M Hebbar1, B Chibaudel2, T André2, L Mineur3, D Smith4, C Louvet5, J L Dutel6, M Ychou7, J L Legoux8, M Mabro9, R Faroux10, D Auby11, D Brusquant12, A Khalil13, S Truant14, A Hadengue12, C Dalban15, B Gayet16, F Paye17, F R Pruvot14, F Bonnetain15, J Taieb18, P Brucker19, B Landi20, M Flesch21, E Carola22, P Martin23, E Vaillant24, A de Gramont2. 1. Department of Medical Oncology, University Hospital, Lille mohamed.hebbar@chru-lille.fr. 2. Department of Medical Oncology, Hospital Saint-Antoine, Paris. 3. Department of Radiotherapy, Institute Sainte-Catherine, Avignon. 4. Department of Medical Oncology and Radiotherapy, Hospital Saint-André, Bordeaux. 5. Department of Oncology, Institute Mutualiste Montsouris, Paris. 6. Department of Medical Oncology, Radiotherapy Service, Hospital Centre Beauvais, Beauvais. 7. Regional Centre against Cancer, Val d'Aurelle-Paul Lamarque, Montpellier. 8. Department of Hepatology and Gastroenterology, Hospital de Haut-Lévêque, Pessac. 9. Department of Medical Oncology, Hospital Foch, Suresnes. 10. Department of Gastroenterology, Hospital La Roche-sur-Yon, La Roche-sur-Yon. 11. Department of Medicine, Hospital Libourne, Libourne. 12. GERCOR, Paris. 13. Department of Medical Oncology, Hospital Tenon, Paris. 14. Department of Digestive Surgery and Transplantation, University Hospital, Lille. 15. Methodology and Quality of Life in Oncology Department EA 3181, Hospital Besançon, Besançon. 16. Department of Surgery, Institute Mutualiste Montsouris, Paris. 17. Department of Digestive Surgery, Hospital Saint-Antoine, Paris. 18. Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Université Paris Descartes, Paris. 19. Department of Gastroenterology, Centre hospitalier François Maillot, Briey. 20. Department of Hepatogastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou Service Hépato-gastroentérologie; Paris. 21. Department of Medical Oncology, Clinique Clément Drevon, Dijon. 22. Department of Medical Oncology, Centre Hospitalier, Senlis. 23. Department of Cancerology, Centre Bourgogne, Lille. 24. Department of Gastroenterology, Clinique Ambroise Paré, Lille, France.
Abstract
BACKGROUND: Perioperative FOLFOX4 (oxaliplatin plus 5-fluorouracil/leucovorin) chemotherapy is the current standard in patients with resectable metastases from colorectal cancer (CRC). We aimed to determine whether a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is superior to FOLFOX4. The chemotherapy timing was not imposed, and was perioperative or postoperative. PATIENTS AND METHODS: In this open-label, phase III trial, patients with resectable or resected metastases were randomly assigned either to 12 cycles of FOLFOX4 (oxaliplatin 85 mg/m(2)) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m(2)) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m(2)). Randomization was done centrally, with stratification by chemotherapy timing, type of local treatment (surgery versus radiofrequency ablation with/without surgery), and Fong's prognostic score. The primary end point was 2-year disease-free survival (DFS). RESULTS: A total of 284 patients were randomized, 142 in each treatment group. Chemotherapy was perioperative in 168 (59.2%) patients and postoperative in 116 (40.8%) patients. Perioperative chemotherapy was preferentially proposed for synchronous metastases, whereas postoperative chemotherapy was more frequently used for metachronous metastases. Two-year DFS was 48.5% in the FOLFOX4 group and 50.0% in the FOLFOX7-FOLFIRI group. In the multivariable analysis, more than one metastasis [hazard ratio (HR) = 2.15] and synchronous metastases (HR = 1.63) were independent prognostic factors for shorter DFS. Five-year overall survival (OS) rate was 69.5% with FOLFOX4 versus 66.6% with FOLFOX7-FOLFIRI. CONCLUSIONS: FOLFOX7-FOLFIRI is not superior to FOLFOX4 in patients with resectable metastatic CRC. Five-year OS rates observed in both groups are the highest ever reported in this setting, possibly reflecting the pragmatic approach to chemotherapy timing. CLINICAL TRIALS NUMBER: NCT00268398.
BACKGROUND: Perioperative FOLFOX4 (oxaliplatin plus 5-fluorouracil/leucovorin) chemotherapy is the current standard in patients with resectable metastases from colorectal cancer (CRC). We aimed to determine whether a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is superior to FOLFOX4. The chemotherapy timing was not imposed, and was perioperative or postoperative. PATIENTS AND METHODS: In this open-label, phase III trial, patients with resectable or resected metastases were randomly assigned either to 12 cycles of FOLFOX4 (oxaliplatin 85 mg/m(2)) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m(2)) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m(2)). Randomization was done centrally, with stratification by chemotherapy timing, type of local treatment (surgery versus radiofrequency ablation with/without surgery), and Fong's prognostic score. The primary end point was 2-year disease-free survival (DFS). RESULTS: A total of 284 patients were randomized, 142 in each treatment group. Chemotherapy was perioperative in 168 (59.2%) patients and postoperative in 116 (40.8%) patients. Perioperative chemotherapy was preferentially proposed for synchronous metastases, whereas postoperative chemotherapy was more frequently used for metachronous metastases. Two-year DFS was 48.5% in the FOLFOX4 group and 50.0% in the FOLFOX7-FOLFIRI group. In the multivariable analysis, more than one metastasis [hazard ratio (HR) = 2.15] and synchronous metastases (HR = 1.63) were independent prognostic factors for shorter DFS. Five-year overall survival (OS) rate was 69.5% with FOLFOX4 versus 66.6% with FOLFOX7-FOLFIRI. CONCLUSIONS: FOLFOX7-FOLFIRI is not superior to FOLFOX4 in patients with resectable metastatic CRC. Five-year OS rates observed in both groups are the highest ever reported in this setting, possibly reflecting the pragmatic approach to chemotherapy timing. CLINICAL TRIALS NUMBER: NCT00268398.