In the safety and tolerability study of a novel FOLFIRABRAX regimen in patients with gastrointestinal cancers by Joshi and colleagues (1), the irinotecan doses were determined by UGT1A1 genotypes: 180, 135, and 90 for wild-type (*1/*1), heterozygous (*1/*28), and homozygous (*28/*28) patients, respectively. The authors reported that this regimen with genotype-guided dosing of irinotecan was tolerable based on the result that dose-limiting toxicities occurred in 5 of 23 (22%) wild-type, 1 of 19 (5%) heterozygous, and 0 of 7 homozygous patients. However, their conclusion truly concerns us that the regimen is not strong enough for patients with any of the genotypes. According to the genotype-guided dose-finding studies of irinotecan in analogous FOLFIRI regimens, the maximum-tolerated or recommended doses for wild-type and heterozygous patients were more than 300 mg/m2 and that for homozygous patients was 130 mg/m2 (2, 3). The irinotecan doses used in the FOLFIRABRAX regimen are clearly too low. It is of our opinion that the standard one-size dose of biweekly irinotecan, regardless of UGT1A1 genotype, should be tailored to at least 300 mg/m2 or more for wild-type and heterozygous patients, and 120–150 mg/m2 would be appropriate for homozygous patients, which corresponds to a 1 or 2 dose level reduction compared with that in the package insert of the drug. This dosing is consistent with the finding of the previous pharmacokinetic study that the exposure to the active metabolite SN-38 is approximately double in homozygous patients compared with patients with the other genotypes. The real benefit of genotype-guided dosing of irinotecan is not only to avoid unnecessary toxicity of irinotecan in homozygous patients by reducing the dose but also to enhance the therapeutic efficacy in wild-type and heterozygous patients by increasing the dose to the optimal one.

See the Response, p. 3890

O. Maeda reports receiving speakers bureau honoraria from Yakult Honsha Co., Ltd. and Taiho Pharmaceutical Co., Ltd. Y. Ando reports receiving commercial research grants from Yakult Honsha, Mochida Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo, and Nippon Kayaku, and reports receiving speakers bureau honoraria from Yakult Honsha, Taiho Pharmaceutical, Daiichi Sankyo, and Sawai Pharmaceutical. No potential conflicts of interest were disclosed by the other author.

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