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This house believes that FOLFIRINOX is the best treatment for patients with metastatic pancreatic adenocarcinoma

This house believes that FOLFIRINOX is the best treatment for patients with metastatic pancreatic adenocarcinoma. Pro Marc YCHOU Montpellier. R A N D O M I Z E. Oxaliplatin 85 mg/m 2 over 2 h Leucovorin 400 mg/ m 2 over 2 h

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This house believes that FOLFIRINOX is the best treatment for patients with metastatic pancreatic adenocarcinoma

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  1. This house believesthat FOLFIRINOX is the best treatment for patients withmetastaticpancreaticadenocarcinoma Pro Marc YCHOU Montpellier

  2. R A N D O M I Z E Oxaliplatin 85 mg/m2 over 2 h Leucovorin 400 mg/m2over 2 h Irinotecan 180 mg/m2in 90 mn infusion5-FU 400 mg/m2bolus 5-FU 2400 mg/m2on 46-h infusion Folfirinox Gemcitabine Prodige 4 - ACCORD 11 trial design 1000 mg/m2 over 30 minutes weekly x 7/8 and then weekly x 3/4

  3. Overall Survival Gemcitabine Folfirinox

  4. ACCORD 11: QUESTIONS ABOUT THIS TRIAL • Didwe have a coherentrationale to test FOLFIRINOX in a phase III trial ? • Gemcitabine : a relevant control arm ? • FOLFIRINOX: efficacious but tootoxic ? • Study population: tooselected ? • DidFOLFIRINOXregimendegradeQuality of Life ?

  5. A Phase I trial to assess the triple combination • Fixed dose level of simplified LV5FU2 • 8 dose levelsplanned for CPT-11 and L-OHP at day 1 Ychou M et al. AnnalsOncol 2003;14(3):481-9

  6. Bolus 5-FU 400 mg/m2 2 h Oxaliplatin 85 mg/m2 Leucovorin 400 mg/m2 Continuous 5-FU 2.400 mg/m2 Irinotecan 180 mg/m2 2 h 46 h 1 h 30 The recommendedPhase II Dose Simplified LV5FU+ 85 mg/m2 l-OHP + 180 mg/m2 CPT-11

  7. Background • Folfirinox regimenassessed in a phase II study(n=35) • Promisingregimen in M1 patients with good PS • Mediansurvival of 9.5 months Conroy T et al. J Clin Oncol 2005;23:1228-36 • A randomizedphase II-III studycomparing Folfirinox regimen to gemcitabinealonewaslaunched • Results of the phase II portion (n=88) presentedat the ASCO 2007 (objective: RR ≥ 24% in the Folfirinox arm) • 31.8% RR in the Folfirinox arm vs 11.4% in the gemcitabinearm Ychou M et al. J Clin Oncol 2007;25:18S:201s Due to encouraginginterimresults, the trial continued as a phase III study

  8. ACCORD 11: QUESTIONS ABOUT THIS TRIAL • Didwe have a coherentrationale to test FOLFIRINOX in a phase III trial ? • Gemcitabine : a relevant control arm ? • FOLFIRINOX: efficacious but tootoxic ? • Study population: tooselected ? • Did FOLFIRINOX regimendegradeQuality of Life ?

  9. Burris et al. : Gemcitabine vs 5FU • 126 locallyadvanced or symptomaticpancreas ADK • Kanorfskybetween 50% and 80% • Primary endpoint: clinicalbenefit(pain. PS. body weight) R Single blind 5FU 600 mg/m². 30' weekly (n = 63) Gemcitabine 1000 mg/m² 30' weekly (n = 63) Burriset al. JCO Jun 1. 1997:2403-13

  10. Burris et al. : Efficacy • Gemcitabine is more effective than 5-FU in alleviation of somedisease-related symptoms • Gemcitabine confers a modest survival advantage Burriset al. JCO Jun 1. 1997:2403-13

  11. Prognosis of patients with metastatic pancreatic cancer is poor • 5-year survival rates is 6% • Although gemcitabine became the reference treatment almost 15 years ago, attempts to improve outcomes since then have been disappointing *statistically significant (p<0.05) 1. Burris et al. J ClinOncol 1997; 2. Berlin et al. J ClinOncol 2002; 3. Louvet et al. J ClinOncol 2005; 4. Heinemann et al. J ClinOncol 2006; 5. Moore et al. J ClinOncol 2007; 6. Poplin et al. J ClinOncol 2009; 7. Cunningham et al. J ClinOncol 2008; 8. Cunningham et al. J ClinOncol 2009; 9. Kindler et al. ASCO 2007; 10. Van Cutsem et al. J ClinOncol 2009; 11. Philip et al. ASCO 2007.

  12. Gemcitabine alone in locally advanced and metastatic pancreatic cancer • ACCORD 11 trial: results for gemcitabineare comparable to thoseobservedacross a variety of studies * Onlymetastatic patients

  13. ACCORD 11: QUESTIONS ABOUT THIS TRIAL • Didwe have a coherentrationale to test FOLFIRINOX in a phase III trial ? • Gemcitabine : a relevant control arm ? • FOLFIRINOX: efficacious but tootoxic ? • Study population: tooselected ? • Did FOLFIRINOX regimendegradeQuality of Life ?

  14. Safety: main adverse events in ACCORD 11 • One toxicdeathin each arm *No prophylactic use of G-CSF

  15. Maximum Grade 3/4 toxicity in the METHEP trial (liver metastases from CRC) * Prophylactic use of GCS-F except in 4 patients**

  16. ACCORD 11: QUESTIONS ABOUT THIS TRIAL • Didwe have a coherentrationale to test FOLFIRINOX in a phase III trial ? • Gemcitabine : a relevant control arm ? • FOLFIRINOX: efficacious but tootoxic ? • Study population: tooselected ? • Did FOLFIRINOX regimendegradeQuality of Life ?

  17. ACCORD 11: patient characteristics

  18. ACCORD 11: disease characteristics

  19. ACCORD 11: Toxicity of Folfirinox in patients withbiliarystent  Similarrisk of developing infections and hematologictoxicity

  20. The OS benefit with FOLFIRINOX is consistent across all subgroups analyzed

  21. The OS benefit with FOLFIRINOX is consistent across all subgroups analyzed

  22. ACCORD 11: QUESTIONS ABOUT THIS TRIAL • Didwe have a coherentrationale to test FOLFIRINOX in a phase III trial ? • Gemcitabine : a relevant control arm ? • FOLFIRINOX: efficacious but tootoxic ? • Study population: tooselected? • Did FOLFIRINOX regimendegradeQuality of Life ?

  23. Change in mean QLQ-C30 score over time (A) Global health status (B) Diarrhea

  24. Time to definitive QoL degradation

  25. ACCORD 11: QUESTIONS ABOUT THIS TRIAL • A coherentrationale to test FOLFIRINOX in a phase III trial ? • Gemcitabine : a relevant control arm ? • FOLFIRINOX: tootoxic? • Study population: tooselected? • Did FOLFIRINOX regimendegradeQualityof Life ? Yes Yes No, toxicityismanageable Generalizable to a quite large population No

  26. Conclusion • I do believethat FOLFIRINOX is the best treatment for patients withmetastaticpancreaticadenocarcinoma if : • Bilirubin <1.5 UNL • PS 0-1 • Age< 75 • This combination is now tested in the adjuvant setting: ACCORD/PRODIGE 24 trial

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