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Yoon-Koo Kang, Heung-Moon Chang, Dae Young Zang,

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Yoon-Koo Kang, Heung-Moon Chang, Dae Young Zang,

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  1. Postoperative adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer: A randomized phase III trial of intraperitonealcisplatin and early mitomycin-C plus long-term doxifluridine plus cisplatin (iceMFP) versus mitomycin-C plus short-term doxifluridine (Mf)(AMC 0101) (NCT00296322) Yoon-Koo Kang, Heung-Moon Chang, Dae Young Zang, Jae-Lyun Lee, Tae Won Kim, Dae Hyun Yang, Se Jin Jang, Jeong Hwan Yook, Sung Tae Oh, Byung Sik Kim Asan Medical Center, Seoul, Hallym University Hospital, Anyang, Korea

  2. Disclosure • Yoon-Koo Kang, M.D., Ph.D. • I have no relevant relationships to disclose.

  3. Meta-analyses suggested small but significant benefit of adjuvant chemotherapy in AGC

  4. Mitomycin-C based adjuvant chemotherapy: shown effective in a meta-analysis of 10 studies conducted in Japan in 1960s – 1980s Nakajima, et al. Gan To Kagaku Ryoho 1994

  5. MMC + short-term oral fluoropyrimidine: effective adjuvant chemotherapy for AGC Tegafur 400 mg po bid for 3 months MMC 20 mg/m2 iv R None N=148 Stage III Ciera, et al. J Clin Oncol 1999

  6. To improve adjuvant chemotherapy with MMC + short-term oral fluoropyrimidine • Add cisplatin • Prolong the administration of low dose oral fluoropyrimidine

  7. AMC0201 Curatively Resected PS II – IV(M0) Gastric Cancer 3-6 weeks after surgery RANDOMIZATION Stratified by center, stage MFP arm Mf arm MMC MMC CDDP DFUR DFUR CDDP DFUR DFUR CDDP DFUR DFUR CDDP DFUR CDDP DFUR CDDP DFUR MMC 20 mg/m2 iv DFUR 460 – 600 mg/m2 po daily Cisplatin 60 mg/m2 iv D1 every 4 weeks DFUR DFUR DFUR DFUR DFUR DFUR DFUR Kang, et al. 2008 ASCO-GI Chang, etal. 2008 ASCO Abst #4531

  8. To improve adjuvant chemotherapy with MMC + short-term oral fluoropyrimidine • Add cisplatin • Prolong the administration of low dose oral fluoropyrimidine • Early start of chemotherapy • Intraperitoneal chemotherapy • For cases with gross serosa involvement

  9. Objectives of the study (AMC 0101) • To determine if addition of these 4 strategies can improve the outcome of adjuvant chemotherapy with mitomycin-C plus short-term oral fluoropyrimidine (Mf) in patients with grossly serosa positive AGC • Primary endpoint: RFS • Secondary endpoints: OS, safety

  10. Eligibility criteria • Histologically proven gastric adenocarcinoma • Curative gastrectomy with D2 dissection • Gross involvement of serosa • Age 18 – 70 years • No prior chemotherapy • No contraindication for chemotherapy • Informed consent

  11. Treatment Schema Grossly Serosa(+), Non-Metastatic Gastric Cancer At surgery RANDOMIZATION Stratified by center iceMFP arm Mf arm 100 mg for 2h before closure Intraperitoneal CDDP 3 - 6 weeks after surgery MMC 15 mg/m2 iv D1 Stage I, IV(M1) MMC 4 weeks later 20 mg/m2 iv Protocol off CDDP DFUR DFUR CDDP DFUR DFUR CDDP DFUR DFUR CDDP DFUR CDDP DFUR CDDP DFUR DFUR DFUR DFUR 460 – 600 mg/m2 po daily Cisplatin 60 mg/m2 iv D1 every 4 weeks DFUR DFUR DFUR DFUR DFUR

  12. Sample size calculation • Primary endpoint = 3yRFSR • Estimated 3yRFSR for Mf = 55% • Improvement of 3yRFSR to 67.5% by iceMFP • HR = 0.6574 • Two-sided a=0.05, b=0.2 • Considering 10% of FU loss • Total 527 patients (192 events) are needed

  13. Interim analysis • In Feb 2004 • Increased the dose of doxifluridine • To 600 mg/m2/d because of good safety

  14. Study summary • Accrual period: Oct 2001 - Apr 2007 • Total patients entered: 640 • 119 (60 in Mf, 59 in iceMFP) excluded after surgery because of stage I (90), IV (M1) (13), positive RM (10), others (6) • Total patients analyzed: 521 • Final analysis: Mar 2008 • Follow-up, median: 3.5 years • Total events: 229 (planned 192) • For HR = 0.6574 (3yRFSR 55% vs 67.5%) • Power = 0.8785

  15. Patients Characteristics (1)

  16. Patients Characteristics (2)

  17. Recurrence Free Survival 1.00 0.75 Recurrence free proportion 0.50 0.25 HR 0.695 [ 95% C.I.: 0.536 - 0.902 ] P = 0.006 by log-rank test 0 0 12 24 36 48 60 72 months after randomization

  18. RFS: Subgroup analysis Subgroup N H.R. (95% C.I.) Favor iceMFP Favor Mf

  19. Overall Survival 1.00 0.75 Surviving proportion 0.50 0.25 HR 0.710 [ 95% C.I.: 0.531-0.950 ] P = 0.02 by log-rank test 0 0 12 24 36 48 60 72 months after randomization

  20. 1.0 0.8 0.6 Surviving proportion 0.4 460 mg/m2/d 600 mg/m2/d 460 mg/m2/d 600 mg/m2/d 1.0 0.2 0.8 0.0 0 12 24 36 48 60 72 0.6 Months Recurrence free proportion 0.4 0.2 0.0 0 12 24 36 48 60 72 Months Dose of doxifluridine460 vs. 600 mg/m2/d RFS OS

  21. Surgery related complications

  22. Recurrences P=0.02

  23. Toxicities of chemotherapyGrade 3 & 4 (%)

  24. Conclusion • Postoperative iceMFP chemotherapy was safe and could significantly improve the RFS and OS in patients with grossly serosa-positive AGC, compared with Mf chemotherapy. • Considering no benefit of adding cisplatin and prolongation of oral doxifluridine to Mf chemotherapy in curatively resected AGC patients (AMC 0201), early start of chemotherapy and/or intraperitoneal cisplatin seemed to be responsible for the improved efficacy of iceMFP chemotherapy in this study.

  25. Acknowledgements

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