title: Pharmacogenetic tailoring of irinotecan-based first-line chemotherapy in metastatic colorectal cancer: results of a pilot study.
abstract: BACKGROUND
  Tolerability to irinotecan may be explained by pharmacogenomic polymorphisms. The purpose of this pharmacogenetic trial was to study the relevance of thymidylate synthase (TS) genotyping and of the isoform 1A1 of uridine diphosphate glucuronosyltransferase (UGT1A1) in order to tailor a combination chemotherapy regimen of 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) in metastatic colorectal cancer.
  
  
  METHODS
  Patients with favourable TS and UGT1A1 profiles received high-dose (HD) FOLFIRI. Patients with TS-3R/3R could not receive HD-FOLFIRI, and those with UGT1A1-7/7 received standard FOLFIRI. The endpoints were overall response rate and safety.
  
  
  RESULTS
  Sixty-nine patients were enrolled in the study. Sixty-five patients received chemotherapy. Twenty patients (30.8%) achieved a partial response. The haematological toxicity was less in the HD-FOLFIRI subgroup. Patients having received HD-FOLFIRI did not experience increased levels of nausea-vomiting, asthenia or alopecia. Diarrhoea was more frequent with HD-FOLFIRI.
  
  
  CONCLUSIONS
  The genotypic assessment allowed a safer use of HD-FOLFIRI. Further investigations may target patients who benefit from intensification.
authors.affiliation: Université de Lyon and Department of Medical Oncology, Centre Hospitalier Lyon Sud, Pierre-Bénite, France. gilles.freyer@chu-lyon.fr
authors.forename: Gilles
authors.initials: G
authors.lastname: Freyer
authors.forename: Aude
authors.initials: A
authors.lastname: Duret
authors.forename: Gerard
authors.initials: G
authors.lastname: Milano
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
authors.forename: Christine
authors.initials: C
authors.lastname: Rebischung
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Delord
authors.forename: Yacine
authors.initials: Y
authors.lastname: Merrouche
authors.forename: Gerard
authors.initials: G
authors.lastname: Lledo
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Etienne
authors.forename: Claire
authors.initials: C
authors.lastname: Falandry
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005500:Follow-Up Studies; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D010597:Pharmacogenetics; D010865:Pilot Projects; D016133:Polymerase Chain Reaction; D015996:Survival Rate; D013940:Thymidylate Synthase / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D004273:DNA, Neoplasm; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D002955:Leucovorin; D013940:Thymidylate Synthase; D000099148:UGT1A1 Enzyme