An Early Phase II Study of Oral S-1, a Newly Developed 5-Fluorouracil Derivative for Advanced and Recurrent Gastrointestinal Cancers

Abstract

5-Fluorouracil (5-FU) or a 5-FU derivative 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) has been widely prescribed for patients with gastrointestinal cancer. However, the phosphorylation of 5-FU in the digestive tract causes gastrointestinal toxicities. 5-FU is also rapidly degraded to α-fluoro-β-alanine after contact with dihydropyrimidine dehydrogenase (DPDase) which is mainly present in the liver. Therefore, to overcome these metabolic events, S-1, an antitumor agent was developed, based on the biochemical modulation 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 examined in Japanese patients with advanced gastric (G) or colorectal (C) cancer in a multicenter early phase II study involving 24 centers throughout Japan. The patients were prescribed a minimum of 2 courses of S-1 orally, with each course consisting of 75 or 50 mg (in terms of FT) twice a day for 28 days followed by withdrawal for 2 weeks. Thirty-one patients with G and 31 C were entered into this study. The clinical response and extent of toxicity were evaluated in G 28 and C 30 cases, respectively. Nine (32.1%) G patients and 14 (46.7%) C patients had been treated previously with other anticancer 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 these 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) the disease progressed (PD). At the time of analysis, the median survival was 298 days (G) and 358 days (C). Major adverse effects consisted of gastrointestinal 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 gastrointestinal cancer.

A multi-center phase II study of S-1 plus paclitaxel as first-line therapy for patients with advanced or recurrent unresectable gastric cancer

“…S-1, as a prodrug of 5-FU, has been developed to increase the eYcacy and decrease the gastrointestinal toxicities of 5-FU [4,8]. In several phase II studies, S-1 alone has had modest antitumor activity in advanced gastric cancer [3,11,14,21,22]. A phase III trial of comparing S-1 with 5-FU was reported that of S-1 showed not inferior to 5-FU in overall survival (S-1 vs. 5-FU; 11.4 month vs. 10.8 month) [19].…”

“…The response rates with S-1 monotherapy, in patients with advanced gastric cancer, as the Wrst-line therapy were variable, 44-49% in Japan, 16.1% in Korea and 26.1% in Europe [3,11,14,21,22]. The response rates reported from the Japanese trials were higher than those from the Korean and European trials were.…”

“…The most common grade 3/4 hematological toxicities identiWed were neutropenia and anemia in several Japanese phase II trials of S-1 monotherapy [14,21,22]. In the early Japanese phase II trials, the dose of S-1 was 100 mg/day or 150 mg/day and the common toxicities were diarrhea and myelosuppression [22]. In the late phase II trials, the dose of S-1 was 80 mg/m 2 and the incidence of grade 3/4 neutropenia was reduced to less than 20% [21].…”

“…In Wve clinical trials, including three Japanese trials, the response rate after treatment with S-1 was 20-50% in patients with advanced gastric cancer as a single agent, when it was administered for 4 weeks with 2 weeks oV [3,11,14,21,22]. The main side eVects of S-1 treatment were diarrhea, fatigue, anemia, and neutropenia.…”

Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer

“…Phase I and early phase II studies of S-1 as a single agent proposed 80 mg m À2 day À1 given orally for 28 consecutive days, followed by a 2-week rest period, as the tentative recommended dosage (Horikoshi et al, 1996;Sugimachi et al, 1999). A number of studies have reported that S-1 monotherapy is effective against gastric cancer, with response rates ranging from 26 to 53% (Horikoshi et al, 1996;Sakata et al, 1998;Koizumi et al, 2000;Chollet et al, 2003).…”