title: Relationship between 5-fluorouracil (5-FU) dose intensity and therapeutic response in patients with advanced colorectal cancer receiving infusional therapy containing 5-FU.
abstract: BACKGROUND
  A phase II prospective trial was carried out to study the concept of 5-fluorouracil (5-FU) dose-intensity in patients with advanced colorectal cancer. Forty patients were treated with 5-FU plus leucovorin (LV), with individually increasing doses of 5-FU. A 5-FU pharmacokinetic follow up was performed and a relationship was sought between its metabolism and its response to treatment, and between 5-FU's toxicity and patient survival.
  
  
  METHODS
  5-FU was administered weekly by 8 hour continuous infusion. The initial dose of 1000 mg/m2 was individually increased every 3 weeks by 250 mg/m2 steps, potentiated by 400 mg/m2 LV. 5-FU plasma concentrations were determined weekly by liquid chromatography.
  
  
  RESULTS
  Eighteen overall objective responses and 22 minor responses, stabilizations, or progressions (NR) were observed. 5-FU plasma levels were significantly higher in cases of complete or partial response, whatever the dose. They reached about 2000 micrograms/l as early as the second dose level (1250 mg/m2). Only seven patients who experienced NR reached equivalent levels after the fourth step (1750 mg/m2). High 5-FU plasma levels were predictive of an objective response and better survival (difference not significant). The acute toxicity, whatever the type, was correlated with 5-FU levels > 3000 micrograms/l and not with the dose.
  
  
  CONCLUSIONS
  This study shows the wide variability of 5-FU metabolism, whatever the dose, the clear relationship between 5-FU plasma levels, toxicity, and efficacy. This relationship points out the problem of the polymorphism of 5-FU metabolism, the usefulness of the therapeutic range determination and the usefulness of the individual 5-FU dose adaptation.
authors.affiliation: Service d'Oncologie Médicale, Centre Paul Papin, Angers, France.
authors.forename: E C
authors.initials: EC
authors.lastname: Gamelin
authors.forename: E M
authors.initials: EM
authors.lastname: Danquechin-Dorval
authors.forename: Y F
authors.initials: YF
authors.lastname: Dumesnil
authors.forename: P J
authors.initials: PJ
authors.lastname: Maillart
authors.forename: M J
authors.initials: MJ
authors.lastname: Goudier
authors.forename: P C
authors.initials: PC
authors.lastname: Burtin
authors.forename: R G
authors.initials: RG
authors.lastname: Delva
authors.forename: A H
authors.initials: AH
authors.lastname: Lortholary
authors.forename: P H
authors.initials: PH
authors.lastname: Gesta
authors.forename: F G
authors.initials: FG
authors.lastname: Larra
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D007263:Infusions, Parenteral; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D005472:Fluorouracil