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Impact of UGT1A1 genotype upon toxicities of combination with low-dose irinotecan plus platinum

2016; Wiley; Volume: 12; Issue: 2 Linguagem: Inglês

10.1111/ajco.12453

1743-7563

Masashi Takano, Kaichiro Yamamoto, Tsutomu Tabata, Yuji Minegishi, Takuma Yokoyama, Eiji Hirata, Takeshi Ikeda, Muneaki Shimada, Kouzo Yamada, Satoshi Morita, Yukio Ando, Koji Hirata, Masahiro Sugihara, Toru Sugiyama, Yasuo Ohashi, Yuh Sakata,

Neuroendocrine Tumor Research Advances

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/m2, range 25–115 mg/m2) 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.