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

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 fluoropyrimidine 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/m² 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 significantly 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 significantly 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 result of this study, S-1 plus CDDP therapy has become a standard first-line treatment for AGC in Japan.