The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer

Pharmacogenomics J. 2008 Aug;8(4):256-67. doi: 10.1038/sj.tpj.6500476. Epub 2007 Aug 14.


The purpose of this study was to determine simple genetic factors helpful to tailor 5-FU administration and determine strategy in first-line chemotherapy of advanced colorectal cancer. In 76 patients initially treated by 5-FU, thymidylate synthase, dihydropyrimidine dehydrogenase and methylene tetrahydrofolate reductase germinal polymorphisms, dihydrouracil/uracil plasma ratio and 5-FU plasma clearance were investigated and correlated for tolerance (10.5% grade 3 and 4 toxicity) and efficacy (32.9% objective response rate and 20 months median overall survival time). Toxicity was linked to performance status >2 (P=0.004), low UH2/U ratio, 2846 A>T, IVS 14+1G>A for DPD (P=0.031), and homozygoty C/C for MTHFR 1298 A>C (P=0.0018). The overall survival of the patients with a 3R/3R TS genotype associated with C/C for 677 C>T or A/A for 1298 A>C was statistically shorter (log-rank test P=0.0065). Genetic factors permit the tailoring of 5-FU treatment. They should occupy center stage in future clinical trials for specifically designing treatment for patients with a given biologic feature.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / mortality
  • Female
  • Fluorouracil / adverse effects
  • Fluorouracil / pharmacology
  • Fluorouracil / therapeutic use*
  • Follow-Up Studies
  • Gastrointestinal Diseases / chemically induced
  • Gastrointestinal Diseases / genetics
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / drug effects
  • Polymorphism, Single Nucleotide / genetics
  • Retrospective Studies
  • Survival Rate / trends
  • Treatment Outcome


  • Fluorouracil