Journal of the National Cancer Institute Advance Access originally published online on August 28, 2007
JNCI Journal of the National Cancer Institute 2007 99(17):1290-1295; doi:10.1093/jnci/djm115
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© The Author 2007. Published by Oxford University Press.
COMMENTARY |
UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Dose Matters
Affiliations of authors: UNC Institute for Pharmacogenomics and Individualized Therapy (JMH, RMG, HLM), Division of Pharmacotherapy and Experimental Therapeutics (JMH, HLM), Division of Hematology and Oncology (RMG, HLM), Department of Biostatistics (PQ, JGI), and Lineberger Comprehensive Cancer Center (RMG, JGI, HLM), University of North Carolina, Chapel Hill, NC
Correspondence to: Howard L. McLeod, PharmD, UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Campus Box 7360, Kerr Hall, Chapel Hill, NC 27599-7360 (e-mail: hmcleod{at}unc.edu).
The Food and Drug Administration and Pfizer changed the package insert for irinotecan to include a patient's UGT1A1*28 genotype as a risk factor for severe neutropenia on the basis of the findings of four pharmacogenetic studies, which found that irinotecan-treated patients who were homozygous for the UGT1A1*28 allele had a greater risk of hematologic toxic effects than patients who had one or two copies of the wild-type allele (UGT1A1*1). Findings of subsequent irinotecan pharmacogenetic studies have been inconsistent. In a meta-analysis, we reviewed data presented in nine studies that included a total of 10 sets of patients (for a total of 821 patients) and assessed the association of irinotecan dose with the risk of irinotecan-related hematologic toxicities (grade III–IV) for patients with a UGT1A1*28/*28 genotype. The risk of toxicity was higher among patients with a UGT1A1*28/*28 genotype than among those with a UGT1A1*1/*1 or UGT1A1*1/*28 genotype at both medium (odds ratio [OR] = 3.22, 95% confidence interval [CI] = 1.52 to 6.81; P = .008) and high (OR = 27.8, 95% CI = 4.0 to 195; P = .005) doses of irinotecan. However, risk was similar at lower doses (OR = 1.80, 95% CI = 0.37 to 8.84; P = .41). Low doses of irinotecan (100–125 mg/m2) are in the commonly used therapeutic range. The risk of experiencing irinotecan-induced hematologic toxicity for patients with a UGT1A1*28/*28 genotype thus appears to be a function of the dose of irinotecan administered.
| CONTEXT AND CAVEATS Prior knowledge In four previous studies, a UGT1A1*28 genotype among irinotecan-treated patients was associated with an increased risk of severe neutropenia. Study design A meta-analysis of nine studies that included 10 sets of patients (for a total of 821 patients) assessed the association between irinotecan dose and the risk of grade III and IV hematologic toxic effects by UGT1A1*1 or UGT1A1*28 genotype. Contribution The risk of hematologic toxic effects at high and medium irinotecan doses was higher among patients with a UGT1A1*28/*28 genotype than among those with a UGT1A1*1/*28 or UGT1A1*1/*1 genotype. However, at lower doses, risk was similar for patients with all genotypes. Low doses of irinotecan (100–125 mg/m2) are in the commonly used therapeutic range. Implications At low doses of irinotecan, decisions about treating individual patients can be made according to standard clinical practice because genotype was not associated with risk. At higher doses, genotype-based decisions are advisable because of the association between the UGT1A1*28/*28 genotype and increased risk of irinotecan-induced toxic effects. Limitations There were many sources of heterogeneity among the studies analyzed. Some sources of heterogeneity could have influenced patient participation in a trial and, therefore, the dose of irinotecan that was received. Others could have been related to the dose of irinotecan administered by trials. These factors may also have directly modulated the association observed. Because of limited power or the unavailability of individual data, the relationship between these factors and the association could not be assessed.
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Manuscript received March 5, 2007; revised June 28, 2007; accepted July 18, 2007.
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J Natl Cancer Inst 2008 100: 224-225.
J Natl Cancer Inst 2007 99: 1277.
J Natl Cancer Inst 2007 99: 1277.
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