title: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer.
abstract: OBJECTIVE
  To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)-leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer.
  
  
  METHODS
  Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m(2)/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m(2), as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans.
  
  
  RESULTS
  Grade 3 to 4 toxicity from 5-FU-LV occurred in </= 5% of the patients (</= 1% of the courses). Grade 3 to 4 diarrhea occurred in 43% of the patients given l-OHP (10% of the courses), and less than 2% of the patients had severe hematotoxicity. Thirteen percent of the patients had moderate functional impairment from peripheral sensory neuropathy. Sixteen percent of the patients receiving 5-FU-LV had an objective response (95% confidence interval [CI], 9% to 24%), compared with 53% of those receiving additional l-OHP (95% CI, 42% to 63%) (P <. 001). The median progression-free survival time was 6.1 months with 5-FU-LV (range, 4.1 to 7.4 months) and 8.7 months (7.4 to 9.2 months) with l-OHP and 5-FU-LV (P =.048). Median survival times were 19.9 and 19.4 months, respectively.
  
  
  CONCLUSIONS
  By chronomodulating 5-FU-LV, we were able to add l-OHP without compromising dose-intensities. l-OHP significantly improved the antitumor efficacy of this regimen.
authors.affiliation: International Organization of Cancer Chronotherapy, Centre de Chronothérapie, Hôpital Paul Brousse, Villejuif, France. sylvie.giacchetti@pbr.ab-hop-paris.fr
authors.forename: S
authors.initials: S
authors.lastname: Giacchetti
authors.forename: B
authors.initials: B
authors.lastname: Perpoint
authors.forename: R
authors.initials: R
authors.lastname: Zidani
authors.forename: N
authors.initials: N
authors.lastname: Le Bail
authors.forename: R
authors.initials: R
authors.lastname: Faggiuolo
authors.forename: C
authors.initials: C
authors.lastname: Focan
authors.forename: P
authors.initials: P
authors.lastname: Chollet
authors.forename: J F
authors.initials: JF
authors.lastname: Llory
authors.forename: Y
authors.initials: Y
authors.lastname: Letourneau
authors.forename: B
authors.initials: B
authors.lastname: Coudert
authors.forename: F
authors.initials: F
authors.lastname: Bertheaut-Cvitkovic
authors.forename: D
authors.initials: D
authors.lastname: Larregain-Fournier
authors.forename: A
authors.initials: A
authors.lastname: Le Rol
authors.forename: S
authors.initials: S
authors.lastname: Walter
authors.forename: R
authors.initials: R
authors.lastname: Adam
authors.forename: J L
authors.initials: JL
authors.lastname: Misset
authors.forename: F
authors.initials: F
authors.lastname: Lévi
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D019454:Chronotherapy; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005060:Europe / Q000453:epidemiology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D000077150:Oxaliplatin; D015996:Survival Rate
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil