Re: UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters.

We read with interest the paper from Hoskins et al. (1) on the meta-analysis of the studies that assessed the association of irinotecan dose with the risk of irinotecan-related toxic effects for patients with the UGT1A1*28/*28 genotype. They indicated that the risk of hematologic toxicity was strongly associated with UGT1A1*28 genotype at higher irinotecan doses (>150 mg/m 2), not at lower doses (≤ 150 mg/m 2). We congratulate the authors for their excellent work. We would like to present support for their work from the ongoing study to establish the appropriate dose-adaptation strategy for irinotecan among Japanese patients who are heterozygous for both UGT1A1*28 and UGT1A1*6 or homozygous for each variant. UGT1A1*6 , which contributes to the hepatic meta bolism of SN-38 (the active metabolite of irinote-can), is more prevalent than UGT1A1*28 in Asian populations (2 , 3). In the Japanese population, the metabolic ratio of the area under the curve (AUC) for SN-38/AUC for SN-38 glucuronide was statistically significantly higher in patients who were hetero-zygous for both UGT1A1*28 and UGT1A1*6 or homozygous for UGT1A1*6 than in those with other genotypes (P = .004, Mann-Whitney U test) (4). In the study, the dose of irinotecan was escalated from 25 to 150 mg/m 2 because the Japanese package insert information limits the dose for irinotecan to 150 mg/m 2 in each biweekly regimen when patients do not experience dose-limiting toxicity, which was defi ned as grade 4 neutropenia or grade 3 or 4 nonhematologic toxic effects according to the Common Toxicity Criteria , version 3.0, of the National Cancer Institute. Genotyping and pharmacokinetic analyses were performed simultaneously as previously reported (4). All patients gave written informed consent approved by the Institutional Review Board of Saitama Medical University. In plots of metabolic ratios at the administered dose of irinotecan for individual patients, gradual changes in the metabolic ratio of patients were observed according to the dose escalation, with one exception that of patient A (Fig. 1). Patients A, B, and C were homozygous for UGT1A1*6 , and patient D was heterozygous for both UGT1A1*28 and UGT1A1*6. Patient A with a primary cancer whose site was unknown had no dose-limiting toxicity but refused to continue irinotecan treatment. During dose escalation , patient B with ovarian cancer experienced grade 4 neutropenia at an irinotecan dose of 100 mg/m 2 , and patient C with lung cancer experienced grade 3 diarrhea with grade 3 neutropenia …