title: Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial.
abstract: BACKGROUND
  In a previous phase II trial, circadian (chronomodulated) delivery of fluorouracil (5-FU), folinic acid (FA; leucovorin), and oxaliplatin (1-OHP; a new platinum complex with no renal and minor hematologic toxic effects) produced an objective response rate of 58% in 93 patients with metastatic colorectal cancer.
  
  
  OBJECTIVE
  To determine whether chronomodulated drug delivery affects therapeutic activity, we again tested this regimen in another trial in patients with previously untreated metastatic colorectal cancer, this time comparing chronomodulated with constant-rate drug delivery.
  
  
  METHODS
  Seven European centers participated in this trial. Ninety-two patients with metastatic colorectal cancer were enrolled and assigned to a treatment schedule by central randomization. Treatment courses consisted of the daily administration of 5-FU (600 mg/m2 per day), FA (300 mg/m2 per day), and 1-OHP (20 mg/m2 per day) for 5 days and were repeated every 21 days (16-day intermission) in ambulatory patients with the use of a programmable in-time pump. Drug delivery was kept constant over a 5-day period in schedule A (47 patients). It was chronomodulated in schedule B (maximum delivery of 5-FU and FA infusions at 0400 hours and maximum delivery of 1-OHP at 1600 hours; 45 patients). A risk of partial chemical inactivation of 1-OHP by its 2-hour exposure to the basic pH of the 5-FU solution in the catheter was documented in schedule A.
  
  
  RESULTS
  Severe stomatitis (grade 3 or 4, World Health Organization [WHO] grading system), the dose-limiting toxic effect of 5-FU, occurred in five times as many patients on schedule A than on schedule B (89% versus 18%; chi 2 = 46; P < .001). The cumulative dose-limiting toxicity of schedule B was peripheral sensitive neuropathy (WHO grade 2). This side effect was reversible following 1-OHP withdrawal. Higher doses of 5-FU were administered in schedule B (median: 700 mg/m2 per day) compared with schedule A (median: 500 mg/m2 per day) (P < .0001; Mann-Whitney U test). On schedule B, 24 of 45 patients (53%; 95% confidence interval [CI] = 38%-68%) exhibited an objective response compared with 15 of 47 patients (32%; 95% CI = 18%-46%) on schedule A (chi 2 = 4.3; P = .038). The median progression-free survival was, respectively, 11 and 8 months (P = .19; logrank). The median survival was 19 months (95% CI = 14.8-23.2) on schedule B and 14.9 months (95% CI = 12.1-17.8) on schedule A (P = .03; logrank).
  
  
  CONCLUSIONS
  This ambulatory treatment modality was both more effective and less toxic if drug delivery was chronomodulated rather than constant over time.
  
  
  CONCLUSIONS
  The respective roles of 1-OHP dose and schedule and circadian peak time of drug delivery are being investigated with regard to the high activity of this three-drug, chronomodulated chemotherapeutic regimen.
authors.affiliation: Laboratoire Rythmes Biologiques et Chronothérapeutique, Hôpital Paul Brousse, Villejuif, France.
authors.forename: F A
authors.initials: FA
authors.lastname: Lévi
authors.forename: R
authors.initials: R
authors.lastname: Zidani
authors.forename: J M
authors.initials: JM
authors.lastname: Vannetzel
authors.forename: B
authors.initials: B
authors.lastname: Perpoint
authors.forename: C
authors.initials: C
authors.lastname: Focan
authors.forename: R
authors.initials: R
authors.lastname: Faggiuolo
authors.forename: P
authors.initials: P
authors.lastname: Chollet
authors.forename: C
authors.initials: C
authors.lastname: Garufi
authors.forename: M
authors.initials: M
authors.lastname: Itzhaki
authors.forename: L
authors.initials: L
authors.lastname: Dogliotti
mesh_terms: D000328:Adult; D000368:Aged; D000553:Ambulatory Care; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002940:Circadian Rhythm; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil