Randomized phase II trial of CODE or AP after chemoradiotherapy for LD-SCLC: Long-term survival and toxicity analysis

Abstract

Background: The objective of this study was to select, for a phase III trial, the more promising of weekly‐dose intensive chemotherapy or amrubicin plus cisplatin as subsequent therapy after induction chemoradiotherapy for previously untreated limited‐disease small cell lung cancer (LD‐SCLC). Methods: Patients (pts) aged 20‐70 years with untreated clinical stage II/III LD‐SCLC were eligible. After one cycle of accelerated hyperfractionation thoracic radiotherapy with etoposide plus cisplatin, pts without progression were randomized to either 3 cycles of cisplatin 25mg/m2 (days 1, 8), doxorubicin 40mg/m2 (day 1), etoposide 80 mg/m2 (days 1‐3), and vincristine 1 mg/m2 (day 8) every 2 weeks (CODE) or amrubicin 40mg/m2 (days 1‐3) and cisplatin 60mg/m2 (day 1) every 3 weeks (AP). The primary endpoint was the 1‐year progression‐ free survival (PFS) after randomization. The sample size was 72 to select the arm yielding a better 1‐year PFS (55%vs. 65%)with a correct selection probability of 80%. Results: From March 2011 to February 2014, 85 pts were registered. After the induction chemoradiotherapy, 75 pts were randomized to CODE (n=39) or AP (n=36). The one‐year PFS (95% CI) was 41.0% (25.7‐55.8) in the CODE arm and 54.3% (36.6‐69.0) in the AP arm. Grade 4 neutropenia and grade 3 febrile neutropenia occurred in 47% and 16% in the CODE arm and 78% and 42% in the AP arm, respectively. In patients aged 61 years or older, they were noted in 48% and 19% in the CODE arm and 88% and 48% in the AP arm, respectively. In women, they were noted in 20% and none in the CODE arm and 86% and 71% in the AP arm, respectively. Grade 3 pneumonitis was noted in one patient each in both arms. Secondary malignancies developed in 4 pts in the CODE arm and 2 pts in the AP arm. The 5‐year survival (95% CI) in all 85 pts was 43.2% (32.5‐53.4). The 5‐year survival in all pts after randomization for CODE and AP arms were 35.3% (20.6‐50.2) and 45.2% (28.3‐60.7), respectively. The HR (95% CI) of AP arms to CODE arm was 0.70 (0.39‐1.25). Conclusions: An overall survival profile of AP was relatively good when compared to that of the historical control, but hematological toxicity was severe in AP, especially in older and female patients.