A randomized phase III trial comparing 4 courses and 8 courses of S-1 adjuvant chemotherapy for p-stage II gastric cancer: JCOG1104 (OPAS-1)

Abstract

Background: Postoperative S‐1 for 1 year (corresponding to 8 courses) is a standard adjuvant chemotherapy for p‐stage II gastric cancer based on ACTS‐GC phase III study comparing surgery alone and S‐1. Duration of adjuvant chemotherapy for 1 year selected in ACTS‐GC was not based on solid evidence while 6 months are established for colon cancer based on several phase III studies to compare duration. It remains unclear whether S‐1 for 1 year could be shortened to 6 months (corresponding to 4 courses) without worsening the survival. Methods: We conducted a multi‐center phase III trial to confirm non‐inferiority in relapse‐free survival (RFS) of 4 courses S‐1 to 8 courses S‐1 in p‐stage II gastric cancer. Key eligibility criteria were p‐stage II except T1 and T3N0 (7th edition of TNM), performance status 0‐1, R0 resection with D2 lymph node dissection for ≥c‐stage II or D1+ lymph node dissection for c‐stage I, within 7 weeks after surgery, and age between 20 and 80 years. Primary endpoint was RFS and secondary endpoints included overall survival (OS), time to treatment failure (TTF), and adverse events. Patients were randomized into 4 course S‐1 or 8 courses S‐1. 80 mg/m2 of S‐1 was administered for 4 weeks with a rest for 2 weeks as one course. Total sample size was determined to be 1,000 with 3‐year RFS of 85% in both arms and non‐inferiority margin of hazard ratio (HR) of 1.37, one‐sided alpha of 5% and 80% power. Results: Between Feb 2012 and Mar 2017, 590 patients were enrolled in this study. Among them, 528 patients were analyzed at the first planned interim analysis at Mar 2017. JCOG Data and Safety Monitoring Committee recommended early termination of the trial because the point estimate of HR was greater than non‐inferiority margin of HR, which met the prespecified criteria for early stopping. The study was closed on the basis of futility. RFS at 3 years was 88.9% for 4‐courses arm and 95.3% for 8‐ courses arm (HR 2.52, 95% CI 1.11‐5.77). OS at 3 years was 91.7% for 4‐courses arm and 97.7% for the 8‐courses arm (HR 5.18, 95% CI 1.50‐17.89). Conclusions: Postoperative S‐1 adjuvant chemotherapy for p‐stage II gastric cancer should be continued until 1 year so far as feasible.