Refining the Optimal Chemotherapy Regimen in Good Prognosis Germ Cell Cancer: Interpretation of the Current Body of Knowledge
Authors: Ronald de Wit
Journal: Journal of Clinical Oncology (2007)

The treatment of metastatic germ cell cancers with modern cisplatin-based chemotherapy results in a cure for approximately 70% to 80% of patients. Factors associated with treatment outcome include the extent of metastatic disease and serum levels of the -subunit of human chorionic gonadotropin, alpha fetoprotein, and lactate dehydrogenase. On the basis of these prognostic factors, clinical trials have focused on attempts either to decrease the toxicity of the standard four cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy in patients with high possibility of cure, or to improve the curative results by intensifying therapy in patients with adverse risk factors. The standard BEP regimen comprises cisplatin 20 mg/m days 1 through 5 (100 mg/m per cycle), etoposide 100 mg/m days 1 through 5 (500 mg/m per cycle), and bleomycin 30 mg/week. Two of the efforts to decrease toxicity in good prognosis patients include the deletion of bleomycin (EP), and the reduction of the chemotherapy by one cycle (three cycles of BEP [3 BEP]). The European Organisation for Research and Treatment of Cancer (EORTC) investigated the relative merits of bleomycin by directly comparing four cycles of BEP with four cycles of EP in patients deemed to be good risk by the criteria used by the EORTC in the 1980s. The etoposide schedule in the study was based on the Royal Marsden Hospital regimen comprising 120 mg/m on days 1, 3, and 5 (360 mg/m per cycle). Four hundred nineteen patients were randomly assigned. More patients allocated to BEP achieved a complete response with chemotherapy alone or after postchemotherapy surgery (95% v 87%; P .0075). In view of the low numbers of unfavorable treatment outcomes, no significant differences were detected in time to progression or survival. Although this study demonstrated that bleomycin contributes to the effectiveness of the BEP chemotherapy regimen, the dose of etoposide of 360 mg/m per cycle was less than is today considered standard EP chemotherapy. Two other studies have demonstrated that bleomycin adds to the effectiveness of the chemotherapy regimen. Both studies demonstrated superiority of the bleomycin-containing regimen, but the bleomycin was part of regimens that are now considered suboptimal. Taken together, these three studies have shown that bleomycin cannot be deleted if suboptimal chemotherapy is used, or when only three cycles are administered. Two randomized trials at Memorial Sloan-Kettering Cancer Center (New York, NY) examined the efficacy and toxicity of four cycles of EP. In these trials, etoposide was given at a dose of 500 mg/m. Long-term follow-up of 214 patients treated with four cycles of EP (4 EP) revealed a progression-free survival of 82% after a median of 7 years, which was comparable with the results of the aforementioned studies investigating the role of bleomycin. A more exact interpretation of the data from these trials is hampered by the lack of uniform prognostic classification criteria in the 1980s. Consequently, complete response rates, progressionfree survival, and overall survival figures could simply not be translated and compared among these trials. To reach consensus on one uniform prognostic model, the International Germ Cell Cancer Collaborative Group (IGCCCG) was established in 1994. Consensus was reached on one uniform model for both nonseminoma and seminoma using a risk classification in three prognostic categories. The proportion of patients falling in the good prognosis group is 60% for nonseminoma and 90% for seminoma. The progression-free and overall survival at 5 years in this category is 86% and 90%, respectively. The first trial in good prognosis patients according to the IGCCC criteria was conducted by the EORTC and the Medical Research Council. This study tested the reduction of the chemotherapy by one cycle, by random comparison of 3 BEP versus four cycles. To avoid a cumulative exposure of bleomycin above 300 mg, bleomycin was omitted in the fourth cycle (ie, 3 BEP plus one cycle of EP). The study methods were aimed to rule out a 5% decrease in the 2-year progression-free survival, requiring 774 patients. The study included an assessment of patient quality of life. A total of 812 patients were randomly assigned. The projected 2-year progression-free survival was 90.4% for three cycles and 89.4% for four cycles (difference, 1%; 80% CI, 3.8% to 1.8%). Hence, equivalence was claimed, since both bounds of the confidence limit were less than 5%. Frequencies of hematologic and nonhematologic toxicities were essentially similar, except for both acute and late sensory neuropathy, which was more frequent with four cycles. Quality of life 1 year after completion of treatment was identical. This study demonstrated that 3 BEP, with etoposide at 500 mg/m is sufficient therapy in good prognosis germ cell cancer by IGCCC criteria. For the purpose of better interpreting the results obtained by four cycles of EP in the two good prognosis trials, and allowing for meaningful intergroup comparisons, the Memorial Sloan-Kettering JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 28 OCTOBER 1 2007