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M. Hebbar, B. Chibaudel, T. André, L. Mineur, D. Smith, C. Louvet,

FOLFOX4 (12 cycles) versus sequential dose-dense FOLFOX7 (6 cycles) followed by FOLFIRI (6 cycles) in patients with initially resectable metastatic colorectal cancer. A GERCOR Randomized Phase III study (MIROX). M. Hebbar, B. Chibaudel, T. André, L. Mineur, D. Smith, C. Louvet,

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M. Hebbar, B. Chibaudel, T. André, L. Mineur, D. Smith, C. Louvet,

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  1. FOLFOX4 (12 cycles) versus sequential dose-dense FOLFOX7 (6 cycles) followed by FOLFIRI (6 cycles) in patients with initially resectable metastatic colorectal cancer. A GERCOR Randomized Phase III study (MIROX) M. Hebbar, B. Chibaudel, T. André, L. Mineur, D. Smith, C. Louvet, J.L. Dutel, M. Ychou, J.L. Legoux, M. Mabro, R. Faroux, D. Auby, D. Brusquant, A. Khalil, S. Truant, A. Hadengue, F. Bonnetain, FR. Pruvot, C. Dalban, A. de Gramont

  2. CONFLICT OF INTEREST DISCLOSURE • No conflict of interest to declare

  3. RATIONALE • Liver is the main metastatic site in patients with colorectal cancer • Metastases are initially resectable in 15-20 % patients • Perioperative FOLFOX chemotherapy is active (EORTC study) 100 90 80 Periop FOLFOX4 HR= 0.73 [CI: 0.55-0.97] P=0.025 70 60 PFS in resected patients (%) 50 42.4% 40 3-yr PFS + 9.2% Surgery only 30 33.2% 20 10 0 (years) 0 1 2 3 4 5 6 Nordlinger B, et al. Lancet 2008, 371:1007-16

  4. RATIONALE Role of Irinotecan ? DFS R A N D O M I Z A T I O N FOLFIRI x12cy postop LV5FU2 x12cy postop OS Ychou M, et al. Ann Oncol 2009, 20:1964-70

  5. RATIONALE Two questions • May sequential administration of FOLFOX followed by FOLFIRI improve results ? • Why should the chronology be imposed ?

  6. RATIONALE MIROX strategy for resectable metastases • 6FOLFOX7 (oxa. 130mg/m²) followed by 6FOLFIRI • To reduce occurrence of oxaliplatin-related neuropathy, • To increase efficacy (absence of cross resistance) • Perioperative OR postoperative chemotherapy • Personalized strategy • To limit selection bias • Prior phase II study in patients with resectable MCRC • N=47 (periop, N=22 ; postop, N=25) • No grade 3 neurotoxicity • Survivals : 2-yr DFS 47%, and 2-yr OS 89% Taïeb J, et al. J Clin Oncol 2005, 23:502-9

  7. DESIGN OF THE PHASE III STUDY R A N D O M I Z A T I O N FOLFOX7 – FOLFIRI (N=142) N=284 From May 2004 to June 2010 FOLFOX4 (N=142) Surgery Surgery 4-6 preop cycles recommended

  8. INCLUSION CRITERIA • Histologically documented colorectal adenocarcinoma • Resected or resectable metastases • Only one metastatic site: liver, lung, ovary, or peritoneum • Age : 18-75 • PS: 0-2 • In case of prior adjuvant FOLFOX after resection of the primary: interval > 12 months required

  9. ENDPOINTS • Primary endpoint : Disease-free survival (DFS) • Secondary endpoints : • Overall survival • Objective response rate with perioperative chemotherapy, • Resection rate (R0, R1, R2) with perioperative chemotherapy, • Safety (NCI CTC v2) • Health related Quality of Life (EORTC QLQ C-30) • Sample Size • Superiority study, power of 80%, 2-sided test  = 0.05, • Δ 2-yr DFS rate : from 30% (FOLFOX4) to 45% (FOLFOX7-FOLFIRI) • 284 patients to be enrolled • 188 events required

  10. STRATIFICATION CRITERIA • Periop vs. postop chemotherapy • Surgery alone vs. radiofrequency ablation +/- surgery • Blumgart’s score (0-1 vs. 2-3 vs. 4-5) Fong Y, et al. Ann Surg 1999, 3:309-21

  11. Randomized: N=284 FOLFOX7 – FOLFIRI arm N=142 N=142 Treatment allocation N=140 N=142 Treated N=142 N=140 ITT analysis Median follow-up : 50.4 months CONSORT DIAGRAM FOLFOX4 arm

  12. PATIENT’S CHARACTERISTICS

  13. TREATMENTS

  14. TOXICITY

  15. DISEASE-FREE SURVIVAL DFS

  16. OVERALL SURVIVAL OS NR, not reached

  17. DFS POSTOP VS PERIOP DFS NR, not reached

  18. DFS POSTOP VS PERIOP Populations not comparable DFS 39.6% synchronous mets 66.0% synchronous mets NR, not reached

  19. CONCLUSIONS • MIROX strategy is not superior to FOLFOX4. • Results in both arms were better than expected, with a 2y-DFS over 45%, and a 4-yr survival over 70%. • Survival difference between perioperative and postoperative schedules mainly explained by differences in patient’s profiles. • Planned: • Multivariate analysis focusing on known prognostic factors, and chronology of chemotherapy. • Overall survival update.

  20. Acknowlegments PATIENTS AND THEIR FAMILIES, INVESTIGATORS AVIGNON:Laurent Mineur BEAUVAIS:Jean-Yves Dutel BORDEAUX:Denis Smith BRIEY:Patrick Brucker CALAIS:Zoher Merad DIJON: Michel Flesch LA ROCHE/YON:Roger Faroux LIBOURNE:Dominique Auby LILLE:Mohamed Hebbar, Eric Vaillant, Philippe Martin, Stéphanie Truant, François-René Pruvot, Christophe Mariette, Jean-Pierre Triboulet MONTPELLIER:Marc Ychou, Eric Assenat PARIS:Aimery de Gramont, Thierry André, Christophe Louvet, Christophe Tournigand, Frédérique Maindrault-Goëbel, Mostepha Bennamoun, Ahmed Khalil, Julien Taïeb PESSAC:Jean-Louis Legoux SENLIS:Elisabeth Carola SURESNES:May Mabro BIOSTATISTICIANS : CGFL (Dijon) Cécile Dalban, Franck Bonnetain GERCOR (Paris) Benoist Chibaudel, David Brusquant, Alexandra Hadengue, Dominique Notelet … SANOFI-AVENTIS Youssef Yataghene

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