumoniae. The patient died on the 61th day of Impella support.
Discussion
To the best of our knowledge, this is the first case of major surgery for cancer performed in a patient supported with Impella 5.0.
We faced two main clinical dilemmas, related to the timing of LVAD implantation and the need for long‐term Impella support.
LVAD before or after oncologic surgery
In patients listed for HTx, the prevalence of malignancies is up to 6%.
1
In patients with active cancer, LVAD implantation has been described in a limited number of cases.
2
International Society of Heart and Lung Transplantation (ISHLT) Guidelines recommend that in patients with active malignancy, LVAD implantation could be considered as a destination therapy after oncologic evaluation and a life expectancy >2 years.
3
In our case, CT scan documented the absence of metastases and a low probability of nodes involvement, but the risk of inadequate regional staging was still present, as pelvic nuclear magnetic resonance was not performed.
4
Moreover, the patient's clinical status played against LVAD implantation: active intestinal bleeding, which would be further worsened by the detrimental interaction with LVAD hemodynamic and coagulation milieu and the high risk of driveline infection due to the probable need for colostomy or ileostomy.
These considerations convinced us to postpone LVAD implantation, tying the definitive decision about LVAD candidacy with the feasibility of enteric anastomosis and final pathological staging.
The uncomplicated perioperative course for both surgical procedures suggests the feasibility of major surgery during Impella support, with an excellent hemodynamic stability. The perioperative management should be focused on the timing of withdrawal and restart of anticoagulation drugs. In our institution, all patients on mechanical circulatory support receive bivalirudin as anticoagulant therapy. Bivalirudin has no antagonists but a very short and predictable half‐life, if renal function is normal.
5
Length of Impella support
Impella 5.0 received CE mark for a maximum of 10 days of support, but many studies described longer runs, with a maximum of 71 days with Impella 5.0.
6
Our patient was supported for 61 days, during which all our efforts were directed towards physical rehabilitation, mobilization—promoted by the axillary arterial access—weaning from MV and restart of oral feeding.
No Impella‐related adverse events were observed. Specifically the degree of hemolysis was limited, neither pump displacement nor pump malfunctioning episodes occurred. We did not report any site complication at the axillary arterial access. Our controversial decision to stop DAPT without any bridging therapy raised from the balance between the higher bleeding risk after abdominal surgery and the risk of stent thrombosis in light of the lack of cardiac recovery after weeks of satisfactory cardiac unloading.
Our experience provides some considerations. First, coronary artery disease and many malignancies share some risk factors, making concomitant cancer a concrete possibility.
Second, strict anticoagulation management and continuous evaluation of the pump performance are essential for a safe long Impella run, allowing for thorough evaluation of comorbidities and their treatment in a de novo presentation of advanced HF; indeed, VA ECMO would not be applicable to this scenario.
Third, a high level of attention should be addressed to common causes of death in ICU. The patient presented with several risk factors for nosocomial infection, such as MV, long ICU‐stay, immunosuppression, and frailty condition, and his final cause of death was septic shock.
Fourth, IABP implantation as a first line of mechanical support could be criticized as no longer recommended. In the real world, however, the rate of IABP implantation is still high and often left to the physician's discretion, as it still represents the fastest and easiest tool in dealing with CS at its onset.
7
Our experience suggests new horizons for the use of Impella in patients requiring mechanical support during non‐cardiac surgery and the feasibility of prolonged support with Impella 5.0 as bridge to decision in STEMI patients (PROPELLA concept).
8
,
9
,
10
|
Fatal
|
ReactionOutcome
|
CC BY-NC
|
33161652
| 19,719,802
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'.
|
Prediction of Stem Cell Mobilization Failure in Patients with Hodgkin and Non-Hodgkin Lymphoma
Autologous stem cell transplantation (ASCT) is a significant and potentially curative treatment modality for patients with relapsed/refractory lymphoma. Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. The aim of this study was to evaluate the factors that might influence mobilization failure in patients with lymphoma.
Eighty-seven patients diagnosed with non-Hodgkin and Hodgkin lymphoma who underwent stem cell mobilization afterwards at the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, between the years of 2000 and 2018 were evaluated.
A total of 87 patients were included in this study. In 66 of 87 patients (75.9%), the first mobilization trial was successful. Adequate (≥2x106/kg) CD34+ cells were collected in the first apheresis for 66 patients (9.5±8.1). For 21 of 87 (24.1%), the first mobilization trial was unsuccessful. Therefore, a second mobilization trial was performed for these patients with plerixafor (5.5±3.3). The number of CD34+ cells was significantly higher in patients who were successful in the first mobilization (p=0.002).
The success rate of the first mobilization trial was found to be higher in patients with high platelet counts before mobilization and patients who received chemotherapy-based mobilization protocols. In the patients who had mobilization failure in the first trial, plerixafor was used in a later mobilization, and those patients had an adequate amount of stem cells for ASCT. Parameters predicting mobilization failure would allow for preemptive, more cost-effective use of such agents during the first mobilization attempt; however, risk factors for mobilization failure are still not clear.
Introduction
Autologous stem cell transplantation (ASCT) is a significant and potentially curative treatment modality for patients with relapsed/refractory lymphoma. However, 5%-40% of lymphoma patients fail to mobilize sufficient peripheral blood stem cells and thus cannot undergo ASCT, which is known to improve survival [1]. Hematopoietic stem cells generally circulate in very small numbers in the peripheral blood and have to be mobilized into the circulation prior to being collected by apheresis. Peripheral blood stem cell (PBSC) mobilization is accomplished by administration of granulocyte colony-stimulating factor (G-CSF) alone or in combination with chemotherapy [2]. Peripheral blood has been shown to be superior to bone marrow as a source of hematopoietic stem cells for ASCT [3]. Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. Currently, a minimum of 2x106 CD34+ cells/kg hematopoietic stem cells is considered appropriate in most centers to proceed to ASCT. This threshold is necessary for a rapid and sustained blood count recovery and for reduced hospitalization, blood product usage, and infections [4]. However, the optimal hematopoietic stem cell dose is about 5x106/kg [5]. Bone marrow infiltration, advanced age, number of prior cytotoxic therapies, and myelodysplastic changes are the best defined factors associated with increased risk of mobilization failure [6,7].
We have collected and analyzed data from a series of non-Hodgkin and Hodgkin lymphoma patients who received ASCT in order to determine the frequency of harvest failure and to identify factors influencing PBSC mobilization outcomes. The aim of this study was to evaluate the factors that might influence mobilization failure in patients with lymphoma.
Materials and Methods
Study Design and Data Collection
This study was performed in a retrospective manner. Demographic data of the patients, treatment regimens, and stem cell mobilization data updates were obtained from the hospital database. As a result of the application standards of the hospitals of the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, it has been recognized from the patient records that all of the studied patients had given informed consent at the time of hospitalization and before the administration of chemotherapy and other relevant diagnostic/therapeutic standards of care. Patients gave informed consent for procedures in accordance with the Declaration of Helsinki.
Patients and Disease Characteristics
Eighty-seven patients diagnosed with non-Hodgkin and Hodgkin lymphoma who underwent stem cell mobilization afterwards at the Hacettepe University Medical School Bone Marrow Transplantation Center between the years of 2000 and 2018 were evaluated. The key inclusion criteria were patients ≥18 years of age diagnosed with non-Hodgkin or Hodgkin lymphoma who required systemic chemotherapy and underwent ASCT with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of <2 [8] with an indication for ASCT.
Median age, gender, ECOG PS, lymphoma subtypes, stage at diagnosis, bone marrow infiltration at diagnosis, induction chemotherapy, salvage chemotherapy, chemotherapy cycles received before mobilization, radiotherapy before mobilization, platelet count before mobilization, mobilization protocols, and disease status before ASCT were compared for patients who had successful stem cell mobilization and those with stem cell mobilization failure. Additionally, disease status after ASCT, relapse rate, and mortality results were evaluated between these groups. The target CD34+ cell dose for collection was >2x106/kg for each planned autograft. All patients received G-CSF at a dose of 10 µg/kg from day +5 until the peripheral stem cell harvest. CD34+ cells were measured in peripheral blood and apheresis products by flow cytometry. We had a CD34+ cut-off level of 20 µL for starting apheresis. We harvested the cells on the 5th and/or 6th day after beginning G-CSF administration. Peripheral blood CD34% and CD34/µL values at the first day on which leukocytes reached the value of 1x109/L and were maintained above that threshold over at least 2 days were correlated with overall CD34+ collection. A harvest of less than 2x106 CD34+/kg was considered as mobilization failure. Twenty-one patients received plerixafor as an additional mobilizing agent for the second apheresis. Subcutaneous plerixafor (0.24 mg/kg) was administered to the patients on the evenings of the 4th and 5th days of the mobilization protocol.
Statistical Analysis
Statistical analyses were performed using SPSS 25 (IBM Corp., Armonk, NY, USA). Variables were investigated using visual (histograms, probability plots) and analytical (Kolmogorov-Smirnov/Shapiro-Wilk test) methods to determine whether they were normally distributed or not. Statistical comparisons were made using chi-square tests for categorical data. Student’s t-test for two independent samples was used for comparison of continuous numerical data. Variables found to be significant (p<0.05) in univariate analysis were tested in multivariate analysis, which was performed using a stepwise logistic regression model. Survival analyses were performed using the Kaplan-Meier test with log rank. Values of p<0.05 were considered statistically significant.
Results
Patient Characteristics
A total of 87 patients were included in this study. The median age was 48 (range: 18-70) years at the time of diagnosis. The baseline clinical and demographic characteristics of the patients are listed in Table 1. For 66 of 87 patients (75.9%), the first mobilization trial was successful. Adequate (≥2x106/kg) CD34+ cells were collected in the first apheresis for 66 patients (9.5±8.1). For 21 of 87 (24.1%), the first mobilization trial was unsuccessful. Therefore, a second mobilization trial was conducted for these patients with plerixafor (5.5±3.3). The number of CD34+ cells was significantly higher in patients who were successful in the first mobilization (p=0.002). There were no differences in hematocrit at the time point of apheresis.
Between the two groups, there was no statistically significant gender (p=0.25) or age (p=0.07) difference. There was no significant difference between the ECOG PS of the patients (p=0.72). No significant difference was found between the groups in terms of lymphoma types (p=0.45). Number of chemotherapy cycles before stem cell mobilization was not statistically significantly different between patients who had mobilization failure and patients who had successful stem cell mobilization (p=0.78). The stages of both groups were similar at the time of diagnosis (p=0.69). There was no significant difference between bone marrow infiltration at diagnosis (p=0.24). There was no significant difference between the groups in terms of induction chemotherapy protocols (p=0.51). Platelet count before mobilization was higher in patients who had successful stem cell mobilization than in patients who had stem cell mobilization failure (p=0.041). After relapse, no significant difference was found between rescue chemotherapies given before mobilization (p=0.49). Disease status before ASCT was complete response (CR) in 27 (40.9%) patients, partial response (PR) in 28 (42.4%) patients, stable disease in 5 (7.6%) patients, and progressive disease in 6 (9.1%) patients in the successful mobilization group. Disease status before ASCT was CR in 8 (38.1%) patients, PR in 10 (47.6%) patients, stable disease in 1 (4.8%) patient, and progressive disease in 2 (9.5%) patients in the stem cell mobilization failure group for the first trial (p=0.95). The use of filgrastim or lenograstim as G-CSF did not affect mobilization success. There was no significant difference between the two groups in terms of filgrastim or lenograstim mobilization (p=0.20). However, when the patients who received only G-CSF or a chemotherapy-based mobilization protocol were evaluated, 19 (29.7%) of the patients who were mobilized with only G-CSF had mobilization failure, while only 2 (8.7%) patients who received a chemotherapy-based mobilization protocol had mobilization failure (p=0.04). This shows the superiority of chemotherapy-based mobilization.
Post-transplant Outcomes
All of the patients finally underwent ASCT. Remarkably, disease status after ASCT (on day +100) was CR in 38 (61.3%) patients, PR in 1 (1.6%) patients, stable disease in 20 (32.3%) patients, and progressive disease in 3 (4.8%) patients in the successful mobilization group. Disease status after ASCT (on day +100) was CR in 13 (65%) patients, PR in 5 (5%) patients, stable disease in 4 (20%) patients, and progressive disease in 2 (10%) patients in the stem cell mobilization failure group for the first trial, as shown in Table 2. The relapse rate was significantly higher in patients who had stem cell mobilization failure than in those with successful stem cell mobilization (47.6% vs. 21.2%, p=0.01). Moreover, the mortality rate was significantly higher among patients who had stem cell mobilization failure than those with successful stem cell mobilization (38.1% vs. 16.7%, p=0.01).
Overall Survival
The overall survival (OS) rate for patients who had successful stem cell mobilization was 151.6±9.3 months versus 71.4±7.8 months for patients with stem cell mobilization failure for the first trial; this was a statistically significant difference, as shown in Figure 1 (p=0.02). The 3-year OS rates for patients with successful stem cell mobilization and those with stem cell mobilization failure for the first trial were 85% and 79%, respectively. The 5-year OS rates for patients with successful stem cell mobilization and stem cell mobilization failure for the first trial were 81% and 63%, respectively. OS was better in patients with lymphoma for whom the first mobilization trial was successful.
The disease-free survival (DFS) rate for patients who had successful stem cell mobilization was 111.9±10.6 months versus 57.6±6.4 months for patients who had stem cell mobilization failure for the first trial; this was a statistically significant difference, as shown in Figure 2 (p=0.004). The 3-year DFS rates for patients with successful stem cell mobilization and those with stem cell mobilization failure for the first trial were 82% and 74%, respectively. The 5-year DFS rates for patients with successful stem cell mobilization and stem cell mobilization failure for the first trial were 68% and 44%, respectively.
Discussion
Stem cell mobilization is still difficult in a significant proportion of patients with lymphoma and the factors predicting poor mobilization are still not fully explained. An obvious reason for these difficulties might be the fact that previous studies have been heterogeneous concerning diagnosis, prior therapy, and mobilization regimen used [7]. The frequency of mobilization failure was 24.1% in the first mobilization in this study, but no factor was detected in analysis that would cause mobilization failure in these lymphoma patients. No statistically significant difference was found between age, sex, stage of diagnosis, ECOG PS, bone marrow infiltration at diagnosis, induction chemotherapy, chemotherapy cycles before stem cell mobilization, disease status before ASCT, receiving radiotherapy before mobilization, lymphoma types, or mobilization regimen in the two groups. On the other hand, OS and DFS were significantly longer in the group with successful mobilization in the first trial. It was observed that survival outcomes were worse in patients who needed plerixafor for mobilization. However, it was thought that the worse survival outcomes might have been due to the poor bone marrow reserve and disease status before ASCT in patients who needed plerixafor for mobilization.
For successful ASCT, one of the most important factors is to mobilize sufficient numbers of CD34+ cells. In this study, the cut-off value of 2x106 CD34+ cells/kg body weight was determined as the target for a successful mobilization procedure. It can be thought that the necessity of using plerixafor can be predicted according to the number of peripheral CD34 cells. CD34 cell count on apheresis day was reported to be the best predictor of mobilization failure [10]. Additionally, CD34 cell count was suggestive of preemptive plerixafor use and the authors suggested a low level of CD34+ in peripheral blood on day +13 as a possible criterion for initiating plerixafor administration [11]. In this study, the number of CD34+ cells of the apheresis product was observed to be significantly higher in patients who were successful in the first mobilization.
Recent studies reported that the incidence of mobilization failure in lymphoma was as high as 46% [12,13,14]. Variables already reported to be associated with mobilization failure include age, body weight, diagnosis, type of lymphoma and dose of chemotherapy, extent of cell recovery from chemotherapy, bone marrow involvement of lymphoma cells, prior radiation therapy, and interval from diagnosis to mobilization [12,13,14,15]. On the other hand, some hematological parameters such as cytopenia at any stage of mobilization, high mean corpuscular volume, long myelosuppression between salvage chemotherapies, and poor bone marrow microenvironment can predict mobilization failure. Özkurt et al. [16] reported that the CD34+ cell count of the first apheresis product was positively correlated with the white blood cell count, platelet count, peripheral CD34+ cell count, and grade of bone marrow reticulin fibrosis. In this study, chemotherapy-based mobilization was seen to be superior to G-CSF mobilization. Additionally, the platelet count before mobilization was higher in patients who had successful stem cell mobilization than in patients with stem cell mobilization failure. Apart from these two prognostic factors, none of the patient or disease characteristics that we analyzed were associated with mobilization failure. Prognostic factors such as patient characteristics (age, gender, diagnosis, bone marrow involvement, previous number of chemotherapy lines, previous radiotherapy) were also not found to be associated with mobilization failure in previous clinical studies [12,14].
It is not clear whether patients with treatment efficiency may be best mobilized by higher doses of chemotherapy and/or G-CSF. Previously, some studies demonstrated the superiority of chemotherapy plus growth factors over growth factors alone for mobilization [6,17,18]. On the other hand, Pusic et al. [17] found similar rates of mobilization failure with chemotherapy plus growth factors and only growth factor. Additionally, André et al. [19] found no significant difference in CD341 cell harvest yields among 131 patients randomized to receive 5 or 10 µg/kg/day of G-CSF following mobilization chemotherapy. In our study, it was observed that mobilization regime did not affect mobilization failure. However, when the patients who received only G-CSF and those who received a chemotherapy-based mobilization protocol were evaluated, chemotherapy-based mobilization was superior.
Conclusion
In this study, the success rate of the first mobilization trial was found to be higher in patients with high platelet counts before mobilization and in patients who received chemotherapy-based mobilization protocols. This study had a few limitations. First, it was retrospective. Second, all patients did not receive the same induction chemotherapy before mobilization. Third, the diagnoses of the patients were very heterogeneous. For the patients who had mobilization failure in the first trial, plerixafor was used in a later mobilization, and those patients then had an adequate amount of stem cells for ASCT. Parameters predicting mobilization failure would allow for a preemptive, more cost-effective use of such agents during the first mobilization attempt. However, the risk factors for mobilization failure are still not clear.
Table 1 Baseline clinical and demographic characteristics of patients.
Table 2 Post-transplantation outcomes.
Figure 1 Overall survival (OS) of patients who had successful stem cell mobilization and patients who had stem cell mobilization failure (p=0.02).
Figure 2 Disease-free survival (DFS) of patients who had successful stem cell mobilization and patients who had stem cell mobilization failure (p=0.004).
Ethics
Ethics Committee Approval: All ethical considerations were strictly followed in accordance with the 1964 Declaration of Helsinki. As standard care/action of the hospitals of the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, it has been recognized from the patient records that all of the studied patients had given informed consent at the time of hospitalization and before the administration of relevant diagnostic/therapeutic standards of care.
Informed Consent: Obtained.
Authorship Contributions
Surgical and Medical Practices: H.G.; Concept: H.D.; Design: H.D.; Data Collection or Processing: R.Ç.; Analysis or Interpretation: R.Ç.; Literature Search: Y.B.; Writing: R.Ç.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.
|
FILGRASTIM
|
DrugsGivenReaction
|
CC BY
|
33161684
| 19,859,879
|
2021-08-25
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Engraft failure'.
|
Prediction of Stem Cell Mobilization Failure in Patients with Hodgkin and Non-Hodgkin Lymphoma
Autologous stem cell transplantation (ASCT) is a significant and potentially curative treatment modality for patients with relapsed/refractory lymphoma. Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. The aim of this study was to evaluate the factors that might influence mobilization failure in patients with lymphoma.
Eighty-seven patients diagnosed with non-Hodgkin and Hodgkin lymphoma who underwent stem cell mobilization afterwards at the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, between the years of 2000 and 2018 were evaluated.
A total of 87 patients were included in this study. In 66 of 87 patients (75.9%), the first mobilization trial was successful. Adequate (≥2x106/kg) CD34+ cells were collected in the first apheresis for 66 patients (9.5±8.1). For 21 of 87 (24.1%), the first mobilization trial was unsuccessful. Therefore, a second mobilization trial was performed for these patients with plerixafor (5.5±3.3). The number of CD34+ cells was significantly higher in patients who were successful in the first mobilization (p=0.002).
The success rate of the first mobilization trial was found to be higher in patients with high platelet counts before mobilization and patients who received chemotherapy-based mobilization protocols. In the patients who had mobilization failure in the first trial, plerixafor was used in a later mobilization, and those patients had an adequate amount of stem cells for ASCT. Parameters predicting mobilization failure would allow for preemptive, more cost-effective use of such agents during the first mobilization attempt; however, risk factors for mobilization failure are still not clear.
Introduction
Autologous stem cell transplantation (ASCT) is a significant and potentially curative treatment modality for patients with relapsed/refractory lymphoma. However, 5%-40% of lymphoma patients fail to mobilize sufficient peripheral blood stem cells and thus cannot undergo ASCT, which is known to improve survival [1]. Hematopoietic stem cells generally circulate in very small numbers in the peripheral blood and have to be mobilized into the circulation prior to being collected by apheresis. Peripheral blood stem cell (PBSC) mobilization is accomplished by administration of granulocyte colony-stimulating factor (G-CSF) alone or in combination with chemotherapy [2]. Peripheral blood has been shown to be superior to bone marrow as a source of hematopoietic stem cells for ASCT [3]. Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. Currently, a minimum of 2x106 CD34+ cells/kg hematopoietic stem cells is considered appropriate in most centers to proceed to ASCT. This threshold is necessary for a rapid and sustained blood count recovery and for reduced hospitalization, blood product usage, and infections [4]. However, the optimal hematopoietic stem cell dose is about 5x106/kg [5]. Bone marrow infiltration, advanced age, number of prior cytotoxic therapies, and myelodysplastic changes are the best defined factors associated with increased risk of mobilization failure [6,7].
We have collected and analyzed data from a series of non-Hodgkin and Hodgkin lymphoma patients who received ASCT in order to determine the frequency of harvest failure and to identify factors influencing PBSC mobilization outcomes. The aim of this study was to evaluate the factors that might influence mobilization failure in patients with lymphoma.
Materials and Methods
Study Design and Data Collection
This study was performed in a retrospective manner. Demographic data of the patients, treatment regimens, and stem cell mobilization data updates were obtained from the hospital database. As a result of the application standards of the hospitals of the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, it has been recognized from the patient records that all of the studied patients had given informed consent at the time of hospitalization and before the administration of chemotherapy and other relevant diagnostic/therapeutic standards of care. Patients gave informed consent for procedures in accordance with the Declaration of Helsinki.
Patients and Disease Characteristics
Eighty-seven patients diagnosed with non-Hodgkin and Hodgkin lymphoma who underwent stem cell mobilization afterwards at the Hacettepe University Medical School Bone Marrow Transplantation Center between the years of 2000 and 2018 were evaluated. The key inclusion criteria were patients ≥18 years of age diagnosed with non-Hodgkin or Hodgkin lymphoma who required systemic chemotherapy and underwent ASCT with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of <2 [8] with an indication for ASCT.
Median age, gender, ECOG PS, lymphoma subtypes, stage at diagnosis, bone marrow infiltration at diagnosis, induction chemotherapy, salvage chemotherapy, chemotherapy cycles received before mobilization, radiotherapy before mobilization, platelet count before mobilization, mobilization protocols, and disease status before ASCT were compared for patients who had successful stem cell mobilization and those with stem cell mobilization failure. Additionally, disease status after ASCT, relapse rate, and mortality results were evaluated between these groups. The target CD34+ cell dose for collection was >2x106/kg for each planned autograft. All patients received G-CSF at a dose of 10 µg/kg from day +5 until the peripheral stem cell harvest. CD34+ cells were measured in peripheral blood and apheresis products by flow cytometry. We had a CD34+ cut-off level of 20 µL for starting apheresis. We harvested the cells on the 5th and/or 6th day after beginning G-CSF administration. Peripheral blood CD34% and CD34/µL values at the first day on which leukocytes reached the value of 1x109/L and were maintained above that threshold over at least 2 days were correlated with overall CD34+ collection. A harvest of less than 2x106 CD34+/kg was considered as mobilization failure. Twenty-one patients received plerixafor as an additional mobilizing agent for the second apheresis. Subcutaneous plerixafor (0.24 mg/kg) was administered to the patients on the evenings of the 4th and 5th days of the mobilization protocol.
Statistical Analysis
Statistical analyses were performed using SPSS 25 (IBM Corp., Armonk, NY, USA). Variables were investigated using visual (histograms, probability plots) and analytical (Kolmogorov-Smirnov/Shapiro-Wilk test) methods to determine whether they were normally distributed or not. Statistical comparisons were made using chi-square tests for categorical data. Student’s t-test for two independent samples was used for comparison of continuous numerical data. Variables found to be significant (p<0.05) in univariate analysis were tested in multivariate analysis, which was performed using a stepwise logistic regression model. Survival analyses were performed using the Kaplan-Meier test with log rank. Values of p<0.05 were considered statistically significant.
Results
Patient Characteristics
A total of 87 patients were included in this study. The median age was 48 (range: 18-70) years at the time of diagnosis. The baseline clinical and demographic characteristics of the patients are listed in Table 1. For 66 of 87 patients (75.9%), the first mobilization trial was successful. Adequate (≥2x106/kg) CD34+ cells were collected in the first apheresis for 66 patients (9.5±8.1). For 21 of 87 (24.1%), the first mobilization trial was unsuccessful. Therefore, a second mobilization trial was conducted for these patients with plerixafor (5.5±3.3). The number of CD34+ cells was significantly higher in patients who were successful in the first mobilization (p=0.002). There were no differences in hematocrit at the time point of apheresis.
Between the two groups, there was no statistically significant gender (p=0.25) or age (p=0.07) difference. There was no significant difference between the ECOG PS of the patients (p=0.72). No significant difference was found between the groups in terms of lymphoma types (p=0.45). Number of chemotherapy cycles before stem cell mobilization was not statistically significantly different between patients who had mobilization failure and patients who had successful stem cell mobilization (p=0.78). The stages of both groups were similar at the time of diagnosis (p=0.69). There was no significant difference between bone marrow infiltration at diagnosis (p=0.24). There was no significant difference between the groups in terms of induction chemotherapy protocols (p=0.51). Platelet count before mobilization was higher in patients who had successful stem cell mobilization than in patients who had stem cell mobilization failure (p=0.041). After relapse, no significant difference was found between rescue chemotherapies given before mobilization (p=0.49). Disease status before ASCT was complete response (CR) in 27 (40.9%) patients, partial response (PR) in 28 (42.4%) patients, stable disease in 5 (7.6%) patients, and progressive disease in 6 (9.1%) patients in the successful mobilization group. Disease status before ASCT was CR in 8 (38.1%) patients, PR in 10 (47.6%) patients, stable disease in 1 (4.8%) patient, and progressive disease in 2 (9.5%) patients in the stem cell mobilization failure group for the first trial (p=0.95). The use of filgrastim or lenograstim as G-CSF did not affect mobilization success. There was no significant difference between the two groups in terms of filgrastim or lenograstim mobilization (p=0.20). However, when the patients who received only G-CSF or a chemotherapy-based mobilization protocol were evaluated, 19 (29.7%) of the patients who were mobilized with only G-CSF had mobilization failure, while only 2 (8.7%) patients who received a chemotherapy-based mobilization protocol had mobilization failure (p=0.04). This shows the superiority of chemotherapy-based mobilization.
Post-transplant Outcomes
All of the patients finally underwent ASCT. Remarkably, disease status after ASCT (on day +100) was CR in 38 (61.3%) patients, PR in 1 (1.6%) patients, stable disease in 20 (32.3%) patients, and progressive disease in 3 (4.8%) patients in the successful mobilization group. Disease status after ASCT (on day +100) was CR in 13 (65%) patients, PR in 5 (5%) patients, stable disease in 4 (20%) patients, and progressive disease in 2 (10%) patients in the stem cell mobilization failure group for the first trial, as shown in Table 2. The relapse rate was significantly higher in patients who had stem cell mobilization failure than in those with successful stem cell mobilization (47.6% vs. 21.2%, p=0.01). Moreover, the mortality rate was significantly higher among patients who had stem cell mobilization failure than those with successful stem cell mobilization (38.1% vs. 16.7%, p=0.01).
Overall Survival
The overall survival (OS) rate for patients who had successful stem cell mobilization was 151.6±9.3 months versus 71.4±7.8 months for patients with stem cell mobilization failure for the first trial; this was a statistically significant difference, as shown in Figure 1 (p=0.02). The 3-year OS rates for patients with successful stem cell mobilization and those with stem cell mobilization failure for the first trial were 85% and 79%, respectively. The 5-year OS rates for patients with successful stem cell mobilization and stem cell mobilization failure for the first trial were 81% and 63%, respectively. OS was better in patients with lymphoma for whom the first mobilization trial was successful.
The disease-free survival (DFS) rate for patients who had successful stem cell mobilization was 111.9±10.6 months versus 57.6±6.4 months for patients who had stem cell mobilization failure for the first trial; this was a statistically significant difference, as shown in Figure 2 (p=0.004). The 3-year DFS rates for patients with successful stem cell mobilization and those with stem cell mobilization failure for the first trial were 82% and 74%, respectively. The 5-year DFS rates for patients with successful stem cell mobilization and stem cell mobilization failure for the first trial were 68% and 44%, respectively.
Discussion
Stem cell mobilization is still difficult in a significant proportion of patients with lymphoma and the factors predicting poor mobilization are still not fully explained. An obvious reason for these difficulties might be the fact that previous studies have been heterogeneous concerning diagnosis, prior therapy, and mobilization regimen used [7]. The frequency of mobilization failure was 24.1% in the first mobilization in this study, but no factor was detected in analysis that would cause mobilization failure in these lymphoma patients. No statistically significant difference was found between age, sex, stage of diagnosis, ECOG PS, bone marrow infiltration at diagnosis, induction chemotherapy, chemotherapy cycles before stem cell mobilization, disease status before ASCT, receiving radiotherapy before mobilization, lymphoma types, or mobilization regimen in the two groups. On the other hand, OS and DFS were significantly longer in the group with successful mobilization in the first trial. It was observed that survival outcomes were worse in patients who needed plerixafor for mobilization. However, it was thought that the worse survival outcomes might have been due to the poor bone marrow reserve and disease status before ASCT in patients who needed plerixafor for mobilization.
For successful ASCT, one of the most important factors is to mobilize sufficient numbers of CD34+ cells. In this study, the cut-off value of 2x106 CD34+ cells/kg body weight was determined as the target for a successful mobilization procedure. It can be thought that the necessity of using plerixafor can be predicted according to the number of peripheral CD34 cells. CD34 cell count on apheresis day was reported to be the best predictor of mobilization failure [10]. Additionally, CD34 cell count was suggestive of preemptive plerixafor use and the authors suggested a low level of CD34+ in peripheral blood on day +13 as a possible criterion for initiating plerixafor administration [11]. In this study, the number of CD34+ cells of the apheresis product was observed to be significantly higher in patients who were successful in the first mobilization.
Recent studies reported that the incidence of mobilization failure in lymphoma was as high as 46% [12,13,14]. Variables already reported to be associated with mobilization failure include age, body weight, diagnosis, type of lymphoma and dose of chemotherapy, extent of cell recovery from chemotherapy, bone marrow involvement of lymphoma cells, prior radiation therapy, and interval from diagnosis to mobilization [12,13,14,15]. On the other hand, some hematological parameters such as cytopenia at any stage of mobilization, high mean corpuscular volume, long myelosuppression between salvage chemotherapies, and poor bone marrow microenvironment can predict mobilization failure. Özkurt et al. [16] reported that the CD34+ cell count of the first apheresis product was positively correlated with the white blood cell count, platelet count, peripheral CD34+ cell count, and grade of bone marrow reticulin fibrosis. In this study, chemotherapy-based mobilization was seen to be superior to G-CSF mobilization. Additionally, the platelet count before mobilization was higher in patients who had successful stem cell mobilization than in patients with stem cell mobilization failure. Apart from these two prognostic factors, none of the patient or disease characteristics that we analyzed were associated with mobilization failure. Prognostic factors such as patient characteristics (age, gender, diagnosis, bone marrow involvement, previous number of chemotherapy lines, previous radiotherapy) were also not found to be associated with mobilization failure in previous clinical studies [12,14].
It is not clear whether patients with treatment efficiency may be best mobilized by higher doses of chemotherapy and/or G-CSF. Previously, some studies demonstrated the superiority of chemotherapy plus growth factors over growth factors alone for mobilization [6,17,18]. On the other hand, Pusic et al. [17] found similar rates of mobilization failure with chemotherapy plus growth factors and only growth factor. Additionally, André et al. [19] found no significant difference in CD341 cell harvest yields among 131 patients randomized to receive 5 or 10 µg/kg/day of G-CSF following mobilization chemotherapy. In our study, it was observed that mobilization regime did not affect mobilization failure. However, when the patients who received only G-CSF and those who received a chemotherapy-based mobilization protocol were evaluated, chemotherapy-based mobilization was superior.
Conclusion
In this study, the success rate of the first mobilization trial was found to be higher in patients with high platelet counts before mobilization and in patients who received chemotherapy-based mobilization protocols. This study had a few limitations. First, it was retrospective. Second, all patients did not receive the same induction chemotherapy before mobilization. Third, the diagnoses of the patients were very heterogeneous. For the patients who had mobilization failure in the first trial, plerixafor was used in a later mobilization, and those patients then had an adequate amount of stem cells for ASCT. Parameters predicting mobilization failure would allow for a preemptive, more cost-effective use of such agents during the first mobilization attempt. However, the risk factors for mobilization failure are still not clear.
Table 1 Baseline clinical and demographic characteristics of patients.
Table 2 Post-transplantation outcomes.
Figure 1 Overall survival (OS) of patients who had successful stem cell mobilization and patients who had stem cell mobilization failure (p=0.02).
Figure 2 Disease-free survival (DFS) of patients who had successful stem cell mobilization and patients who had stem cell mobilization failure (p=0.004).
Ethics
Ethics Committee Approval: All ethical considerations were strictly followed in accordance with the 1964 Declaration of Helsinki. As standard care/action of the hospitals of the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, it has been recognized from the patient records that all of the studied patients had given informed consent at the time of hospitalization and before the administration of relevant diagnostic/therapeutic standards of care.
Informed Consent: Obtained.
Authorship Contributions
Surgical and Medical Practices: H.G.; Concept: H.D.; Design: H.D.; Data Collection or Processing: R.Ç.; Analysis or Interpretation: R.Ç.; Literature Search: Y.B.; Writing: R.Ç.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.
|
FILGRASTIM
|
DrugsGivenReaction
|
CC BY
|
33161684
| 19,859,879
|
2021-08-25
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lymphoma'.
|
Prediction of Stem Cell Mobilization Failure in Patients with Hodgkin and Non-Hodgkin Lymphoma
Autologous stem cell transplantation (ASCT) is a significant and potentially curative treatment modality for patients with relapsed/refractory lymphoma. Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. The aim of this study was to evaluate the factors that might influence mobilization failure in patients with lymphoma.
Eighty-seven patients diagnosed with non-Hodgkin and Hodgkin lymphoma who underwent stem cell mobilization afterwards at the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, between the years of 2000 and 2018 were evaluated.
A total of 87 patients were included in this study. In 66 of 87 patients (75.9%), the first mobilization trial was successful. Adequate (≥2x106/kg) CD34+ cells were collected in the first apheresis for 66 patients (9.5±8.1). For 21 of 87 (24.1%), the first mobilization trial was unsuccessful. Therefore, a second mobilization trial was performed for these patients with plerixafor (5.5±3.3). The number of CD34+ cells was significantly higher in patients who were successful in the first mobilization (p=0.002).
The success rate of the first mobilization trial was found to be higher in patients with high platelet counts before mobilization and patients who received chemotherapy-based mobilization protocols. In the patients who had mobilization failure in the first trial, plerixafor was used in a later mobilization, and those patients had an adequate amount of stem cells for ASCT. Parameters predicting mobilization failure would allow for preemptive, more cost-effective use of such agents during the first mobilization attempt; however, risk factors for mobilization failure are still not clear.
Introduction
Autologous stem cell transplantation (ASCT) is a significant and potentially curative treatment modality for patients with relapsed/refractory lymphoma. However, 5%-40% of lymphoma patients fail to mobilize sufficient peripheral blood stem cells and thus cannot undergo ASCT, which is known to improve survival [1]. Hematopoietic stem cells generally circulate in very small numbers in the peripheral blood and have to be mobilized into the circulation prior to being collected by apheresis. Peripheral blood stem cell (PBSC) mobilization is accomplished by administration of granulocyte colony-stimulating factor (G-CSF) alone or in combination with chemotherapy [2]. Peripheral blood has been shown to be superior to bone marrow as a source of hematopoietic stem cells for ASCT [3]. Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. Currently, a minimum of 2x106 CD34+ cells/kg hematopoietic stem cells is considered appropriate in most centers to proceed to ASCT. This threshold is necessary for a rapid and sustained blood count recovery and for reduced hospitalization, blood product usage, and infections [4]. However, the optimal hematopoietic stem cell dose is about 5x106/kg [5]. Bone marrow infiltration, advanced age, number of prior cytotoxic therapies, and myelodysplastic changes are the best defined factors associated with increased risk of mobilization failure [6,7].
We have collected and analyzed data from a series of non-Hodgkin and Hodgkin lymphoma patients who received ASCT in order to determine the frequency of harvest failure and to identify factors influencing PBSC mobilization outcomes. The aim of this study was to evaluate the factors that might influence mobilization failure in patients with lymphoma.
Materials and Methods
Study Design and Data Collection
This study was performed in a retrospective manner. Demographic data of the patients, treatment regimens, and stem cell mobilization data updates were obtained from the hospital database. As a result of the application standards of the hospitals of the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, it has been recognized from the patient records that all of the studied patients had given informed consent at the time of hospitalization and before the administration of chemotherapy and other relevant diagnostic/therapeutic standards of care. Patients gave informed consent for procedures in accordance with the Declaration of Helsinki.
Patients and Disease Characteristics
Eighty-seven patients diagnosed with non-Hodgkin and Hodgkin lymphoma who underwent stem cell mobilization afterwards at the Hacettepe University Medical School Bone Marrow Transplantation Center between the years of 2000 and 2018 were evaluated. The key inclusion criteria were patients ≥18 years of age diagnosed with non-Hodgkin or Hodgkin lymphoma who required systemic chemotherapy and underwent ASCT with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of <2 [8] with an indication for ASCT.
Median age, gender, ECOG PS, lymphoma subtypes, stage at diagnosis, bone marrow infiltration at diagnosis, induction chemotherapy, salvage chemotherapy, chemotherapy cycles received before mobilization, radiotherapy before mobilization, platelet count before mobilization, mobilization protocols, and disease status before ASCT were compared for patients who had successful stem cell mobilization and those with stem cell mobilization failure. Additionally, disease status after ASCT, relapse rate, and mortality results were evaluated between these groups. The target CD34+ cell dose for collection was >2x106/kg for each planned autograft. All patients received G-CSF at a dose of 10 µg/kg from day +5 until the peripheral stem cell harvest. CD34+ cells were measured in peripheral blood and apheresis products by flow cytometry. We had a CD34+ cut-off level of 20 µL for starting apheresis. We harvested the cells on the 5th and/or 6th day after beginning G-CSF administration. Peripheral blood CD34% and CD34/µL values at the first day on which leukocytes reached the value of 1x109/L and were maintained above that threshold over at least 2 days were correlated with overall CD34+ collection. A harvest of less than 2x106 CD34+/kg was considered as mobilization failure. Twenty-one patients received plerixafor as an additional mobilizing agent for the second apheresis. Subcutaneous plerixafor (0.24 mg/kg) was administered to the patients on the evenings of the 4th and 5th days of the mobilization protocol.
Statistical Analysis
Statistical analyses were performed using SPSS 25 (IBM Corp., Armonk, NY, USA). Variables were investigated using visual (histograms, probability plots) and analytical (Kolmogorov-Smirnov/Shapiro-Wilk test) methods to determine whether they were normally distributed or not. Statistical comparisons were made using chi-square tests for categorical data. Student’s t-test for two independent samples was used for comparison of continuous numerical data. Variables found to be significant (p<0.05) in univariate analysis were tested in multivariate analysis, which was performed using a stepwise logistic regression model. Survival analyses were performed using the Kaplan-Meier test with log rank. Values of p<0.05 were considered statistically significant.
Results
Patient Characteristics
A total of 87 patients were included in this study. The median age was 48 (range: 18-70) years at the time of diagnosis. The baseline clinical and demographic characteristics of the patients are listed in Table 1. For 66 of 87 patients (75.9%), the first mobilization trial was successful. Adequate (≥2x106/kg) CD34+ cells were collected in the first apheresis for 66 patients (9.5±8.1). For 21 of 87 (24.1%), the first mobilization trial was unsuccessful. Therefore, a second mobilization trial was conducted for these patients with plerixafor (5.5±3.3). The number of CD34+ cells was significantly higher in patients who were successful in the first mobilization (p=0.002). There were no differences in hematocrit at the time point of apheresis.
Between the two groups, there was no statistically significant gender (p=0.25) or age (p=0.07) difference. There was no significant difference between the ECOG PS of the patients (p=0.72). No significant difference was found between the groups in terms of lymphoma types (p=0.45). Number of chemotherapy cycles before stem cell mobilization was not statistically significantly different between patients who had mobilization failure and patients who had successful stem cell mobilization (p=0.78). The stages of both groups were similar at the time of diagnosis (p=0.69). There was no significant difference between bone marrow infiltration at diagnosis (p=0.24). There was no significant difference between the groups in terms of induction chemotherapy protocols (p=0.51). Platelet count before mobilization was higher in patients who had successful stem cell mobilization than in patients who had stem cell mobilization failure (p=0.041). After relapse, no significant difference was found between rescue chemotherapies given before mobilization (p=0.49). Disease status before ASCT was complete response (CR) in 27 (40.9%) patients, partial response (PR) in 28 (42.4%) patients, stable disease in 5 (7.6%) patients, and progressive disease in 6 (9.1%) patients in the successful mobilization group. Disease status before ASCT was CR in 8 (38.1%) patients, PR in 10 (47.6%) patients, stable disease in 1 (4.8%) patient, and progressive disease in 2 (9.5%) patients in the stem cell mobilization failure group for the first trial (p=0.95). The use of filgrastim or lenograstim as G-CSF did not affect mobilization success. There was no significant difference between the two groups in terms of filgrastim or lenograstim mobilization (p=0.20). However, when the patients who received only G-CSF or a chemotherapy-based mobilization protocol were evaluated, 19 (29.7%) of the patients who were mobilized with only G-CSF had mobilization failure, while only 2 (8.7%) patients who received a chemotherapy-based mobilization protocol had mobilization failure (p=0.04). This shows the superiority of chemotherapy-based mobilization.
Post-transplant Outcomes
All of the patients finally underwent ASCT. Remarkably, disease status after ASCT (on day +100) was CR in 38 (61.3%) patients, PR in 1 (1.6%) patients, stable disease in 20 (32.3%) patients, and progressive disease in 3 (4.8%) patients in the successful mobilization group. Disease status after ASCT (on day +100) was CR in 13 (65%) patients, PR in 5 (5%) patients, stable disease in 4 (20%) patients, and progressive disease in 2 (10%) patients in the stem cell mobilization failure group for the first trial, as shown in Table 2. The relapse rate was significantly higher in patients who had stem cell mobilization failure than in those with successful stem cell mobilization (47.6% vs. 21.2%, p=0.01). Moreover, the mortality rate was significantly higher among patients who had stem cell mobilization failure than those with successful stem cell mobilization (38.1% vs. 16.7%, p=0.01).
Overall Survival
The overall survival (OS) rate for patients who had successful stem cell mobilization was 151.6±9.3 months versus 71.4±7.8 months for patients with stem cell mobilization failure for the first trial; this was a statistically significant difference, as shown in Figure 1 (p=0.02). The 3-year OS rates for patients with successful stem cell mobilization and those with stem cell mobilization failure for the first trial were 85% and 79%, respectively. The 5-year OS rates for patients with successful stem cell mobilization and stem cell mobilization failure for the first trial were 81% and 63%, respectively. OS was better in patients with lymphoma for whom the first mobilization trial was successful.
The disease-free survival (DFS) rate for patients who had successful stem cell mobilization was 111.9±10.6 months versus 57.6±6.4 months for patients who had stem cell mobilization failure for the first trial; this was a statistically significant difference, as shown in Figure 2 (p=0.004). The 3-year DFS rates for patients with successful stem cell mobilization and those with stem cell mobilization failure for the first trial were 82% and 74%, respectively. The 5-year DFS rates for patients with successful stem cell mobilization and stem cell mobilization failure for the first trial were 68% and 44%, respectively.
Discussion
Stem cell mobilization is still difficult in a significant proportion of patients with lymphoma and the factors predicting poor mobilization are still not fully explained. An obvious reason for these difficulties might be the fact that previous studies have been heterogeneous concerning diagnosis, prior therapy, and mobilization regimen used [7]. The frequency of mobilization failure was 24.1% in the first mobilization in this study, but no factor was detected in analysis that would cause mobilization failure in these lymphoma patients. No statistically significant difference was found between age, sex, stage of diagnosis, ECOG PS, bone marrow infiltration at diagnosis, induction chemotherapy, chemotherapy cycles before stem cell mobilization, disease status before ASCT, receiving radiotherapy before mobilization, lymphoma types, or mobilization regimen in the two groups. On the other hand, OS and DFS were significantly longer in the group with successful mobilization in the first trial. It was observed that survival outcomes were worse in patients who needed plerixafor for mobilization. However, it was thought that the worse survival outcomes might have been due to the poor bone marrow reserve and disease status before ASCT in patients who needed plerixafor for mobilization.
For successful ASCT, one of the most important factors is to mobilize sufficient numbers of CD34+ cells. In this study, the cut-off value of 2x106 CD34+ cells/kg body weight was determined as the target for a successful mobilization procedure. It can be thought that the necessity of using plerixafor can be predicted according to the number of peripheral CD34 cells. CD34 cell count on apheresis day was reported to be the best predictor of mobilization failure [10]. Additionally, CD34 cell count was suggestive of preemptive plerixafor use and the authors suggested a low level of CD34+ in peripheral blood on day +13 as a possible criterion for initiating plerixafor administration [11]. In this study, the number of CD34+ cells of the apheresis product was observed to be significantly higher in patients who were successful in the first mobilization.
Recent studies reported that the incidence of mobilization failure in lymphoma was as high as 46% [12,13,14]. Variables already reported to be associated with mobilization failure include age, body weight, diagnosis, type of lymphoma and dose of chemotherapy, extent of cell recovery from chemotherapy, bone marrow involvement of lymphoma cells, prior radiation therapy, and interval from diagnosis to mobilization [12,13,14,15]. On the other hand, some hematological parameters such as cytopenia at any stage of mobilization, high mean corpuscular volume, long myelosuppression between salvage chemotherapies, and poor bone marrow microenvironment can predict mobilization failure. Özkurt et al. [16] reported that the CD34+ cell count of the first apheresis product was positively correlated with the white blood cell count, platelet count, peripheral CD34+ cell count, and grade of bone marrow reticulin fibrosis. In this study, chemotherapy-based mobilization was seen to be superior to G-CSF mobilization. Additionally, the platelet count before mobilization was higher in patients who had successful stem cell mobilization than in patients with stem cell mobilization failure. Apart from these two prognostic factors, none of the patient or disease characteristics that we analyzed were associated with mobilization failure. Prognostic factors such as patient characteristics (age, gender, diagnosis, bone marrow involvement, previous number of chemotherapy lines, previous radiotherapy) were also not found to be associated with mobilization failure in previous clinical studies [12,14].
It is not clear whether patients with treatment efficiency may be best mobilized by higher doses of chemotherapy and/or G-CSF. Previously, some studies demonstrated the superiority of chemotherapy plus growth factors over growth factors alone for mobilization [6,17,18]. On the other hand, Pusic et al. [17] found similar rates of mobilization failure with chemotherapy plus growth factors and only growth factor. Additionally, André et al. [19] found no significant difference in CD341 cell harvest yields among 131 patients randomized to receive 5 or 10 µg/kg/day of G-CSF following mobilization chemotherapy. In our study, it was observed that mobilization regime did not affect mobilization failure. However, when the patients who received only G-CSF and those who received a chemotherapy-based mobilization protocol were evaluated, chemotherapy-based mobilization was superior.
Conclusion
In this study, the success rate of the first mobilization trial was found to be higher in patients with high platelet counts before mobilization and in patients who received chemotherapy-based mobilization protocols. This study had a few limitations. First, it was retrospective. Second, all patients did not receive the same induction chemotherapy before mobilization. Third, the diagnoses of the patients were very heterogeneous. For the patients who had mobilization failure in the first trial, plerixafor was used in a later mobilization, and those patients then had an adequate amount of stem cells for ASCT. Parameters predicting mobilization failure would allow for a preemptive, more cost-effective use of such agents during the first mobilization attempt. However, the risk factors for mobilization failure are still not clear.
Table 1 Baseline clinical and demographic characteristics of patients.
Table 2 Post-transplantation outcomes.
Figure 1 Overall survival (OS) of patients who had successful stem cell mobilization and patients who had stem cell mobilization failure (p=0.02).
Figure 2 Disease-free survival (DFS) of patients who had successful stem cell mobilization and patients who had stem cell mobilization failure (p=0.004).
Ethics
Ethics Committee Approval: All ethical considerations were strictly followed in accordance with the 1964 Declaration of Helsinki. As standard care/action of the hospitals of the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, it has been recognized from the patient records that all of the studied patients had given informed consent at the time of hospitalization and before the administration of relevant diagnostic/therapeutic standards of care.
Informed Consent: Obtained.
Authorship Contributions
Surgical and Medical Practices: H.G.; Concept: H.D.; Design: H.D.; Data Collection or Processing: R.Ç.; Analysis or Interpretation: R.Ç.; Literature Search: Y.B.; Writing: R.Ç.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.
|
FILGRASTIM
|
DrugsGivenReaction
|
CC BY
|
33161684
| 19,859,879
|
2021-08-25
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy partial responder'.
|
Prediction of Stem Cell Mobilization Failure in Patients with Hodgkin and Non-Hodgkin Lymphoma
Autologous stem cell transplantation (ASCT) is a significant and potentially curative treatment modality for patients with relapsed/refractory lymphoma. Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. The aim of this study was to evaluate the factors that might influence mobilization failure in patients with lymphoma.
Eighty-seven patients diagnosed with non-Hodgkin and Hodgkin lymphoma who underwent stem cell mobilization afterwards at the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, between the years of 2000 and 2018 were evaluated.
A total of 87 patients were included in this study. In 66 of 87 patients (75.9%), the first mobilization trial was successful. Adequate (≥2x106/kg) CD34+ cells were collected in the first apheresis for 66 patients (9.5±8.1). For 21 of 87 (24.1%), the first mobilization trial was unsuccessful. Therefore, a second mobilization trial was performed for these patients with plerixafor (5.5±3.3). The number of CD34+ cells was significantly higher in patients who were successful in the first mobilization (p=0.002).
The success rate of the first mobilization trial was found to be higher in patients with high platelet counts before mobilization and patients who received chemotherapy-based mobilization protocols. In the patients who had mobilization failure in the first trial, plerixafor was used in a later mobilization, and those patients had an adequate amount of stem cells for ASCT. Parameters predicting mobilization failure would allow for preemptive, more cost-effective use of such agents during the first mobilization attempt; however, risk factors for mobilization failure are still not clear.
Introduction
Autologous stem cell transplantation (ASCT) is a significant and potentially curative treatment modality for patients with relapsed/refractory lymphoma. However, 5%-40% of lymphoma patients fail to mobilize sufficient peripheral blood stem cells and thus cannot undergo ASCT, which is known to improve survival [1]. Hematopoietic stem cells generally circulate in very small numbers in the peripheral blood and have to be mobilized into the circulation prior to being collected by apheresis. Peripheral blood stem cell (PBSC) mobilization is accomplished by administration of granulocyte colony-stimulating factor (G-CSF) alone or in combination with chemotherapy [2]. Peripheral blood has been shown to be superior to bone marrow as a source of hematopoietic stem cells for ASCT [3]. Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. Currently, a minimum of 2x106 CD34+ cells/kg hematopoietic stem cells is considered appropriate in most centers to proceed to ASCT. This threshold is necessary for a rapid and sustained blood count recovery and for reduced hospitalization, blood product usage, and infections [4]. However, the optimal hematopoietic stem cell dose is about 5x106/kg [5]. Bone marrow infiltration, advanced age, number of prior cytotoxic therapies, and myelodysplastic changes are the best defined factors associated with increased risk of mobilization failure [6,7].
We have collected and analyzed data from a series of non-Hodgkin and Hodgkin lymphoma patients who received ASCT in order to determine the frequency of harvest failure and to identify factors influencing PBSC mobilization outcomes. The aim of this study was to evaluate the factors that might influence mobilization failure in patients with lymphoma.
Materials and Methods
Study Design and Data Collection
This study was performed in a retrospective manner. Demographic data of the patients, treatment regimens, and stem cell mobilization data updates were obtained from the hospital database. As a result of the application standards of the hospitals of the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, it has been recognized from the patient records that all of the studied patients had given informed consent at the time of hospitalization and before the administration of chemotherapy and other relevant diagnostic/therapeutic standards of care. Patients gave informed consent for procedures in accordance with the Declaration of Helsinki.
Patients and Disease Characteristics
Eighty-seven patients diagnosed with non-Hodgkin and Hodgkin lymphoma who underwent stem cell mobilization afterwards at the Hacettepe University Medical School Bone Marrow Transplantation Center between the years of 2000 and 2018 were evaluated. The key inclusion criteria were patients ≥18 years of age diagnosed with non-Hodgkin or Hodgkin lymphoma who required systemic chemotherapy and underwent ASCT with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of <2 [8] with an indication for ASCT.
Median age, gender, ECOG PS, lymphoma subtypes, stage at diagnosis, bone marrow infiltration at diagnosis, induction chemotherapy, salvage chemotherapy, chemotherapy cycles received before mobilization, radiotherapy before mobilization, platelet count before mobilization, mobilization protocols, and disease status before ASCT were compared for patients who had successful stem cell mobilization and those with stem cell mobilization failure. Additionally, disease status after ASCT, relapse rate, and mortality results were evaluated between these groups. The target CD34+ cell dose for collection was >2x106/kg for each planned autograft. All patients received G-CSF at a dose of 10 µg/kg from day +5 until the peripheral stem cell harvest. CD34+ cells were measured in peripheral blood and apheresis products by flow cytometry. We had a CD34+ cut-off level of 20 µL for starting apheresis. We harvested the cells on the 5th and/or 6th day after beginning G-CSF administration. Peripheral blood CD34% and CD34/µL values at the first day on which leukocytes reached the value of 1x109/L and were maintained above that threshold over at least 2 days were correlated with overall CD34+ collection. A harvest of less than 2x106 CD34+/kg was considered as mobilization failure. Twenty-one patients received plerixafor as an additional mobilizing agent for the second apheresis. Subcutaneous plerixafor (0.24 mg/kg) was administered to the patients on the evenings of the 4th and 5th days of the mobilization protocol.
Statistical Analysis
Statistical analyses were performed using SPSS 25 (IBM Corp., Armonk, NY, USA). Variables were investigated using visual (histograms, probability plots) and analytical (Kolmogorov-Smirnov/Shapiro-Wilk test) methods to determine whether they were normally distributed or not. Statistical comparisons were made using chi-square tests for categorical data. Student’s t-test for two independent samples was used for comparison of continuous numerical data. Variables found to be significant (p<0.05) in univariate analysis were tested in multivariate analysis, which was performed using a stepwise logistic regression model. Survival analyses were performed using the Kaplan-Meier test with log rank. Values of p<0.05 were considered statistically significant.
Results
Patient Characteristics
A total of 87 patients were included in this study. The median age was 48 (range: 18-70) years at the time of diagnosis. The baseline clinical and demographic characteristics of the patients are listed in Table 1. For 66 of 87 patients (75.9%), the first mobilization trial was successful. Adequate (≥2x106/kg) CD34+ cells were collected in the first apheresis for 66 patients (9.5±8.1). For 21 of 87 (24.1%), the first mobilization trial was unsuccessful. Therefore, a second mobilization trial was conducted for these patients with plerixafor (5.5±3.3). The number of CD34+ cells was significantly higher in patients who were successful in the first mobilization (p=0.002). There were no differences in hematocrit at the time point of apheresis.
Between the two groups, there was no statistically significant gender (p=0.25) or age (p=0.07) difference. There was no significant difference between the ECOG PS of the patients (p=0.72). No significant difference was found between the groups in terms of lymphoma types (p=0.45). Number of chemotherapy cycles before stem cell mobilization was not statistically significantly different between patients who had mobilization failure and patients who had successful stem cell mobilization (p=0.78). The stages of both groups were similar at the time of diagnosis (p=0.69). There was no significant difference between bone marrow infiltration at diagnosis (p=0.24). There was no significant difference between the groups in terms of induction chemotherapy protocols (p=0.51). Platelet count before mobilization was higher in patients who had successful stem cell mobilization than in patients who had stem cell mobilization failure (p=0.041). After relapse, no significant difference was found between rescue chemotherapies given before mobilization (p=0.49). Disease status before ASCT was complete response (CR) in 27 (40.9%) patients, partial response (PR) in 28 (42.4%) patients, stable disease in 5 (7.6%) patients, and progressive disease in 6 (9.1%) patients in the successful mobilization group. Disease status before ASCT was CR in 8 (38.1%) patients, PR in 10 (47.6%) patients, stable disease in 1 (4.8%) patient, and progressive disease in 2 (9.5%) patients in the stem cell mobilization failure group for the first trial (p=0.95). The use of filgrastim or lenograstim as G-CSF did not affect mobilization success. There was no significant difference between the two groups in terms of filgrastim or lenograstim mobilization (p=0.20). However, when the patients who received only G-CSF or a chemotherapy-based mobilization protocol were evaluated, 19 (29.7%) of the patients who were mobilized with only G-CSF had mobilization failure, while only 2 (8.7%) patients who received a chemotherapy-based mobilization protocol had mobilization failure (p=0.04). This shows the superiority of chemotherapy-based mobilization.
Post-transplant Outcomes
All of the patients finally underwent ASCT. Remarkably, disease status after ASCT (on day +100) was CR in 38 (61.3%) patients, PR in 1 (1.6%) patients, stable disease in 20 (32.3%) patients, and progressive disease in 3 (4.8%) patients in the successful mobilization group. Disease status after ASCT (on day +100) was CR in 13 (65%) patients, PR in 5 (5%) patients, stable disease in 4 (20%) patients, and progressive disease in 2 (10%) patients in the stem cell mobilization failure group for the first trial, as shown in Table 2. The relapse rate was significantly higher in patients who had stem cell mobilization failure than in those with successful stem cell mobilization (47.6% vs. 21.2%, p=0.01). Moreover, the mortality rate was significantly higher among patients who had stem cell mobilization failure than those with successful stem cell mobilization (38.1% vs. 16.7%, p=0.01).
Overall Survival
The overall survival (OS) rate for patients who had successful stem cell mobilization was 151.6±9.3 months versus 71.4±7.8 months for patients with stem cell mobilization failure for the first trial; this was a statistically significant difference, as shown in Figure 1 (p=0.02). The 3-year OS rates for patients with successful stem cell mobilization and those with stem cell mobilization failure for the first trial were 85% and 79%, respectively. The 5-year OS rates for patients with successful stem cell mobilization and stem cell mobilization failure for the first trial were 81% and 63%, respectively. OS was better in patients with lymphoma for whom the first mobilization trial was successful.
The disease-free survival (DFS) rate for patients who had successful stem cell mobilization was 111.9±10.6 months versus 57.6±6.4 months for patients who had stem cell mobilization failure for the first trial; this was a statistically significant difference, as shown in Figure 2 (p=0.004). The 3-year DFS rates for patients with successful stem cell mobilization and those with stem cell mobilization failure for the first trial were 82% and 74%, respectively. The 5-year DFS rates for patients with successful stem cell mobilization and stem cell mobilization failure for the first trial were 68% and 44%, respectively.
Discussion
Stem cell mobilization is still difficult in a significant proportion of patients with lymphoma and the factors predicting poor mobilization are still not fully explained. An obvious reason for these difficulties might be the fact that previous studies have been heterogeneous concerning diagnosis, prior therapy, and mobilization regimen used [7]. The frequency of mobilization failure was 24.1% in the first mobilization in this study, but no factor was detected in analysis that would cause mobilization failure in these lymphoma patients. No statistically significant difference was found between age, sex, stage of diagnosis, ECOG PS, bone marrow infiltration at diagnosis, induction chemotherapy, chemotherapy cycles before stem cell mobilization, disease status before ASCT, receiving radiotherapy before mobilization, lymphoma types, or mobilization regimen in the two groups. On the other hand, OS and DFS were significantly longer in the group with successful mobilization in the first trial. It was observed that survival outcomes were worse in patients who needed plerixafor for mobilization. However, it was thought that the worse survival outcomes might have been due to the poor bone marrow reserve and disease status before ASCT in patients who needed plerixafor for mobilization.
For successful ASCT, one of the most important factors is to mobilize sufficient numbers of CD34+ cells. In this study, the cut-off value of 2x106 CD34+ cells/kg body weight was determined as the target for a successful mobilization procedure. It can be thought that the necessity of using plerixafor can be predicted according to the number of peripheral CD34 cells. CD34 cell count on apheresis day was reported to be the best predictor of mobilization failure [10]. Additionally, CD34 cell count was suggestive of preemptive plerixafor use and the authors suggested a low level of CD34+ in peripheral blood on day +13 as a possible criterion for initiating plerixafor administration [11]. In this study, the number of CD34+ cells of the apheresis product was observed to be significantly higher in patients who were successful in the first mobilization.
Recent studies reported that the incidence of mobilization failure in lymphoma was as high as 46% [12,13,14]. Variables already reported to be associated with mobilization failure include age, body weight, diagnosis, type of lymphoma and dose of chemotherapy, extent of cell recovery from chemotherapy, bone marrow involvement of lymphoma cells, prior radiation therapy, and interval from diagnosis to mobilization [12,13,14,15]. On the other hand, some hematological parameters such as cytopenia at any stage of mobilization, high mean corpuscular volume, long myelosuppression between salvage chemotherapies, and poor bone marrow microenvironment can predict mobilization failure. Özkurt et al. [16] reported that the CD34+ cell count of the first apheresis product was positively correlated with the white blood cell count, platelet count, peripheral CD34+ cell count, and grade of bone marrow reticulin fibrosis. In this study, chemotherapy-based mobilization was seen to be superior to G-CSF mobilization. Additionally, the platelet count before mobilization was higher in patients who had successful stem cell mobilization than in patients with stem cell mobilization failure. Apart from these two prognostic factors, none of the patient or disease characteristics that we analyzed were associated with mobilization failure. Prognostic factors such as patient characteristics (age, gender, diagnosis, bone marrow involvement, previous number of chemotherapy lines, previous radiotherapy) were also not found to be associated with mobilization failure in previous clinical studies [12,14].
It is not clear whether patients with treatment efficiency may be best mobilized by higher doses of chemotherapy and/or G-CSF. Previously, some studies demonstrated the superiority of chemotherapy plus growth factors over growth factors alone for mobilization [6,17,18]. On the other hand, Pusic et al. [17] found similar rates of mobilization failure with chemotherapy plus growth factors and only growth factor. Additionally, André et al. [19] found no significant difference in CD341 cell harvest yields among 131 patients randomized to receive 5 or 10 µg/kg/day of G-CSF following mobilization chemotherapy. In our study, it was observed that mobilization regime did not affect mobilization failure. However, when the patients who received only G-CSF and those who received a chemotherapy-based mobilization protocol were evaluated, chemotherapy-based mobilization was superior.
Conclusion
In this study, the success rate of the first mobilization trial was found to be higher in patients with high platelet counts before mobilization and in patients who received chemotherapy-based mobilization protocols. This study had a few limitations. First, it was retrospective. Second, all patients did not receive the same induction chemotherapy before mobilization. Third, the diagnoses of the patients were very heterogeneous. For the patients who had mobilization failure in the first trial, plerixafor was used in a later mobilization, and those patients then had an adequate amount of stem cells for ASCT. Parameters predicting mobilization failure would allow for a preemptive, more cost-effective use of such agents during the first mobilization attempt. However, the risk factors for mobilization failure are still not clear.
Table 1 Baseline clinical and demographic characteristics of patients.
Table 2 Post-transplantation outcomes.
Figure 1 Overall survival (OS) of patients who had successful stem cell mobilization and patients who had stem cell mobilization failure (p=0.02).
Figure 2 Disease-free survival (DFS) of patients who had successful stem cell mobilization and patients who had stem cell mobilization failure (p=0.004).
Ethics
Ethics Committee Approval: All ethical considerations were strictly followed in accordance with the 1964 Declaration of Helsinki. As standard care/action of the hospitals of the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, it has been recognized from the patient records that all of the studied patients had given informed consent at the time of hospitalization and before the administration of relevant diagnostic/therapeutic standards of care.
Informed Consent: Obtained.
Authorship Contributions
Surgical and Medical Practices: H.G.; Concept: H.D.; Design: H.D.; Data Collection or Processing: R.Ç.; Analysis or Interpretation: R.Ç.; Literature Search: Y.B.; Writing: R.Ç.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.
|
FILGRASTIM
|
DrugsGivenReaction
|
CC BY
|
33161684
| 19,859,879
|
2021-08-25
|
What was the dosage of drug 'FILGRASTIM'?
|
Prediction of Stem Cell Mobilization Failure in Patients with Hodgkin and Non-Hodgkin Lymphoma
Autologous stem cell transplantation (ASCT) is a significant and potentially curative treatment modality for patients with relapsed/refractory lymphoma. Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. The aim of this study was to evaluate the factors that might influence mobilization failure in patients with lymphoma.
Eighty-seven patients diagnosed with non-Hodgkin and Hodgkin lymphoma who underwent stem cell mobilization afterwards at the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, between the years of 2000 and 2018 were evaluated.
A total of 87 patients were included in this study. In 66 of 87 patients (75.9%), the first mobilization trial was successful. Adequate (≥2x106/kg) CD34+ cells were collected in the first apheresis for 66 patients (9.5±8.1). For 21 of 87 (24.1%), the first mobilization trial was unsuccessful. Therefore, a second mobilization trial was performed for these patients with plerixafor (5.5±3.3). The number of CD34+ cells was significantly higher in patients who were successful in the first mobilization (p=0.002).
The success rate of the first mobilization trial was found to be higher in patients with high platelet counts before mobilization and patients who received chemotherapy-based mobilization protocols. In the patients who had mobilization failure in the first trial, plerixafor was used in a later mobilization, and those patients had an adequate amount of stem cells for ASCT. Parameters predicting mobilization failure would allow for preemptive, more cost-effective use of such agents during the first mobilization attempt; however, risk factors for mobilization failure are still not clear.
Introduction
Autologous stem cell transplantation (ASCT) is a significant and potentially curative treatment modality for patients with relapsed/refractory lymphoma. However, 5%-40% of lymphoma patients fail to mobilize sufficient peripheral blood stem cells and thus cannot undergo ASCT, which is known to improve survival [1]. Hematopoietic stem cells generally circulate in very small numbers in the peripheral blood and have to be mobilized into the circulation prior to being collected by apheresis. Peripheral blood stem cell (PBSC) mobilization is accomplished by administration of granulocyte colony-stimulating factor (G-CSF) alone or in combination with chemotherapy [2]. Peripheral blood has been shown to be superior to bone marrow as a source of hematopoietic stem cells for ASCT [3]. Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. Currently, a minimum of 2x106 CD34+ cells/kg hematopoietic stem cells is considered appropriate in most centers to proceed to ASCT. This threshold is necessary for a rapid and sustained blood count recovery and for reduced hospitalization, blood product usage, and infections [4]. However, the optimal hematopoietic stem cell dose is about 5x106/kg [5]. Bone marrow infiltration, advanced age, number of prior cytotoxic therapies, and myelodysplastic changes are the best defined factors associated with increased risk of mobilization failure [6,7].
We have collected and analyzed data from a series of non-Hodgkin and Hodgkin lymphoma patients who received ASCT in order to determine the frequency of harvest failure and to identify factors influencing PBSC mobilization outcomes. The aim of this study was to evaluate the factors that might influence mobilization failure in patients with lymphoma.
Materials and Methods
Study Design and Data Collection
This study was performed in a retrospective manner. Demographic data of the patients, treatment regimens, and stem cell mobilization data updates were obtained from the hospital database. As a result of the application standards of the hospitals of the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, it has been recognized from the patient records that all of the studied patients had given informed consent at the time of hospitalization and before the administration of chemotherapy and other relevant diagnostic/therapeutic standards of care. Patients gave informed consent for procedures in accordance with the Declaration of Helsinki.
Patients and Disease Characteristics
Eighty-seven patients diagnosed with non-Hodgkin and Hodgkin lymphoma who underwent stem cell mobilization afterwards at the Hacettepe University Medical School Bone Marrow Transplantation Center between the years of 2000 and 2018 were evaluated. The key inclusion criteria were patients ≥18 years of age diagnosed with non-Hodgkin or Hodgkin lymphoma who required systemic chemotherapy and underwent ASCT with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of <2 [8] with an indication for ASCT.
Median age, gender, ECOG PS, lymphoma subtypes, stage at diagnosis, bone marrow infiltration at diagnosis, induction chemotherapy, salvage chemotherapy, chemotherapy cycles received before mobilization, radiotherapy before mobilization, platelet count before mobilization, mobilization protocols, and disease status before ASCT were compared for patients who had successful stem cell mobilization and those with stem cell mobilization failure. Additionally, disease status after ASCT, relapse rate, and mortality results were evaluated between these groups. The target CD34+ cell dose for collection was >2x106/kg for each planned autograft. All patients received G-CSF at a dose of 10 µg/kg from day +5 until the peripheral stem cell harvest. CD34+ cells were measured in peripheral blood and apheresis products by flow cytometry. We had a CD34+ cut-off level of 20 µL for starting apheresis. We harvested the cells on the 5th and/or 6th day after beginning G-CSF administration. Peripheral blood CD34% and CD34/µL values at the first day on which leukocytes reached the value of 1x109/L and were maintained above that threshold over at least 2 days were correlated with overall CD34+ collection. A harvest of less than 2x106 CD34+/kg was considered as mobilization failure. Twenty-one patients received plerixafor as an additional mobilizing agent for the second apheresis. Subcutaneous plerixafor (0.24 mg/kg) was administered to the patients on the evenings of the 4th and 5th days of the mobilization protocol.
Statistical Analysis
Statistical analyses were performed using SPSS 25 (IBM Corp., Armonk, NY, USA). Variables were investigated using visual (histograms, probability plots) and analytical (Kolmogorov-Smirnov/Shapiro-Wilk test) methods to determine whether they were normally distributed or not. Statistical comparisons were made using chi-square tests for categorical data. Student’s t-test for two independent samples was used for comparison of continuous numerical data. Variables found to be significant (p<0.05) in univariate analysis were tested in multivariate analysis, which was performed using a stepwise logistic regression model. Survival analyses were performed using the Kaplan-Meier test with log rank. Values of p<0.05 were considered statistically significant.
Results
Patient Characteristics
A total of 87 patients were included in this study. The median age was 48 (range: 18-70) years at the time of diagnosis. The baseline clinical and demographic characteristics of the patients are listed in Table 1. For 66 of 87 patients (75.9%), the first mobilization trial was successful. Adequate (≥2x106/kg) CD34+ cells were collected in the first apheresis for 66 patients (9.5±8.1). For 21 of 87 (24.1%), the first mobilization trial was unsuccessful. Therefore, a second mobilization trial was conducted for these patients with plerixafor (5.5±3.3). The number of CD34+ cells was significantly higher in patients who were successful in the first mobilization (p=0.002). There were no differences in hematocrit at the time point of apheresis.
Between the two groups, there was no statistically significant gender (p=0.25) or age (p=0.07) difference. There was no significant difference between the ECOG PS of the patients (p=0.72). No significant difference was found between the groups in terms of lymphoma types (p=0.45). Number of chemotherapy cycles before stem cell mobilization was not statistically significantly different between patients who had mobilization failure and patients who had successful stem cell mobilization (p=0.78). The stages of both groups were similar at the time of diagnosis (p=0.69). There was no significant difference between bone marrow infiltration at diagnosis (p=0.24). There was no significant difference between the groups in terms of induction chemotherapy protocols (p=0.51). Platelet count before mobilization was higher in patients who had successful stem cell mobilization than in patients who had stem cell mobilization failure (p=0.041). After relapse, no significant difference was found between rescue chemotherapies given before mobilization (p=0.49). Disease status before ASCT was complete response (CR) in 27 (40.9%) patients, partial response (PR) in 28 (42.4%) patients, stable disease in 5 (7.6%) patients, and progressive disease in 6 (9.1%) patients in the successful mobilization group. Disease status before ASCT was CR in 8 (38.1%) patients, PR in 10 (47.6%) patients, stable disease in 1 (4.8%) patient, and progressive disease in 2 (9.5%) patients in the stem cell mobilization failure group for the first trial (p=0.95). The use of filgrastim or lenograstim as G-CSF did not affect mobilization success. There was no significant difference between the two groups in terms of filgrastim or lenograstim mobilization (p=0.20). However, when the patients who received only G-CSF or a chemotherapy-based mobilization protocol were evaluated, 19 (29.7%) of the patients who were mobilized with only G-CSF had mobilization failure, while only 2 (8.7%) patients who received a chemotherapy-based mobilization protocol had mobilization failure (p=0.04). This shows the superiority of chemotherapy-based mobilization.
Post-transplant Outcomes
All of the patients finally underwent ASCT. Remarkably, disease status after ASCT (on day +100) was CR in 38 (61.3%) patients, PR in 1 (1.6%) patients, stable disease in 20 (32.3%) patients, and progressive disease in 3 (4.8%) patients in the successful mobilization group. Disease status after ASCT (on day +100) was CR in 13 (65%) patients, PR in 5 (5%) patients, stable disease in 4 (20%) patients, and progressive disease in 2 (10%) patients in the stem cell mobilization failure group for the first trial, as shown in Table 2. The relapse rate was significantly higher in patients who had stem cell mobilization failure than in those with successful stem cell mobilization (47.6% vs. 21.2%, p=0.01). Moreover, the mortality rate was significantly higher among patients who had stem cell mobilization failure than those with successful stem cell mobilization (38.1% vs. 16.7%, p=0.01).
Overall Survival
The overall survival (OS) rate for patients who had successful stem cell mobilization was 151.6±9.3 months versus 71.4±7.8 months for patients with stem cell mobilization failure for the first trial; this was a statistically significant difference, as shown in Figure 1 (p=0.02). The 3-year OS rates for patients with successful stem cell mobilization and those with stem cell mobilization failure for the first trial were 85% and 79%, respectively. The 5-year OS rates for patients with successful stem cell mobilization and stem cell mobilization failure for the first trial were 81% and 63%, respectively. OS was better in patients with lymphoma for whom the first mobilization trial was successful.
The disease-free survival (DFS) rate for patients who had successful stem cell mobilization was 111.9±10.6 months versus 57.6±6.4 months for patients who had stem cell mobilization failure for the first trial; this was a statistically significant difference, as shown in Figure 2 (p=0.004). The 3-year DFS rates for patients with successful stem cell mobilization and those with stem cell mobilization failure for the first trial were 82% and 74%, respectively. The 5-year DFS rates for patients with successful stem cell mobilization and stem cell mobilization failure for the first trial were 68% and 44%, respectively.
Discussion
Stem cell mobilization is still difficult in a significant proportion of patients with lymphoma and the factors predicting poor mobilization are still not fully explained. An obvious reason for these difficulties might be the fact that previous studies have been heterogeneous concerning diagnosis, prior therapy, and mobilization regimen used [7]. The frequency of mobilization failure was 24.1% in the first mobilization in this study, but no factor was detected in analysis that would cause mobilization failure in these lymphoma patients. No statistically significant difference was found between age, sex, stage of diagnosis, ECOG PS, bone marrow infiltration at diagnosis, induction chemotherapy, chemotherapy cycles before stem cell mobilization, disease status before ASCT, receiving radiotherapy before mobilization, lymphoma types, or mobilization regimen in the two groups. On the other hand, OS and DFS were significantly longer in the group with successful mobilization in the first trial. It was observed that survival outcomes were worse in patients who needed plerixafor for mobilization. However, it was thought that the worse survival outcomes might have been due to the poor bone marrow reserve and disease status before ASCT in patients who needed plerixafor for mobilization.
For successful ASCT, one of the most important factors is to mobilize sufficient numbers of CD34+ cells. In this study, the cut-off value of 2x106 CD34+ cells/kg body weight was determined as the target for a successful mobilization procedure. It can be thought that the necessity of using plerixafor can be predicted according to the number of peripheral CD34 cells. CD34 cell count on apheresis day was reported to be the best predictor of mobilization failure [10]. Additionally, CD34 cell count was suggestive of preemptive plerixafor use and the authors suggested a low level of CD34+ in peripheral blood on day +13 as a possible criterion for initiating plerixafor administration [11]. In this study, the number of CD34+ cells of the apheresis product was observed to be significantly higher in patients who were successful in the first mobilization.
Recent studies reported that the incidence of mobilization failure in lymphoma was as high as 46% [12,13,14]. Variables already reported to be associated with mobilization failure include age, body weight, diagnosis, type of lymphoma and dose of chemotherapy, extent of cell recovery from chemotherapy, bone marrow involvement of lymphoma cells, prior radiation therapy, and interval from diagnosis to mobilization [12,13,14,15]. On the other hand, some hematological parameters such as cytopenia at any stage of mobilization, high mean corpuscular volume, long myelosuppression between salvage chemotherapies, and poor bone marrow microenvironment can predict mobilization failure. Özkurt et al. [16] reported that the CD34+ cell count of the first apheresis product was positively correlated with the white blood cell count, platelet count, peripheral CD34+ cell count, and grade of bone marrow reticulin fibrosis. In this study, chemotherapy-based mobilization was seen to be superior to G-CSF mobilization. Additionally, the platelet count before mobilization was higher in patients who had successful stem cell mobilization than in patients with stem cell mobilization failure. Apart from these two prognostic factors, none of the patient or disease characteristics that we analyzed were associated with mobilization failure. Prognostic factors such as patient characteristics (age, gender, diagnosis, bone marrow involvement, previous number of chemotherapy lines, previous radiotherapy) were also not found to be associated with mobilization failure in previous clinical studies [12,14].
It is not clear whether patients with treatment efficiency may be best mobilized by higher doses of chemotherapy and/or G-CSF. Previously, some studies demonstrated the superiority of chemotherapy plus growth factors over growth factors alone for mobilization [6,17,18]. On the other hand, Pusic et al. [17] found similar rates of mobilization failure with chemotherapy plus growth factors and only growth factor. Additionally, André et al. [19] found no significant difference in CD341 cell harvest yields among 131 patients randomized to receive 5 or 10 µg/kg/day of G-CSF following mobilization chemotherapy. In our study, it was observed that mobilization regime did not affect mobilization failure. However, when the patients who received only G-CSF and those who received a chemotherapy-based mobilization protocol were evaluated, chemotherapy-based mobilization was superior.
Conclusion
In this study, the success rate of the first mobilization trial was found to be higher in patients with high platelet counts before mobilization and in patients who received chemotherapy-based mobilization protocols. This study had a few limitations. First, it was retrospective. Second, all patients did not receive the same induction chemotherapy before mobilization. Third, the diagnoses of the patients were very heterogeneous. For the patients who had mobilization failure in the first trial, plerixafor was used in a later mobilization, and those patients then had an adequate amount of stem cells for ASCT. Parameters predicting mobilization failure would allow for a preemptive, more cost-effective use of such agents during the first mobilization attempt. However, the risk factors for mobilization failure are still not clear.
Table 1 Baseline clinical and demographic characteristics of patients.
Table 2 Post-transplantation outcomes.
Figure 1 Overall survival (OS) of patients who had successful stem cell mobilization and patients who had stem cell mobilization failure (p=0.02).
Figure 2 Disease-free survival (DFS) of patients who had successful stem cell mobilization and patients who had stem cell mobilization failure (p=0.004).
Ethics
Ethics Committee Approval: All ethical considerations were strictly followed in accordance with the 1964 Declaration of Helsinki. As standard care/action of the hospitals of the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, it has been recognized from the patient records that all of the studied patients had given informed consent at the time of hospitalization and before the administration of relevant diagnostic/therapeutic standards of care.
Informed Consent: Obtained.
Authorship Contributions
Surgical and Medical Practices: H.G.; Concept: H.D.; Design: H.D.; Data Collection or Processing: R.Ç.; Analysis or Interpretation: R.Ç.; Literature Search: Y.B.; Writing: R.Ç.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.
|
10 MICROGRAM/KILOGRAM
|
DrugDosageText
|
CC BY
|
33161684
| 19,859,879
|
2021-08-25
|
What was the outcome of reaction 'Death'?
|
Prediction of Stem Cell Mobilization Failure in Patients with Hodgkin and Non-Hodgkin Lymphoma
Autologous stem cell transplantation (ASCT) is a significant and potentially curative treatment modality for patients with relapsed/refractory lymphoma. Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. The aim of this study was to evaluate the factors that might influence mobilization failure in patients with lymphoma.
Eighty-seven patients diagnosed with non-Hodgkin and Hodgkin lymphoma who underwent stem cell mobilization afterwards at the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, between the years of 2000 and 2018 were evaluated.
A total of 87 patients were included in this study. In 66 of 87 patients (75.9%), the first mobilization trial was successful. Adequate (≥2x106/kg) CD34+ cells were collected in the first apheresis for 66 patients (9.5±8.1). For 21 of 87 (24.1%), the first mobilization trial was unsuccessful. Therefore, a second mobilization trial was performed for these patients with plerixafor (5.5±3.3). The number of CD34+ cells was significantly higher in patients who were successful in the first mobilization (p=0.002).
The success rate of the first mobilization trial was found to be higher in patients with high platelet counts before mobilization and patients who received chemotherapy-based mobilization protocols. In the patients who had mobilization failure in the first trial, plerixafor was used in a later mobilization, and those patients had an adequate amount of stem cells for ASCT. Parameters predicting mobilization failure would allow for preemptive, more cost-effective use of such agents during the first mobilization attempt; however, risk factors for mobilization failure are still not clear.
Introduction
Autologous stem cell transplantation (ASCT) is a significant and potentially curative treatment modality for patients with relapsed/refractory lymphoma. However, 5%-40% of lymphoma patients fail to mobilize sufficient peripheral blood stem cells and thus cannot undergo ASCT, which is known to improve survival [1]. Hematopoietic stem cells generally circulate in very small numbers in the peripheral blood and have to be mobilized into the circulation prior to being collected by apheresis. Peripheral blood stem cell (PBSC) mobilization is accomplished by administration of granulocyte colony-stimulating factor (G-CSF) alone or in combination with chemotherapy [2]. Peripheral blood has been shown to be superior to bone marrow as a source of hematopoietic stem cells for ASCT [3]. Insufficient mobilization and harvest of peripheral stem cells can be a major obstacle for performing ASCT. Currently, a minimum of 2x106 CD34+ cells/kg hematopoietic stem cells is considered appropriate in most centers to proceed to ASCT. This threshold is necessary for a rapid and sustained blood count recovery and for reduced hospitalization, blood product usage, and infections [4]. However, the optimal hematopoietic stem cell dose is about 5x106/kg [5]. Bone marrow infiltration, advanced age, number of prior cytotoxic therapies, and myelodysplastic changes are the best defined factors associated with increased risk of mobilization failure [6,7].
We have collected and analyzed data from a series of non-Hodgkin and Hodgkin lymphoma patients who received ASCT in order to determine the frequency of harvest failure and to identify factors influencing PBSC mobilization outcomes. The aim of this study was to evaluate the factors that might influence mobilization failure in patients with lymphoma.
Materials and Methods
Study Design and Data Collection
This study was performed in a retrospective manner. Demographic data of the patients, treatment regimens, and stem cell mobilization data updates were obtained from the hospital database. As a result of the application standards of the hospitals of the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, it has been recognized from the patient records that all of the studied patients had given informed consent at the time of hospitalization and before the administration of chemotherapy and other relevant diagnostic/therapeutic standards of care. Patients gave informed consent for procedures in accordance with the Declaration of Helsinki.
Patients and Disease Characteristics
Eighty-seven patients diagnosed with non-Hodgkin and Hodgkin lymphoma who underwent stem cell mobilization afterwards at the Hacettepe University Medical School Bone Marrow Transplantation Center between the years of 2000 and 2018 were evaluated. The key inclusion criteria were patients ≥18 years of age diagnosed with non-Hodgkin or Hodgkin lymphoma who required systemic chemotherapy and underwent ASCT with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of <2 [8] with an indication for ASCT.
Median age, gender, ECOG PS, lymphoma subtypes, stage at diagnosis, bone marrow infiltration at diagnosis, induction chemotherapy, salvage chemotherapy, chemotherapy cycles received before mobilization, radiotherapy before mobilization, platelet count before mobilization, mobilization protocols, and disease status before ASCT were compared for patients who had successful stem cell mobilization and those with stem cell mobilization failure. Additionally, disease status after ASCT, relapse rate, and mortality results were evaluated between these groups. The target CD34+ cell dose for collection was >2x106/kg for each planned autograft. All patients received G-CSF at a dose of 10 µg/kg from day +5 until the peripheral stem cell harvest. CD34+ cells were measured in peripheral blood and apheresis products by flow cytometry. We had a CD34+ cut-off level of 20 µL for starting apheresis. We harvested the cells on the 5th and/or 6th day after beginning G-CSF administration. Peripheral blood CD34% and CD34/µL values at the first day on which leukocytes reached the value of 1x109/L and were maintained above that threshold over at least 2 days were correlated with overall CD34+ collection. A harvest of less than 2x106 CD34+/kg was considered as mobilization failure. Twenty-one patients received plerixafor as an additional mobilizing agent for the second apheresis. Subcutaneous plerixafor (0.24 mg/kg) was administered to the patients on the evenings of the 4th and 5th days of the mobilization protocol.
Statistical Analysis
Statistical analyses were performed using SPSS 25 (IBM Corp., Armonk, NY, USA). Variables were investigated using visual (histograms, probability plots) and analytical (Kolmogorov-Smirnov/Shapiro-Wilk test) methods to determine whether they were normally distributed or not. Statistical comparisons were made using chi-square tests for categorical data. Student’s t-test for two independent samples was used for comparison of continuous numerical data. Variables found to be significant (p<0.05) in univariate analysis were tested in multivariate analysis, which was performed using a stepwise logistic regression model. Survival analyses were performed using the Kaplan-Meier test with log rank. Values of p<0.05 were considered statistically significant.
Results
Patient Characteristics
A total of 87 patients were included in this study. The median age was 48 (range: 18-70) years at the time of diagnosis. The baseline clinical and demographic characteristics of the patients are listed in Table 1. For 66 of 87 patients (75.9%), the first mobilization trial was successful. Adequate (≥2x106/kg) CD34+ cells were collected in the first apheresis for 66 patients (9.5±8.1). For 21 of 87 (24.1%), the first mobilization trial was unsuccessful. Therefore, a second mobilization trial was conducted for these patients with plerixafor (5.5±3.3). The number of CD34+ cells was significantly higher in patients who were successful in the first mobilization (p=0.002). There were no differences in hematocrit at the time point of apheresis.
Between the two groups, there was no statistically significant gender (p=0.25) or age (p=0.07) difference. There was no significant difference between the ECOG PS of the patients (p=0.72). No significant difference was found between the groups in terms of lymphoma types (p=0.45). Number of chemotherapy cycles before stem cell mobilization was not statistically significantly different between patients who had mobilization failure and patients who had successful stem cell mobilization (p=0.78). The stages of both groups were similar at the time of diagnosis (p=0.69). There was no significant difference between bone marrow infiltration at diagnosis (p=0.24). There was no significant difference between the groups in terms of induction chemotherapy protocols (p=0.51). Platelet count before mobilization was higher in patients who had successful stem cell mobilization than in patients who had stem cell mobilization failure (p=0.041). After relapse, no significant difference was found between rescue chemotherapies given before mobilization (p=0.49). Disease status before ASCT was complete response (CR) in 27 (40.9%) patients, partial response (PR) in 28 (42.4%) patients, stable disease in 5 (7.6%) patients, and progressive disease in 6 (9.1%) patients in the successful mobilization group. Disease status before ASCT was CR in 8 (38.1%) patients, PR in 10 (47.6%) patients, stable disease in 1 (4.8%) patient, and progressive disease in 2 (9.5%) patients in the stem cell mobilization failure group for the first trial (p=0.95). The use of filgrastim or lenograstim as G-CSF did not affect mobilization success. There was no significant difference between the two groups in terms of filgrastim or lenograstim mobilization (p=0.20). However, when the patients who received only G-CSF or a chemotherapy-based mobilization protocol were evaluated, 19 (29.7%) of the patients who were mobilized with only G-CSF had mobilization failure, while only 2 (8.7%) patients who received a chemotherapy-based mobilization protocol had mobilization failure (p=0.04). This shows the superiority of chemotherapy-based mobilization.
Post-transplant Outcomes
All of the patients finally underwent ASCT. Remarkably, disease status after ASCT (on day +100) was CR in 38 (61.3%) patients, PR in 1 (1.6%) patients, stable disease in 20 (32.3%) patients, and progressive disease in 3 (4.8%) patients in the successful mobilization group. Disease status after ASCT (on day +100) was CR in 13 (65%) patients, PR in 5 (5%) patients, stable disease in 4 (20%) patients, and progressive disease in 2 (10%) patients in the stem cell mobilization failure group for the first trial, as shown in Table 2. The relapse rate was significantly higher in patients who had stem cell mobilization failure than in those with successful stem cell mobilization (47.6% vs. 21.2%, p=0.01). Moreover, the mortality rate was significantly higher among patients who had stem cell mobilization failure than those with successful stem cell mobilization (38.1% vs. 16.7%, p=0.01).
Overall Survival
The overall survival (OS) rate for patients who had successful stem cell mobilization was 151.6±9.3 months versus 71.4±7.8 months for patients with stem cell mobilization failure for the first trial; this was a statistically significant difference, as shown in Figure 1 (p=0.02). The 3-year OS rates for patients with successful stem cell mobilization and those with stem cell mobilization failure for the first trial were 85% and 79%, respectively. The 5-year OS rates for patients with successful stem cell mobilization and stem cell mobilization failure for the first trial were 81% and 63%, respectively. OS was better in patients with lymphoma for whom the first mobilization trial was successful.
The disease-free survival (DFS) rate for patients who had successful stem cell mobilization was 111.9±10.6 months versus 57.6±6.4 months for patients who had stem cell mobilization failure for the first trial; this was a statistically significant difference, as shown in Figure 2 (p=0.004). The 3-year DFS rates for patients with successful stem cell mobilization and those with stem cell mobilization failure for the first trial were 82% and 74%, respectively. The 5-year DFS rates for patients with successful stem cell mobilization and stem cell mobilization failure for the first trial were 68% and 44%, respectively.
Discussion
Stem cell mobilization is still difficult in a significant proportion of patients with lymphoma and the factors predicting poor mobilization are still not fully explained. An obvious reason for these difficulties might be the fact that previous studies have been heterogeneous concerning diagnosis, prior therapy, and mobilization regimen used [7]. The frequency of mobilization failure was 24.1% in the first mobilization in this study, but no factor was detected in analysis that would cause mobilization failure in these lymphoma patients. No statistically significant difference was found between age, sex, stage of diagnosis, ECOG PS, bone marrow infiltration at diagnosis, induction chemotherapy, chemotherapy cycles before stem cell mobilization, disease status before ASCT, receiving radiotherapy before mobilization, lymphoma types, or mobilization regimen in the two groups. On the other hand, OS and DFS were significantly longer in the group with successful mobilization in the first trial. It was observed that survival outcomes were worse in patients who needed plerixafor for mobilization. However, it was thought that the worse survival outcomes might have been due to the poor bone marrow reserve and disease status before ASCT in patients who needed plerixafor for mobilization.
For successful ASCT, one of the most important factors is to mobilize sufficient numbers of CD34+ cells. In this study, the cut-off value of 2x106 CD34+ cells/kg body weight was determined as the target for a successful mobilization procedure. It can be thought that the necessity of using plerixafor can be predicted according to the number of peripheral CD34 cells. CD34 cell count on apheresis day was reported to be the best predictor of mobilization failure [10]. Additionally, CD34 cell count was suggestive of preemptive plerixafor use and the authors suggested a low level of CD34+ in peripheral blood on day +13 as a possible criterion for initiating plerixafor administration [11]. In this study, the number of CD34+ cells of the apheresis product was observed to be significantly higher in patients who were successful in the first mobilization.
Recent studies reported that the incidence of mobilization failure in lymphoma was as high as 46% [12,13,14]. Variables already reported to be associated with mobilization failure include age, body weight, diagnosis, type of lymphoma and dose of chemotherapy, extent of cell recovery from chemotherapy, bone marrow involvement of lymphoma cells, prior radiation therapy, and interval from diagnosis to mobilization [12,13,14,15]. On the other hand, some hematological parameters such as cytopenia at any stage of mobilization, high mean corpuscular volume, long myelosuppression between salvage chemotherapies, and poor bone marrow microenvironment can predict mobilization failure. Özkurt et al. [16] reported that the CD34+ cell count of the first apheresis product was positively correlated with the white blood cell count, platelet count, peripheral CD34+ cell count, and grade of bone marrow reticulin fibrosis. In this study, chemotherapy-based mobilization was seen to be superior to G-CSF mobilization. Additionally, the platelet count before mobilization was higher in patients who had successful stem cell mobilization than in patients with stem cell mobilization failure. Apart from these two prognostic factors, none of the patient or disease characteristics that we analyzed were associated with mobilization failure. Prognostic factors such as patient characteristics (age, gender, diagnosis, bone marrow involvement, previous number of chemotherapy lines, previous radiotherapy) were also not found to be associated with mobilization failure in previous clinical studies [12,14].
It is not clear whether patients with treatment efficiency may be best mobilized by higher doses of chemotherapy and/or G-CSF. Previously, some studies demonstrated the superiority of chemotherapy plus growth factors over growth factors alone for mobilization [6,17,18]. On the other hand, Pusic et al. [17] found similar rates of mobilization failure with chemotherapy plus growth factors and only growth factor. Additionally, André et al. [19] found no significant difference in CD341 cell harvest yields among 131 patients randomized to receive 5 or 10 µg/kg/day of G-CSF following mobilization chemotherapy. In our study, it was observed that mobilization regime did not affect mobilization failure. However, when the patients who received only G-CSF and those who received a chemotherapy-based mobilization protocol were evaluated, chemotherapy-based mobilization was superior.
Conclusion
In this study, the success rate of the first mobilization trial was found to be higher in patients with high platelet counts before mobilization and in patients who received chemotherapy-based mobilization protocols. This study had a few limitations. First, it was retrospective. Second, all patients did not receive the same induction chemotherapy before mobilization. Third, the diagnoses of the patients were very heterogeneous. For the patients who had mobilization failure in the first trial, plerixafor was used in a later mobilization, and those patients then had an adequate amount of stem cells for ASCT. Parameters predicting mobilization failure would allow for a preemptive, more cost-effective use of such agents during the first mobilization attempt. However, the risk factors for mobilization failure are still not clear.
Table 1 Baseline clinical and demographic characteristics of patients.
Table 2 Post-transplantation outcomes.
Figure 1 Overall survival (OS) of patients who had successful stem cell mobilization and patients who had stem cell mobilization failure (p=0.02).
Figure 2 Disease-free survival (DFS) of patients who had successful stem cell mobilization and patients who had stem cell mobilization failure (p=0.004).
Ethics
Ethics Committee Approval: All ethical considerations were strictly followed in accordance with the 1964 Declaration of Helsinki. As standard care/action of the hospitals of the Hacettepe University Medical School Bone Marrow Transplantation Center, Turkey, it has been recognized from the patient records that all of the studied patients had given informed consent at the time of hospitalization and before the administration of relevant diagnostic/therapeutic standards of care.
Informed Consent: Obtained.
Authorship Contributions
Surgical and Medical Practices: H.G.; Concept: H.D.; Design: H.D.; Data Collection or Processing: R.Ç.; Analysis or Interpretation: R.Ç.; Literature Search: Y.B.; Writing: R.Ç.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.
|
Fatal
|
ReactionOutcome
|
CC BY
|
33161684
| 19,859,879
|
2021-08-25
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypothyroidism'.
|
A Durable Response after the Discontinuation of Nivolumab in an Advanced Gastric Cancer Patient.
A durable response after the discontinuation of immune checkpoint-inhibitor therapy has previously been reported in several cancers. We herein describe a patient with gastric cancer who maintained a durable response after the discontinuation of nivolumab. A 65-year-old man was treated with nivolumab as a sixth-line therapy for recurrent gastric cancer. After four cycles of nivolumab therapy, he showed a partial response. But the treatment was discontinued when two immune-related adverse events occurred after six cycles. Disease regression was sustained for approximately 2 years, without the re-administration of nivolumab. The characteristics leading to such responses are unclear, and further studies are warranted in this regard.
Introduction
Nivolumab, a monoclonal antibody targeting programmed cell death-1 (PD-1), has been shown to provide remarkable efficacy in the treatment of patients with various kinds of malignant tumors and it is approved for the treatment of several cancers, including melanoma (1), non-small cell lung cancer (NSCLC) (2), renal cell carcinoma (RCC) (3), squamous cell carcinoma of the head and neck (4), and Hodgkin's lymphoma (5). The ATTRACTION-2 study was conducted to investigate the efficacy and safety of nivolumab for heavily pretreated advanced gastric cancer (AGC) patients (6). This randomized, double-blind, placebo-controlled phase 3 trial showed the superiority of nivolumab over a placebo, with an objective response rate of 11.2% [95% confidence interval (CI): 7.7-15.6], a median progression-free survival (PFS) of 1.61 months (95% CI: 1.54-2.30), and a median overall survival (OS) of 5.26 months (95% CI: 4.60- 6.37). Based on the results of this study, nivolumab was approved for AGC as either a third- or later-line treatment, and it has been recently recognized as a standard chemotherapeutic regimen in Japan.
Unlike in the case of conventional cytotoxic anticancer drugs or molecular targeted drugs, the blockade of the PD-1 pathway confers an adaptive memory immune response that resets the equilibrium between the tumor and host immune responses, thus indicating its potential to sustain an antitumor response even after treatment cessation (7). Recent studies have reported cases wherein a durable response was observed even after the discontinuation of therapy with immune checkpoint inhibitors (ICIs), including nivolumab, in melanoma, NSCLC, and RCC (8-10), but no such studies have so far been reported in patients with AGC.
Thus, in this study, we report a rare case of an AGC patient who maintained a durable response for approximately 2 years after the discontinuation of nivolumab due to immune-related adverse events (irAEs).
Case Report
The patient was a 65-year-old man who had been diagnosed with gastric cancer and had undergone total gastrectomy with D2 dissection 7.5 years previously, namely in August 2010. The pathological diagnosis was of a moderately differentiated HER2-negative, pT1N1, pStage IB adenocarcinoma. Six months postoperatively, a solitary liver metastasis was discovered. He then received S-1 treatment as palliative chemotherapy 7 years perviously in March 2011, following which he received nab-paclitaxel alone from May 2013, irinotecan alone from February 2016, capecitabine plus oxaliplatin from June 2016, and ramucirumab alone from February 2017. The disappearance of liver metastasis was observed after the administration of nab-paclitaxel alone. However, treatment with S-1, irinotecan, and ramucirumab was considered to be a failure owing to multiple abdominal lymph node metastases, portal tumor thrombus, and solitary lung metastasis, respectively (Fig. 1A).
Figure 1. (A) Abdominal computed tomography images before the commencement of nivolumab treatment. Solitary lung metastasis (arrow), portal tumor thrombus (solid circle), and multiple lymph node metastases (dotted circle) were observed. (B) After four cycles of nivolumab (approximately 2 months after start of nivolumab), the metastatic lesions shrank to 61.2% of the original size (before nivolumab treatment). (C) Twenty-three months after the discontinuation of nivolumab, the metastatic lesions further shrank to 39.1% of the original size (before nivolumab treatment).
Since he exhibited an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, he began to receive nivolumab as sixth-line therapy from March 2018. The laboratory data showed no abnormal findings (Table). The carcinoembryonic antigen and carbohydrate antigen 19-9 levels were within the normal range, which were similar to his preoperative levels. The patient's clinical course during nivolumab treatment is shown in Fig. 2. No adverse events were observed during the first five cycles of nivolumab therapy. However, after the sixth cycle, 15 weeks after the initial treatment, he was hospitalized for severe fatigue (grade 3 by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0). During hospitalization, he exhibited ECOG PS 3. Physical examination revealed that his body temperature was 36.8℃, blood pressure was 81/48 mmHg, pulse rate was 88/min, and oxygen saturation was 99% on room air. No other abnormal findings were identified. A serum examination revealed a decreased level of thyroid-stimulating hormone (TSH) and increased levels of free triiodothyronine and free thyroxine (T4) compared with the levels before nivolumab initiation (Table). The patient tested negative for thyroid autoantibodies. In addition, there was a decrease in the levels of adrenocorticotropic hormone (ACTH) and cortisol. A stimulation test revealed a minor impact of corticotropin-releasing hormone loading on the ACTH and cortisol levels, while growth hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, and TSH showed sufficient responses according to the corresponding stimulation tests. The ultrasound findings of the thyroid and magnetic resonance imaging findings of the pituitary gland showed no abnormalities. Consequently, he was diagnosed to have grade 3 isolated ACTH deficiency with secondary adrenal insufficiency and nivolumab-related grade 3 destructive thyroiditis. Nivolumab therapy was discontinued and prednisolone was supplemented at a starting dose of 15 mg/day for adrenal insufficiency. The patient's fatigue was alleviated within a few days, following which the prednisolone dose was tapered. His serum cortisol level returned to normal, whereas ACTH deficiency persisted. Prednisolone was maintained at a dosage of 5 mg/day since day 37, and no relapse was noted thereafter. The free T4 level decreased on day 23, confirming the hypothyroidism phase of destructive thyroiditis. Levothyroxine (25 μg/day) was administrated until the free T4 level recovered on day 95, and no relapse occurred thereafter.
Table. Laboratory Data.
Reference range Before nivolumab After 6 cycles of nivolumab
White blood cells /µL 4,000-9,000 3,500 3,400
Neutrophils % 45-55 47.8 47.7
Lymophocyte % 25-45 36.9 36.5
Hemoglobin g/dL 14-18 14.4 13.8
Platelets /µL 15-35×104 11.3×104 19.9×104
Lactate dehydrogenase U/I 106-211 155 249
Total bilirubin mg/dL 0.3-1.2 1.2 1.1
Sodium mEq/L 135-147 141 138
Potassium mEq/L 3.6-5.0 4.0 4.7
Chloride mEq/L 98-108 105 101
Calcium mg/dL 8.6-10.1 8.7 9.4
Urea nitrogen mg/dL 8-20 10.7 16.7
Creatinine mg/dL 0.61-1.04 0.95 1.00
C-reactive protein mg/dL 0-0.2 <0.03 0.46
Casual blood glucose mg/dL 70-199 – 192
Hemoglobin A1c % 4.6-6.2 5.5 5.4
CA19-9 U/mL <37.0 8.6 –
CEA ng/mL <5.0 2.3 –
TSH µU/mL 0.5-5.0 4.16 0.021
FT4 ng/dL 0.9-1.7 0.99 2.48
FT3 pg/mL 2.3-4.3 2.6 7.9
ACTH pg/mL 7.2-63.3 78.6 3.5
Cortisol µg/dL 7.07-19.6 14.6 0.2
GH ng/mL 0.0-2.0 – 1.2
LH mIU/mL 0.79-5.72 – 6.1
FSH mIU/mL 2.00-8.30 – 12.8
Prolactin ng/mL 4.29-13.69 – 9.7
ACTH: adrenocorticotropic hormone, CA19-9: carbohydrate antigen 19-9, CEA: carcinoembryonic antigen, FSH: follicle stimulating hormone, FT3: free triiodothyronine, FT4: free thyroxine, GH: growth hormone, LH: luteinizing hormone, TSH: thyroid stimulating hormone
Figure 2. The patient’s clinical course during nivolumab treatment. ACTH: adrenocorticotropic hormone, CORT: cortisol, FT4: free thyroxine, LT4: levothyroxine, PSL: prednisolone, TSH: thyroid stimulating hormone
After four cycles of nivolumab (approximately 2 months after the start of nivolumab therapy), all metastatic lesions shrank to around 61.2% of the size before nivolumab treatment (Fig. 1B). We determined to observe his course without the re-administration of nivolumab even after the improvement of irAEs. The metastatic lesions further decreased in size after the discontinuation of nivolumab, and the effect was sustained for 23 months after nivolumab initiation (final size, 39.1% of that before nivolumab treatment) (Fig. 1C); the tumor markers were within the normal ranges.
Discussion
Recently, a durable response after the discontinuation of ICIs in patients with residual disease has been reported for other kinds of cancers (8-10). It has previously been reported that PD-1/PD-L1 blockade rescued “exhausted” T cells, leading to the activation of T-cell effectors and transition to memory cells (7). The level of PD-1 occupancy on circulating T cells was shown to persist much longer than the serum half-life of the PD-1 antibodies (11,12). This might mean that there is no need to perform continuous treatment with ICIs. In fact, our patient showed that the metastatic lesions further decreased after the discontinuation of nivolumab.
Several predictive markers of an effective response to ICIs have been previously proposed for many cancers including AGC, such as better ECOG PS, no liver or lung metastases, a higher peripheral lymphocyte count, a lower neutrophil-to-lymphocyte ratio, a higher tumor PD-L1 expression, and a high degree of microsatellite instability (6,13-17). However, there have been a limited number of case reviews about the predictive markers for a durable clinical benefit after the discontinuation of ICIs, namely only in melanoma and RCC cases (8,10,18). In the KEYNOTE-001 study on pembrolizumab in patients with melanoma, 61 of 67 patients (91.0%), who were followed up after pembrolizumab discontinuation after a complete response (CR), achieved a disease-free survival of 24 months (18). It was suggested that the patients with CR were more likely to achieve a durable response. A univariate analysis revealed that high CR rates were associated with a target tumor size between 1 and 5 cm and PD-L1-positive tumors (≥1% staining in tumor cells and mononuclear inflammatory cells) (18). A retrospective cohort study on melanoma patients showed that the risk of disease progression following treatment discontinuation was significantly associated with the overall response and it was lower in patients with CR (19). However, none of these conditions were seen in our patient (no CR, unknown tumor PD-L1 status, and target tumor size: 7.7 cm; data not shown). In addition, our patient did not exhibit any microsatellite instability (data not shown). Since the Epstein-Barr virus (EBV)-positive status might be a marker of an effective response to ICIs in AGC (20,21), we performed EBV-encoded small RNA in situ hybridization on the primary tumor, which showed positivity in the nuclei of the tumor cells (Fig. 3). This result was consistent with that reported in previous reports (20,21). However, there are no reports on the predictive markers for a durable clinical benefit after the discontinuation of ICIs in AGC, and further study in many similar cases will be needed to clarify this, regardless of the distinctive features seen in our patient.
Figure 3. Hematoxylin and Eosin staining (A magnification 40×, C magnification 200×) and Epstein-Barr virus-encoded small RNA in situ hybridization (B magnification 40×, D magnification 200×) in the resected primary tumor.
Recent studies have shown that the development of irAE was associated with a clinical benefit in several cancers, including AGC (22-28). In NSCLC patients, in whom irAEs developed within 2 weeks from the start of nivolumab treatment (25), in whom more than two irAEs were reported (26), or in whom either endocrine irAEs or skin irAEs (28), a more pronounced benefit was observed. In melanoma cases, the occurrence of vitiligo as an irAE was associated with a clinical benefit (23,29,30), while endocrine irAE was not (23). In our patient, although the time to irAE occurrence was 15 weeks, which was longer than 2 weeks, two irAEs were detected, both of which were endocrine irAEs. The association between the types of irAEs and the clinical outcomes in different cancer types is still unclear.
ICIs induce multiple-organ irAEs via immune system overactivation (31). Two irAEs were observed in our patient. The incidence of endocrine irAEs varies depending on the agent, and nivolumab induces thyroid disorders in approximately 10% of such patients and hypophysitis in less than 1% of such patients (32,33). A patient often shows the development of multiple irAEs, but the common patterns of irAEs have been rarely reported. Although the pathogenic mechanism of ICI-triggered hypophysitis is unknown, the characteristic symptoms and imaging findings resemble those of autoimmune hypophysitis (34), which was also seen in our patient. The current guidelines suggest corticosteroid therapy and the replacement of deficient hormones to manage endocrine irAEs (35), and long-term hormonal replacement is indicated for ACTH deficiency secondary to hypophysitis (36), which was also effective in our patient.
Recent studies have reported that recurrence of the same or different irAEs was observed in 18-52% of patients who received ICI re-administration (37-39), and these were milder than the initial events (38-40). A large-scale observational study using data from the World Health Organization database reported that colitis, hepatitis, and pneumonitis are associated with a higher recurrence rate, whereas adrenal events are associated with a lower recurrence rate compared with other irAEs (40). The efficacy of ICI re-administration is not yet established. A large retrospective analysis of NSCLC patients who were discontinued nivolumab therapy for any reason showed that OS in patients who received ICI re-administration was significantly better than that in patients who received chemotherapy only after nivolumab, in a sub-group analysis among the patients who initially received nivolumab therapy for more than 3 months (41). On the other hand, a retrospective cohort study on ICI re-administration in patients with solid tumors after the occurrence of an initial grade 2 or higher irAE showed that PFS in the re-administered patients was not better than that in the non-re-administered patients (38). If recurrence is observed in our case, then we will consider the re-administration of ICI while carefully monitoring irAEs.
In conclusion, we treated a patient with AGC who maintained a durable response for approximately 2 years after discontinuation of nivolumab. To the best of our knowledge, this is the first report to describe a durable clinical benefit after the discontinuation of nivolumab in gastric cancer. Further studies are necessary to elucidate the mechanism and the predictive markers of a durable clinical benefit after ICI discontinuation. The risks and benefits of ICI re-administration should be considered on the basis of the type of initial irAE.
The authors state that they have no Conflict of Interest (COI).
|
CAPECITABINE, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, NIVOLUMAB, OXALIPLATIN, PACLITAXEL, RAMUCIRUMAB
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33162479
| 19,477,673
|
2021-04-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Secondary adrenocortical insufficiency'.
|
A Durable Response after the Discontinuation of Nivolumab in an Advanced Gastric Cancer Patient.
A durable response after the discontinuation of immune checkpoint-inhibitor therapy has previously been reported in several cancers. We herein describe a patient with gastric cancer who maintained a durable response after the discontinuation of nivolumab. A 65-year-old man was treated with nivolumab as a sixth-line therapy for recurrent gastric cancer. After four cycles of nivolumab therapy, he showed a partial response. But the treatment was discontinued when two immune-related adverse events occurred after six cycles. Disease regression was sustained for approximately 2 years, without the re-administration of nivolumab. The characteristics leading to such responses are unclear, and further studies are warranted in this regard.
Introduction
Nivolumab, a monoclonal antibody targeting programmed cell death-1 (PD-1), has been shown to provide remarkable efficacy in the treatment of patients with various kinds of malignant tumors and it is approved for the treatment of several cancers, including melanoma (1), non-small cell lung cancer (NSCLC) (2), renal cell carcinoma (RCC) (3), squamous cell carcinoma of the head and neck (4), and Hodgkin's lymphoma (5). The ATTRACTION-2 study was conducted to investigate the efficacy and safety of nivolumab for heavily pretreated advanced gastric cancer (AGC) patients (6). This randomized, double-blind, placebo-controlled phase 3 trial showed the superiority of nivolumab over a placebo, with an objective response rate of 11.2% [95% confidence interval (CI): 7.7-15.6], a median progression-free survival (PFS) of 1.61 months (95% CI: 1.54-2.30), and a median overall survival (OS) of 5.26 months (95% CI: 4.60- 6.37). Based on the results of this study, nivolumab was approved for AGC as either a third- or later-line treatment, and it has been recently recognized as a standard chemotherapeutic regimen in Japan.
Unlike in the case of conventional cytotoxic anticancer drugs or molecular targeted drugs, the blockade of the PD-1 pathway confers an adaptive memory immune response that resets the equilibrium between the tumor and host immune responses, thus indicating its potential to sustain an antitumor response even after treatment cessation (7). Recent studies have reported cases wherein a durable response was observed even after the discontinuation of therapy with immune checkpoint inhibitors (ICIs), including nivolumab, in melanoma, NSCLC, and RCC (8-10), but no such studies have so far been reported in patients with AGC.
Thus, in this study, we report a rare case of an AGC patient who maintained a durable response for approximately 2 years after the discontinuation of nivolumab due to immune-related adverse events (irAEs).
Case Report
The patient was a 65-year-old man who had been diagnosed with gastric cancer and had undergone total gastrectomy with D2 dissection 7.5 years previously, namely in August 2010. The pathological diagnosis was of a moderately differentiated HER2-negative, pT1N1, pStage IB adenocarcinoma. Six months postoperatively, a solitary liver metastasis was discovered. He then received S-1 treatment as palliative chemotherapy 7 years perviously in March 2011, following which he received nab-paclitaxel alone from May 2013, irinotecan alone from February 2016, capecitabine plus oxaliplatin from June 2016, and ramucirumab alone from February 2017. The disappearance of liver metastasis was observed after the administration of nab-paclitaxel alone. However, treatment with S-1, irinotecan, and ramucirumab was considered to be a failure owing to multiple abdominal lymph node metastases, portal tumor thrombus, and solitary lung metastasis, respectively (Fig. 1A).
Figure 1. (A) Abdominal computed tomography images before the commencement of nivolumab treatment. Solitary lung metastasis (arrow), portal tumor thrombus (solid circle), and multiple lymph node metastases (dotted circle) were observed. (B) After four cycles of nivolumab (approximately 2 months after start of nivolumab), the metastatic lesions shrank to 61.2% of the original size (before nivolumab treatment). (C) Twenty-three months after the discontinuation of nivolumab, the metastatic lesions further shrank to 39.1% of the original size (before nivolumab treatment).
Since he exhibited an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, he began to receive nivolumab as sixth-line therapy from March 2018. The laboratory data showed no abnormal findings (Table). The carcinoembryonic antigen and carbohydrate antigen 19-9 levels were within the normal range, which were similar to his preoperative levels. The patient's clinical course during nivolumab treatment is shown in Fig. 2. No adverse events were observed during the first five cycles of nivolumab therapy. However, after the sixth cycle, 15 weeks after the initial treatment, he was hospitalized for severe fatigue (grade 3 by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0). During hospitalization, he exhibited ECOG PS 3. Physical examination revealed that his body temperature was 36.8℃, blood pressure was 81/48 mmHg, pulse rate was 88/min, and oxygen saturation was 99% on room air. No other abnormal findings were identified. A serum examination revealed a decreased level of thyroid-stimulating hormone (TSH) and increased levels of free triiodothyronine and free thyroxine (T4) compared with the levels before nivolumab initiation (Table). The patient tested negative for thyroid autoantibodies. In addition, there was a decrease in the levels of adrenocorticotropic hormone (ACTH) and cortisol. A stimulation test revealed a minor impact of corticotropin-releasing hormone loading on the ACTH and cortisol levels, while growth hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, and TSH showed sufficient responses according to the corresponding stimulation tests. The ultrasound findings of the thyroid and magnetic resonance imaging findings of the pituitary gland showed no abnormalities. Consequently, he was diagnosed to have grade 3 isolated ACTH deficiency with secondary adrenal insufficiency and nivolumab-related grade 3 destructive thyroiditis. Nivolumab therapy was discontinued and prednisolone was supplemented at a starting dose of 15 mg/day for adrenal insufficiency. The patient's fatigue was alleviated within a few days, following which the prednisolone dose was tapered. His serum cortisol level returned to normal, whereas ACTH deficiency persisted. Prednisolone was maintained at a dosage of 5 mg/day since day 37, and no relapse was noted thereafter. The free T4 level decreased on day 23, confirming the hypothyroidism phase of destructive thyroiditis. Levothyroxine (25 μg/day) was administrated until the free T4 level recovered on day 95, and no relapse occurred thereafter.
Table. Laboratory Data.
Reference range Before nivolumab After 6 cycles of nivolumab
White blood cells /µL 4,000-9,000 3,500 3,400
Neutrophils % 45-55 47.8 47.7
Lymophocyte % 25-45 36.9 36.5
Hemoglobin g/dL 14-18 14.4 13.8
Platelets /µL 15-35×104 11.3×104 19.9×104
Lactate dehydrogenase U/I 106-211 155 249
Total bilirubin mg/dL 0.3-1.2 1.2 1.1
Sodium mEq/L 135-147 141 138
Potassium mEq/L 3.6-5.0 4.0 4.7
Chloride mEq/L 98-108 105 101
Calcium mg/dL 8.6-10.1 8.7 9.4
Urea nitrogen mg/dL 8-20 10.7 16.7
Creatinine mg/dL 0.61-1.04 0.95 1.00
C-reactive protein mg/dL 0-0.2 <0.03 0.46
Casual blood glucose mg/dL 70-199 – 192
Hemoglobin A1c % 4.6-6.2 5.5 5.4
CA19-9 U/mL <37.0 8.6 –
CEA ng/mL <5.0 2.3 –
TSH µU/mL 0.5-5.0 4.16 0.021
FT4 ng/dL 0.9-1.7 0.99 2.48
FT3 pg/mL 2.3-4.3 2.6 7.9
ACTH pg/mL 7.2-63.3 78.6 3.5
Cortisol µg/dL 7.07-19.6 14.6 0.2
GH ng/mL 0.0-2.0 – 1.2
LH mIU/mL 0.79-5.72 – 6.1
FSH mIU/mL 2.00-8.30 – 12.8
Prolactin ng/mL 4.29-13.69 – 9.7
ACTH: adrenocorticotropic hormone, CA19-9: carbohydrate antigen 19-9, CEA: carcinoembryonic antigen, FSH: follicle stimulating hormone, FT3: free triiodothyronine, FT4: free thyroxine, GH: growth hormone, LH: luteinizing hormone, TSH: thyroid stimulating hormone
Figure 2. The patient’s clinical course during nivolumab treatment. ACTH: adrenocorticotropic hormone, CORT: cortisol, FT4: free thyroxine, LT4: levothyroxine, PSL: prednisolone, TSH: thyroid stimulating hormone
After four cycles of nivolumab (approximately 2 months after the start of nivolumab therapy), all metastatic lesions shrank to around 61.2% of the size before nivolumab treatment (Fig. 1B). We determined to observe his course without the re-administration of nivolumab even after the improvement of irAEs. The metastatic lesions further decreased in size after the discontinuation of nivolumab, and the effect was sustained for 23 months after nivolumab initiation (final size, 39.1% of that before nivolumab treatment) (Fig. 1C); the tumor markers were within the normal ranges.
Discussion
Recently, a durable response after the discontinuation of ICIs in patients with residual disease has been reported for other kinds of cancers (8-10). It has previously been reported that PD-1/PD-L1 blockade rescued “exhausted” T cells, leading to the activation of T-cell effectors and transition to memory cells (7). The level of PD-1 occupancy on circulating T cells was shown to persist much longer than the serum half-life of the PD-1 antibodies (11,12). This might mean that there is no need to perform continuous treatment with ICIs. In fact, our patient showed that the metastatic lesions further decreased after the discontinuation of nivolumab.
Several predictive markers of an effective response to ICIs have been previously proposed for many cancers including AGC, such as better ECOG PS, no liver or lung metastases, a higher peripheral lymphocyte count, a lower neutrophil-to-lymphocyte ratio, a higher tumor PD-L1 expression, and a high degree of microsatellite instability (6,13-17). However, there have been a limited number of case reviews about the predictive markers for a durable clinical benefit after the discontinuation of ICIs, namely only in melanoma and RCC cases (8,10,18). In the KEYNOTE-001 study on pembrolizumab in patients with melanoma, 61 of 67 patients (91.0%), who were followed up after pembrolizumab discontinuation after a complete response (CR), achieved a disease-free survival of 24 months (18). It was suggested that the patients with CR were more likely to achieve a durable response. A univariate analysis revealed that high CR rates were associated with a target tumor size between 1 and 5 cm and PD-L1-positive tumors (≥1% staining in tumor cells and mononuclear inflammatory cells) (18). A retrospective cohort study on melanoma patients showed that the risk of disease progression following treatment discontinuation was significantly associated with the overall response and it was lower in patients with CR (19). However, none of these conditions were seen in our patient (no CR, unknown tumor PD-L1 status, and target tumor size: 7.7 cm; data not shown). In addition, our patient did not exhibit any microsatellite instability (data not shown). Since the Epstein-Barr virus (EBV)-positive status might be a marker of an effective response to ICIs in AGC (20,21), we performed EBV-encoded small RNA in situ hybridization on the primary tumor, which showed positivity in the nuclei of the tumor cells (Fig. 3). This result was consistent with that reported in previous reports (20,21). However, there are no reports on the predictive markers for a durable clinical benefit after the discontinuation of ICIs in AGC, and further study in many similar cases will be needed to clarify this, regardless of the distinctive features seen in our patient.
Figure 3. Hematoxylin and Eosin staining (A magnification 40×, C magnification 200×) and Epstein-Barr virus-encoded small RNA in situ hybridization (B magnification 40×, D magnification 200×) in the resected primary tumor.
Recent studies have shown that the development of irAE was associated with a clinical benefit in several cancers, including AGC (22-28). In NSCLC patients, in whom irAEs developed within 2 weeks from the start of nivolumab treatment (25), in whom more than two irAEs were reported (26), or in whom either endocrine irAEs or skin irAEs (28), a more pronounced benefit was observed. In melanoma cases, the occurrence of vitiligo as an irAE was associated with a clinical benefit (23,29,30), while endocrine irAE was not (23). In our patient, although the time to irAE occurrence was 15 weeks, which was longer than 2 weeks, two irAEs were detected, both of which were endocrine irAEs. The association between the types of irAEs and the clinical outcomes in different cancer types is still unclear.
ICIs induce multiple-organ irAEs via immune system overactivation (31). Two irAEs were observed in our patient. The incidence of endocrine irAEs varies depending on the agent, and nivolumab induces thyroid disorders in approximately 10% of such patients and hypophysitis in less than 1% of such patients (32,33). A patient often shows the development of multiple irAEs, but the common patterns of irAEs have been rarely reported. Although the pathogenic mechanism of ICI-triggered hypophysitis is unknown, the characteristic symptoms and imaging findings resemble those of autoimmune hypophysitis (34), which was also seen in our patient. The current guidelines suggest corticosteroid therapy and the replacement of deficient hormones to manage endocrine irAEs (35), and long-term hormonal replacement is indicated for ACTH deficiency secondary to hypophysitis (36), which was also effective in our patient.
Recent studies have reported that recurrence of the same or different irAEs was observed in 18-52% of patients who received ICI re-administration (37-39), and these were milder than the initial events (38-40). A large-scale observational study using data from the World Health Organization database reported that colitis, hepatitis, and pneumonitis are associated with a higher recurrence rate, whereas adrenal events are associated with a lower recurrence rate compared with other irAEs (40). The efficacy of ICI re-administration is not yet established. A large retrospective analysis of NSCLC patients who were discontinued nivolumab therapy for any reason showed that OS in patients who received ICI re-administration was significantly better than that in patients who received chemotherapy only after nivolumab, in a sub-group analysis among the patients who initially received nivolumab therapy for more than 3 months (41). On the other hand, a retrospective cohort study on ICI re-administration in patients with solid tumors after the occurrence of an initial grade 2 or higher irAE showed that PFS in the re-administered patients was not better than that in the non-re-administered patients (38). If recurrence is observed in our case, then we will consider the re-administration of ICI while carefully monitoring irAEs.
In conclusion, we treated a patient with AGC who maintained a durable response for approximately 2 years after discontinuation of nivolumab. To the best of our knowledge, this is the first report to describe a durable clinical benefit after the discontinuation of nivolumab in gastric cancer. Further studies are necessary to elucidate the mechanism and the predictive markers of a durable clinical benefit after ICI discontinuation. The risks and benefits of ICI re-administration should be considered on the basis of the type of initial irAE.
The authors state that they have no Conflict of Interest (COI).
|
CAPECITABINE, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, NIVOLUMAB, OXALIPLATIN, PACLITAXEL, RAMUCIRUMAB
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33162479
| 19,477,673
|
2021-04-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thyroiditis'.
|
A Durable Response after the Discontinuation of Nivolumab in an Advanced Gastric Cancer Patient.
A durable response after the discontinuation of immune checkpoint-inhibitor therapy has previously been reported in several cancers. We herein describe a patient with gastric cancer who maintained a durable response after the discontinuation of nivolumab. A 65-year-old man was treated with nivolumab as a sixth-line therapy for recurrent gastric cancer. After four cycles of nivolumab therapy, he showed a partial response. But the treatment was discontinued when two immune-related adverse events occurred after six cycles. Disease regression was sustained for approximately 2 years, without the re-administration of nivolumab. The characteristics leading to such responses are unclear, and further studies are warranted in this regard.
Introduction
Nivolumab, a monoclonal antibody targeting programmed cell death-1 (PD-1), has been shown to provide remarkable efficacy in the treatment of patients with various kinds of malignant tumors and it is approved for the treatment of several cancers, including melanoma (1), non-small cell lung cancer (NSCLC) (2), renal cell carcinoma (RCC) (3), squamous cell carcinoma of the head and neck (4), and Hodgkin's lymphoma (5). The ATTRACTION-2 study was conducted to investigate the efficacy and safety of nivolumab for heavily pretreated advanced gastric cancer (AGC) patients (6). This randomized, double-blind, placebo-controlled phase 3 trial showed the superiority of nivolumab over a placebo, with an objective response rate of 11.2% [95% confidence interval (CI): 7.7-15.6], a median progression-free survival (PFS) of 1.61 months (95% CI: 1.54-2.30), and a median overall survival (OS) of 5.26 months (95% CI: 4.60- 6.37). Based on the results of this study, nivolumab was approved for AGC as either a third- or later-line treatment, and it has been recently recognized as a standard chemotherapeutic regimen in Japan.
Unlike in the case of conventional cytotoxic anticancer drugs or molecular targeted drugs, the blockade of the PD-1 pathway confers an adaptive memory immune response that resets the equilibrium between the tumor and host immune responses, thus indicating its potential to sustain an antitumor response even after treatment cessation (7). Recent studies have reported cases wherein a durable response was observed even after the discontinuation of therapy with immune checkpoint inhibitors (ICIs), including nivolumab, in melanoma, NSCLC, and RCC (8-10), but no such studies have so far been reported in patients with AGC.
Thus, in this study, we report a rare case of an AGC patient who maintained a durable response for approximately 2 years after the discontinuation of nivolumab due to immune-related adverse events (irAEs).
Case Report
The patient was a 65-year-old man who had been diagnosed with gastric cancer and had undergone total gastrectomy with D2 dissection 7.5 years previously, namely in August 2010. The pathological diagnosis was of a moderately differentiated HER2-negative, pT1N1, pStage IB adenocarcinoma. Six months postoperatively, a solitary liver metastasis was discovered. He then received S-1 treatment as palliative chemotherapy 7 years perviously in March 2011, following which he received nab-paclitaxel alone from May 2013, irinotecan alone from February 2016, capecitabine plus oxaliplatin from June 2016, and ramucirumab alone from February 2017. The disappearance of liver metastasis was observed after the administration of nab-paclitaxel alone. However, treatment with S-1, irinotecan, and ramucirumab was considered to be a failure owing to multiple abdominal lymph node metastases, portal tumor thrombus, and solitary lung metastasis, respectively (Fig. 1A).
Figure 1. (A) Abdominal computed tomography images before the commencement of nivolumab treatment. Solitary lung metastasis (arrow), portal tumor thrombus (solid circle), and multiple lymph node metastases (dotted circle) were observed. (B) After four cycles of nivolumab (approximately 2 months after start of nivolumab), the metastatic lesions shrank to 61.2% of the original size (before nivolumab treatment). (C) Twenty-three months after the discontinuation of nivolumab, the metastatic lesions further shrank to 39.1% of the original size (before nivolumab treatment).
Since he exhibited an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, he began to receive nivolumab as sixth-line therapy from March 2018. The laboratory data showed no abnormal findings (Table). The carcinoembryonic antigen and carbohydrate antigen 19-9 levels were within the normal range, which were similar to his preoperative levels. The patient's clinical course during nivolumab treatment is shown in Fig. 2. No adverse events were observed during the first five cycles of nivolumab therapy. However, after the sixth cycle, 15 weeks after the initial treatment, he was hospitalized for severe fatigue (grade 3 by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0). During hospitalization, he exhibited ECOG PS 3. Physical examination revealed that his body temperature was 36.8℃, blood pressure was 81/48 mmHg, pulse rate was 88/min, and oxygen saturation was 99% on room air. No other abnormal findings were identified. A serum examination revealed a decreased level of thyroid-stimulating hormone (TSH) and increased levels of free triiodothyronine and free thyroxine (T4) compared with the levels before nivolumab initiation (Table). The patient tested negative for thyroid autoantibodies. In addition, there was a decrease in the levels of adrenocorticotropic hormone (ACTH) and cortisol. A stimulation test revealed a minor impact of corticotropin-releasing hormone loading on the ACTH and cortisol levels, while growth hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, and TSH showed sufficient responses according to the corresponding stimulation tests. The ultrasound findings of the thyroid and magnetic resonance imaging findings of the pituitary gland showed no abnormalities. Consequently, he was diagnosed to have grade 3 isolated ACTH deficiency with secondary adrenal insufficiency and nivolumab-related grade 3 destructive thyroiditis. Nivolumab therapy was discontinued and prednisolone was supplemented at a starting dose of 15 mg/day for adrenal insufficiency. The patient's fatigue was alleviated within a few days, following which the prednisolone dose was tapered. His serum cortisol level returned to normal, whereas ACTH deficiency persisted. Prednisolone was maintained at a dosage of 5 mg/day since day 37, and no relapse was noted thereafter. The free T4 level decreased on day 23, confirming the hypothyroidism phase of destructive thyroiditis. Levothyroxine (25 μg/day) was administrated until the free T4 level recovered on day 95, and no relapse occurred thereafter.
Table. Laboratory Data.
Reference range Before nivolumab After 6 cycles of nivolumab
White blood cells /µL 4,000-9,000 3,500 3,400
Neutrophils % 45-55 47.8 47.7
Lymophocyte % 25-45 36.9 36.5
Hemoglobin g/dL 14-18 14.4 13.8
Platelets /µL 15-35×104 11.3×104 19.9×104
Lactate dehydrogenase U/I 106-211 155 249
Total bilirubin mg/dL 0.3-1.2 1.2 1.1
Sodium mEq/L 135-147 141 138
Potassium mEq/L 3.6-5.0 4.0 4.7
Chloride mEq/L 98-108 105 101
Calcium mg/dL 8.6-10.1 8.7 9.4
Urea nitrogen mg/dL 8-20 10.7 16.7
Creatinine mg/dL 0.61-1.04 0.95 1.00
C-reactive protein mg/dL 0-0.2 <0.03 0.46
Casual blood glucose mg/dL 70-199 – 192
Hemoglobin A1c % 4.6-6.2 5.5 5.4
CA19-9 U/mL <37.0 8.6 –
CEA ng/mL <5.0 2.3 –
TSH µU/mL 0.5-5.0 4.16 0.021
FT4 ng/dL 0.9-1.7 0.99 2.48
FT3 pg/mL 2.3-4.3 2.6 7.9
ACTH pg/mL 7.2-63.3 78.6 3.5
Cortisol µg/dL 7.07-19.6 14.6 0.2
GH ng/mL 0.0-2.0 – 1.2
LH mIU/mL 0.79-5.72 – 6.1
FSH mIU/mL 2.00-8.30 – 12.8
Prolactin ng/mL 4.29-13.69 – 9.7
ACTH: adrenocorticotropic hormone, CA19-9: carbohydrate antigen 19-9, CEA: carcinoembryonic antigen, FSH: follicle stimulating hormone, FT3: free triiodothyronine, FT4: free thyroxine, GH: growth hormone, LH: luteinizing hormone, TSH: thyroid stimulating hormone
Figure 2. The patient’s clinical course during nivolumab treatment. ACTH: adrenocorticotropic hormone, CORT: cortisol, FT4: free thyroxine, LT4: levothyroxine, PSL: prednisolone, TSH: thyroid stimulating hormone
After four cycles of nivolumab (approximately 2 months after the start of nivolumab therapy), all metastatic lesions shrank to around 61.2% of the size before nivolumab treatment (Fig. 1B). We determined to observe his course without the re-administration of nivolumab even after the improvement of irAEs. The metastatic lesions further decreased in size after the discontinuation of nivolumab, and the effect was sustained for 23 months after nivolumab initiation (final size, 39.1% of that before nivolumab treatment) (Fig. 1C); the tumor markers were within the normal ranges.
Discussion
Recently, a durable response after the discontinuation of ICIs in patients with residual disease has been reported for other kinds of cancers (8-10). It has previously been reported that PD-1/PD-L1 blockade rescued “exhausted” T cells, leading to the activation of T-cell effectors and transition to memory cells (7). The level of PD-1 occupancy on circulating T cells was shown to persist much longer than the serum half-life of the PD-1 antibodies (11,12). This might mean that there is no need to perform continuous treatment with ICIs. In fact, our patient showed that the metastatic lesions further decreased after the discontinuation of nivolumab.
Several predictive markers of an effective response to ICIs have been previously proposed for many cancers including AGC, such as better ECOG PS, no liver or lung metastases, a higher peripheral lymphocyte count, a lower neutrophil-to-lymphocyte ratio, a higher tumor PD-L1 expression, and a high degree of microsatellite instability (6,13-17). However, there have been a limited number of case reviews about the predictive markers for a durable clinical benefit after the discontinuation of ICIs, namely only in melanoma and RCC cases (8,10,18). In the KEYNOTE-001 study on pembrolizumab in patients with melanoma, 61 of 67 patients (91.0%), who were followed up after pembrolizumab discontinuation after a complete response (CR), achieved a disease-free survival of 24 months (18). It was suggested that the patients with CR were more likely to achieve a durable response. A univariate analysis revealed that high CR rates were associated with a target tumor size between 1 and 5 cm and PD-L1-positive tumors (≥1% staining in tumor cells and mononuclear inflammatory cells) (18). A retrospective cohort study on melanoma patients showed that the risk of disease progression following treatment discontinuation was significantly associated with the overall response and it was lower in patients with CR (19). However, none of these conditions were seen in our patient (no CR, unknown tumor PD-L1 status, and target tumor size: 7.7 cm; data not shown). In addition, our patient did not exhibit any microsatellite instability (data not shown). Since the Epstein-Barr virus (EBV)-positive status might be a marker of an effective response to ICIs in AGC (20,21), we performed EBV-encoded small RNA in situ hybridization on the primary tumor, which showed positivity in the nuclei of the tumor cells (Fig. 3). This result was consistent with that reported in previous reports (20,21). However, there are no reports on the predictive markers for a durable clinical benefit after the discontinuation of ICIs in AGC, and further study in many similar cases will be needed to clarify this, regardless of the distinctive features seen in our patient.
Figure 3. Hematoxylin and Eosin staining (A magnification 40×, C magnification 200×) and Epstein-Barr virus-encoded small RNA in situ hybridization (B magnification 40×, D magnification 200×) in the resected primary tumor.
Recent studies have shown that the development of irAE was associated with a clinical benefit in several cancers, including AGC (22-28). In NSCLC patients, in whom irAEs developed within 2 weeks from the start of nivolumab treatment (25), in whom more than two irAEs were reported (26), or in whom either endocrine irAEs or skin irAEs (28), a more pronounced benefit was observed. In melanoma cases, the occurrence of vitiligo as an irAE was associated with a clinical benefit (23,29,30), while endocrine irAE was not (23). In our patient, although the time to irAE occurrence was 15 weeks, which was longer than 2 weeks, two irAEs were detected, both of which were endocrine irAEs. The association between the types of irAEs and the clinical outcomes in different cancer types is still unclear.
ICIs induce multiple-organ irAEs via immune system overactivation (31). Two irAEs were observed in our patient. The incidence of endocrine irAEs varies depending on the agent, and nivolumab induces thyroid disorders in approximately 10% of such patients and hypophysitis in less than 1% of such patients (32,33). A patient often shows the development of multiple irAEs, but the common patterns of irAEs have been rarely reported. Although the pathogenic mechanism of ICI-triggered hypophysitis is unknown, the characteristic symptoms and imaging findings resemble those of autoimmune hypophysitis (34), which was also seen in our patient. The current guidelines suggest corticosteroid therapy and the replacement of deficient hormones to manage endocrine irAEs (35), and long-term hormonal replacement is indicated for ACTH deficiency secondary to hypophysitis (36), which was also effective in our patient.
Recent studies have reported that recurrence of the same or different irAEs was observed in 18-52% of patients who received ICI re-administration (37-39), and these were milder than the initial events (38-40). A large-scale observational study using data from the World Health Organization database reported that colitis, hepatitis, and pneumonitis are associated with a higher recurrence rate, whereas adrenal events are associated with a lower recurrence rate compared with other irAEs (40). The efficacy of ICI re-administration is not yet established. A large retrospective analysis of NSCLC patients who were discontinued nivolumab therapy for any reason showed that OS in patients who received ICI re-administration was significantly better than that in patients who received chemotherapy only after nivolumab, in a sub-group analysis among the patients who initially received nivolumab therapy for more than 3 months (41). On the other hand, a retrospective cohort study on ICI re-administration in patients with solid tumors after the occurrence of an initial grade 2 or higher irAE showed that PFS in the re-administered patients was not better than that in the non-re-administered patients (38). If recurrence is observed in our case, then we will consider the re-administration of ICI while carefully monitoring irAEs.
In conclusion, we treated a patient with AGC who maintained a durable response for approximately 2 years after discontinuation of nivolumab. To the best of our knowledge, this is the first report to describe a durable clinical benefit after the discontinuation of nivolumab in gastric cancer. Further studies are necessary to elucidate the mechanism and the predictive markers of a durable clinical benefit after ICI discontinuation. The risks and benefits of ICI re-administration should be considered on the basis of the type of initial irAE.
The authors state that they have no Conflict of Interest (COI).
|
CAPECITABINE, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, NIVOLUMAB, OXALIPLATIN, PACLITAXEL, RAMUCIRUMAB
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33162479
| 19,477,673
|
2021-04-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'.
|
A Durable Response after the Discontinuation of Nivolumab in an Advanced Gastric Cancer Patient.
A durable response after the discontinuation of immune checkpoint-inhibitor therapy has previously been reported in several cancers. We herein describe a patient with gastric cancer who maintained a durable response after the discontinuation of nivolumab. A 65-year-old man was treated with nivolumab as a sixth-line therapy for recurrent gastric cancer. After four cycles of nivolumab therapy, he showed a partial response. But the treatment was discontinued when two immune-related adverse events occurred after six cycles. Disease regression was sustained for approximately 2 years, without the re-administration of nivolumab. The characteristics leading to such responses are unclear, and further studies are warranted in this regard.
Introduction
Nivolumab, a monoclonal antibody targeting programmed cell death-1 (PD-1), has been shown to provide remarkable efficacy in the treatment of patients with various kinds of malignant tumors and it is approved for the treatment of several cancers, including melanoma (1), non-small cell lung cancer (NSCLC) (2), renal cell carcinoma (RCC) (3), squamous cell carcinoma of the head and neck (4), and Hodgkin's lymphoma (5). The ATTRACTION-2 study was conducted to investigate the efficacy and safety of nivolumab for heavily pretreated advanced gastric cancer (AGC) patients (6). This randomized, double-blind, placebo-controlled phase 3 trial showed the superiority of nivolumab over a placebo, with an objective response rate of 11.2% [95% confidence interval (CI): 7.7-15.6], a median progression-free survival (PFS) of 1.61 months (95% CI: 1.54-2.30), and a median overall survival (OS) of 5.26 months (95% CI: 4.60- 6.37). Based on the results of this study, nivolumab was approved for AGC as either a third- or later-line treatment, and it has been recently recognized as a standard chemotherapeutic regimen in Japan.
Unlike in the case of conventional cytotoxic anticancer drugs or molecular targeted drugs, the blockade of the PD-1 pathway confers an adaptive memory immune response that resets the equilibrium between the tumor and host immune responses, thus indicating its potential to sustain an antitumor response even after treatment cessation (7). Recent studies have reported cases wherein a durable response was observed even after the discontinuation of therapy with immune checkpoint inhibitors (ICIs), including nivolumab, in melanoma, NSCLC, and RCC (8-10), but no such studies have so far been reported in patients with AGC.
Thus, in this study, we report a rare case of an AGC patient who maintained a durable response for approximately 2 years after the discontinuation of nivolumab due to immune-related adverse events (irAEs).
Case Report
The patient was a 65-year-old man who had been diagnosed with gastric cancer and had undergone total gastrectomy with D2 dissection 7.5 years previously, namely in August 2010. The pathological diagnosis was of a moderately differentiated HER2-negative, pT1N1, pStage IB adenocarcinoma. Six months postoperatively, a solitary liver metastasis was discovered. He then received S-1 treatment as palliative chemotherapy 7 years perviously in March 2011, following which he received nab-paclitaxel alone from May 2013, irinotecan alone from February 2016, capecitabine plus oxaliplatin from June 2016, and ramucirumab alone from February 2017. The disappearance of liver metastasis was observed after the administration of nab-paclitaxel alone. However, treatment with S-1, irinotecan, and ramucirumab was considered to be a failure owing to multiple abdominal lymph node metastases, portal tumor thrombus, and solitary lung metastasis, respectively (Fig. 1A).
Figure 1. (A) Abdominal computed tomography images before the commencement of nivolumab treatment. Solitary lung metastasis (arrow), portal tumor thrombus (solid circle), and multiple lymph node metastases (dotted circle) were observed. (B) After four cycles of nivolumab (approximately 2 months after start of nivolumab), the metastatic lesions shrank to 61.2% of the original size (before nivolumab treatment). (C) Twenty-three months after the discontinuation of nivolumab, the metastatic lesions further shrank to 39.1% of the original size (before nivolumab treatment).
Since he exhibited an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, he began to receive nivolumab as sixth-line therapy from March 2018. The laboratory data showed no abnormal findings (Table). The carcinoembryonic antigen and carbohydrate antigen 19-9 levels were within the normal range, which were similar to his preoperative levels. The patient's clinical course during nivolumab treatment is shown in Fig. 2. No adverse events were observed during the first five cycles of nivolumab therapy. However, after the sixth cycle, 15 weeks after the initial treatment, he was hospitalized for severe fatigue (grade 3 by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0). During hospitalization, he exhibited ECOG PS 3. Physical examination revealed that his body temperature was 36.8℃, blood pressure was 81/48 mmHg, pulse rate was 88/min, and oxygen saturation was 99% on room air. No other abnormal findings were identified. A serum examination revealed a decreased level of thyroid-stimulating hormone (TSH) and increased levels of free triiodothyronine and free thyroxine (T4) compared with the levels before nivolumab initiation (Table). The patient tested negative for thyroid autoantibodies. In addition, there was a decrease in the levels of adrenocorticotropic hormone (ACTH) and cortisol. A stimulation test revealed a minor impact of corticotropin-releasing hormone loading on the ACTH and cortisol levels, while growth hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, and TSH showed sufficient responses according to the corresponding stimulation tests. The ultrasound findings of the thyroid and magnetic resonance imaging findings of the pituitary gland showed no abnormalities. Consequently, he was diagnosed to have grade 3 isolated ACTH deficiency with secondary adrenal insufficiency and nivolumab-related grade 3 destructive thyroiditis. Nivolumab therapy was discontinued and prednisolone was supplemented at a starting dose of 15 mg/day for adrenal insufficiency. The patient's fatigue was alleviated within a few days, following which the prednisolone dose was tapered. His serum cortisol level returned to normal, whereas ACTH deficiency persisted. Prednisolone was maintained at a dosage of 5 mg/day since day 37, and no relapse was noted thereafter. The free T4 level decreased on day 23, confirming the hypothyroidism phase of destructive thyroiditis. Levothyroxine (25 μg/day) was administrated until the free T4 level recovered on day 95, and no relapse occurred thereafter.
Table. Laboratory Data.
Reference range Before nivolumab After 6 cycles of nivolumab
White blood cells /µL 4,000-9,000 3,500 3,400
Neutrophils % 45-55 47.8 47.7
Lymophocyte % 25-45 36.9 36.5
Hemoglobin g/dL 14-18 14.4 13.8
Platelets /µL 15-35×104 11.3×104 19.9×104
Lactate dehydrogenase U/I 106-211 155 249
Total bilirubin mg/dL 0.3-1.2 1.2 1.1
Sodium mEq/L 135-147 141 138
Potassium mEq/L 3.6-5.0 4.0 4.7
Chloride mEq/L 98-108 105 101
Calcium mg/dL 8.6-10.1 8.7 9.4
Urea nitrogen mg/dL 8-20 10.7 16.7
Creatinine mg/dL 0.61-1.04 0.95 1.00
C-reactive protein mg/dL 0-0.2 <0.03 0.46
Casual blood glucose mg/dL 70-199 – 192
Hemoglobin A1c % 4.6-6.2 5.5 5.4
CA19-9 U/mL <37.0 8.6 –
CEA ng/mL <5.0 2.3 –
TSH µU/mL 0.5-5.0 4.16 0.021
FT4 ng/dL 0.9-1.7 0.99 2.48
FT3 pg/mL 2.3-4.3 2.6 7.9
ACTH pg/mL 7.2-63.3 78.6 3.5
Cortisol µg/dL 7.07-19.6 14.6 0.2
GH ng/mL 0.0-2.0 – 1.2
LH mIU/mL 0.79-5.72 – 6.1
FSH mIU/mL 2.00-8.30 – 12.8
Prolactin ng/mL 4.29-13.69 – 9.7
ACTH: adrenocorticotropic hormone, CA19-9: carbohydrate antigen 19-9, CEA: carcinoembryonic antigen, FSH: follicle stimulating hormone, FT3: free triiodothyronine, FT4: free thyroxine, GH: growth hormone, LH: luteinizing hormone, TSH: thyroid stimulating hormone
Figure 2. The patient’s clinical course during nivolumab treatment. ACTH: adrenocorticotropic hormone, CORT: cortisol, FT4: free thyroxine, LT4: levothyroxine, PSL: prednisolone, TSH: thyroid stimulating hormone
After four cycles of nivolumab (approximately 2 months after the start of nivolumab therapy), all metastatic lesions shrank to around 61.2% of the size before nivolumab treatment (Fig. 1B). We determined to observe his course without the re-administration of nivolumab even after the improvement of irAEs. The metastatic lesions further decreased in size after the discontinuation of nivolumab, and the effect was sustained for 23 months after nivolumab initiation (final size, 39.1% of that before nivolumab treatment) (Fig. 1C); the tumor markers were within the normal ranges.
Discussion
Recently, a durable response after the discontinuation of ICIs in patients with residual disease has been reported for other kinds of cancers (8-10). It has previously been reported that PD-1/PD-L1 blockade rescued “exhausted” T cells, leading to the activation of T-cell effectors and transition to memory cells (7). The level of PD-1 occupancy on circulating T cells was shown to persist much longer than the serum half-life of the PD-1 antibodies (11,12). This might mean that there is no need to perform continuous treatment with ICIs. In fact, our patient showed that the metastatic lesions further decreased after the discontinuation of nivolumab.
Several predictive markers of an effective response to ICIs have been previously proposed for many cancers including AGC, such as better ECOG PS, no liver or lung metastases, a higher peripheral lymphocyte count, a lower neutrophil-to-lymphocyte ratio, a higher tumor PD-L1 expression, and a high degree of microsatellite instability (6,13-17). However, there have been a limited number of case reviews about the predictive markers for a durable clinical benefit after the discontinuation of ICIs, namely only in melanoma and RCC cases (8,10,18). In the KEYNOTE-001 study on pembrolizumab in patients with melanoma, 61 of 67 patients (91.0%), who were followed up after pembrolizumab discontinuation after a complete response (CR), achieved a disease-free survival of 24 months (18). It was suggested that the patients with CR were more likely to achieve a durable response. A univariate analysis revealed that high CR rates were associated with a target tumor size between 1 and 5 cm and PD-L1-positive tumors (≥1% staining in tumor cells and mononuclear inflammatory cells) (18). A retrospective cohort study on melanoma patients showed that the risk of disease progression following treatment discontinuation was significantly associated with the overall response and it was lower in patients with CR (19). However, none of these conditions were seen in our patient (no CR, unknown tumor PD-L1 status, and target tumor size: 7.7 cm; data not shown). In addition, our patient did not exhibit any microsatellite instability (data not shown). Since the Epstein-Barr virus (EBV)-positive status might be a marker of an effective response to ICIs in AGC (20,21), we performed EBV-encoded small RNA in situ hybridization on the primary tumor, which showed positivity in the nuclei of the tumor cells (Fig. 3). This result was consistent with that reported in previous reports (20,21). However, there are no reports on the predictive markers for a durable clinical benefit after the discontinuation of ICIs in AGC, and further study in many similar cases will be needed to clarify this, regardless of the distinctive features seen in our patient.
Figure 3. Hematoxylin and Eosin staining (A magnification 40×, C magnification 200×) and Epstein-Barr virus-encoded small RNA in situ hybridization (B magnification 40×, D magnification 200×) in the resected primary tumor.
Recent studies have shown that the development of irAE was associated with a clinical benefit in several cancers, including AGC (22-28). In NSCLC patients, in whom irAEs developed within 2 weeks from the start of nivolumab treatment (25), in whom more than two irAEs were reported (26), or in whom either endocrine irAEs or skin irAEs (28), a more pronounced benefit was observed. In melanoma cases, the occurrence of vitiligo as an irAE was associated with a clinical benefit (23,29,30), while endocrine irAE was not (23). In our patient, although the time to irAE occurrence was 15 weeks, which was longer than 2 weeks, two irAEs were detected, both of which were endocrine irAEs. The association between the types of irAEs and the clinical outcomes in different cancer types is still unclear.
ICIs induce multiple-organ irAEs via immune system overactivation (31). Two irAEs were observed in our patient. The incidence of endocrine irAEs varies depending on the agent, and nivolumab induces thyroid disorders in approximately 10% of such patients and hypophysitis in less than 1% of such patients (32,33). A patient often shows the development of multiple irAEs, but the common patterns of irAEs have been rarely reported. Although the pathogenic mechanism of ICI-triggered hypophysitis is unknown, the characteristic symptoms and imaging findings resemble those of autoimmune hypophysitis (34), which was also seen in our patient. The current guidelines suggest corticosteroid therapy and the replacement of deficient hormones to manage endocrine irAEs (35), and long-term hormonal replacement is indicated for ACTH deficiency secondary to hypophysitis (36), which was also effective in our patient.
Recent studies have reported that recurrence of the same or different irAEs was observed in 18-52% of patients who received ICI re-administration (37-39), and these were milder than the initial events (38-40). A large-scale observational study using data from the World Health Organization database reported that colitis, hepatitis, and pneumonitis are associated with a higher recurrence rate, whereas adrenal events are associated with a lower recurrence rate compared with other irAEs (40). The efficacy of ICI re-administration is not yet established. A large retrospective analysis of NSCLC patients who were discontinued nivolumab therapy for any reason showed that OS in patients who received ICI re-administration was significantly better than that in patients who received chemotherapy only after nivolumab, in a sub-group analysis among the patients who initially received nivolumab therapy for more than 3 months (41). On the other hand, a retrospective cohort study on ICI re-administration in patients with solid tumors after the occurrence of an initial grade 2 or higher irAE showed that PFS in the re-administered patients was not better than that in the non-re-administered patients (38). If recurrence is observed in our case, then we will consider the re-administration of ICI while carefully monitoring irAEs.
In conclusion, we treated a patient with AGC who maintained a durable response for approximately 2 years after discontinuation of nivolumab. To the best of our knowledge, this is the first report to describe a durable clinical benefit after the discontinuation of nivolumab in gastric cancer. Further studies are necessary to elucidate the mechanism and the predictive markers of a durable clinical benefit after ICI discontinuation. The risks and benefits of ICI re-administration should be considered on the basis of the type of initial irAE.
The authors state that they have no Conflict of Interest (COI).
|
CAPECITABINE, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, NIVOLUMAB, OXALIPLATIN, PACLITAXEL, RAMUCIRUMAB
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33162479
| 19,477,673
|
2021-04-01
|
What was the outcome of reaction 'Hypothyroidism'?
|
A Durable Response after the Discontinuation of Nivolumab in an Advanced Gastric Cancer Patient.
A durable response after the discontinuation of immune checkpoint-inhibitor therapy has previously been reported in several cancers. We herein describe a patient with gastric cancer who maintained a durable response after the discontinuation of nivolumab. A 65-year-old man was treated with nivolumab as a sixth-line therapy for recurrent gastric cancer. After four cycles of nivolumab therapy, he showed a partial response. But the treatment was discontinued when two immune-related adverse events occurred after six cycles. Disease regression was sustained for approximately 2 years, without the re-administration of nivolumab. The characteristics leading to such responses are unclear, and further studies are warranted in this regard.
Introduction
Nivolumab, a monoclonal antibody targeting programmed cell death-1 (PD-1), has been shown to provide remarkable efficacy in the treatment of patients with various kinds of malignant tumors and it is approved for the treatment of several cancers, including melanoma (1), non-small cell lung cancer (NSCLC) (2), renal cell carcinoma (RCC) (3), squamous cell carcinoma of the head and neck (4), and Hodgkin's lymphoma (5). The ATTRACTION-2 study was conducted to investigate the efficacy and safety of nivolumab for heavily pretreated advanced gastric cancer (AGC) patients (6). This randomized, double-blind, placebo-controlled phase 3 trial showed the superiority of nivolumab over a placebo, with an objective response rate of 11.2% [95% confidence interval (CI): 7.7-15.6], a median progression-free survival (PFS) of 1.61 months (95% CI: 1.54-2.30), and a median overall survival (OS) of 5.26 months (95% CI: 4.60- 6.37). Based on the results of this study, nivolumab was approved for AGC as either a third- or later-line treatment, and it has been recently recognized as a standard chemotherapeutic regimen in Japan.
Unlike in the case of conventional cytotoxic anticancer drugs or molecular targeted drugs, the blockade of the PD-1 pathway confers an adaptive memory immune response that resets the equilibrium between the tumor and host immune responses, thus indicating its potential to sustain an antitumor response even after treatment cessation (7). Recent studies have reported cases wherein a durable response was observed even after the discontinuation of therapy with immune checkpoint inhibitors (ICIs), including nivolumab, in melanoma, NSCLC, and RCC (8-10), but no such studies have so far been reported in patients with AGC.
Thus, in this study, we report a rare case of an AGC patient who maintained a durable response for approximately 2 years after the discontinuation of nivolumab due to immune-related adverse events (irAEs).
Case Report
The patient was a 65-year-old man who had been diagnosed with gastric cancer and had undergone total gastrectomy with D2 dissection 7.5 years previously, namely in August 2010. The pathological diagnosis was of a moderately differentiated HER2-negative, pT1N1, pStage IB adenocarcinoma. Six months postoperatively, a solitary liver metastasis was discovered. He then received S-1 treatment as palliative chemotherapy 7 years perviously in March 2011, following which he received nab-paclitaxel alone from May 2013, irinotecan alone from February 2016, capecitabine plus oxaliplatin from June 2016, and ramucirumab alone from February 2017. The disappearance of liver metastasis was observed after the administration of nab-paclitaxel alone. However, treatment with S-1, irinotecan, and ramucirumab was considered to be a failure owing to multiple abdominal lymph node metastases, portal tumor thrombus, and solitary lung metastasis, respectively (Fig. 1A).
Figure 1. (A) Abdominal computed tomography images before the commencement of nivolumab treatment. Solitary lung metastasis (arrow), portal tumor thrombus (solid circle), and multiple lymph node metastases (dotted circle) were observed. (B) After four cycles of nivolumab (approximately 2 months after start of nivolumab), the metastatic lesions shrank to 61.2% of the original size (before nivolumab treatment). (C) Twenty-three months after the discontinuation of nivolumab, the metastatic lesions further shrank to 39.1% of the original size (before nivolumab treatment).
Since he exhibited an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, he began to receive nivolumab as sixth-line therapy from March 2018. The laboratory data showed no abnormal findings (Table). The carcinoembryonic antigen and carbohydrate antigen 19-9 levels were within the normal range, which were similar to his preoperative levels. The patient's clinical course during nivolumab treatment is shown in Fig. 2. No adverse events were observed during the first five cycles of nivolumab therapy. However, after the sixth cycle, 15 weeks after the initial treatment, he was hospitalized for severe fatigue (grade 3 by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0). During hospitalization, he exhibited ECOG PS 3. Physical examination revealed that his body temperature was 36.8℃, blood pressure was 81/48 mmHg, pulse rate was 88/min, and oxygen saturation was 99% on room air. No other abnormal findings were identified. A serum examination revealed a decreased level of thyroid-stimulating hormone (TSH) and increased levels of free triiodothyronine and free thyroxine (T4) compared with the levels before nivolumab initiation (Table). The patient tested negative for thyroid autoantibodies. In addition, there was a decrease in the levels of adrenocorticotropic hormone (ACTH) and cortisol. A stimulation test revealed a minor impact of corticotropin-releasing hormone loading on the ACTH and cortisol levels, while growth hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, and TSH showed sufficient responses according to the corresponding stimulation tests. The ultrasound findings of the thyroid and magnetic resonance imaging findings of the pituitary gland showed no abnormalities. Consequently, he was diagnosed to have grade 3 isolated ACTH deficiency with secondary adrenal insufficiency and nivolumab-related grade 3 destructive thyroiditis. Nivolumab therapy was discontinued and prednisolone was supplemented at a starting dose of 15 mg/day for adrenal insufficiency. The patient's fatigue was alleviated within a few days, following which the prednisolone dose was tapered. His serum cortisol level returned to normal, whereas ACTH deficiency persisted. Prednisolone was maintained at a dosage of 5 mg/day since day 37, and no relapse was noted thereafter. The free T4 level decreased on day 23, confirming the hypothyroidism phase of destructive thyroiditis. Levothyroxine (25 μg/day) was administrated until the free T4 level recovered on day 95, and no relapse occurred thereafter.
Table. Laboratory Data.
Reference range Before nivolumab After 6 cycles of nivolumab
White blood cells /µL 4,000-9,000 3,500 3,400
Neutrophils % 45-55 47.8 47.7
Lymophocyte % 25-45 36.9 36.5
Hemoglobin g/dL 14-18 14.4 13.8
Platelets /µL 15-35×104 11.3×104 19.9×104
Lactate dehydrogenase U/I 106-211 155 249
Total bilirubin mg/dL 0.3-1.2 1.2 1.1
Sodium mEq/L 135-147 141 138
Potassium mEq/L 3.6-5.0 4.0 4.7
Chloride mEq/L 98-108 105 101
Calcium mg/dL 8.6-10.1 8.7 9.4
Urea nitrogen mg/dL 8-20 10.7 16.7
Creatinine mg/dL 0.61-1.04 0.95 1.00
C-reactive protein mg/dL 0-0.2 <0.03 0.46
Casual blood glucose mg/dL 70-199 – 192
Hemoglobin A1c % 4.6-6.2 5.5 5.4
CA19-9 U/mL <37.0 8.6 –
CEA ng/mL <5.0 2.3 –
TSH µU/mL 0.5-5.0 4.16 0.021
FT4 ng/dL 0.9-1.7 0.99 2.48
FT3 pg/mL 2.3-4.3 2.6 7.9
ACTH pg/mL 7.2-63.3 78.6 3.5
Cortisol µg/dL 7.07-19.6 14.6 0.2
GH ng/mL 0.0-2.0 – 1.2
LH mIU/mL 0.79-5.72 – 6.1
FSH mIU/mL 2.00-8.30 – 12.8
Prolactin ng/mL 4.29-13.69 – 9.7
ACTH: adrenocorticotropic hormone, CA19-9: carbohydrate antigen 19-9, CEA: carcinoembryonic antigen, FSH: follicle stimulating hormone, FT3: free triiodothyronine, FT4: free thyroxine, GH: growth hormone, LH: luteinizing hormone, TSH: thyroid stimulating hormone
Figure 2. The patient’s clinical course during nivolumab treatment. ACTH: adrenocorticotropic hormone, CORT: cortisol, FT4: free thyroxine, LT4: levothyroxine, PSL: prednisolone, TSH: thyroid stimulating hormone
After four cycles of nivolumab (approximately 2 months after the start of nivolumab therapy), all metastatic lesions shrank to around 61.2% of the size before nivolumab treatment (Fig. 1B). We determined to observe his course without the re-administration of nivolumab even after the improvement of irAEs. The metastatic lesions further decreased in size after the discontinuation of nivolumab, and the effect was sustained for 23 months after nivolumab initiation (final size, 39.1% of that before nivolumab treatment) (Fig. 1C); the tumor markers were within the normal ranges.
Discussion
Recently, a durable response after the discontinuation of ICIs in patients with residual disease has been reported for other kinds of cancers (8-10). It has previously been reported that PD-1/PD-L1 blockade rescued “exhausted” T cells, leading to the activation of T-cell effectors and transition to memory cells (7). The level of PD-1 occupancy on circulating T cells was shown to persist much longer than the serum half-life of the PD-1 antibodies (11,12). This might mean that there is no need to perform continuous treatment with ICIs. In fact, our patient showed that the metastatic lesions further decreased after the discontinuation of nivolumab.
Several predictive markers of an effective response to ICIs have been previously proposed for many cancers including AGC, such as better ECOG PS, no liver or lung metastases, a higher peripheral lymphocyte count, a lower neutrophil-to-lymphocyte ratio, a higher tumor PD-L1 expression, and a high degree of microsatellite instability (6,13-17). However, there have been a limited number of case reviews about the predictive markers for a durable clinical benefit after the discontinuation of ICIs, namely only in melanoma and RCC cases (8,10,18). In the KEYNOTE-001 study on pembrolizumab in patients with melanoma, 61 of 67 patients (91.0%), who were followed up after pembrolizumab discontinuation after a complete response (CR), achieved a disease-free survival of 24 months (18). It was suggested that the patients with CR were more likely to achieve a durable response. A univariate analysis revealed that high CR rates were associated with a target tumor size between 1 and 5 cm and PD-L1-positive tumors (≥1% staining in tumor cells and mononuclear inflammatory cells) (18). A retrospective cohort study on melanoma patients showed that the risk of disease progression following treatment discontinuation was significantly associated with the overall response and it was lower in patients with CR (19). However, none of these conditions were seen in our patient (no CR, unknown tumor PD-L1 status, and target tumor size: 7.7 cm; data not shown). In addition, our patient did not exhibit any microsatellite instability (data not shown). Since the Epstein-Barr virus (EBV)-positive status might be a marker of an effective response to ICIs in AGC (20,21), we performed EBV-encoded small RNA in situ hybridization on the primary tumor, which showed positivity in the nuclei of the tumor cells (Fig. 3). This result was consistent with that reported in previous reports (20,21). However, there are no reports on the predictive markers for a durable clinical benefit after the discontinuation of ICIs in AGC, and further study in many similar cases will be needed to clarify this, regardless of the distinctive features seen in our patient.
Figure 3. Hematoxylin and Eosin staining (A magnification 40×, C magnification 200×) and Epstein-Barr virus-encoded small RNA in situ hybridization (B magnification 40×, D magnification 200×) in the resected primary tumor.
Recent studies have shown that the development of irAE was associated with a clinical benefit in several cancers, including AGC (22-28). In NSCLC patients, in whom irAEs developed within 2 weeks from the start of nivolumab treatment (25), in whom more than two irAEs were reported (26), or in whom either endocrine irAEs or skin irAEs (28), a more pronounced benefit was observed. In melanoma cases, the occurrence of vitiligo as an irAE was associated with a clinical benefit (23,29,30), while endocrine irAE was not (23). In our patient, although the time to irAE occurrence was 15 weeks, which was longer than 2 weeks, two irAEs were detected, both of which were endocrine irAEs. The association between the types of irAEs and the clinical outcomes in different cancer types is still unclear.
ICIs induce multiple-organ irAEs via immune system overactivation (31). Two irAEs were observed in our patient. The incidence of endocrine irAEs varies depending on the agent, and nivolumab induces thyroid disorders in approximately 10% of such patients and hypophysitis in less than 1% of such patients (32,33). A patient often shows the development of multiple irAEs, but the common patterns of irAEs have been rarely reported. Although the pathogenic mechanism of ICI-triggered hypophysitis is unknown, the characteristic symptoms and imaging findings resemble those of autoimmune hypophysitis (34), which was also seen in our patient. The current guidelines suggest corticosteroid therapy and the replacement of deficient hormones to manage endocrine irAEs (35), and long-term hormonal replacement is indicated for ACTH deficiency secondary to hypophysitis (36), which was also effective in our patient.
Recent studies have reported that recurrence of the same or different irAEs was observed in 18-52% of patients who received ICI re-administration (37-39), and these were milder than the initial events (38-40). A large-scale observational study using data from the World Health Organization database reported that colitis, hepatitis, and pneumonitis are associated with a higher recurrence rate, whereas adrenal events are associated with a lower recurrence rate compared with other irAEs (40). The efficacy of ICI re-administration is not yet established. A large retrospective analysis of NSCLC patients who were discontinued nivolumab therapy for any reason showed that OS in patients who received ICI re-administration was significantly better than that in patients who received chemotherapy only after nivolumab, in a sub-group analysis among the patients who initially received nivolumab therapy for more than 3 months (41). On the other hand, a retrospective cohort study on ICI re-administration in patients with solid tumors after the occurrence of an initial grade 2 or higher irAE showed that PFS in the re-administered patients was not better than that in the non-re-administered patients (38). If recurrence is observed in our case, then we will consider the re-administration of ICI while carefully monitoring irAEs.
In conclusion, we treated a patient with AGC who maintained a durable response for approximately 2 years after discontinuation of nivolumab. To the best of our knowledge, this is the first report to describe a durable clinical benefit after the discontinuation of nivolumab in gastric cancer. Further studies are necessary to elucidate the mechanism and the predictive markers of a durable clinical benefit after ICI discontinuation. The risks and benefits of ICI re-administration should be considered on the basis of the type of initial irAE.
The authors state that they have no Conflict of Interest (COI).
|
Recovering
|
ReactionOutcome
|
CC BY-NC-ND
|
33162479
| 19,477,673
|
2021-04-01
|
What was the outcome of reaction 'Secondary adrenocortical insufficiency'?
|
A Durable Response after the Discontinuation of Nivolumab in an Advanced Gastric Cancer Patient.
A durable response after the discontinuation of immune checkpoint-inhibitor therapy has previously been reported in several cancers. We herein describe a patient with gastric cancer who maintained a durable response after the discontinuation of nivolumab. A 65-year-old man was treated with nivolumab as a sixth-line therapy for recurrent gastric cancer. After four cycles of nivolumab therapy, he showed a partial response. But the treatment was discontinued when two immune-related adverse events occurred after six cycles. Disease regression was sustained for approximately 2 years, without the re-administration of nivolumab. The characteristics leading to such responses are unclear, and further studies are warranted in this regard.
Introduction
Nivolumab, a monoclonal antibody targeting programmed cell death-1 (PD-1), has been shown to provide remarkable efficacy in the treatment of patients with various kinds of malignant tumors and it is approved for the treatment of several cancers, including melanoma (1), non-small cell lung cancer (NSCLC) (2), renal cell carcinoma (RCC) (3), squamous cell carcinoma of the head and neck (4), and Hodgkin's lymphoma (5). The ATTRACTION-2 study was conducted to investigate the efficacy and safety of nivolumab for heavily pretreated advanced gastric cancer (AGC) patients (6). This randomized, double-blind, placebo-controlled phase 3 trial showed the superiority of nivolumab over a placebo, with an objective response rate of 11.2% [95% confidence interval (CI): 7.7-15.6], a median progression-free survival (PFS) of 1.61 months (95% CI: 1.54-2.30), and a median overall survival (OS) of 5.26 months (95% CI: 4.60- 6.37). Based on the results of this study, nivolumab was approved for AGC as either a third- or later-line treatment, and it has been recently recognized as a standard chemotherapeutic regimen in Japan.
Unlike in the case of conventional cytotoxic anticancer drugs or molecular targeted drugs, the blockade of the PD-1 pathway confers an adaptive memory immune response that resets the equilibrium between the tumor and host immune responses, thus indicating its potential to sustain an antitumor response even after treatment cessation (7). Recent studies have reported cases wherein a durable response was observed even after the discontinuation of therapy with immune checkpoint inhibitors (ICIs), including nivolumab, in melanoma, NSCLC, and RCC (8-10), but no such studies have so far been reported in patients with AGC.
Thus, in this study, we report a rare case of an AGC patient who maintained a durable response for approximately 2 years after the discontinuation of nivolumab due to immune-related adverse events (irAEs).
Case Report
The patient was a 65-year-old man who had been diagnosed with gastric cancer and had undergone total gastrectomy with D2 dissection 7.5 years previously, namely in August 2010. The pathological diagnosis was of a moderately differentiated HER2-negative, pT1N1, pStage IB adenocarcinoma. Six months postoperatively, a solitary liver metastasis was discovered. He then received S-1 treatment as palliative chemotherapy 7 years perviously in March 2011, following which he received nab-paclitaxel alone from May 2013, irinotecan alone from February 2016, capecitabine plus oxaliplatin from June 2016, and ramucirumab alone from February 2017. The disappearance of liver metastasis was observed after the administration of nab-paclitaxel alone. However, treatment with S-1, irinotecan, and ramucirumab was considered to be a failure owing to multiple abdominal lymph node metastases, portal tumor thrombus, and solitary lung metastasis, respectively (Fig. 1A).
Figure 1. (A) Abdominal computed tomography images before the commencement of nivolumab treatment. Solitary lung metastasis (arrow), portal tumor thrombus (solid circle), and multiple lymph node metastases (dotted circle) were observed. (B) After four cycles of nivolumab (approximately 2 months after start of nivolumab), the metastatic lesions shrank to 61.2% of the original size (before nivolumab treatment). (C) Twenty-three months after the discontinuation of nivolumab, the metastatic lesions further shrank to 39.1% of the original size (before nivolumab treatment).
Since he exhibited an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, he began to receive nivolumab as sixth-line therapy from March 2018. The laboratory data showed no abnormal findings (Table). The carcinoembryonic antigen and carbohydrate antigen 19-9 levels were within the normal range, which were similar to his preoperative levels. The patient's clinical course during nivolumab treatment is shown in Fig. 2. No adverse events were observed during the first five cycles of nivolumab therapy. However, after the sixth cycle, 15 weeks after the initial treatment, he was hospitalized for severe fatigue (grade 3 by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0). During hospitalization, he exhibited ECOG PS 3. Physical examination revealed that his body temperature was 36.8℃, blood pressure was 81/48 mmHg, pulse rate was 88/min, and oxygen saturation was 99% on room air. No other abnormal findings were identified. A serum examination revealed a decreased level of thyroid-stimulating hormone (TSH) and increased levels of free triiodothyronine and free thyroxine (T4) compared with the levels before nivolumab initiation (Table). The patient tested negative for thyroid autoantibodies. In addition, there was a decrease in the levels of adrenocorticotropic hormone (ACTH) and cortisol. A stimulation test revealed a minor impact of corticotropin-releasing hormone loading on the ACTH and cortisol levels, while growth hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, and TSH showed sufficient responses according to the corresponding stimulation tests. The ultrasound findings of the thyroid and magnetic resonance imaging findings of the pituitary gland showed no abnormalities. Consequently, he was diagnosed to have grade 3 isolated ACTH deficiency with secondary adrenal insufficiency and nivolumab-related grade 3 destructive thyroiditis. Nivolumab therapy was discontinued and prednisolone was supplemented at a starting dose of 15 mg/day for adrenal insufficiency. The patient's fatigue was alleviated within a few days, following which the prednisolone dose was tapered. His serum cortisol level returned to normal, whereas ACTH deficiency persisted. Prednisolone was maintained at a dosage of 5 mg/day since day 37, and no relapse was noted thereafter. The free T4 level decreased on day 23, confirming the hypothyroidism phase of destructive thyroiditis. Levothyroxine (25 μg/day) was administrated until the free T4 level recovered on day 95, and no relapse occurred thereafter.
Table. Laboratory Data.
Reference range Before nivolumab After 6 cycles of nivolumab
White blood cells /µL 4,000-9,000 3,500 3,400
Neutrophils % 45-55 47.8 47.7
Lymophocyte % 25-45 36.9 36.5
Hemoglobin g/dL 14-18 14.4 13.8
Platelets /µL 15-35×104 11.3×104 19.9×104
Lactate dehydrogenase U/I 106-211 155 249
Total bilirubin mg/dL 0.3-1.2 1.2 1.1
Sodium mEq/L 135-147 141 138
Potassium mEq/L 3.6-5.0 4.0 4.7
Chloride mEq/L 98-108 105 101
Calcium mg/dL 8.6-10.1 8.7 9.4
Urea nitrogen mg/dL 8-20 10.7 16.7
Creatinine mg/dL 0.61-1.04 0.95 1.00
C-reactive protein mg/dL 0-0.2 <0.03 0.46
Casual blood glucose mg/dL 70-199 – 192
Hemoglobin A1c % 4.6-6.2 5.5 5.4
CA19-9 U/mL <37.0 8.6 –
CEA ng/mL <5.0 2.3 –
TSH µU/mL 0.5-5.0 4.16 0.021
FT4 ng/dL 0.9-1.7 0.99 2.48
FT3 pg/mL 2.3-4.3 2.6 7.9
ACTH pg/mL 7.2-63.3 78.6 3.5
Cortisol µg/dL 7.07-19.6 14.6 0.2
GH ng/mL 0.0-2.0 – 1.2
LH mIU/mL 0.79-5.72 – 6.1
FSH mIU/mL 2.00-8.30 – 12.8
Prolactin ng/mL 4.29-13.69 – 9.7
ACTH: adrenocorticotropic hormone, CA19-9: carbohydrate antigen 19-9, CEA: carcinoembryonic antigen, FSH: follicle stimulating hormone, FT3: free triiodothyronine, FT4: free thyroxine, GH: growth hormone, LH: luteinizing hormone, TSH: thyroid stimulating hormone
Figure 2. The patient’s clinical course during nivolumab treatment. ACTH: adrenocorticotropic hormone, CORT: cortisol, FT4: free thyroxine, LT4: levothyroxine, PSL: prednisolone, TSH: thyroid stimulating hormone
After four cycles of nivolumab (approximately 2 months after the start of nivolumab therapy), all metastatic lesions shrank to around 61.2% of the size before nivolumab treatment (Fig. 1B). We determined to observe his course without the re-administration of nivolumab even after the improvement of irAEs. The metastatic lesions further decreased in size after the discontinuation of nivolumab, and the effect was sustained for 23 months after nivolumab initiation (final size, 39.1% of that before nivolumab treatment) (Fig. 1C); the tumor markers were within the normal ranges.
Discussion
Recently, a durable response after the discontinuation of ICIs in patients with residual disease has been reported for other kinds of cancers (8-10). It has previously been reported that PD-1/PD-L1 blockade rescued “exhausted” T cells, leading to the activation of T-cell effectors and transition to memory cells (7). The level of PD-1 occupancy on circulating T cells was shown to persist much longer than the serum half-life of the PD-1 antibodies (11,12). This might mean that there is no need to perform continuous treatment with ICIs. In fact, our patient showed that the metastatic lesions further decreased after the discontinuation of nivolumab.
Several predictive markers of an effective response to ICIs have been previously proposed for many cancers including AGC, such as better ECOG PS, no liver or lung metastases, a higher peripheral lymphocyte count, a lower neutrophil-to-lymphocyte ratio, a higher tumor PD-L1 expression, and a high degree of microsatellite instability (6,13-17). However, there have been a limited number of case reviews about the predictive markers for a durable clinical benefit after the discontinuation of ICIs, namely only in melanoma and RCC cases (8,10,18). In the KEYNOTE-001 study on pembrolizumab in patients with melanoma, 61 of 67 patients (91.0%), who were followed up after pembrolizumab discontinuation after a complete response (CR), achieved a disease-free survival of 24 months (18). It was suggested that the patients with CR were more likely to achieve a durable response. A univariate analysis revealed that high CR rates were associated with a target tumor size between 1 and 5 cm and PD-L1-positive tumors (≥1% staining in tumor cells and mononuclear inflammatory cells) (18). A retrospective cohort study on melanoma patients showed that the risk of disease progression following treatment discontinuation was significantly associated with the overall response and it was lower in patients with CR (19). However, none of these conditions were seen in our patient (no CR, unknown tumor PD-L1 status, and target tumor size: 7.7 cm; data not shown). In addition, our patient did not exhibit any microsatellite instability (data not shown). Since the Epstein-Barr virus (EBV)-positive status might be a marker of an effective response to ICIs in AGC (20,21), we performed EBV-encoded small RNA in situ hybridization on the primary tumor, which showed positivity in the nuclei of the tumor cells (Fig. 3). This result was consistent with that reported in previous reports (20,21). However, there are no reports on the predictive markers for a durable clinical benefit after the discontinuation of ICIs in AGC, and further study in many similar cases will be needed to clarify this, regardless of the distinctive features seen in our patient.
Figure 3. Hematoxylin and Eosin staining (A magnification 40×, C magnification 200×) and Epstein-Barr virus-encoded small RNA in situ hybridization (B magnification 40×, D magnification 200×) in the resected primary tumor.
Recent studies have shown that the development of irAE was associated with a clinical benefit in several cancers, including AGC (22-28). In NSCLC patients, in whom irAEs developed within 2 weeks from the start of nivolumab treatment (25), in whom more than two irAEs were reported (26), or in whom either endocrine irAEs or skin irAEs (28), a more pronounced benefit was observed. In melanoma cases, the occurrence of vitiligo as an irAE was associated with a clinical benefit (23,29,30), while endocrine irAE was not (23). In our patient, although the time to irAE occurrence was 15 weeks, which was longer than 2 weeks, two irAEs were detected, both of which were endocrine irAEs. The association between the types of irAEs and the clinical outcomes in different cancer types is still unclear.
ICIs induce multiple-organ irAEs via immune system overactivation (31). Two irAEs were observed in our patient. The incidence of endocrine irAEs varies depending on the agent, and nivolumab induces thyroid disorders in approximately 10% of such patients and hypophysitis in less than 1% of such patients (32,33). A patient often shows the development of multiple irAEs, but the common patterns of irAEs have been rarely reported. Although the pathogenic mechanism of ICI-triggered hypophysitis is unknown, the characteristic symptoms and imaging findings resemble those of autoimmune hypophysitis (34), which was also seen in our patient. The current guidelines suggest corticosteroid therapy and the replacement of deficient hormones to manage endocrine irAEs (35), and long-term hormonal replacement is indicated for ACTH deficiency secondary to hypophysitis (36), which was also effective in our patient.
Recent studies have reported that recurrence of the same or different irAEs was observed in 18-52% of patients who received ICI re-administration (37-39), and these were milder than the initial events (38-40). A large-scale observational study using data from the World Health Organization database reported that colitis, hepatitis, and pneumonitis are associated with a higher recurrence rate, whereas adrenal events are associated with a lower recurrence rate compared with other irAEs (40). The efficacy of ICI re-administration is not yet established. A large retrospective analysis of NSCLC patients who were discontinued nivolumab therapy for any reason showed that OS in patients who received ICI re-administration was significantly better than that in patients who received chemotherapy only after nivolumab, in a sub-group analysis among the patients who initially received nivolumab therapy for more than 3 months (41). On the other hand, a retrospective cohort study on ICI re-administration in patients with solid tumors after the occurrence of an initial grade 2 or higher irAE showed that PFS in the re-administered patients was not better than that in the non-re-administered patients (38). If recurrence is observed in our case, then we will consider the re-administration of ICI while carefully monitoring irAEs.
In conclusion, we treated a patient with AGC who maintained a durable response for approximately 2 years after discontinuation of nivolumab. To the best of our knowledge, this is the first report to describe a durable clinical benefit after the discontinuation of nivolumab in gastric cancer. Further studies are necessary to elucidate the mechanism and the predictive markers of a durable clinical benefit after ICI discontinuation. The risks and benefits of ICI re-administration should be considered on the basis of the type of initial irAE.
The authors state that they have no Conflict of Interest (COI).
|
Recovering
|
ReactionOutcome
|
CC BY-NC-ND
|
33162479
| 19,477,673
|
2021-04-01
|
What was the outcome of reaction 'Thyroiditis'?
|
A Durable Response after the Discontinuation of Nivolumab in an Advanced Gastric Cancer Patient.
A durable response after the discontinuation of immune checkpoint-inhibitor therapy has previously been reported in several cancers. We herein describe a patient with gastric cancer who maintained a durable response after the discontinuation of nivolumab. A 65-year-old man was treated with nivolumab as a sixth-line therapy for recurrent gastric cancer. After four cycles of nivolumab therapy, he showed a partial response. But the treatment was discontinued when two immune-related adverse events occurred after six cycles. Disease regression was sustained for approximately 2 years, without the re-administration of nivolumab. The characteristics leading to such responses are unclear, and further studies are warranted in this regard.
Introduction
Nivolumab, a monoclonal antibody targeting programmed cell death-1 (PD-1), has been shown to provide remarkable efficacy in the treatment of patients with various kinds of malignant tumors and it is approved for the treatment of several cancers, including melanoma (1), non-small cell lung cancer (NSCLC) (2), renal cell carcinoma (RCC) (3), squamous cell carcinoma of the head and neck (4), and Hodgkin's lymphoma (5). The ATTRACTION-2 study was conducted to investigate the efficacy and safety of nivolumab for heavily pretreated advanced gastric cancer (AGC) patients (6). This randomized, double-blind, placebo-controlled phase 3 trial showed the superiority of nivolumab over a placebo, with an objective response rate of 11.2% [95% confidence interval (CI): 7.7-15.6], a median progression-free survival (PFS) of 1.61 months (95% CI: 1.54-2.30), and a median overall survival (OS) of 5.26 months (95% CI: 4.60- 6.37). Based on the results of this study, nivolumab was approved for AGC as either a third- or later-line treatment, and it has been recently recognized as a standard chemotherapeutic regimen in Japan.
Unlike in the case of conventional cytotoxic anticancer drugs or molecular targeted drugs, the blockade of the PD-1 pathway confers an adaptive memory immune response that resets the equilibrium between the tumor and host immune responses, thus indicating its potential to sustain an antitumor response even after treatment cessation (7). Recent studies have reported cases wherein a durable response was observed even after the discontinuation of therapy with immune checkpoint inhibitors (ICIs), including nivolumab, in melanoma, NSCLC, and RCC (8-10), but no such studies have so far been reported in patients with AGC.
Thus, in this study, we report a rare case of an AGC patient who maintained a durable response for approximately 2 years after the discontinuation of nivolumab due to immune-related adverse events (irAEs).
Case Report
The patient was a 65-year-old man who had been diagnosed with gastric cancer and had undergone total gastrectomy with D2 dissection 7.5 years previously, namely in August 2010. The pathological diagnosis was of a moderately differentiated HER2-negative, pT1N1, pStage IB adenocarcinoma. Six months postoperatively, a solitary liver metastasis was discovered. He then received S-1 treatment as palliative chemotherapy 7 years perviously in March 2011, following which he received nab-paclitaxel alone from May 2013, irinotecan alone from February 2016, capecitabine plus oxaliplatin from June 2016, and ramucirumab alone from February 2017. The disappearance of liver metastasis was observed after the administration of nab-paclitaxel alone. However, treatment with S-1, irinotecan, and ramucirumab was considered to be a failure owing to multiple abdominal lymph node metastases, portal tumor thrombus, and solitary lung metastasis, respectively (Fig. 1A).
Figure 1. (A) Abdominal computed tomography images before the commencement of nivolumab treatment. Solitary lung metastasis (arrow), portal tumor thrombus (solid circle), and multiple lymph node metastases (dotted circle) were observed. (B) After four cycles of nivolumab (approximately 2 months after start of nivolumab), the metastatic lesions shrank to 61.2% of the original size (before nivolumab treatment). (C) Twenty-three months after the discontinuation of nivolumab, the metastatic lesions further shrank to 39.1% of the original size (before nivolumab treatment).
Since he exhibited an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, he began to receive nivolumab as sixth-line therapy from March 2018. The laboratory data showed no abnormal findings (Table). The carcinoembryonic antigen and carbohydrate antigen 19-9 levels were within the normal range, which were similar to his preoperative levels. The patient's clinical course during nivolumab treatment is shown in Fig. 2. No adverse events were observed during the first five cycles of nivolumab therapy. However, after the sixth cycle, 15 weeks after the initial treatment, he was hospitalized for severe fatigue (grade 3 by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0). During hospitalization, he exhibited ECOG PS 3. Physical examination revealed that his body temperature was 36.8℃, blood pressure was 81/48 mmHg, pulse rate was 88/min, and oxygen saturation was 99% on room air. No other abnormal findings were identified. A serum examination revealed a decreased level of thyroid-stimulating hormone (TSH) and increased levels of free triiodothyronine and free thyroxine (T4) compared with the levels before nivolumab initiation (Table). The patient tested negative for thyroid autoantibodies. In addition, there was a decrease in the levels of adrenocorticotropic hormone (ACTH) and cortisol. A stimulation test revealed a minor impact of corticotropin-releasing hormone loading on the ACTH and cortisol levels, while growth hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, and TSH showed sufficient responses according to the corresponding stimulation tests. The ultrasound findings of the thyroid and magnetic resonance imaging findings of the pituitary gland showed no abnormalities. Consequently, he was diagnosed to have grade 3 isolated ACTH deficiency with secondary adrenal insufficiency and nivolumab-related grade 3 destructive thyroiditis. Nivolumab therapy was discontinued and prednisolone was supplemented at a starting dose of 15 mg/day for adrenal insufficiency. The patient's fatigue was alleviated within a few days, following which the prednisolone dose was tapered. His serum cortisol level returned to normal, whereas ACTH deficiency persisted. Prednisolone was maintained at a dosage of 5 mg/day since day 37, and no relapse was noted thereafter. The free T4 level decreased on day 23, confirming the hypothyroidism phase of destructive thyroiditis. Levothyroxine (25 μg/day) was administrated until the free T4 level recovered on day 95, and no relapse occurred thereafter.
Table. Laboratory Data.
Reference range Before nivolumab After 6 cycles of nivolumab
White blood cells /µL 4,000-9,000 3,500 3,400
Neutrophils % 45-55 47.8 47.7
Lymophocyte % 25-45 36.9 36.5
Hemoglobin g/dL 14-18 14.4 13.8
Platelets /µL 15-35×104 11.3×104 19.9×104
Lactate dehydrogenase U/I 106-211 155 249
Total bilirubin mg/dL 0.3-1.2 1.2 1.1
Sodium mEq/L 135-147 141 138
Potassium mEq/L 3.6-5.0 4.0 4.7
Chloride mEq/L 98-108 105 101
Calcium mg/dL 8.6-10.1 8.7 9.4
Urea nitrogen mg/dL 8-20 10.7 16.7
Creatinine mg/dL 0.61-1.04 0.95 1.00
C-reactive protein mg/dL 0-0.2 <0.03 0.46
Casual blood glucose mg/dL 70-199 – 192
Hemoglobin A1c % 4.6-6.2 5.5 5.4
CA19-9 U/mL <37.0 8.6 –
CEA ng/mL <5.0 2.3 –
TSH µU/mL 0.5-5.0 4.16 0.021
FT4 ng/dL 0.9-1.7 0.99 2.48
FT3 pg/mL 2.3-4.3 2.6 7.9
ACTH pg/mL 7.2-63.3 78.6 3.5
Cortisol µg/dL 7.07-19.6 14.6 0.2
GH ng/mL 0.0-2.0 – 1.2
LH mIU/mL 0.79-5.72 – 6.1
FSH mIU/mL 2.00-8.30 – 12.8
Prolactin ng/mL 4.29-13.69 – 9.7
ACTH: adrenocorticotropic hormone, CA19-9: carbohydrate antigen 19-9, CEA: carcinoembryonic antigen, FSH: follicle stimulating hormone, FT3: free triiodothyronine, FT4: free thyroxine, GH: growth hormone, LH: luteinizing hormone, TSH: thyroid stimulating hormone
Figure 2. The patient’s clinical course during nivolumab treatment. ACTH: adrenocorticotropic hormone, CORT: cortisol, FT4: free thyroxine, LT4: levothyroxine, PSL: prednisolone, TSH: thyroid stimulating hormone
After four cycles of nivolumab (approximately 2 months after the start of nivolumab therapy), all metastatic lesions shrank to around 61.2% of the size before nivolumab treatment (Fig. 1B). We determined to observe his course without the re-administration of nivolumab even after the improvement of irAEs. The metastatic lesions further decreased in size after the discontinuation of nivolumab, and the effect was sustained for 23 months after nivolumab initiation (final size, 39.1% of that before nivolumab treatment) (Fig. 1C); the tumor markers were within the normal ranges.
Discussion
Recently, a durable response after the discontinuation of ICIs in patients with residual disease has been reported for other kinds of cancers (8-10). It has previously been reported that PD-1/PD-L1 blockade rescued “exhausted” T cells, leading to the activation of T-cell effectors and transition to memory cells (7). The level of PD-1 occupancy on circulating T cells was shown to persist much longer than the serum half-life of the PD-1 antibodies (11,12). This might mean that there is no need to perform continuous treatment with ICIs. In fact, our patient showed that the metastatic lesions further decreased after the discontinuation of nivolumab.
Several predictive markers of an effective response to ICIs have been previously proposed for many cancers including AGC, such as better ECOG PS, no liver or lung metastases, a higher peripheral lymphocyte count, a lower neutrophil-to-lymphocyte ratio, a higher tumor PD-L1 expression, and a high degree of microsatellite instability (6,13-17). However, there have been a limited number of case reviews about the predictive markers for a durable clinical benefit after the discontinuation of ICIs, namely only in melanoma and RCC cases (8,10,18). In the KEYNOTE-001 study on pembrolizumab in patients with melanoma, 61 of 67 patients (91.0%), who were followed up after pembrolizumab discontinuation after a complete response (CR), achieved a disease-free survival of 24 months (18). It was suggested that the patients with CR were more likely to achieve a durable response. A univariate analysis revealed that high CR rates were associated with a target tumor size between 1 and 5 cm and PD-L1-positive tumors (≥1% staining in tumor cells and mononuclear inflammatory cells) (18). A retrospective cohort study on melanoma patients showed that the risk of disease progression following treatment discontinuation was significantly associated with the overall response and it was lower in patients with CR (19). However, none of these conditions were seen in our patient (no CR, unknown tumor PD-L1 status, and target tumor size: 7.7 cm; data not shown). In addition, our patient did not exhibit any microsatellite instability (data not shown). Since the Epstein-Barr virus (EBV)-positive status might be a marker of an effective response to ICIs in AGC (20,21), we performed EBV-encoded small RNA in situ hybridization on the primary tumor, which showed positivity in the nuclei of the tumor cells (Fig. 3). This result was consistent with that reported in previous reports (20,21). However, there are no reports on the predictive markers for a durable clinical benefit after the discontinuation of ICIs in AGC, and further study in many similar cases will be needed to clarify this, regardless of the distinctive features seen in our patient.
Figure 3. Hematoxylin and Eosin staining (A magnification 40×, C magnification 200×) and Epstein-Barr virus-encoded small RNA in situ hybridization (B magnification 40×, D magnification 200×) in the resected primary tumor.
Recent studies have shown that the development of irAE was associated with a clinical benefit in several cancers, including AGC (22-28). In NSCLC patients, in whom irAEs developed within 2 weeks from the start of nivolumab treatment (25), in whom more than two irAEs were reported (26), or in whom either endocrine irAEs or skin irAEs (28), a more pronounced benefit was observed. In melanoma cases, the occurrence of vitiligo as an irAE was associated with a clinical benefit (23,29,30), while endocrine irAE was not (23). In our patient, although the time to irAE occurrence was 15 weeks, which was longer than 2 weeks, two irAEs were detected, both of which were endocrine irAEs. The association between the types of irAEs and the clinical outcomes in different cancer types is still unclear.
ICIs induce multiple-organ irAEs via immune system overactivation (31). Two irAEs were observed in our patient. The incidence of endocrine irAEs varies depending on the agent, and nivolumab induces thyroid disorders in approximately 10% of such patients and hypophysitis in less than 1% of such patients (32,33). A patient often shows the development of multiple irAEs, but the common patterns of irAEs have been rarely reported. Although the pathogenic mechanism of ICI-triggered hypophysitis is unknown, the characteristic symptoms and imaging findings resemble those of autoimmune hypophysitis (34), which was also seen in our patient. The current guidelines suggest corticosteroid therapy and the replacement of deficient hormones to manage endocrine irAEs (35), and long-term hormonal replacement is indicated for ACTH deficiency secondary to hypophysitis (36), which was also effective in our patient.
Recent studies have reported that recurrence of the same or different irAEs was observed in 18-52% of patients who received ICI re-administration (37-39), and these were milder than the initial events (38-40). A large-scale observational study using data from the World Health Organization database reported that colitis, hepatitis, and pneumonitis are associated with a higher recurrence rate, whereas adrenal events are associated with a lower recurrence rate compared with other irAEs (40). The efficacy of ICI re-administration is not yet established. A large retrospective analysis of NSCLC patients who were discontinued nivolumab therapy for any reason showed that OS in patients who received ICI re-administration was significantly better than that in patients who received chemotherapy only after nivolumab, in a sub-group analysis among the patients who initially received nivolumab therapy for more than 3 months (41). On the other hand, a retrospective cohort study on ICI re-administration in patients with solid tumors after the occurrence of an initial grade 2 or higher irAE showed that PFS in the re-administered patients was not better than that in the non-re-administered patients (38). If recurrence is observed in our case, then we will consider the re-administration of ICI while carefully monitoring irAEs.
In conclusion, we treated a patient with AGC who maintained a durable response for approximately 2 years after discontinuation of nivolumab. To the best of our knowledge, this is the first report to describe a durable clinical benefit after the discontinuation of nivolumab in gastric cancer. Further studies are necessary to elucidate the mechanism and the predictive markers of a durable clinical benefit after ICI discontinuation. The risks and benefits of ICI re-administration should be considered on the basis of the type of initial irAE.
The authors state that they have no Conflict of Interest (COI).
|
Recovering
|
ReactionOutcome
|
CC BY-NC-ND
|
33162479
| 19,477,673
|
2021-04-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'JC virus infection'.
|
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.
|
CYCLOSPORINE, PREDNISOLONE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33162483
| 19,962,956
|
2021-04-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia'.
|
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.
|
CYCLOSPORINE, PREDNISOLONE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33162483
| 19,962,956
|
2021-04-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced '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.
|
CYCLOSPORINE, PREDNISOLONE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33162483
| 19,962,956
|
2021-04-15
|
What was the outcome of reaction 'JC virus infection'?
|
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 was the outcome of reaction 'Pneumonia'?
|
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.
|
Fatal
|
ReactionOutcome
|
CC BY-NC-ND
|
33162483
| 19,962,956
|
2021-04-15
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.