Comparison of Two Standard Chemotherapy Regimens for Germ Cell Tumors
Background The Australian and New Zealand Germ Cell Trials Group conducted a multicenter randomized phase III trial in men with good-prognosis germ cell tumors of two standard chemotherapy regimens that contained bleomycin, etoposide, and cisplatin but differed in the scheduling and total dose of cisplatin, the total dose of bleomycin, and the scheduling and dose intensity of etoposide. The trial was stopped early at a median follow-up of 33 months after a planned interim analysis found a survival benefit for the more dose-intense regimen. The aim of this analysis was to determine if this survival benefit was maintained with long-term follow-up.
Methods Between February 1994 and April 2000, 166 men with good-prognosis metastatic germ cell tumors defined by modified Memorial Sloan-Kettering criteria were randomly assigned to receive 3B90E500P (three cycles, repeated every 21 days, of 30 kU bleomycin on days 1, 8, and 15; 100 mg/m etoposide on days 1–5; and 20 mg/m cisplatin on days 1–5; n = 83) or 4B30E360P (four cycles, repeated every 21 days, of 30 kU bleomycin on day 1, 120 mg/m etoposide on days 1–3, and 100 mg/m cisplatin on day 1; n = 83). Endpoints included overall survival, progression-free survival, and quality of life and side effects, which were assessed using the Spitzer Quality of Life Index and the GLQ-8, respectively, before random assignment and during and after treatment. All analyses were by intention to treat. All P values are two-sided.
Results The median follow-up was 8.5 years. All but five survivors (3%) were followed up for at least 5 years. Overall survival remained better in those assigned to 3B90E500P than in those assigned to 4B30E360P (8-year survival: 92% vs 83%; hazard ratio of death = 0.38, 95% confidence interval = 0.15 to 0.97, P = .037). Progression-free survival favored 3B90E500P but was not statistically significantly different between the treatment groups (8-year progression-free survival, 3B90E500P vs 4B30E360P: 86% vs 79%; hazard ratio of progression = 0.6, 95% confidence interval = 0.3 to 1.1, P = .15). At the end of treatment, average scores for most side effect scales favored 3B90E500P. After the completion of treatment, average GLQ-8 scores for numbness (P = .003) and hair loss (P = .04) and the Spitzer Quality of Life Index (P = .05) favored 3B90E500P.
Conclusion The survival benefit of 3B90E500P over 4B30E360P was maintained with long-term follow-up.
The Australian and New Zealand Germ Cell Trials Group (ANZGCTG) conducted a prospective randomized phase III trial comparing two combination chemotherapy regimens consisting of bleomycin (B), etoposide (E), and cisplatin (P) (ie, BEP) in men with good-prognosis metastatic germ cell tumors, with accrual from February 1994 to April 2000. When the trial was designed in the early 1990s, there was uncertainty about the appropriate dose, dose intensity, and duration of BEP chemotherapy in this population. Some of the trial group's participating sites were using regimens that were developed in North America and included three cycles of BEP with etoposide dosing at 500 mg/m per cycle. Other sites were using regimens that were developed in the United Kingdom and Europe, which included four cycles of BEP with etoposide dosing at 360 mg/m per cycle. There was also uncertainty about the importance of bleomycin. An earlier trial by our group showed an advantage to including bleomycin with cisplatin and vinblastine, but there was continued concern about bleomycin toxicity. Therefore, the concept of testing a BEP regimen with a lower dose of bleomycin was attractive.
In the ANZGCTG trial, patients were randomly assigned to receive one of the two BEP regimens, which differed in the number of cycles, the scheduling and total dose of cisplatin, the scheduling and dose intensity of etoposide, and the total dose of bleomycin (Table 1). One regimen—three cycles, repeated every 21 days, of 30 kU bleomycin on days 1, 8, and 15; 100 mg/m etoposide on days 1–5; and 20 mg/m cisplatin on days 1–5 (3B90E500P)—was based on a regimen that was used at Indiana University since the mid-1980s, except that in the trial, each dose of bleomycin was given 1 day earlier. The other regimen—four cycles, repeated every 21 days, of 30 kU bleomycin on day 1, 120 mg/m etoposide on days 1–3, and 100 mg/m cisplatin on day 1 (4B30E360P)—was based on the control arm in a Medical Research Council and European Organization for Research and Treatment of Cancer (MRC/EORTC) trial that was under way when the ANZGCTG trial was being designed; the MRC/EORTC trial tested the substitution of carboplatin for cisplatin, and bleomycin was given on day 2 and cisplatin was given for a period of 2 or 5 days. The results of the MRC/EORTC trial showed an overall survival rate of 97% at 3 years with the BEP control arm vs 90% in the experimental arm, supporting the use of the BEP control arm as a comparator in the ANZGCTG trial.
Patients in the ANZGCTG trial were classified as good prognosis according to modified Memorial Sloan-Kettering Cancer Center (MSKCC) criteria, which was the best prognostic classification available at the time for predicting complete response to initial treatment. The modification of this classification was based on subsequently published research from MSKCC and allowed patients with retroperitoneal primary nonseminoma to be potentially eligible. When the International Germ Cell Consensus Classification (IGCCC) for prognosis became available 3 years after this trial began, the trial was modified to exclude patients with poor-prognosis disease according to IGCCC criteria.
Of a planned 260 patients, 166 were recruited to the trial and randomly assigned to receive 3B90E500P or 4B30E360P (83 patients per arm). The trial was stopped early after a second planned interim analysis at a median follow-up of 33 months showed a substantial survival benefit for 3B90E500P compared with 4B30E360P (three vs 15 deaths; overall survival at 3 years: 90% vs 81%; hazard ratio [HR] of death = 0.22, 95% confidence interval [CI] = 0.06 to 0.77, P = .008). The aim of this updated analysis was to determine if the survival benefit was maintained with long-term follow-up. We also report for the first time on patterns of relapse, treatment received after relapse, response to subsequent treatment, and effects on health-related quality of life (HRQL).
Abstract and Introduction
Abstract
Background The Australian and New Zealand Germ Cell Trials Group conducted a multicenter randomized phase III trial in men with good-prognosis germ cell tumors of two standard chemotherapy regimens that contained bleomycin, etoposide, and cisplatin but differed in the scheduling and total dose of cisplatin, the total dose of bleomycin, and the scheduling and dose intensity of etoposide. The trial was stopped early at a median follow-up of 33 months after a planned interim analysis found a survival benefit for the more dose-intense regimen. The aim of this analysis was to determine if this survival benefit was maintained with long-term follow-up.
Methods Between February 1994 and April 2000, 166 men with good-prognosis metastatic germ cell tumors defined by modified Memorial Sloan-Kettering criteria were randomly assigned to receive 3B90E500P (three cycles, repeated every 21 days, of 30 kU bleomycin on days 1, 8, and 15; 100 mg/m etoposide on days 1–5; and 20 mg/m cisplatin on days 1–5; n = 83) or 4B30E360P (four cycles, repeated every 21 days, of 30 kU bleomycin on day 1, 120 mg/m etoposide on days 1–3, and 100 mg/m cisplatin on day 1; n = 83). Endpoints included overall survival, progression-free survival, and quality of life and side effects, which were assessed using the Spitzer Quality of Life Index and the GLQ-8, respectively, before random assignment and during and after treatment. All analyses were by intention to treat. All P values are two-sided.
Results The median follow-up was 8.5 years. All but five survivors (3%) were followed up for at least 5 years. Overall survival remained better in those assigned to 3B90E500P than in those assigned to 4B30E360P (8-year survival: 92% vs 83%; hazard ratio of death = 0.38, 95% confidence interval = 0.15 to 0.97, P = .037). Progression-free survival favored 3B90E500P but was not statistically significantly different between the treatment groups (8-year progression-free survival, 3B90E500P vs 4B30E360P: 86% vs 79%; hazard ratio of progression = 0.6, 95% confidence interval = 0.3 to 1.1, P = .15). At the end of treatment, average scores for most side effect scales favored 3B90E500P. After the completion of treatment, average GLQ-8 scores for numbness (P = .003) and hair loss (P = .04) and the Spitzer Quality of Life Index (P = .05) favored 3B90E500P.
Conclusion The survival benefit of 3B90E500P over 4B30E360P was maintained with long-term follow-up.
Introduction
The Australian and New Zealand Germ Cell Trials Group (ANZGCTG) conducted a prospective randomized phase III trial comparing two combination chemotherapy regimens consisting of bleomycin (B), etoposide (E), and cisplatin (P) (ie, BEP) in men with good-prognosis metastatic germ cell tumors, with accrual from February 1994 to April 2000. When the trial was designed in the early 1990s, there was uncertainty about the appropriate dose, dose intensity, and duration of BEP chemotherapy in this population. Some of the trial group's participating sites were using regimens that were developed in North America and included three cycles of BEP with etoposide dosing at 500 mg/m per cycle. Other sites were using regimens that were developed in the United Kingdom and Europe, which included four cycles of BEP with etoposide dosing at 360 mg/m per cycle. There was also uncertainty about the importance of bleomycin. An earlier trial by our group showed an advantage to including bleomycin with cisplatin and vinblastine, but there was continued concern about bleomycin toxicity. Therefore, the concept of testing a BEP regimen with a lower dose of bleomycin was attractive.
In the ANZGCTG trial, patients were randomly assigned to receive one of the two BEP regimens, which differed in the number of cycles, the scheduling and total dose of cisplatin, the scheduling and dose intensity of etoposide, and the total dose of bleomycin (Table 1). One regimen—three cycles, repeated every 21 days, of 30 kU bleomycin on days 1, 8, and 15; 100 mg/m etoposide on days 1–5; and 20 mg/m cisplatin on days 1–5 (3B90E500P)—was based on a regimen that was used at Indiana University since the mid-1980s, except that in the trial, each dose of bleomycin was given 1 day earlier. The other regimen—four cycles, repeated every 21 days, of 30 kU bleomycin on day 1, 120 mg/m etoposide on days 1–3, and 100 mg/m cisplatin on day 1 (4B30E360P)—was based on the control arm in a Medical Research Council and European Organization for Research and Treatment of Cancer (MRC/EORTC) trial that was under way when the ANZGCTG trial was being designed; the MRC/EORTC trial tested the substitution of carboplatin for cisplatin, and bleomycin was given on day 2 and cisplatin was given for a period of 2 or 5 days. The results of the MRC/EORTC trial showed an overall survival rate of 97% at 3 years with the BEP control arm vs 90% in the experimental arm, supporting the use of the BEP control arm as a comparator in the ANZGCTG trial.
Patients in the ANZGCTG trial were classified as good prognosis according to modified Memorial Sloan-Kettering Cancer Center (MSKCC) criteria, which was the best prognostic classification available at the time for predicting complete response to initial treatment. The modification of this classification was based on subsequently published research from MSKCC and allowed patients with retroperitoneal primary nonseminoma to be potentially eligible. When the International Germ Cell Consensus Classification (IGCCC) for prognosis became available 3 years after this trial began, the trial was modified to exclude patients with poor-prognosis disease according to IGCCC criteria.
Of a planned 260 patients, 166 were recruited to the trial and randomly assigned to receive 3B90E500P or 4B30E360P (83 patients per arm). The trial was stopped early after a second planned interim analysis at a median follow-up of 33 months showed a substantial survival benefit for 3B90E500P compared with 4B30E360P (three vs 15 deaths; overall survival at 3 years: 90% vs 81%; hazard ratio [HR] of death = 0.22, 95% confidence interval [CI] = 0.06 to 0.77, P = .008). The aim of this updated analysis was to determine if the survival benefit was maintained with long-term follow-up. We also report for the first time on patterns of relapse, treatment received after relapse, response to subsequent treatment, and effects on health-related quality of life (HRQL).
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