Etoposide plus cisplatin with or without the combination of 4'-epidoxorubicin plus cyclophosphamide in treatment of extensive small-cell lung cancer: a French Federation of Cancer Institutes multicenter phase III randomized study.

BACKGROUND: The combination of etoposide plus cisplatin (EP) is considered to be standard therapy for small-cell lung cancer (SCLC). To determine whether drug intensification improves survival of patients with extensive SCLC, we compared this treatment with a four-drug regimen containing EP plus cyclophosphamide and 4'-epidoxorubicin (PCDE). METHODS: In a phase III clinical trial organized by the French Federation of Cancer Institutes, patients were randomly assigned to receive either EP (n = 109; etoposide at a dose of 100 mg/m(2) on days 1-3 plus cisplatin at 100 mg/m(2) on day 2) or PCDE (n = 117; etoposide and cisplatin given as in EP plus cyclophosphamide at 400 mg/m(2) on days 1-3 and 4'-epidoxorubicin at 40 mg/m(2) on day 1) every 4 weeks. Both groups received a total of six cycles. Survival differences were analyzed by Wilcoxon and log-rank tests. Associations of treatment group and putative prognostic variables with survival were tested in the Cox proportional hazards model. Quality of life was assessed from the responses to the European Organization for Research and Treatment of Cancer quality-of-life questionnaire (C30, health status and lung cancer module 13). All statistical tests were two-sided. RESULTS: Patients in the PCDE arm had a statistically significant higher frequency of combined complete plus partial responses compared with those in the EP arm (21% plus 55% versus 13% plus 48%, respectively; P =.02 for difference in combined objective responses). Patients in the PCDE arm survived longer than those in the EP arm (1-year survival rate: 40% and 29%, respectively; median survival: 10.5 and 9.3 months, respectively; log-rank P =.0067). In the Cox model, the relative risk of death for patients in the PCDE arm compared with those in the EP arm was 0.70 (95% confidence interval = 0.51 to 0.95); the disease also progressed more slowly in patients in the PCDE arm. Hematologic toxicity was higher in the PCDE arm (22% with documented infections compared with 8% in the EP arm; P =.0038), and the toxicity-related death rate was 9% in the PCDE arm versus 5.5% in the EP arm (P =.22). The global health status showed similar improvement in both arms during treatment. CONCLUSION: Compared with the EP regimen, the PCDE regimen yielded higher response rates and better survival rates in patients with extensive SCLC without affecting the quality of life of the patients during chemotherapy.