title: A Phase II study of clinical outcomes of 3-week cycles of irinotecan and S-1 in patients with previously untreated metastatic colorectal cancer: influence of the UGT1A1 and CYP2A6 polymorphisms on clinical activity.
abstract: OBJECTIVE
  We investigated the efficacy and safety of the combination of irinotecan (CPT-11) and S-1 (IRIS regimen) as a first-line treatment in patients with metastatic colorectal cancer. We also evaluated the association between UGT1A1 and CYP2A6 polymorphisms and clinical phenotypes.
  
  
  METHODS
  The patients received CPT-11 (225 mg/m(2)) on day 1 and S-1 (80 mg/m(2)) on days 1-14 every 3 weeks. The association of the UGT1A1 (*6 and *28) and CYP2A6(*4, *7, *9, and *10) polymorphisms with toxicities and efficacy were analyzed.
  
  
  RESULTS
  Thirty patients were treated. The overall response rate was 66.7% (95% CI 48.7-84.6). The median time to progression was 7.6 months (95% CI 5.8-9.5). The most common grade 3/4 hematologic and non-hematologic toxicity were neutropenia (53.4%) and diarrhea (16.7%), respectively. The allele frequencies of UGT1A1*6 and *28 were 15.5 and 10.3%, respectively. The frequencies of CYP2A6*4, *7, *9, and *10 were 15.5, 8.6, 29.3, and 3.5%, respectively. Stratification of patients according to the number of UGT1A1*28 and *6 alleles showed a significant correlation between the number of defective alleles and the incidence of grade 3/4 neutropenia.
  
  
  CONCLUSIONS
  Our results indicate that IRIS is a promising first-line regimen in patients with metastatic colorectal cancer. Severe neutropenia may be associated with interindividual variations in UGT1A1 polymorphisms.
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Choi
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
authors.forename: Kyu-Pyo
authors.initials: KP
authors.lastname: Kim
authors.forename: Sung Sook
authors.initials: SS
authors.lastname: Lee
authors.forename: Yong Sang
authors.initials: YS
authors.lastname: Hong
authors.forename: Min-Hee
authors.initials: MH
authors.lastname: Ryu
authors.forename: Jae-Lyun
authors.initials: JL
authors.lastname: Lee
authors.forename: Heung Moon
authors.initials: HM
authors.lastname: Chang
authors.forename: Baek-Yeol
authors.initials: BY
authors.lastname: Ryoo
authors.forename: Ho-Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D065637:Cytochrome P-450 CYP2A6; D004338:Drug Combinations; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid / Q000008:administration & dosage; D011110:Polymorphism, Genetic; D005641:Tegafur / Q000008:administration & dosage; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D002166:Camptothecin; D065637:Cytochrome P-450 CYP2A6; D004338:Drug Combinations; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D010094:Oxonic Acid; D005641:Tegafur; D000099148:UGT1A1 Enzyme; C079198:S 1 (combination); C585710:CYP2A6 protein, human