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F. Maindrault-Gœbel, G. LLedo, B. Chibaudel, L. Mineur, T. André, M. Bennamoun, M. Mabro,

OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC). A GERCOR study. F. Maindrault-Gœbel, G. LLedo, B. Chibaudel, L. Mineur, T. André, M. Bennamoun, M. Mabro,

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F. Maindrault-Gœbel, G. LLedo, B. Chibaudel, L. Mineur, T. André, M. Bennamoun, M. Mabro,

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  1. OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC). A GERCOR study. F. Maindrault-Gœbel, G. LLedo, B. Chibaudel, L. Mineur, T. André, M. Bennamoun, M. Mabro, P.Artru, C. Louvet, A. de Gramont

  2. Rationale New combination therapies have improved survival but also increased toxicity, especially the cumulative toxicities like the oxaliplatin sensory neuropathy. The need to preserve the quality of life is the clinical rationale to evaluate CFI. Chemotherapy-free intervals (CFI) have previously been studied in patients receiving 5FU- based therapy (Hejna et al. Br J Cancer 1998, Maughan et al. Lancet 2003). The goal of the OPTIMOX2 study is to further evaluate the oxaliplatin stop and go strategy and the role of maintenance therapy.

  3. RANDOMI SAT ION OPTIMOX 2 Study design maintenance therapyvs chemotherapy-free interval with oxaliplatin stop and go OPTIMOX1 : maintenance therapy mFOLFOX7 x 6 cy sLV5FU2 before « baseline » progression FOLFOX7 reintroduction A OPTIMOX2 : chemotherapy-free interval mFOLFOX7 x 6 cy No maintenance until progression FOLFOX7 reintroduction B Only 6 pts in both arms had FOLFOX reintroduction more than 30 days after the first progression

  4. CHEMOTHERAPY mFOLFOX7 6 cycles (Both arms) LV 400 5-FU 3000 Oxali 100 H0 H2 H24 H48 sLV5FU2 5FUb 400 Maintenance until progression (OPTIMOX1) LV 400 5-FU 3000 H0 H2 H24 H48 Cycles every 14 days, dose mg/m²

  5. Inclusion criteria Histologically proven colorectal cancer Unresectable metastases Mesurable or evaluable metastasis No prior CT except adjuvant CT if ended  6 months before study entry 18 - 80 years alk. ph.<5 UNL , platelets> 100 109, creatinin <3 UNL WHO PS  2 No peripheral sensory neuropathy

  6. Statistics • Randomisation using minimization technique • Stratification by • center, PS (0-1 vs 2), • number of sites (1 vs > 1), • age (18 - 50 vs 51-75 vs 76 - 80), • Alk Ph. ( 3x UNL vs  3 - 5 ULN), • adjuvant chemo or not • Initial sample size was 600, downgraded to 200 when bevacizumab was approved in France; no formal hypothesis were done between the two arms but sample size was enough to detect a 20% difference in 2-year survival (30 vs 50%).

  7. Duration of Disease Control DDC = PFS 1 + PFS 2 (if no PD) T size PFS 1 PFS 2 t FOLFOX FOLFOX Progression at reintroduction Progression

  8. Patients Characteristics 202 patients enrolled from 12 centers

  9. OPTIMOX2 results

  10. OPTIMOX2 results

  11. OPTIMOX 2 Responses Response was evaluated at 4 and 6 cycles then every 2 months.

  12. OPTIMOX 2 Responses Reintroduction 1

  13. Grade 3-4 Toxicity per Patient (%) OPTIMOX 1OPTIMOX2 C1-C6 maintenance R1 C1-C6 R1 570 cy 662 cy 591 cy Neutropenia 19 6 12 12 12 Anemia 1 0 0 0 2 Thrombopenia 12 1 6 4 2 Mucitis 3 2 0 2 2 Vomiting 6 0 0 4 3 Diarrhea 7 0 0 4 2 HFS 0 3 0 0 0

  14. Neuropathy Optimox 1 Optimox 2 Grade 1 70.7 % 2 18.1 % 3 0 % Grade 1 70.8 % 2 16.5 % 3 0 % During C1-C6 Grade 1 8 % 2 21.2 % 3 2 % Grade 1 6.8 % 2 15.5 % 3 3.9 % 2 months after FOLFOX After the first reintroduction Grade 1 29.4 % 2 35.3 % 3 5.9 % Grade 1 36.8 % 2 19.2 % 3 7 %

  15. Progression-free Survival

  16. Duration of Disease Control

  17. Chemotherapy-free Interval

  18. CFI according to Pc factors PS 2 LDH ↑ Alk Ph >3ULN > 2 sites

  19. CFI according to Initial Response

  20. Overall Survival

  21. OS according to Pc factors PS <2 LDH N Alk Ph <3ULN < 3 sites

  22. OS according to Pc factors PS 2 LDH ↑ Alk Ph >3ULN > 2 sites

  23. PFS at Reintroduction

  24. Conclusions (1) OPTIMOX 1 without targeted therapies in first-line therapy achieved a prolonged DDC and overall survival (median 26 months) with a good tolerance in patients with MCRC. Maintenance therapy followed by oxaliplatin reintroduction may improve PFS and OS, but not DDC. Median duration of chemotherapy-free interval is 4 months in patients who did not have surgery. This CFI was comparable in patients with or without adverse prognostic factors Response rate and PFS after reintroduction of FOLFOX was the same in patients who did or did not receive maintenance therapy

  25. Conclusions (2) Despite the advantages for the patients, a full break in therapy can not be recommended based on the results of this study. A shorter break or intermittent chemotherapy (Labianca, ASCO 2006) deserve to be evaluated The ongoing GERCOR study, DREAM, is evaluating maintenance therapy with targeted drugs alone.

  26. Acknowlegments: • Dr Gérard Lledo – Lyon • Pr Aimery de Gramont– Paris • Dr Laurent Mineur – Avignon • Pr Thierry André – Paris • Dr Mustapha Bennamoun – • Montfermeil • Dr May Mabro – Suresnes • Dr Elisabeth Carola – Senlis • Dr Michel Flesch - Dijon • Dr Gérard Ganem – Le Mans • Dr Philippe Colin – Reims • Dr Dominique Auby - Libourne • For the GERCOR : • Dr Benoist Chibaudel • Pr Christophe Louvet • Nourredine Ait Rahmoune • Nora Zeghib • Gaelle le Guludec • Katia Neveu • Kristell Gélard • Rachel Moukoko

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