M Karoui1, A Rullier2, G Piessen3, J L Legoux4, E Barbier5, C De Chaisemartin6, C Lecaille7, O Bouche8, H Ammarguellat9, F Brunetti10, M Prudhomme11, J M Regimbeau12, O Glehen13, A Lievre14, G Portier15, J Hartwig16, G Goujon17, B Romain18, C Lepage19, J Taieb20. 1. Medicine Sorbonne University, Paris VI, AP-HP; Pitié-Salpêtrière University Hospital, Department of Digestive and Hepato-Pancreato-Biliary Surgery, University Institute of Cancerology Paris VI, Paris, France. 2. Department of Pathology, Pellegrin University Hospital, Bordeaux, France. 3. Department of Digestive and Oncological Surgery, Lille University Hospital, Lille, France. 4. Department of Gastroenterology, CHR La Source, Orléans, France. 5. Biostatistics, University of Burgundy and Franche Comté, Dijon, France. 6. Department of Digestive Surgery, Institut Paoli Calmettes, Marseille, France. 7. Department of Oncology, Polyclinique Bordeaux Nord, Bordeaux, France. 8. Department of Medicine-Oncology, CHU Robert Debré, Reims, France. 9. Department of Medical Oncology, CH Beauvais, Beauvais, France. 10. Department of Digestive Surgery, AP-HP, CHU Henri Mondor, Créteil, France. 11. Department of Digestive Surgery, CHU Carémeau, Nîmes, France. 12. Department of Digestive Surgery, Amiens University Hospital, France. 13. Department of Digestive Surgery, CHU Lyon Sud, Lyon, France. 14. Department of Gastroenterology, CHU Rennes, Rennes 1 University, Rennes, France. 15. Department of Digestive Surgery, CHU Purpan, Toulouse, France. 16. Department of Gastroenterology, Infirmerie Protestante, Caluire-et-Cuire, France. 17. Department of Gastroenterology, Paris VII, AP-HP, BCHU Bichat, Paris, France. 18. Department of Digestive Surgery, CHU Hautepierre, Strasbourg, France. 19. Hepatogastroenterology and Digestive Oncology department, CHU Dijon, University of Burgundy and Franche Comté, FFCD, EPICAD INSERM LNC-UMR 1231, Dijon, France. 20. Sorbonne Paris Cité, Paris Descartes University, AP-HP; Departement of Hepatogastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France.
Abstract
BACKGROUND:Perioperative chemotherapy has proven valuable in several tumors, but not in colon cancer (CC). OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of perioperative chemotherapy in patients with locally advanced nonmetastatic CC. METHODS: This is a French multicenter randomized phase II trial in patients with resectable high-risk T3, T4, and/or N2 CC on baseline computed tomography (CT) scan. Patients were randomized to receive either 6 months of adjuvant FOLFOX after colectomy (control) or perioperative FOLFOX for 4 cycles before surgery and 8 cycles after (FOLFOX peri-op). In RAS wild-type patients, a third arm testing perioperative FOLFOX-cetuximab was added. Tumor Regression Grade (TRG1) of Ryan et al was the primary endpoint. Secondary endpoints were toxicity, perioperative morbidity, and quality of surgery. RESULTS: A total of 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped (lack of efficacy). The remaining 104 patients (control, n = 52; FOLFOX preop n = 52) represented our intention-to-treat population. In the FOLFOX perioperative group, 96% received the scheduled 4 cycles before surgery. R0 resection and complete mesocolic excision rate were 94% and 93%, respectively. Overall mortality and morbidity rates were similar in both groups. Perioperative FOLFOX chemotherapy did not improve major pathological response rate (TRG1 = 8%) but was associated with a significant pathological regression (TRG1-2 = 44% vs 8%, P < 0.001) and a trend to tumor downstaging as compared to the control group. CT scan criteria were associated with a 33% rate of overstaging in control group. CONCLUSIONS: Perioperative FOLFOX for locally advanced resectable CC is feasible with an acceptable tolerability but is not associated with an increased major pathological response rate as expected. However, perioperative FOLFOX induces pathological regression and downstaging. Better preoperative staging tools are needed to decrease the risk of overtreating patients.
RCT Entities:
BACKGROUND: Perioperative chemotherapy has proven valuable in several tumors, but not in colon cancer (CC). OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of perioperative chemotherapy in patients with locally advanced nonmetastatic CC. METHODS: This is a French multicenter randomized phase II trial in patients with resectable high-risk T3, T4, and/or N2 CC on baseline computed tomography (CT) scan. Patients were randomized to receive either 6 months of adjuvant FOLFOX after colectomy (control) or perioperative FOLFOX for 4 cycles before surgery and 8 cycles after (FOLFOX peri-op). In RAS wild-type patients, a third arm testing perioperative FOLFOX-cetuximab was added. Tumor Regression Grade (TRG1) of Ryan et al was the primary endpoint. Secondary endpoints were toxicity, perioperative morbidity, and quality of surgery. RESULTS: A total of 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped (lack of efficacy). The remaining 104 patients (control, n = 52; FOLFOX preop n = 52) represented our intention-to-treat population. In the FOLFOX perioperative group, 96% received the scheduled 4 cycles before surgery. R0 resection and complete mesocolic excision rate were 94% and 93%, respectively. Overall mortality and morbidity rates were similar in both groups. Perioperative FOLFOX chemotherapy did not improve major pathological response rate (TRG1 = 8%) but was associated with a significant pathological regression (TRG1-2 = 44% vs 8%, P < 0.001) and a trend to tumor downstaging as compared to the control group. CT scan criteria were associated with a 33% rate of overstaging in control group. CONCLUSIONS: Perioperative FOLFOX for locally advanced resectable CC is feasible with an acceptable tolerability but is not associated with an increased major pathological response rate as expected. However, perioperative FOLFOX induces pathological regression and downstaging. Better preoperative staging tools are needed to decrease the risk of overtreating patients.
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