Masashi Takano1, Kaichiro Yamamoto2, Tsutomu Tabata3, Yuji Minegishi4, Takuma Yokoyama5, Eiji Hirata6, Takeshi Ikeda7, Muneaki Shimada8, Kouzo Yamada9, Satoshi Morita10, Yuichi Ando11, Koji Hirata12, Masahiro Sugihara13, Toru Sugiyama14, Yasuo Ohashi15, Yuh Sakata16. 1. Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Japan. 2. Department of Obstetrics and Gynecology, Sakai Hospital, Kinki University Faculty of Medicine, Sakai, Japan. 3. Department of Obstetrics and Gynecology, Mie University Graduate School of Medicine, Tsu, Japan. 4. Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. 5. Department of Respiratory Medicine, Kyorin University Hospital, Mitaka, Japan. 6. Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. 7. Department of Respiratory Medicine, Naga Municipal Hospital, Kinokawa, Japan. 8. Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Japan. 9. Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan. 10. Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan. 11. Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan. 12. Pharmacovigilance Department, Daiichi Sankyo, Tokyo, Japan. 13. Clinical Data and Biostatistics Department, Daiichi Sankyo, Tokyo, Japan. 14. Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan. 15. Department of Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan. 16. CEO, Misawa City Hospital, Misawa, Japan.
Abstract
AIM: 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. CONCLUSION: 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.
AIM: 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. CONCLUSION: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.