Clinical development of S-1 plus cisplatin therapy as first-line treatment for advanced gastric cancer

Abstract

annually [1,2]. In Japan, gastric cancer is one of the most frequent causes of death from cancer, despite dramatic advances in diagnosis and therapy [3]. Outcomes are extremely poor among patients with unresectable gastric cancer, with the median survival ranging from 3 to 5 months with the best supportive care [4][5][6].Randomized controlled trials of various treatment regimens have produced disappointing results in patients with advanced gastric cancer (AGC), with survival of only 6 to 11 months. Median survival times (MSTs) have gradually improved, but are still less than 1 year [7][8][9][10][11][12][13]. Standard treatments remain a matter of debate.In this context, we evaluated the effectiveness of S-1 plus cisplatin (CDDP) therapy in a randomized phase III study based on the promising activity of several clinical studies of S-1. This review focuses on the clinical development of S-1 and S-1 plus CDDP therapy for AGC. Drug concept of S-1S-1 (TS-1; Taiho Pharmaceutical, Tokyo, Japan) is an oral anticancer drug that combines tegafur (FT), a prodrug of 5-fl uorouracil (5-FU), with 5-chloro-2, 4dihydropyridine (CDHP; gimeracil) and potassium oxonate (Oxo; oteracil potassium) in a molar ratio of 1 : 0.4 : 1. CDHP reversibly antagonizes the activity of dihydropyrimidine dehydrogenase (DPD), the ratelimiting enzyme for the degradation of 5-FU. CDHP has 180-fold higher DPD inhibitory activity than that of uracil in vitro [14]. High concentrations of 5-FU in serum and tumors are thereby maintained for prolonged periods. Potassium oxonate blocks the phosphorylation of 5-FU in the gastrointestinal tract, reducing gastrointestinal adverse effects, the prime dose-limiting toxicity of 5-FU [15]. Abstract We reviewed the clinical development of S-1 and S-1 plus cisplatin (CDDP) therapy for advanced gastric cancer (AGC). S-1 is an active oral fl uoropyrimidine in patients with AGC.Phase I/II clinical trials of S-1 plus CDDP for AGC have yielded high response rates and the agents were well tolerated. On the basis of these phase I/II studies, we performed a randomized phase III study comparing S-1 plus CDDP with S-1 alone in patients with AGC. In the S-1 plus CDDP group, S-1 was given orally, twice daily for 3 consecutive weeks, and 60 mg/m 2 CDDP was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. In the S-1 alone group, S-1 was given orally, twice daily for 4 consecutive weeks, followed by 2 weeks of rest, within a 6-week cycle. Median overall survival was signifi cantly longer in the S-1 plus CDDP group (13.0 months) than in the S-1 alone group (11.0 months; P = 0.04). Progression-free survival was signifi cantly longer in the S-1 plus CDDP group (median, 6.0 months vs 4.0 months; P < 0.0001) and the response rate was also significantly higher (54.0% vs 31.1%; P = 0.002). There were more grade 3 or 4 adverse events, including leukopenia, neutropenia, anemia, nausea, and anorexia in the S-1 plus CDDP group, but the events were manageable. No treatment-related deaths were observed. As a...

Pharmaceutical Care for Patients Undergoing S-1 Plus Cisplatin Therapy for Unresectable Recurrent Gastric Cancer

“…However, higher frequencies of adverse events in the digestive system (including nausea, anorexia, and diarrhea) have been reported with S-1 plus cisplatin therapy compared to S-1 monotherapy. 9,11…”