#4514: Updated results of randomized phase III study of 5-fluorouracil (5-FU) alone versus

1. #4514: Updated results of randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG 9912) N. Fuse, H. Fukuda, Y. Yamada, A. Sawaki, W. Koizumi, Y. Suzuki, K. Yamaguchi, H. Takiuchi, A. Ohtsu, N. Boku Gastrointestinal Oncology Study Group of Japan Clinical Oncology Group (JCOG) 5-FUci 800 mg/m2/day, ci, days 1-5, q4 weeks #4514 CPT-11 + CDDP CPT-11 70 mg/m2, div, d 1&15 CDDP 80 mg/m2, div, d 1 q4 weeks Background Multivariate analysis for OS Updated overall survival (OS) Statistical considerations (cont.) S-1 • This updated analysis: • The survival information of all surviving 103 pts at the primary analysis was updated in Apr 2008;we had the updated estimates of 2-year survival proportion. • Multivariate analyses with Cox proportional hazard model were conducted. • We conducted 3-arm randomized phase III trial in advanced gastric cancer which evaluated followings; • - Superiority of irinotecan + cisplatin (CP) compared to 5-fluorouracil continuous infusion (5-FUci). • - Non-inferiority of S-1 compared to 5-FUci. • At primary analysis of this study presented in ASCO 2007, • - S-1 showed statistically significant non-inferiority to 5-FUci. • - Either CP or S-1 failed to show statistically significant superiority to 5-FUci after adjusting for multiplicity. Proportion surviving 40 mg/m2, po, bid, days 1-28, q6 weeks Study design Randomization (n=704) (Nov. 2000 - Jan. 2006) Stratified by Institution/PS/Tumor status 234 were assigned to 1 ineligible case 236 were assigned to No ineligible case 2 were not treated 234 were assigned to No ineligible case 2 were not treated (month) Objectives To clarify the long-term results of JCOG 9912, an updated analyses with multivariate analyses were conducted. Subgroup analysisfor OS Eligibility criteria Summary and Conclusions Primary Analysis (Feb. 2007) 204 Events 196 Events 201 Events 1) Histologically confirmed unresectable or recurrent gastric adenocarcinoma 2) Adequate oral intake 3) Age: ≥ 20, ≤ 75 4) PS (ECOG)： 0, 1, 2 5) Preserved organ functions 6) No history of chemotherapy or radiation therapy except adjuvant chemotherapy completed 6 months before 7) Measurable lesion is not mandatory small metastatic disease detected by laparotomy is allowed 8) No severe peritoneal dissemination such as impaired bowel passage, ascites beyond pelvic cavity, wall deformity detected by barium enema 9) Written informed consent • The estimates of OS and HR of the updated analyses were almost identical to the previous report. • Actual %2-year OS of 5-FUci, CP, S-1 were 14%, 18%, 21%. • Each hazard ratio, adjusted by multivariate analyses with baseline factors, was essentially the same as that by univariate analyses. • The updated results • - reconfirmed the primary conclusion that S-1 monotherapy can be a new standard regimen for advanced gastric cancer. • - suggest that CP is still worthy for further clinical investigation. • Multivariate analyses showed that number of metastatic sites (> 2), • PS (> 1), presence of TL were associated with shorter survival. Updated Analysis(Apr. 2008) 220 Events 224 Events 216 Events Patient characteristics Statistical considerations • Study design: • Assumed 6-month, 1-year survival proportion of 5-FUci: 50-55%, 25-30% • Expected superiority of CPT-11+CDDP: +10% • Margin of non-inferiority of S-1: -5% (HR< 1.16) • One-sided alpha 0.05, power 0.7 -multiplicity adjusted by modified Bonferroni (Holm’s method) • Sample size: 450 (150/arm), planned accrual: 4 years -amended to 690 (230/arm) to achieve power= 0.8 (Mar. 2005) • Actual accrual: 704 patients between Nov. 2000 – Jan. 2006 • Primary analysis: One year follow-up after closing, Feb. 2007 Acknowledgement We would like to express sincere thanks to all participating patients, Data and Safety Monitoring Committee, Audit Committee of JCOG, and JCOG Data Center Support This study was mainly supported by the Grant-in-Aid for Cancer Research (11S-3, 14S-3, 17S-3, 11S-4, 14S-4, 17S-5, 20S-3, 20S-6) from the Ministry of Health, Labour and Welfare of Japan, and in part by the contract of periodical safety reports for S-1 to TAIHO PHARMACEUTICAL CO., LTD and for CPT-11 to Yakult Honsha Co., Ltd. * HRs and CIs from univariate Cox model by each subgroup, not including interaction term ** p-value from multivariate Cox model including arm,subgroup, and those interaction term