title: A genotype-directed phase I-IV dose-finding study of irinotecan in combination with fluorouracil/leucovorin as first-line treatment in advanced colorectal cancer.
abstract: BACKGROUND
  Infusional fluorouracil/leucovorin (FU/LV) plus irinotecan (FOLFIRI) is one of the standard first-line options for patients with metastatic colorectal cancer (mCRC). Irinotecan is converted into 7-ethyl-10-hydroxycamptothecin (SN-38) by a carboxylsterase and metabolised through uridine diphosphate glucuronosyl transferase (UGT1A1). The UGT1A1*28 allele has been associated with the risk of developing severe toxicities. The present trial was designed to define the maximum tolerated dose according to UGT1A1 genotype. This report focuses on the results of tolerance to different escalated doses of FOLFIRI first-line of chemotherapy.
  
  
  METHODS
  Patients undergoing first-line treatment for mCRC and eligible for treatment with FOLFIRI were classified according to UGT1A1 genotype. A total of 94 patients were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 180 mg m(-2) for the *1/*1, 110 mg m(-2) for the *1/*28 and 90 mg m(-2) for the *28/*28 genotypes.
  
  
  RESULTS
  The dose of irinotecan was escalated to 450 mg m(-2) in patients with the *1/*1 genotype, to 390 mg m(-2) in those with the *1/*28 genotype and to 150 mg m(-2) in those with the *28/*28 genotype. Neutropenia and diarrhoea were the most common grade 3 or 4 toxicities.
  
  
  CONCLUSIONS
  Our results demonstrated that the recommended dose of 180 mg m(-2) for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated for patients with the UGT1A1 *1/*1 and *1/*28 genotypes. The maximum tolerable dose (MTD) in patients with a high-risk UGT1A1 *28/*28 genotype is 30% lower than the standard dose of 180 mg m(-2).
authors.affiliation: Medical Oncology, Universitat Autònoma de Barcelona, Pare Claret 167, Barcelona 08025, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Marcuello
authors.forename: D
authors.initials: D
authors.lastname: Páez
authors.forename: L
authors.initials: L
authors.lastname: Paré
authors.forename: J
authors.initials: J
authors.lastname: Salazar
authors.forename: A
authors.initials: A
authors.lastname: Sebio
authors.forename: E
authors.initials: E
authors.lastname: del Rio
authors.forename: M
authors.initials: M
authors.lastname: Baiget
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics; D016879:Salvage Therapy; D015996:Survival Rate; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D002955:Leucovorin; D000099148:UGT1A1 Enzyme