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Originally published as JCO Early Release 10.1200/JCO.2008.18.8565 on September 22 2008 © 2008 American Society of Clinical Oncology.
Is Fluorouracil-Induced Severe Toxicity in DPYD*2A Individuals Related to Sex or to Treatment Regimen?
Department of Medical Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam; Faculty of Science, Department of Pharmaceutical Sciences, Section of Biomedical Analysis, Division of Drug Toxicology, Utrecht University, Utrecht, the Netherlands
Department of Medical Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam; Faculty of Science, Department of Pharmaceutical Sciences, Section of Biomedical Analysis, Division of Drug Toxicology, Utrecht University, Utrecht, the Netherlands To the Editor: We very much appreciate the prospective manner of the study conducted by Schwab et al,1 in which fluorouracil (FU) treatment-related toxicity was correlated with genetic and nongenetic factors in patients treated with FU monotherapy-based regimens. The study elegantly illustrated the complex and diverse clinical picture allelic variants may induce, and serves as a model for prospective pharmacogenetic validation studies. However, we propose that the authors take another potentially crucial parameter in their analysis into account that might lead to a different interpretation of the study results. Toxicity to FU depends on the type of treatment regimen, also illustrated by Schwab et al, with the bolus Mayo regimen resulting in the highest overall grade 3/4 toxicity rate. Based on the study results presented, we believe that development of severe toxicity in DPYD*2A heterozygotes is determined by the treatment regimen and not by mode of administration nor by sex. Schwab et al observed that only six out of 13 DPYD*2A heterozygous patients developed grade 3/4 toxicity after treatment with FU monotherapy.1 This positive predictive value of 0.46 seems strikingly low, and does raise some questions. If we assume that the DPYD*2A polymorphism is equally distributed over the different types of treatment regimens, then the expected number of DPYD*2A heterozygotes treated in the bolus Mayo treatment group (n = 254) would be four to five patients. Interestingly, four patients with the DPYD*2A mutation have developed grade 4 FU-related toxicity, all treated according to the bolus Mayo regimen, suggesting that the type of treatment regimen is a predictive factor for development of toxicity in patients with the DPYD*2A mutation, which has not been noticed by the authors. If these four patients were the sole DPYD*2A mutants in the bolus Mayo regimen population, then the positive predictive value for developing grade 4 toxicity would be as high as 100% for DPYD*2A heterozygotes treated according to the bolus Mayo regimen. Unfortunately however, only the mode of application (ie, infusion v bolus in general), was statistically analyzed by Schwab et al in relation to toxicity, despite the fact that seven different treatment regimens were applied. Therefore, we propose that authors investigate the distribution of DPYD*2A over the different treatment regimens in relation to toxicity instead of evaluating only the mode of administration. In addition, given that dose is a clear determinant of toxicity, we are interested in the FU doses per cycle applied in the other nine individuals with DPYD*2A mutations. Additionally, Schwab et al reported an intriguing finding between DPYD*2A genotype and sex. Male DPYD*2A allele carriers had an odds ratio for toxicity of 41.8 versus 1.33 for females.1 The study results indicate however, that DPYD*2A heterozygotes have a higher likelihood of developing grade 4 toxicity after FU treatment according to the bolus Mayo regimen, and lower likelihood in other treatment regimens. This would be a new finding, and would put the DPYD*2A gene/sex relationship as observed in the study by Schwab et al into question. If severe toxicity to FU induced by DPYD*2A is related to treatment regimen, and the male/female proportion is unequally distributed over the different regimens, the findings of a gene/sex relation for DPYD*2A would be biased. The observed gene/sex association also contrasts with the theoretical expectation. Consistent with the fact that females possess a lower FU clearance by dihydropyrimidine dehydrogenase (DPD) than male patients, females are at higher risk for development of severe FU-related toxicity.2-4 A DPYD*2A-induced DPD deficiency would pose an even greater risk to women given that the initial DPD activity is already lower and an equivalent FU dose/m2 as in males needs to be metabolized. Other studies have extensively shown that DPYD*2A mutant females may develop severe (lethal) toxicity on FU treatment.5-7 Finally, the authors correctly assumed that 15% of the total population would develop severe toxicity. However, their initial expectation that 20% of these could be attributable to the DPYD*2A polymorphism seems to be an overestimation, as this would correspond with a minimal expected heterozygous frequency for DPYD*2A of 3%. In case of a positive predictive value smaller than 1, it would result even in a higher frequency. This is unlikely given that the white population frequency of DPYD*2A has been well established to range between 1 and 2 heterozygotes per 100 individuals.6-9 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Maarten J. Deenen, Fonds Nutsohra Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on September 22, 2008 REFERENCES
1. Schwab M, Zanger UM, Marx C, et al: Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: A prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol 26:2131-2138, 2008 2. Milano G, Etienne MC, Cassuto-Viguier E, et al: Influence of sex and age on fluorouracil clearance. J Clin Oncol 10:1171-1175, 1992[Abstract] 3. Port RE, Daniel B, Ding RW, et al: Relative importance of dose, body surface area, sex, and age for 5-fluorouracil clearance. Oncology 48:277-281, 1991[Medline] 4. Sloan JA, Goldberg RM, Sargent DJ, et al: Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. J Clin Oncol 20:1491-1498, 2002 5. Ezzeldin H, Johnson MR, Okamoto Y, et al: Denaturing high performance liquid chromatography analysis of the DPYD gene in patients with lethal 5-fluorouracil toxicity. Clin Cancer Res 9:3021-3028, 2003 6. Morel A, Boisdron-Celle M, Fey L, et al: Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther 5:2895-2904, 2006 7. Raida M, Schwabe W, Hausler P, et al: Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5`-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)-related toxicity compared with controls. Clin Cancer Res 7:2832-2839, 2001 8. Nauck M, Gierens H, Marz W, et al: Rapid detection of a common dihydropyrimidine dehydrogenase mutation associated with 5-fluorouracil toxicity and congenital thymine uraciluria using fluorogenic hybridization probes. Clin Biochem 34:103-105, 2001[CrossRef][Medline] 9. van Kuilenburg AB, Muller EW, Haasjes J, et al: Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: Frequency of the common IVS14 + 1G > A mutation causing DPD deficiency. Clin Cancer Res 7:1149-1153, 2001
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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