Background: The best chemotherapy regimen for metastatic gastric cancer is uncertain, but promising findings have been reported with irinotecan plus cisplatin and S-1 (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate). We aimed to investigate the superiority of irinotecan plus cisplatin and non-inferiority of S-1 compared with fluorouracil, with respect to overall survival, in patients with metastatic gastric cancer. Methods: We undertook a phase 3 open label randomised trial in 34 institutions in Japan. We enrolled patients aged 20-75 years or younger, who had histologically proven gastric adenocarcinoma, and randomly assigned them by minimisation to receive either: a continuous infusion of fluorouracil (800 mg/m2 per day, on days 1-5) every 4 weeks (n=234); intravenous irinotecan (70 mg/m2, on days 1 and 15) and cisplatin (80 mg/m2, on day 1) every 4 weeks (n=236); or oral S-1 (40 mg/m2, twice a day, on days 1-28) every 6 weeks (n=234). The primary endpoint was overall survival. Analyses were done by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00142350, and with UMIN-CTR, number C000000062. Findings: All randomised patients were included in the primary analysis. Median overall survival was 10·8 months (IQR 5·7-17·8) for individuals assigned fluorouracil, 12·3 months (8·1-19·5) for those allocated irinotecan plus cisplatin (hazard ratio 0·85 [95% CI 0·70-1·04]; p=0·0552), and 11·4 months (6·4-21·3) for those assigned S-1 (0·83 [0·68-1·01]; p=0·0005 for non-inferiority). Three treatment-related deaths occurred in the irinotecan plus cisplatin group and one was recorded in the S-1 group. Interpretation: S-1 is non-inferior to fluorouracil and, in view of the convenience of an oral administration, could replace intravenous fluorouracil for treatment of unresectable or recurrent gastric cancer, at least in Asia. Irinotecan plus cisplatin is not superior to fluorouracil in this setting. Funding: Ministry of Health, Labour, and Welfare of Japan; Taiho Pharmaceutical; Yakult Honsha.
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