The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer.
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.
Capitain
O
O
Department of Medical Oncology and Clinical Pharmacology, INSERM U564 Centre Paul Papin, Centre Régional de Lutte Contre le Cancer, Angers, Cedex, France.
Boisdron-Celle
M
M
Poirier
A-L
AL
Abadie-Lacourtoisie
S
S
Morel
A
A
Gamelin
E
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D005500:Follow-Up Studies; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects / Q000235:genetics; D012189:Retrospective Studies; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome
D005472:Fluorouracil