title: Impact of UGT1A1 genotype upon toxicities of combination with low-dose irinotecan plus platinum.
abstract: OBJECTIVE
  Irinotecan-induced severe toxicities are possibly related to UGT1A1*6 and *28 genotypes. However, the correlation between UGT1A1 polymorphisms and the risk of toxicities induced by low-dose irinotecan plus platinum combination therapy still remains controversial. This prospective observational study aimed to examine the correlation between UGT1A1 genotypes and clinical outcomes of low-dose irinotecan (median 60 mg/m(2) , range 25-115 mg/m(2) ) plus platinum in Japanese patients with solid tumors.
  
  
  METHODS
  Toxicity profiles were compared between UGT1A1 SNP heterozygotes (hetero-group) and patients with homozygous SNP profile (*6/*6, *28/*28 and *6/*28). Logistic regression models were used to identify independent risk factors for these toxicities.
  
  
  RESULTS
  A total of 331 patients were enrolled: 84% with hetero-group and 16% with homo-group. Although the initial irinotecan dose was similar, the dose intensities during the three cycles were significantly lower in the homo-group (P < 0.01). Grade 3/4 hematological toxicities were significantly more frequent in the homo-group. Multivariable analysis identified UGT1A1 genotype (P < 0.01) as an independent factor for grade 4 hematological toxicity in the first treatment cycle.
  
  
  CONCLUSIONS
  UGT1A1 genotype has a major impact on the increased risk of severe hematological toxicities, even in low-dose irinotecan regimens. UGT1A1 genotypes are useful biomarkers for predicting severe hematological toxicities in patients treated with irinotecan plus platinum analog.
authors: Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Japan.
authors: Masashi
authors: M
authors: Takano
authors: Department of Obstetrics and Gynecology, Sakai Hospital, Kinki University Faculty of Medicine, Sakai, Japan.
authors: Kaichiro
authors: K
authors: Yamamoto
authors: Department of Obstetrics and Gynecology, Mie University Graduate School of Medicine, Tsu, Japan.
authors: Tsutomu
authors: T
authors: Tabata
authors: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
authors: Yuji
authors: Y
authors: Minegishi
authors: Department of Respiratory Medicine, Kyorin University Hospital, Mitaka, Japan.
authors: Takuma
authors: T
authors: Yokoyama
authors: Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors: Eiji
authors: E
authors: Hirata
authors: Department of Respiratory Medicine, Naga Municipal Hospital, Kinokawa, Japan.
authors: Takeshi
authors: T
authors: Ikeda
authors: Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Japan.
authors: Muneaki
authors: M
authors: Shimada
authors: Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan.
authors: Kouzo
authors: K
authors: Yamada
authors: Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Satoshi
authors: S
authors: Morita
authors: Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.
authors: Yuichi
authors: Y
authors: Ando
authors: Pharmacovigilance Department, Daiichi Sankyo, Tokyo, Japan.
authors: Koji
authors: K
authors: Hirata
authors: Clinical Data and Biostatistics Department, Daiichi Sankyo, Tokyo, Japan.
authors: Masahiro
authors: M
authors: Sugihara
authors: Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan.
authors: Toru
authors: T
authors: Sugiyama
authors: Department of Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan.
authors: Yasuo
authors: Y
authors: Ohashi
authors: CEO, Misawa City Hospital, Misawa, Japan.
authors: Yuh
authors: Y
authors: Sakata
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D009944:Organoplatinum Compounds; D000099148:UGT1A1 Enzyme
keywords: UGT1A1; irinotecan plus platinum; toxicity