title: Neoadjuvant FOLFOX 4 versus FOLFOX 4 with Cetuximab versus immediate surgery for high-risk stage II and III colon cancers: a multicentre randomised controlled phase II trial--the PRODIGE 22--ECKINOXE trial.
abstract: BACKGROUND
  In patients with high risk stage II and stage III colon cancer (CC), curative surgery followed by adjuvant FOLFOX-4 chemotherapy has become the standard of care. However, for 20 to 30% of these patients, the current curative treatment strategy of surgical excision followed by adjuvant chemotherapy fails either to clear locoregional spread or to eradicate distant micrometastases, leading to disease recurrence. Preoperative chemotherapy is an attractive concept for these CCs and has the potential to impact upon both of these causes of failure. Optimum systemic therapy at the earliest possible opportunity may be more effective at eradicating distant metastases than the same treatment given after the delay and immunological stress of surgery. Added to this, shrinking the primary tumor before surgery may reduce the risk of incomplete surgical excision, and the risk of tumor cell shedding during surgery.
  
  
  METHODS
  PRODIGE 22--ECKINOXE is a multicenter randomized phase II trial designed to evaluate efficacy and feasibility of two chemotherapy regimens (FOLFOX-4 alone and FOLFOX-4 + Cetuximab) in a peri-operative strategy in patients with bulky CCs. Patients with CC deemed as high risk T3, T4 and/or N2 on initial abdominopelvic CT scan are randomized to either colectomy and adjuvant chemotherapy (control arm), or 4 cycles of neoadjuvant chemotherapy with FOLFOX-4 (for RAS mutated patients). In RAS wild-type patients a third arm testing FOLFOX+ cetuximab has been added prior to colectomy. Patients in the neoadjuvant chemotherapy arms will receive postoperative treatment for 4 months (8 cycles) to complete their therapeutic schedule. The primary endpoint of the study is the histological Tumor Regression Grade (TRG) as defined by Ryan. The secondary endpoints are: treatment strategy safety (toxicity, primary tumor related complications under chemotherapy, peri-operative morbidity), disease-free and recurrence free survivals at 3 years, quality of life, carcinologic quality and completeness of the surgery, initial radiological staging and radiological response to neoadjuvant chemotherapy, and the correlation between histopathological and radiological response. Taking into account a 50% prevalence of CC without RAS mutation, accrual of 165 patients is needed for this Phase II trial.
  
  
  BACKGROUND
  NCT01675999 (ClinicalTrials.gov).
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Digestive and Hepato-Pancreato-Biliary Surgery, University Institute of Cancerology (Paris VI), Pierre & Marie Curie University (Paris VI), 47-83 Boulevard de l'Hôpital, 75013, Paris, France. mehdi.karoui@psl.aphp.fr.|FFCD (Fédération Francophone de Cancérologie Digestive), Dijon, France. mehdi.karoui@psl.aphp.fr.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Karoui
authors.affiliation: Department of Pathology, Pellegrin University Hospital, Bordeaux, France. anne.rullier@chu-bordeaux.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Rullier
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Department of Radiology, Henri Mondor University Hospital, Paris XII university, Créteil, France. anne.rullier@chu-bordeaux.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Luciani
authors.affiliation: Department of Medical Oncology and public health, Centre Hospitalier Régional Universitaire Hôpital Jean Minjoz, Besançon, France. franck.bonnetain@univ-fcomte.fr.
authors.forename: Franck
authors.initials: F
authors.lastname: Bonnetain
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Department of Pathology, Henri Mondor University Hospital, Créteil, France. marie-luce.auriault@hmn.aphp.fr.
authors.forename: Marie-Luce
authors.initials: ML
authors.lastname: Auriault
authors.affiliation: Department of Radiology, Institut Paoli Calmettes, Marseille, France. sarrana@marseille.fnclcc.fr.
authors.forename: Antony
authors.initials: A
authors.lastname: Sarran
authors.affiliation: Department of Pathology, Institut Paoli Calmettes, Marseille, France. MONGESG@ipc.unicancer.fr.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Monges
authors.affiliation: Department of Radiology, St André University Hospital, Bordeaux, France. herve.trillaud@chu-bordeaux.fr.
authors.forename: Hervé
authors.initials: H
authors.lastname: Trillaud
authors.affiliation: FFCD (Fédération Francophone de Cancérologie Digestive), Dijon, France. karine.le-malicot@u-bourgogne.fr.
authors.forename: Karine
authors.initials: K
authors.lastname: Le Malicot
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Department of Pathology, Henri Mondor University Hospital, Créteil, France. karen.leroy@hmn.aphp.fr.
authors.forename: Karen
authors.initials: K
authors.lastname: Leroy
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Department of Gastroenterology, Henri Mondor University Hospital, Créteil, France. iradj.sobhani@hmn.aphp.fr.
authors.forename: Iradj
authors.initials: I
authors.lastname: Sobhani
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Department of Pathology, Pitié-Salpêtrière University Hospital, Paris, France. armelle.bardier@psl.aphp.fr.
authors.forename: Armelle
authors.initials: A
authors.lastname: Bardier
authors.affiliation: FFCD (Fédération Francophone de Cancérologie Digestive), Dijon, France. marie.moreau@u-bourgogne.fr.
authors.forename: Marie
authors.initials: M
authors.lastname: Moreau
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Département de la Recherche Clinique et du Développement (DRCD), Paris, France. isabelle.brindel@drc.aphp.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Brindel
authors.affiliation: FFCD (Fédération Francophone de Cancérologie Digestive), Dijon, France. Jean-francois.SEITZ@ap-hm.fr.
authors.forename: Jean François
authors.initials: JF
authors.lastname: Seitz
authors.affiliation: FFCD (Fédération Francophone de Cancérologie Digestive), Dijon, France. julien.taieb@egp.aphp.fr.|Assistance Publique-Hôpitaux de Paris, Department of Digestive Oncology, European Georges Pompidou - Paris Descartes University, Paris, France. julien.taieb@egp.aphp.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Taieb
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000068818:Cetuximab / Q000008:administration & dosage; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage
chemical_list: D009944:Organoplatinum Compounds; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil