Relationship between 5-fluorouracil (5-FU) dose intensity and therapeutic response in patients with advanced colorectal cancer receiving infusional therapy containing 5-FU

Cancer. 1996 Feb 1;77(3):441-51. doi: 10.1002/(SICI)1097-0142(19960201)77:3<441::AID-CNCR4>3.0.CO;2-N.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase II

MeSH terms

  • Adult
  • Aged
  • Antimetabolites, Antineoplastic / administration & dosage*
  • Antimetabolites, Antineoplastic / pharmacokinetics
  • Antimetabolites, Antineoplastic / toxicity
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / mortality
  • Drug Therapy, Combination
  • Female
  • Fluorouracil / administration & dosage*
  • Fluorouracil / pharmacokinetics
  • Fluorouracil / toxicity
  • Humans
  • Infusions, Parenteral
  • Leucovorin / administration & dosage
  • Male
  • Middle Aged
  • Prospective Studies
  • Survival Rate
  • Treatment Outcome


  • Antimetabolites, Antineoplastic
  • Leucovorin
  • Fluorouracil