Julien Taieb1, Josep Tabernero2, Enrico Mini3, Fabien Subtil4, Gunnar Folprecht5, Jean-Luc Van Laethem6, Josef Thaler7, John Bridgewater8, Lone Nørgård Petersen9, Hélène Blons10, Laurence Collette11, Eric Van Cutsem12, Philippe Rougier13, Ramon Salazar14, Laurent Bedenne15, Jean-François Emile16, Pierre Laurent-Puig17, Come Lepage15. 1. Department of Gastroenterology and Digestive Oncology, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France. Electronic address: jtaieb75@gmail.com. 2. Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain. 3. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. 4. Francophone Federation of Digestive Oncology, Cedex Dijon, France; University of Lyon, Lyon, France; Laboratoire de Biométrie et Biologie Evolutive, Villeurbanne, France; Hospices Civils de Lyon, Service de Biostatistique, Lyon, France. 5. 1st Medical Department, University Hospital Carl Gustav Carus, Dresden, Germany. 6. Department of Gastroenterology, Hôpital Universitaire Erasme, Brussels, Belgium. 7. Department of Internal Medicine IV, Klinikum Kreuzschwestern Wels, Austria. 8. UCL Cancer Institute, University College London, London, UK. 9. Department of Oncology, Rigshospitalet, København, Denmark. 10. Université Paris Descartes, Sorbonne Paris Cité, France; Assistance Publique Hôpitaux de Paris, Department of Biology, Hôpital Européen Georges Pompidou, Paris, France; UMR-S775, INSERM, Centre Universitaire des Saints Pères, Paris, France. 11. Statistics Department, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium. 12. Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium. 13. Department of Gastroenterology and Digestive Oncology, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France. 14. Catalan Institute of Oncology (IDIBELL), Barcelona, Spain. 15. Hepato-Gastroenterology Department Dijon University Hospital and INSERM U 866, France. 16. EA4340 and Pathology Department, Versailles University and Ambroise Paré Hospital APHP, Boulogne, France. 17. Université Paris Descartes Sorbonne Paris Cité France; UMR-S775, INSERM, Bases Moléculaires de la Réponse aux Xénobiotiques, Paris France; Assistance Publique Hôpitaux de Paris, Department of Biology, Hôpital Européen Georges Pompidou, Paris, France.
Abstract
BACKGROUND: Since the 1990s, fluorouracil-based adjuvant chemotherapy has significantly reduced the risk of tumour recurrence in patients with stage III colon cancer. We aimed to assess whether the addition of cetuximab to standard adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) in patients with stageIII colon cancer improved disease-free survival (DFS). METHODS: For this open-label, randomised phase 3 study done in nine European countries, we enrolled patients through an interactive voice response system to the central randomisation centre, with a central stratified permuted block randomisation procedure. We randomly assigned patients with resected (R0) stage III disease (1:1) to receive 12 cycles ofFOLFOX4 twice a week with or without cetuximab. Patients were stratified by N-status (N1 vs N2), T-status (T1-3 vs T4), and obstruction or perforation status (no obstruction and no perforation vs obstruction or perforation or both). A protocol amendment (applied in June, 2008, after 2096 patients had been randomly assigned to treatment-restricted enrolment to patients with tumours wild-type at codons 12 and 13 in exon 2 of the KRAS gene (KRAS exon 2 wild-type). The primary endpoint was DFS. Analysis was intention to treat in all patients with KRAS exon 2 wild-type tumours. The study is registered at EudraCT, number 2005-003463-23. FINDINGS: Between Dec 22, 2005, and Nov 5, 2009, 2559 patients from 340 sites in Europe were randomly assigned. Of these patients, 1602 had KRAS exon 2 wild-type tumours (intention-to-treat population), 791 in the FOLFOX4 plus cetuximab group and 811 in the FOLFOX4 group. Median follow-up was 3·3 years (IQR 3·2-3·4). In the experimental and control groups, DFS was similar in the intention-to-treat population (hazard ratio [HR] 1·05; 95% CI 0·85-1·29; p=0·66), and in patients with KRAS exon 2/BRAF wild-type (n=984, HR 0·99; 95% CI 0·76-1·28) or KRAS exon 2-mutated tumours (n=742, HR 1·06; 95% CI 0·82-1·37). We noted heterogeneous responses to the addition of cetuximab in preplanned subgroup analyses. Grade 3 or 4 acne-like rash (in 209 of 785 patients [27%] vs four of 805 [<1%]), diarrhoea (113 [14%] vs 70 [9%]), mucositis (63 [8%] vs 10 [1%]), and infusion-related reactions (55 [7%] vs 30 [4%]) were more frequent in patients treated with FOLFOX4 plus cetuximab than in those patients who received FOLFOX4 alone. INTERPRETATION: The addition of cetuximab to FOLFOX4 did not improve DFS compared with FOLFOX4 alone in patients with KRAS exon 2 wild-type resected stage III colon cancer. This trial cannot conclude on the benefit of cetuximab in the studied population, but the heterogeneity of response suggests that further investigation of the role of FOLFOX4 plus cetuximab in specific patient subgroups is warranted. FUNDING: Fédération Francophone de Cancérologie Digestive (FFCD), Merck KGaA, and Sanofi-Aventis.
RCT Entities:
BACKGROUND: Since the 1990s, fluorouracil-based adjuvant chemotherapy has significantly reduced the risk of tumour recurrence in patients with stage III colon cancer. We aimed to assess whether the addition of cetuximab to standard adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) in patients with stage III colon cancer improved disease-free survival (DFS). METHODS: For this open-label, randomised phase 3 study done in nine European countries, we enrolled patients through an interactive voice response system to the central randomisation centre, with a central stratified permuted block randomisation procedure. We randomly assigned patients with resected (R0) stage III disease (1:1) to receive 12 cycles of FOLFOX4 twice a week with or without cetuximab. Patients were stratified by N-status (N1 vs N2), T-status (T1-3 vs T4), and obstruction or perforation status (no obstruction and no perforation vs obstruction or perforation or both). A protocol amendment (applied in June, 2008, after 2096 patients had been randomly assigned to treatment-restricted enrolment to patients with tumours wild-type at codons 12 and 13 in exon 2 of the KRAS gene (KRAS exon 2 wild-type). The primary endpoint was DFS. Analysis was intention to treat in all patients with KRAS exon 2 wild-type tumours. The study is registered at EudraCT, number 2005-003463-23. FINDINGS: Between Dec 22, 2005, and Nov 5, 2009, 2559 patients from 340 sites in Europe were randomly assigned. Of these patients, 1602 had KRAS exon 2 wild-type tumours (intention-to-treat population), 791 in the FOLFOX4 plus cetuximab group and 811 in the FOLFOX4 group. Median follow-up was 3·3 years (IQR 3·2-3·4). In the experimental and control groups, DFS was similar in the intention-to-treat population (hazard ratio [HR] 1·05; 95% CI 0·85-1·29; p=0·66), and in patients with KRAS exon 2/BRAF wild-type (n=984, HR 0·99; 95% CI 0·76-1·28) or KRAS exon 2-mutated tumours (n=742, HR 1·06; 95% CI 0·82-1·37). We noted heterogeneous responses to the addition of cetuximab in preplanned subgroup analyses. Grade 3 or 4 acne-like rash (in 209 of 785 patients [27%] vs four of 805 [<1%]), diarrhoea (113 [14%] vs 70 [9%]), mucositis (63 [8%] vs 10 [1%]), and infusion-related reactions (55 [7%] vs 30 [4%]) were more frequent in patients treated with FOLFOX4 plus cetuximab than in those patients who received FOLFOX4 alone. INTERPRETATION: The addition of cetuximab to FOLFOX4 did not improve DFS compared with FOLFOX4 alone in patients with KRAS exon 2 wild-type resected stage III colon cancer. This trial cannot conclude on the benefit of cetuximab in the studied population, but the heterogeneity of response suggests that further investigation of the role of FOLFOX4 plus cetuximab in specific patient subgroups is warranted. FUNDING: Fédération Francophone de Cancérologie Digestive (FFCD), Merck KGaA, and Sanofi-Aventis.
Authors: Julien Taieb; Karine Le Malicot; Qian Shi; Frédérique Penault-Llorca; Olivier Bouché; Josep Tabernero; Enrico Mini; Richard M Goldberg; Gunnar Folprecht; Jean Luc Van Laethem; Daniel J Sargent; Steven R Alberts; Jean Francois Emile; Pierre Laurent Puig; Frank A Sinicrope Journal: J Natl Cancer Inst Date: 2016-12-31 Impact factor: 13.506
Authors: Frank A Sinicrope; Michelle R Mahoney; Harry H Yoon; Thomas C Smyrk; Stephen N Thibodeau; Richard M Goldberg; Garth D Nelson; Daniel J Sargent; Steven R Alberts Journal: Clin Cancer Res Date: 2015-07-17 Impact factor: 12.531
Authors: Chelsie K Sievers; Jeremy D Kratz; Luke D Zurbriggen; Noelle K LoConte; Sam J Lubner; Natalya Uboha; Daniel Mulkerin; Kristina A Matkowskyj; Dustin A Deming Journal: Clin Colon Rectal Surg Date: 2016-09
Authors: Julien Taieb; Hampig Raphael Kourie; Jean-François Emile; Karine Le Malicot; Ralyath Balogoun; Josep Tabernero; Enrico Mini; Gunnar Folprecht; Jean-Luc Van Laethem; Claire Mulot; Olivier Bouché; Thomas Aparicio; Pierre Michel; Josef Thaler; John Bridgewater; Eric Van Cutsem; Géraldine Perkins; Come Lepage; Ramon Salazar; Pierre Laurent-Puig Journal: JAMA Oncol Date: 2018-07-12 Impact factor: 31.777