title: UDP-glucuronosyltransferase 1A1*6 and *28 polymorphisms as indicators of initial dose level of irinotecan to reduce risk of neutropenia in patients receiving FOLFIRI for colorectal cancer.
abstract: Irinotecan (CPT-11)-induced neutropenia is associated with UDP-glucuronosyltransferase (UGT) 1A1*6 and *28 polymorphisms. This prospective study investigated whether using these polymorphisms to adjust the initial dose of CPT-11 as part of FOLFIRI treatment in colorectal cancer patients might improve safety.
  
  
  
  All data were collected by a physician. The relationship between UGT1A1 polymorphisms and first-cycle neutropenia, reasons for treatment discontinuation, and time-to-treatment failure were evaluated. Multivariate analysis was used to assess the risk of neutropenia.
  
  
  
  A total of 795 patients were divided into wild-type (*1/*1) (50.1 %), heterozygous (*28/*1, *6/*1) (41.1 %), and homozygous (*28/*28, *6/*6, *28/*6) (8.8 %) groups, in which the median starting dose of CPT-11 was 143.0, 143.0, and 115.0 mg/m(2), respectively. First-cycle grade ≥3 neutropenia occurred in 17.3, 25.4, and 28.6 % of these patients, respectively. Multivariate analysis revealed that the incidence of grade ≥3 neutropenia was significantly greater in the heterozygous and homozygous groups than in the wild-type group [odds ratio (OR) 1.67; 95 % confidence interval (CI) 1.16-2.42; p = 0.0060, and OR 2.22; 95 % CI 1.22-4.02; p = 0.0088, respectively]. Age (OR 1.77; 95 % CI 1.24-2.53; p = 0.0017), coelomic fluid (OR 1.84; 95 % CI 1.05-3.25; p = 0.0343), and non-reduction in starting dose (OR 1.53; 95 % CI 1.08-2.18; p = 0.0176) were also identified as significant risk factors.
  
  
  
  The risk of neutropenia was higher in the heterozygous and homozygous groups at initiation of CPT-11 treatment. This suggests that when a reduction in dose is required in patients harboring two variant alleles, the decrease should be approximately 20 %.
authors.affiliation: Department of Medical Oncology, Saku Central Hospital Advanced Care Center, 3400-28 Nakagomi, Saku, Nagano, 385-0051, Japan. miyata.yoshinori@sakuhp.or.jp.
authors.forename: Yoshinori
authors.identifier: http://orcid.org/0000-0003-1155-1038
authors.initials: Y
authors.lastname: Miyata
authors.affiliation: Department of Surgery, Nakagami Hospital, Okinawa, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Touyama
authors.affiliation: Department of Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Kusumi
authors.affiliation: Department of Radiology, National Hospital Organization Kobe Medical Center, Kobe, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Morita
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Mizunuma
authors.affiliation: Hepato-Pancreatic Surgery Division, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Taniguchi
authors.affiliation: Yakult Honsha Co., Ltd., Tokyo, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Manabe
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D015415:Biomarkers; D001826:Body Fluids; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D014453:Glucuronosyltransferase / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control*; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012307:Risk Factors; D000099148:UGT1A1 Enzyme
chemical_list: D015415:Biomarkers; D002166:Camptothecin; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D002955:Leucovorin; D000099148:UGT1A1 Enzyme
keywords: Colorectal; Irinotecan; Neutropenia; Polymorphism; UGT1A1 enzyme