1 / 30

ALM CAO

ALM CAO. AGITG. g. Peri-operative FOLFOX4 chemotherapy and surgery for resectable liver metastases from colorectal cancer Final efficacy results of the EORTC Intergroup phase III study 40983.

aden
Download Presentation

ALM CAO

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. ALMCAO AGITG g Peri-operative FOLFOX4 chemotherapy and surgery for resectable liver metastases from colorectal cancer Final efficacy results of the EORTC Intergroup phase III study 40983. B. Nordlinger, H. Sorbye, B. Glimelius, G.J. Poston, P.M. Schlag, P. Rougier, W.O. Bechstein, J. Primrose, E.T. Walpole, T. Gruenberger Statistical analysis L. Collette For the EORTC GI Group, CR UK, ALMCAO, AGITG and FFCD

  2. Aim of this study To demonstrate that chemotherapy combined with surgery is a better treatment than surgery alone

  3. Study design Randomize FOLFOX4 Surgery FOLFOX4 6 cycles (3 months) 6 cycles (3 months) Surgery N=364 patients

  4. Rationale for FOLFOX4 • FOLFOX4 demonstrated a response rate above 50%, and improved PFS in metastatic colorectal cancer De Gramont et al.JCO 2000

  5. Rationale for timing of chemotherapy • Preoperative : tumor response to chemotherapy allows to resect smaller metastases and to test their chemoresponsivness • Postoperative: dormant cancer cells are present in remnant liver; chemotherapy is beneficial for stage III colon cancer (André et al.,NEJM 2004) • Pragmatic approach: the design is not meant to validate the value of post vs pre-operative chemotherapy

  6. Main eligibility criteria • Potentially resectable liver metastases of colorectal cancer (metachronous or synchronous) • Up to 4 deposits (on CT-scan, at randomization) • No extra-hepatic disease • No previous chemotherapy with oxaliplatin • WHO/EGOG 0-2 • Informed consent

  7. Objectives of the trial • Primary endpoint: demonstrate an improvement in progression-free survival with peri-operative FOLFOX4 compared to surgery alone • Secondary endpoints : overall survival, tumor resectability, tumor response, safety

  8. Statistical hypothesis and sample size • Definition of progression • Recurrent or progressive disease • Metastases not resectable at surgery • Death of any cause if prior to progression • Objective: to demonstrate a 40% increase in median PFS (HR=0.71) with 80% power and 2-sided significance level 5% • Sample size: 330 patients (for 278 events) • 364 patients (182 x 2) recruited from September ‘00 to July ‘04

  9. Patient population (N=364)

  10. Compliance to pre-op chemotherapy

  11. Tolerance to pre-operative CT (Gr 3-4 toxicities ) *No grade 4; No toxic death during preop CT; One patient not resected due to liver damage probably due to CT

  12. Size of lesions after pre-operative CT* • Before preop CT (median) : 45 mm (5-255) • After preop CT (median) : 30 mm (0-230) • Relative change : - 29.5 % * SUM of the largest diameters

  13. RECIST Response after pre-operative CT Complete response: 7 ( 3.8%) Partial response: 73 (40.1%) Stable disease: 64 (35.2%) Progressive disease: 12 ( 6.6%) 8 progressed after 3-4 cycles, 3 were resected 4 progressed after 6 cycles, 1 was resected Not evaluable 26 (14.3%) Ineligible 7 Benign lesion 3 <3 cycles 12 No follow-up measures 4 Total: 182 pts

  14. Surgery

  15. Complications of surgery *P=0.04

  16. Compliance to post-op chemotherapy * No postop protocol CT : No protocol CT at all (11), Not operated or not resected (22), refusal (9), complications (14; including 2 gr 3 neurotoxicity), progression (5), other (6)

  17. Tolerance to post-operative CT (Gr 3-4 Toxicities ) * No grade 4 N=115

  18. Interim analysis – Early release of results December 2006 • 235/ 278 PFS events • IDMC reviewed the dataand authorized the present release of the results At the cut off date of March 2007 • median follow-up of 48 months • 254/278 PFS events • Final analysis performed • 2-sided p= 0.0434 significance level

  19. Patient Flow Patient flow Informed consent Randomized: 364 Pre&Postop CT182 Surgery 182 Resectable on imaging 11 Ineligible 11 Started pre-op CT 171 Resected 151 Resectable at surgery Resected 152 Started post-op CT 115

  20. Results

  21. Results

  22. Results

  23. Progression-free survival in eligible patients HR= 0.77; CI:0.60-1.00, p=0.041 100 90 +8.1%At 3 years Periop CT 80 70 60 50 36.2% 40 Surgery only 30 28.1% 20 10 0 (years) 0 1 2 3 4 5 6 O N Number of patients at risk : 125 171 83 57 37 22 8 115 171 115 74 43 21 5

  24. Progression-free survival in resected patients HR= 0.73; CI:0.55-0.97, p=0.025 100 90 +9.2%At 3 years 80 Periop CT 70 60 50 42.4% 40 Surgery only 30 33.2% 20 10 0 (years) 0 1 2 3 4 5 6 O N Number of patients at risk : 104 152 85 59 39 24 10 93 151 118 76 45 23 6

  25. Conclusions Peri-operative chemotherapy with FOLFOX4 improved PFS in patients with resectable liver metastases, and even more in patients whose metastases were actually resected, and was safe. This treatment should be proposed as the new standard for these patients, and should be delivered by a multidisciplinary team.

  26. Perspectives • Progress in imaging with spiral CT, MRI, contrast US, PET scans … reduces the rate of patients deemed non resectable at surgery • Timing and duration of chemotherapy may be optimized • Combination with new agents will be tested

  27. Trial 40051 (BOS) SURGERY FOLFOX6 modified + cetuximab + bevacizumab 6 cycles (no bevacizumab in cycle #6) FOLFOX6 modified + cetuximab + bevacizumab 6 cycles Resectable Liver Metastases from Colorectal Cancer no extrahepatic disease WHO PS 0,1 No previous chemo for mets follow up RANDOMIZATION SURGERY FOLFOX6 modified + cetuximab 6 cycles FOLFOX6 modified + cetuximab 6 cycles follow up

  28. Acknowledgments Norway 24 Sweden 24 Netherlands 5 UK 76 Belgium 19 Germany 67 France 60 Austria 49 Italy 1 • Patients and Participating Centers • EORTC Data Center:, M. Praet, M.A.Lentz, M.Debois, U.Bethe, P.Therasse • Sanofi-Aventis: I.Tabah-Fisch, T.Pearce Australia: 35 Hong Kong: 6 EORTC GI Group, CR UK, ALMCAO, AGITG and FFCD

  29. Other Participating investigators Finch-Jones - Jaeck - Mirza - Parks - Hugh - Hohenberger - Karner - De Greve - Chan - Davidson - Iesalnieks / Jauch - Lindner - Parnis - Peeters - Diamond - Ducreux - Graeven - Paillot - Doran - Gouillat - Jagot-Lacoussiere - Jansen - Konopke / Koehne - Otto - Sherlock - Van Hazel - Ackland - Bedenne - Bories - Clavero-Fabri - Conroy - Husseini - Karapetis - Mueller - Price - Rosenberg - Schott - Tschmelitsch - Van Laethem - Wals - Weimann - Arnaud - Arsene - Auby - Bhattacharya - Cebon - Cherqui - Confente - Dousset - Frickhofen - Frilling - Ganju - Hoeffken - Lazorthes - Letoublon - Nitti - Orr - Pariente - Pector - Raoul - Rees - Ridwelski - Rouanet - Toogood – Van Cutsem - Vergauwe - Wilke - Madroszyk

  30. Matthias Lorenz

More Related