IP is the standard treatment for ED-SCLC, however often cause severe diarrhea. AP have shown promising activity in SCLC with fewer diarrhea. We conducted a phase III trial comparing AP with IP.Methods
Eligibility criteria included patients with chemotherapy-naïve, ED-SCLC, aged 20–70, and ECOG PS 0-1. Patients were randomized to receive either IP or AP, balancing for site, sex, and PS. IP comprised administration of I (60 mg/m2) iv on days 1, 8, and 15, and P (60 mg/m2) iv on day 1, every 4 weeks. AP comprised administration of A (40 mg/m2) iv on day 1–3, and P (60 mg/m2) iv on day 1, every 3 weeks. The planned sample size was 141 patients in each arm with a one-sided alpha of 5% and power of 70% and a non-inferiority margin of hazard ratio (HR) as 1.31. The primary end point was overall survival (OS). The secondary end points were response rate (RR), progression-free survival (PFS), adverse events (AEs), and quality of life (QOL). We evaluated patients' QOL twice: at the baseline and after completion of the second course.Results
Two hundred eighty-four patients were randomized to IP (n = 142) and AP (n = 142). Median age was 63, 84% were male, and 56% had PS 0. When 191 patients enrolled, more febrile neutropenia (FN) was observed in AP than anticipated, and the initial dose of A was decreased from 40 to 35 mg/m2. At the second interim analysis conducted after the completion of patient accrual, the median OS of AP (15.0 months) was much worse than that of IP (18.3 months) and the HR (1.41; 96.3% CI, 1.03–1.93) exceeds even the non-inferiority margin, so the Data and Safety Monitoring Committee recommended early publication of the results. Median PFS was 5.7 (IP) versus 5.2 months (AP) (HR 1.43, 95% CI, 1.13–1.82). The RR was 69.5 (IP) versus 77.9% (AP) (P = 0.14). AEs in IP and AP arm were grade 4 neutropenia (22.5% versus 78.6%), G3-4 FN (10.7% versus 32.1%), and G3-4 diarrhea (7.1% versus1.4%). The proportion of improvement in physical status of QOL was 37.1% (IP) versus 31.7% (AP) (odds ratio 0.72; 95% CI, 0.43–1.22; P = 0.227).Conclusions
AP showed more bone marrow suppression than expected although it caused less diarrhea. The non-inferiority of AP to IP was not demonstrated and IP remains the standard treatment for ED-SCLC.