Individual 5-FU dose adaptation in metastatic colorectal cancer: results of a phase II study using a bimonthly pharmacokinetically intensified LV5FU2 regimen

Cancer Chemother Pharmacol. 2003 Oct;52(4):282-90. doi: 10.1007/s00280-003-0658-0. Epub 2003 Jun 19.


Aim: The aim of this phase II study was to determine the efficacy and tolerability of the bimonthly, pharmacokinetically intensified LV5FU2 regimen in the treatment of metastatic colorectal cancers.

Methods: A total of 53 patients (23% second-line; 25 male/28 female; mean age 67 years; WHO performance status 0 in 38, 1 in 10 and 2 in 5) were treated in cycle 1 with the standard LV5FU2 regimen (leucovorin 200 mg/m2 per day followed by a 5-FU bolus 400 mg/m2 per day and a 22-h 5-FU continuous infusion 600 mg/m2 per day for two consecutive days every 2 weeks), and the AUC in mg.h/l.m2 was calculated. For cycle 2, according to a predefined schedule depending on the cycle-1 AUC value, in the absence of grade 3 toxicity, the 5-FU infusion dose was increased by 150% for AUC < or =5, by 100% for AUC >5-10, by 50% for AUC >10-15, and by 25% for AUC >15-20. 5-FU plasma concentrations were determined using high-performance liquid chromatography. A Bayesian methodology was used to assess individual pharmacokinetic parameters using the NONMEM computer program.

Results: Among the 53 eligible patients, 87% (per-protocol population) received an increased dose in cycle 2 and 72% received the same dose. The median relative dose intensity was 1.28 (range 0.5-1.54) compared with the non-adapted theoretical total 5-FU dose. The objective response rate was 37% (95% CI 23-50%) in the intention-to-treat population and 47% (95% CI 29-65%) in the first-line per-protocol population. The median response duration was 10.4 months. The median progression-free survival (PFS) and overall survival (OS) were, respectively, 7 and 18.6 months. PFS and OS in first-line per-protocol patients were, respectively, 9.2 and 20 months. No deaths were attributed to toxicity of 5-FU despite the high doses administered. Of the 53 patients, 19% experienced gastrointestinal and 30% haematological grade 3/4 toxicities. Hand-foot syndrome was common but mild (grade 3 in one patient).

Conclusions: This strategy could be compared in a phase III trial with the standard LV5FU2 regimen.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / pathology
  • Adult
  • Aged
  • Antimetabolites, Antineoplastic / administration & dosage*
  • Antimetabolites, Antineoplastic / adverse effects
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Area Under Curve
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Female
  • Fluorouracil / administration & dosage*
  • Fluorouracil / adverse effects
  • Fluorouracil / therapeutic use*
  • Humans
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Survival Analysis


  • Antimetabolites, Antineoplastic
  • Fluorouracil