title: Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial.
abstract: BACKGROUND
  Definitive chemoradiotherapy is a curative treatment option for oesophageal carcinoma, especially in patients unsuitable for surgery. The PRODIGE5/ACCORD17 trial aimed to assess the efficacy and safety of the FOLFOX treatment regimen (fluorouracil plus leucovorin and oxaliplatin) versus fluorouracil and cisplatin as part of chemoradiotherapy in patients with localised oesophageal cancer.
  
  
  METHODS
  We did a multicentre, randomised, open-label, parallel-group, phase 2/3 trial of patients aged 18 years or older enrolled from 24 centres in France between Oct 15, 2004, and Aug 25, 2011. Eligible participants had confirmed stage I-IVA oesophageal carcinoma (adenocarcinoma, squamous-cell, or adenosquamous), Eastern Cooperative Oncology Group (ECOG) status 0-2, sufficient caloric intake, adequate haematological, renal, and hepatic function, and had been selected to receive definitive chemoradiotherapy. Patients were randomly assigned (1:1) to receive either six cycles (three concomitant to radiotherapy) of oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), bolus fluorouracil 400 mg/m(2), and infusional fluorouracil 1600 mg/m(2) (FOLFOX) over 46 h, or four cycles (two concomitant to radiotherapy) of fluorouracil 1000 mg/m(2) per day for 4 days and cisplatin 75 mg/m(2) on day 1. Both groups also received 50 Gy radiotherapy in 25 fractions (five fractions per week). Random allocation to treatment groups was done by a central computerised randomisation procedure by minimisation, stratified by centre, histology, weight loss, and ECOG status, and was achieved independently from the study investigators. The primary endpoint was progression-free survival. Data analysis was primarily done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00861094.
  
  
  RESULTS
  134 participants were randomly allocated to the FOLFOX group and 133 to the fluorouracil and cisplatin group (intention-to-treat population), and 131 patients in the FOLFOX group and 128 in the fluorouracil and cisplatin group actually received the study drugs (safety population). Median follow-up was 25·3 months (IQR 15·9-36·4). Median progression-free survival was 9·7 months (95% CI 8·1-14·5) in the FOLFOX group and 9·4 months (8·1-10·6) in the fluorouracil and cisplatin group (HR 0·93, 95% CI 0·70-1·24; p=0·64). One toxic death occurred in the FOLFOX group and six in the fluorouracil-cisplatin group (p=0·066). No significant differences were recorded in the rates of most frequent grade 3 or 4 adverse events between the treatment groups. Of all-grade adverse events that occurred in 5% or more of patients, paraesthesia (61 [47%] events in 131 patients in the FOLFOX group vs three [2%] in 128 patients in the cisplatin-fluorouracil group, p<0·0001), sensory neuropathy (24 [18%] vs one [1%], p<0·0001), increases in aspartate aminotransferase concentrations (14 [11%] vs two [2%], p=0·002), and increases in alanine aminotransferase concentrations (11 [8%] vs two [2%], p=0·012) were more common in the FOLFOX group, whereas serum creatinine increases (four [3%] vs 15 [12%], p=0·007), mucositis (35 [27%] vs 41 [32%], p=0·011), and alopecia (two [2%] vs 12 [9%], p=0·005) were more common in the fluorouracil and cisplatin group.
  
  
  CONCLUSIONS
  Although chemoradiotherapy with FOLFOX did not increase progression-free survival compared with chemoradiotherapy with fluorouracil and cisplatin, FOLFOX might be a more convenient option for patients with localised oesophageal cancer unsuitable for surgery.
  
  
  BACKGROUND
  UNICANCER, French Health Ministry, Sanofi-Aventis, and National League Against Cancer.
authors.affiliation: Département d'Oncologie Médicale, Institut de Cancérologie de Lorraine and Lorraine University, Vandoeuvre-lès-Nancy, France. Electronic address: t.conroy@nancy.unicancer.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Conroy
authors.affiliation: Service de Pathologie Digestive, Centre François Baclesse, Caen, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Galais
authors.affiliation: Service d'Oncologie Médicale, Centre Eugène Marquis, Rennes, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Raoul
authors.affiliation: Service d'Hépatogastroentérologie et de Cancérologie Digestive, Centre Hospitalier Universitaire Robert Debré, Reims, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bouché
authors.affiliation: Unité de Biométrie, Institut régional du Cancer de Montpellier - Val d'Aurelle, Montpellier, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Gourgou-Bourgade
authors.affiliation: Institut de Cancérologie de l'Ouest - Centre René Gauducheau, Nantes Saint-Herblain, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douillard
authors.affiliation: Clinique Armoricaine de Radiologie, Saint Brieuc, France.
authors.forename: Pierre-Luc
authors.initials: PL
authors.lastname: Etienne
authors.affiliation: Service de Gastroentérologie, Institut Gustave Roussy, Villejuif, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Boige
authors.affiliation: Service de Radiothérapie, Centre Léon Bérard, Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Martel-Lafay
authors.affiliation: Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire Charles Nicolle, Rouen, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Michel
authors.affiliation: Institut du Cancer de Montpellier, Montpellier, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Llacer-Moscardo
authors.affiliation: Pôle de Médecine, Centre Antoine Lacassagne, Nice, France.
authors.forename: Eric
authors.initials: E
authors.lastname: François
authors.affiliation: Département de Radiothérapie, Centre Georges François Leclerc, Dijon, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Créhange
authors.affiliation: Centre Paul Strauss, Strasbourg, France.
authors.forename: Meher Ben
authors.initials: MB
authors.lastname: Abdelghani
authors.affiliation: R&D UNICANCER, Fédération Nationale des Centres de Lutte Contre le Cancer, Paris, France.
authors.forename: Beata
authors.initials: B
authors.lastname: Juzyna
authors.affiliation: Service Hépato-Gastro-Entérologie, Centre Hospitalier Universitaire du Bocage, Dijon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bedenne
authors.affiliation: Département de Cancérologie Digestive et Urologique, Centre Oscar Lambret, Lille, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Adenis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms / Q000401:mortality / Q000628:therapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use
chemical_list: D009944:Organoplatinum Compounds; D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil