title: Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group.
abstract: OBJECTIVE
  In two previous randomized trials, the adjustment of chemotherapy delivery to circadian rhythms improved tolerability and anticancer activity compared with constant-rate infusion during 5 days in patients with metastatic colorectal cancer.
  
  
  METHODS
  For this multicenter randomized trial, it was hypothesized that a chronomodulated infusion of fluorouracil, leucovorin, and oxaliplatin for 4 days (chronoFLO4) would improve survival by 10% compared with conventional 2-day delivery of the same drugs (FOLFOX2). Patients were treated every 2 weeks with intrapatient dose escalation.
  
  
  RESULTS
  Baseline characteristics were similar in both arms for the 564 patients (36 institutions, 10 countries). Median survival was 19.6 months (95% confidence limit [CL] = 18.2, 21.2) with chronoFLO4 and 18.7 months with FOLFOX2 (95% CL = 17.7, 21.0; P = .55). The main dose-limiting toxicities were diarrhea for chronoFLO4 and neutropenia for FOLFOX2. The analysis of survival predictors showed that sex was the single most important factor (P = .001). In women, the risk of an earlier death with chronoFLO4 was increased by 38% compared with FOLFOX2, with median survival times of 16.3 and 19.1 months (P = .03), respectively. In men, the risk of death was decreased by 25% with chronoFLO4 compared with FOLFOX2, with median survival times of 21.4 and 18.3 months (P = .02), respectively.
  
  
  CONCLUSIONS
  Both regimens achieved similar median survival times more than 18 months with an acceptable toxicity. The chronomodulated schedule produced a survival advantage over FOLFOX in men. The strong sex dependency of optimal scheduling of fluorouracil, leucovorin, and oxaliplatin calls for translational investigations of determinants related to the patient's molecular clock.
authors.affiliation: Hopital Paul Brousse and INSERM, Villejuif, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Giacchetti
authors.forename: Georg
authors.initials: G
authors.lastname: Bjarnason
authors.forename: Carlo
authors.initials: C
authors.lastname: Garufi
authors.forename: Dominique
authors.initials: D
authors.lastname: Genet
authors.forename: Stefano
authors.initials: S
authors.lastname: Iacobelli
authors.forename: Marco
authors.initials: M
authors.lastname: Tampellini
authors.forename: Rune
authors.initials: R
authors.lastname: Smaaland
authors.forename: Christian
authors.initials: C
authors.lastname: Focan
authors.forename: Bruno
authors.initials: B
authors.lastname: Coudert
authors.forename: Yves
authors.initials: Y
authors.lastname: Humblet
authors.forename: Jean Luc
authors.initials: JL
authors.lastname: Canon
authors.forename: Antoine
authors.initials: A
authors.lastname: Adenis
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lo Re
authors.forename: Carlos
authors.initials: C
authors.lastname: Carvalho
authors.forename: Johannes
authors.initials: J
authors.lastname: Schueller
authors.forename: Nicole
authors.initials: N
authors.lastname: Anciaux
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Lentz
authors.forename: Benoît
authors.initials: B
authors.lastname: Baron
authors.forename: Thierry
authors.initials: T
authors.lastname: Gorlia
authors.forename: Francis
authors.initials: F
authors.lastname: Lévi
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D019454:Chronotherapy / Q000379:methods; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D005060:Europe; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D012307:Risk Factors; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil