Randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912)

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LBA4513 Backgrounds: We conducted a 3-arm phase III study to investigate superiority of CP and non-inferiority of S-1 to 5-FU for advanced gastric cancer in the primary endpoint of overall survival (OS) and secondary endpoints of response rate (RR), time to treatment failure (TTF), non-hospitalized survival (NHS) and toxicities. Methods: Treatments with 5-FU (800mg/m2/d, ci, d1–5, q4w), CP (irinotecan, 70mg/m2, div, d1&15 and cisplatin, 80mg/m2, div, d1, q4w) and S-1 (40mg/m2, b.i.d., d1- 28, q6w) were continued until disease progression or unacceptable toxicities. Tumors were evaluated every two months. With 230 patients (pts) per arm, this study had 80% power to demonstrate 10% superiority of CP and non-inferiority with 5% margin (hazard ratio, HR=1.16) of S-1 and 0.05 study-wise 1-sided alpha. Results: 704 pts having unresectable or recurrent gastric adenocarcinoma with/without target lesions (TL) were randomized between Nov 2000 and Jan 2006. Final analysis was performed in Feb 2007 when 601 pts (85%) were dead. The results of OS are shown in Table . Median TTF/NHS were 2.3M/7.2M for 5-FU, 3.7M/9.5M for CP, and 4.0M/9.2M for S-1. Incidences (%) of grade 4 neutropenia, grade ≥3 febrile neutropenia, infection with neutropenia, anorexia, diarrhea within 6M, and treatment related death (5- FU/CP/S-1) were 0/37/0, 0/9/0, 0/8/0, 13/33/12, 0/9/8, and 0/1.3/0.4. In the subset having TL, RRs of 5-FU/CP/S-1 (n=175/181/175) were 9%/38%/28%, and their median survival times (MST) were 9.0M/12.1M/10.5M and HRs to 5-FU were 0.78 (95%CI, 0.63–0.98) for CP and 0.85 (0.68–1.06) for S-1. In the subset not having TL, the MSTs of 5-FU/CP/S-1 (n=59/55/59) were 13.5M/14.4M/18.1M and HRs were 1.02 (0.68–1.55) for CP and 0.82 (0.55–1.24) for S-1. Conclusions: S-1 showed a significant non-inferiority to 5-FU. Although CP did not show statistically significant superiority to 5-FU in all pts, it may have a benefit for some subgroups such as pts with measurable metastatic diseases. [Table: see text] [Table: see text]