title: Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer.
abstract: OBJECTIVE
  This study sought to determine the feasibility and antitumor efficacy of an intensified three-drug chronomodulated regimen with maximum delivery at 4:00 AM for fluorouracil (5-FU)-leucovorin (folinic acid [FA]) and at 4:00 PM for oxaliplatin (I-OHP).
  
  
  METHODS
  Fifty patients with metastatic colorectal cancer were enrolled in the trial. The first treatment course consisted of daily administration of 5-FU (700 mg/m2/d), FA (300 mg/m2/d), and L-OHP (25 mg/m2/d) for 4 days with a multichannel programmable pump. Courses were repeated every 14 days, with 5-FU escalation by 100 mg/m2/d if toxicity was less than grade 2.
  
  
  RESULTS
  World Health Organization (WHO)-modified grade 3 or 4 diarrhea (40% of patients and 7% of courses) or stomatitis (28% of patients and 4% of courses) or grade 2 cumulative peripheral sensitive neuropathy (28% of patients) were dose-limiting. Median 5-FU and L-OHP dose-intensities (DIs), were increased by 32% and 18%, respectively, as compared with our previous 5 days on-16 days off schedule. The overall objective response rate was 48% (95% confidence limits [CL], 34% to 62%), being 40% (24% to 57%) in 37 previously treated patients and 69% (48% to 90%) in 13 chemotherapy-naive patients. A 5-FU DI > 1,400 mg/m2/wk over four courses was associated with a near doubling of the response rate. Residual metastases were surgically removed in 13 patients (26%). Median progression-free survival and survival durations were 9.3 months (95% CL, 6.6 to 11.2) and 17.8 months (95% CL, 14.1 to 21.4), respectively.
  
  
  CONCLUSIONS
  This highly effective fully ambulatory outpatient regimen deserves further testing in randomized trials both in chemotherapy-naive patients and before surgery to remove metastases.
authors.affiliation: Centre de Chronothérapie, Service des Maladies Sanguines, Immunitaires et Tumorales, France.
authors.forename: F
authors.initials: F
authors.lastname: Bertheault-Cvitkovic
authors.forename: A
authors.initials: A
authors.lastname: Jami
authors.forename: M
authors.initials: M
authors.lastname: Ithzaki
authors.forename: P D
authors.initials: PD
authors.lastname: Brummer
authors.forename: S
authors.initials: S
authors.lastname: Brienza
authors.forename: R
authors.initials: R
authors.lastname: Adam
authors.forename: F
authors.initials: F
authors.lastname: Kunstlinger
authors.forename: H
authors.initials: H
authors.lastname: Bismuth
authors.forename: J L
authors.initials: JL
authors.lastname: Misset
authors.forename: F
authors.initials: F
authors.lastname: Lévi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000553:Ambulatory Care; D000931:Antidotes / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000473:pathology*; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin
chemical_list: D000931:Antidotes; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil