Journal of the National Cancer Institute Advance Access originally published online on January 29, 2008
JNCI Journal of the National Cancer Institute 2008 100(3):224-225; doi:10.1093/jnci/djm302
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2008. Published by Oxford University Press.
CORRESPONDENCE |
Re: UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Dose Matters
Affiliations of authors: Department of Medical Oncology, Comprehensive Cancer Center (WI, KA, KF, WY, HE, FN, RT, TM, K. Kodama, Y. Sunakawa, MN, Y. Ando, Y. Akiyama, K. Kawara, Y. Sasaki) and Project Research Laboratory, Research Center for Genomic Medicine (KF, Y. Sasaki), Saitama Medical University, Saitama, Japan
Correspondence to: Wataru Ichikawa, MD, Department of Medical Oncology, Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan (e-mail: wataru{at}saitama-med.ac.jp).
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/m2), not at lower doses (
150 mg/m2).
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 metabolism of SN-38 (the active metabolite of irinotecan), 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 heterozygous 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/m2 because the Japanese package insert information limits the dose for irinotecan to 150 mg/m2 in each biweekly regimen when patients do not experience dose-limiting toxicity, which was defined 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/m2, and patient C with lung cancer experienced grade 3 diarrhea with grade 3 neutropenia at a dose of 75 mg/m2. Patient D with colon cancer experienced grade 4 neutropenia at an irinotecan dose of 150 mg/m2.
|
Although the dosage of irinotecan in our study was lower than that in Hoskins et al. (1), the intrapatient variability in metabolic ratio according to the administered irinotecan dose might explain, in part, the association between irinotecan dose and the risk of irinotecan-related hematologic toxic effects in patients who were expected to have low UGT1A1 activity. In addition, the interpatient heterogeneity of metabolic ratio among patients with a mutated UGT1A1 genotype may likely be due to factors other than UGT1A1 genotype, either genetic or nongenetic, as discussed by Hoskins et al. (1). Further studies on the pharmacokinetics, pharmacodynamics, and pharmacogenetics of irinotecan are needed to clarify these issues.
Funding
Grant-in-Aid for Cancer Research and Health and Labor Sciences Research Grant from the Ministry of Health, Labor and Welfare of Japan (17-8 to Y. Sasaki); Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science; Japan Research Foundation for Clinical Pharmacology (A-16200038 to Y. Sasaki).
NOTES
The authors take full responsibility for the design of the study, the collection of the data, the analysis and interpretation of the data, the decision to submit the manuscript for publication, and the writing of the manuscript.
REFERENCES
1. Hoskins JM, Goldberg RM, Qu P, Ibrahim JG, McLeod HL. UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J Natl Cancer Inst (2007) 99:1290–1295.
2. Sai K, Saeki M, Saito Y, et al. UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer. Clin Pharmacol Ther (2004) 75:501–515.[CrossRef][Web of Science][Medline]
3. Han JY, Lim HS, Shin ES, et al. Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non-small-cell lung cancer treated with irinotecan and cisplatin. J Clin Oncol (2006) 24:2237–2244.
4. Araki K, Fujita K, Ando Y, et al. Pharmacogenetic impact of polymorphisms in the coding region of the UGT1A1 gene on SN-38 glucuronidation in Japanese patients with cancer. Cancer Sci. (2006) 97:1255–1259.[CrossRef][Medline]
Related Article in JNCI
Response to this Correspondence
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2007 99: 1290-1295.
J Natl Cancer Inst 2008 100: 225.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||