Randomized phase III study of a new oral fluoropyrimidine; S-1, combined with cisplatin versus S-1 alone in advanced gastric cancer (the SPIRITS trial). Analyses of efficacy data.

A144 Background: A new oral fluoropyrimidine with DPD inhibitory effect, S-1 (TS-1 TM ) has been widely used in Japan as a single agent, for advanced gastric cancer (AGC) with high response rates of 44-54% and median overall survival (OS) around 7- 10months. Results of a phase I/II study combining S-1 and cisplatin are encouraging with a response rate (RR) of 74%, and a median OS of 12.6 months (Koizumi et al, Br J Cancer, 2003). Based on these results, a phase III study comparing combination of S-1 and cisplatin with S-1 alone has been conducted in Japan to further evaluate the efficacy of S-1 for patients with AGC.
 Method: In this randomized, controlled, open-label, parallel, multicenter study, patients were randomly assigned to S-1 plus cisplatin (SP) arm or S-1 (S) arm. On the SP arm, patients received oral S-1 (40mg/m 2 ) twice daily 21 days followed by 14 days rest plus cisplatin (60mg/m 2 ) intravenously on day 8. On the S arm, patients received S-1 twice daily 28 days followed by 14 days rest. Selection criteria included metastatic AGC, age 20-74, no prior chemotherapy for advanced disease. Primary endpoint was OS. Secondary endpoints included RR, progression-free survival (PFS) and toxicity. Additional exploratory subset analyses of OS were conducted.
 Results: 305 pts (SP/S arm, 153/152) were randomized between Mar 2002 and Nov 2004. The full analysis set comprised 298 patients (SP/S arm, 148/150). At a follow-up of 2 yrs after the last patient was randomized, OS was significantly superior for the SP arm vs. the S arm (in median, 13 months vs. 11 months, HR: 0.774, 95% CI: 0.610 - 0.982; P=0.0366). PFS was significantly longer in the SP arm than in the S arm (in median, 6 months vs. 4 months; P Conclusion: The combination of S-1 and cisplatin was found to be effective and well tolerated in patients with AGC. In the combination therapy, the high rate of continued therapy with other regimens have probably contributed to better overall survival in both arms. S-1 plus cisplatin is particularly effective in subgroups of patients with characteristics described above, potentially contributing to substantially longer survival. Furthermore, this is also the first phase III trial to show significantly better results with combination chemotherapy than with monotherapy. Accordingly, this regimen can be regarded as one of first-line standard treatment for advanced gastric cancer.