title: Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial.
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 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Fédération Francophone de Cancérologie Digestive (FFCD), Merck KGaA, and Sanofi-Aventis.
authors.affiliation: Department of Gastroenterology and Digestive Oncology, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France. Electronic address: jtaieb75@gmail.com.
authors.forename: Julien
authors.initials: J
authors.lastname: Taieb
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Mini
authors.affiliation: 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.
authors.forename: Fabien
authors.initials: F
authors.lastname: Subtil
authors.affiliation: 1st Medical Department, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Folprecht
authors.affiliation: Department of Gastroenterology, Hôpital Universitaire Erasme, Brussels, Belgium.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Van Laethem
authors.affiliation: Department of Internal Medicine IV, Klinikum Kreuzschwestern Wels, Austria.
authors.forename: Josef
authors.initials: J
authors.lastname: Thaler
authors.affiliation: UCL Cancer Institute, University College London, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Bridgewater
authors.affiliation: Department of Oncology, Rigshospitalet, København, Denmark.
authors.forename: Lone Nørgård
authors.initials: LN
authors.lastname: Petersen
authors.affiliation: 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.
authors.forename: Hélène
authors.initials: H
authors.lastname: Blons
authors.affiliation: Statistics Department, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Collette
authors.affiliation: Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.affiliation: Department of Gastroenterology and Digestive Oncology, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rougier
authors.affiliation: Catalan Institute of Oncology (IDIBELL), Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Salazar
authors.affiliation: Hepato-Gastroenterology Department Dijon University Hospital and INSERM U 866, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bedenne
authors.affiliation: EA4340 and Pathology Department, Versailles University and Ambroise Paré Hospital APHP, Boulogne, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
authors.affiliation: 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.
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.affiliation: Hepato-Gastroenterology Department Dijon University Hospital and INSERM U 866, France.
authors.forename: Come
authors.initials: C
authors.lastname: Lepage
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068818:Cetuximab; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D003967:Diarrhea / Q000139:chemically induced; D018572:Disease-Free Survival; D003875:Drug Eruptions / Q000209:etiology; D005091:Exons / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous / Q000009:adverse effects; D057194:Intention to Treat Analysis; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil