1 / 20

N. Boku, S. Yamamoto, K. Shirao, T. Doi, A. Sawaki,

R andomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912). N. Boku, S. Yamamoto, K. Shirao, T. Doi, A. Sawaki, W. Koizumi, H. Saito, K. Yamaguchi, A. Kimura, A. Ohtsu

krysta
Télécharger la présentation

N. Boku, S. Yamamoto, K. Shirao, T. Doi, A. Sawaki,

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 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 (JCOG9912) • N. Boku, S. Yamamoto, K. Shirao, T. Doi, A. Sawaki, • W. Koizumi, H. Saito, K. Yamaguchi, A. Kimura, A. Ohtsu • Gastrointestinal Oncology Study Group • of Japan Clinical Oncology Group

  2. Background For advanced gastric cancer, there is no established standard chemotherapy. In our previous phase III study (JCOG9205), combination chemotherapy of 5-FU+CDDP did not show a survival benefit over 5-FU alone. (Ohtsu, J Clin Oncol 2003) Phase II studies of S-1 (oral fluoropyrimidine) alone and combination chemotherapy ofCPT-11+CDDP showed promising activity and acceptable toxicities. (Sakata, Eur J Cancer 1998; Koizumi, Oncology 2000; Boku, J Clin Oncol 1999)

  3. Objectives • Compared to 5-FU continuous infusion (5-FUci) • 　・Superiority of CPT-11+CDDP • 　・Non-inferiority of S-1 • Primary endpoint： • Overall survival • Secondary endpoints： • Time to treatment failure (TTF) • Non-hospitalized survival (NHS) • Adverse Events (NCI-CTC ver.2) • Response rate (RECIST, central review)

  4. Inclusion Criteria • 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

  5. Present Phase III Study (JCOG9912) 5-FUci 800 mg/m2/day, ci, days 1-5 q 4 weeks CPT-11 + CDDP CPT-11 70 mg/m2, div, days 1&15 CDDP 80 mg/m2, div, day 1 q 4 weeks Randomization Stratified by (minimization) ・Institution ・PS 0/1/2 ・Unresectable/ Recurrence with adjuvant Cx/ Recurrence without adjuvant Cx S-1 S-140mg/m2, po, bid, days 1-28 q 6 weeks BSA < 1.25 80 mg/body/day 1.25 < BSA < 1.5 100 mg/body/day 1.5 < BSA 120 mg/body/day Continued until disease progression, unacceptable toxicities, patient’s refusal

  6. Statistical Considerations • Study design • Assumed 6-M, 1-Y survival rates 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) • One interim analysisat accrual of 300 patients (Mar. 2004) • using O’Brien & Fleming type alpha spending function • Actual accrual • 704 patients between Nov. 2000 – Jan. 2006 • Final analysis(Feb. 2007) on intention-to-treat (ITT) basis

  7. Background (Patient) 5-FUci CPT-11+CDDP S-1 No. of patients 234 236 234* Age median (range) 63 (24-75) 63 (32-75) 64 (39-75) Gender 176/58 180/56 175/59 M / F PS 0 / 1 / 2 152/79/3 151/81/4 151/80/3 Unresectable / Recurrent 189/45 190/46 188/46 Adjuvant Cx - / + 233/1 235/1 233/1 * One patient was ineligible; adenosquamous cell carcinoma.

  8. Background (Tumor) 5-FUci CPT-11+CDDP S-1 No. of patients 234 236 234 Macroscopic type* 5/63/164 5/73/155 5/68/161 0 / 1,2 / 3,4,5 Histological type** 111/121 102/134 110/124*** intestinal / diffuse Target lesion - / + 55/181 59/175 59/175 No. of metastatic sites 103/90/41 100/105/31 102/101/31 0,1 / 2 / >3 147/87 160/76 165/69 Peritoneal metastasis - / + *Japanese Classification of Gastric Carcinoma **Lauren classification, no data available in 2 pts **1 pt with adenosquamous type included

  9. Incidences(%) of Gr.>3 Adverse Events within 6 months (1) 5-FUci CPT-11+CDDP S-1 234 236 234 No. of patients Leukocytes 0 41.5 0.9 Neutrophils 1.3 65.0 5.6 Hemoglobin 15.5 39.3 12.8 Platelets 0.4 4.7 1.3 Febrile neutropenia 0 9.4 0 Infection with Gr.3 or 4 neutropenia 0 7.7 0.4 Infection without neutropenia 3.9 3.8 5.6 0 1.3 0.4 Treatment related death* * Judged by Data and Safety Monitoring Committee

  10. Incidences(%) of Gr.>3 Adverse Events within 6 months (2) 5-FUci CPT-11+CDDP S-1 No. of patients 234 236 234 AST 4.7 2.6 4.7 ALT 3.4 2.6 3.4 Bilirubin 3.0 1.3 4.3 Creatinine 0 2.1 0.9 Hyponatremia 6.5 22.6 5.2 Fatigue 1.7 10.3 5.1 Anorexia 12.5 32.9 12.4 Diarrhea 0.4 9.0 7.7 Nausea 6.9 20.5 5.6 Stomatitis 3.0 0 1.7

  11. Progression-free Survival and Response rate (%) 100 PFS 50 0 12 24 (months) P-value† Median n HR 95%C.I. 5-FUci - 2.9M 234 - - CPT-11+CDDP <0.001 4.8M 236 0.69 0.57-0.83 S-1 0.001 4.2M 234 0.75 0.62-0.90 †: one-sided log-rank test (superiority) Response rate - in pts with target lesion - CR and PR were confirmed by central review

  12. (%) 100 50 0 12 24 (months) Time to Treatment Failure P-value† n Median HR 95%C.I. 5-FUci 234 2.3M - - - CPT-11+CDDP 236 3.7M 0.81 0.67-0.98 0.014 S-1 234 4.0M 0.71 0.59-0.85 <0.001 †: one-sided log-rank test (superiority)

  13. Reasons for Treatment Failure 5-FUci CPT-11+CDDP S-1 234 236 234 No. of patients Continuing at final analysis 1 0 6 Disease progression 199 143 203 Toxicities 9 36 14 Refusal related to toxicity 9 39 8 Refusal not related to toxicity 9 8 0 Death 1 1 1 Other 6 9 2

  14. (%) 100 50 0 12 24 36 (months) Overall Survival Significance level‡ P-value n MST 1-yr HR 95%C.I. 5-FUci 234 10.8M 44.0% - - - 0.05 CPT-11+CDDP 236 12.3M 52.5% 0.85 0.70-1.04 0.055† S-1 234 11.4M 47.9% 0.83 0.68-1.01 0.034† 0.025 non-inferiority<0.001 0.025 †: one-sided log-rank test (superiority) ‡: multiplicity adjusted by Holm’s method

  15. (%) 100 50 0 12 24 36 (months) Non-hospitalized Survival = overall survival time – hospitalized days P-value† n Median HR 95%C.I. 5-FUci 234 7.2M - - - CPT-11+CDDP 236 9.5M 0.82 0.68-1.00 0.027 S-1 234 9.2M 0.76 0.62-0.92 0.003 †: one-sided log-rank test (superiority)

  16. Subset Analysis for Overall Survival- Hazard Ratio to 5-FUci and 95% Confidence Interval - CPT-11+CDDP S-1 Age <65 (n=372) >65 (n=332) PS 0 (n=454) 1,2 (n=250) Unresectable (n=567) Recurrent (n=137) Intestinal (n=323)* Diffuse (n=379) No. of met sites 0,1 (n=305) >2 (n=399) Target lesion (+) (n=531) (-) (n=173) Peritoneal mets (-) (n=472) (+) (n=232) All randomized (n=704) Hazard ratio *type unknown were excluded from the analysis

  17. Subset Analysis of Overall Survival - Target Lesion (+) - - Target Lesion (-) - (%) 100 (%) 100 50 50 24 0 12 36 (months) 0 24 12 36 (months) n PFS MST P-value† n MST P-value† 175 9.0M - 59 13.5M - 2.2M 5-FUci 5-FUci 181 12.1M 0.015 55 14.4M 0.54 4.8M CPT-11+CDDP CPT-11+CDDP 175 10.5M 0.070 59 18.1M 0.18 3.8M S-1 S-1 †: one-sided log-rank test (superiority)

  18. Summary and Conclusion • S-1 showed a significant non-inferiority to 5-FUci in survival • mild toxicities • favorable results of RR, TTF, NHS and PFS • longer survival than 5-FUci in almost all subsets • CPT-11+CDDP did not show superiority to 5-FUci in survival • substantial toxicities causing treatment failure • favorable results of RR, TTF, NHS and PFS • longer survival than 5-FUci in the subset of TL (+) • poor results in TL (-) and peritoneal mets (+) • S-1 should be considered for the standard chemotherapy of unresectable or recurrent gastric cancer.

  19. 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) 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.

  20. Y. Komatsu Y. Tsuji S. Saito A. Murakami T. Yoshioka H. Saito K. Amagai Y. Hamamoto K. Yamaguchi H. Endo T. Doi T. Denda A. Nakamura K. Shirao K. Kaneko K. Chin W. Koizumi S. Ohkawa Y. Hara K. Tanaka K. Hotta N. Boku H. Kawai H. Kojima H. Iwase S. Matsumoto H. Takiuchi T. Tamura H. Nishisaki M. Taniguchi J. Nasu A. Tsuji E. Baba M. Yoshida Investigators

More Related