An early phase II study of oral S-1, a newly developed 5-fluorouracil derivative for advanced and recurrent gastrointestinal cancers

5-Fluorouracil (5-FU) or a 5-FU derivative 1-(2-tetrahydrofuryl)-5-fluorour acil (FT) has been widely prescribed for patients with gastrointestinal can cer. However, the phosphorylation of 5-FU in the digestive tract causes gas trointestinal toxicities. 5-FU is also rapidly degraded to alpha-fluoro-bet a-alanine after contact with dihydropyrimidine dehydrogenase (DPDase) which is mainly present in the liver. Therefore, to overcome these metabolic eve nts, S-1, an antitumor agent was developed, based on the biochemical modula tion of FT by 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate ( Oxo), in a molar ratio of 1:0.4:1. The antineoplastic effect of S-1, was ex amined in Japanese patients with advanced gastric (G) or colorectal (C) can cer in a multicenter early phase II study involving 24 centers throughout J apan. The patients were prescribed a minimum of 2 courses of S-1 orally, wi th each course consisting of 75 or 50 mg (in terms of FT) twice a day for 2 8 days followed by withdrawal for 2 weeks. Thirty-one patients with G and 3 1 C were entered into this study. The clinical response and extent of toxic ity were evaluated in G 28 and C 30 cases, respectively. Nine (32.1%) G pat ients and 14 (46.7%) C patients had been treated previously with other anti cancer drugs. In G patients, there was a 53.6% (15/28) and in C patients a 16.7% (5/30) response rate (90% confidence interval G 38.4-68.1% and C 8.4- 30.5%) with 15 (53.6%) (G) and 5 (16.7%) (C) partial responses (PR), and th ese responses persisted for 79 days (G) and 120 days (C) (median value). In particular, the response rate for the primary lesion was 27.8% (5/18) (G) and 33.3% (1/3) (C). No change (NC) in the disease was observed in 4 (14.3% ) (G) and 13 (43.3%) (C) patients, and in 6 (21.4%) (G) and 7 (23.3%) (C) t he disease progressed (PD). At the time of analysis, the median survival wa s 298 days (G) and 358 days (C). Major adverse effects consisted of gastroi ntestinal symptoms and myelosuppression while toxicities of grade 3 or more occurred in 35.7% (10/28) (G) and 33.3% (10/30) (C). Based on these data, S-1 is considered to have positive effects in patients with advanced gastro intestinal cancer.