title: Association between the low-dose irinotecan regimen-induced occurrence of grade 4 neutropenia and genetic variants ofUGT1A1in patients with gynecological cancers.
abstract: The occurrence of severe neutropenia during treatment with irinotecan (CPT-11) is associated with the*6and*28alleles of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). However, the correlation between these variants and the occurrence of severe neutropenia in a low-dose CPT-11 regimen for the treatment of gynecological cancers has not been extensively studied. There are also no studies regarding the association between the 421C>A mutation in ATP-binding cassette sub-family G member 2 (ABCG2) and the occurrence of severe neutropenia in CPT-11-treated patients with gynecological cancers. The present study was designed to determine the factors associated with the occurrence of grade 4 neutropenia during chemotherapy for gynecological cancers with combinations of CPT-11 and cisplatin or mitomycin C. In total, 44 patients with gynecological cancer were enrolled in the study. The association between the absolute neutrophil count (ANC) nadir values, the total dose of CPT-11 and the genotypes ofUGT1A1orABCG2was studied. No correlation was observed between the ANC nadir values and the total dose of CPT-11. The ANC nadir values in theUGT1A1*6/*28and*6/*6groups were significantly lower compared with those in the*1/*1group (P<0.01). Univariate analysis showed no association between the occurrence of grade 4 neutropenia and theABCG2421C>A mutation. Subsequent to narrowing the factors by univariate analysis, multivariate logistic regression analysis only detected significant correlations between the occurrence of grade 4 neutropenia and theUGT1A1*6/*6and*6/*28groups (P=0.029; odds ratio, 6.90; 95% confidence interval, 1.22-38.99). No associations were detected between the occurrence of grade 4 neutropenia and the heterozygous variant (*1/*6or*1/*28) genotype, type of regimen or age. In conclusion, theUGT1A1*6/*28and*6/*6genotypes were found to be associated with the occurrence of severe neutropenia in the low-dose CPT-11 regimen for gynecological cancers. This finding indicates that the determination ofUGT1A1variants may be as useful in CPT-11 chemotherapy for gynecological conditions as it is in colorectal and lung cancer patients treated with this drug.
authors.affiliation: Department of Pharmacy, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Moriya
authors.affiliation: Department of Pharmacy, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Saito
authors.affiliation: Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Nuala
authors.initials: N
authors.lastname: Helsby
authors.affiliation: Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Sugino
authors.affiliation: Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Yamakage
authors.affiliation: Department of Pharmacy, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Sawaguchi
authors.affiliation: Department of Pharmacy, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Takasaki
authors.affiliation: Department of Gynecology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kato
authors.affiliation: Department of Pharmacy, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan.
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kurosawa
keywords: UDP-glucuronosyltransferase 1A1; gynecologic cancers; irinotecan; neutropenia; polymorphism