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Originally published as JCO Early Release 10.1200/JCO.2008.18.8714 on September 22 2008 © 2008 American Society of Clinical Oncology.
In Reply
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart; Department of Clinical Pharmacology, University of Tuebingen, Tuebingen, Germany In their letter, Drs Deenen, Beijnen and Schellens raise some interesting questions and suggest alternative explanations for some of our observations. In particular, they propose that severe fluorouracil (FU) toxicity in heterozygous carriers of DPYD*2A is determined by treatment regimen rather than by mode of administration or sex. The combination of DPYD*2A plus bolus Mayo regimen would then be a much more reliable predictor of toxicity. As pointed out in our study, we indeed found and confirmed a significant relationship between treatment regimen and development of severe toxicity as patients treated with the bolus Mayo regimen had a greater risk compared with those who received high-dose infusion (odds ratio, 2.44; 95% CI, 1.52 to 3.91; P < .001). Additional analyses were not presented in the original study1 because the other treatment groups were much smaller and because we did not observe additional significant relationships, in particular no interaction between genotype and treatment regimen.
In Table 1, we present additional data on all DPYD*2A heterozygous patients identified in our study. As evident from these data, the bolus Mayo regimen was tolerated by three heterozygous female patients who did not develop toxicity with World Health Organization grade greater than 2. Thus, of seven mutation carriers treated with this regimen, only four developed severe toxicity graded
Extending their assumption of treatment regimen as an unidentified important factor, Deenen et al also point out that this may also explain our surprising finding of an interaction between the patients sex and toxicity risk conferred by DPYD*2A heterozygosity. They cite other studies that have allegedly shown extensively severe and lethal toxicity in women treated with FU. We are aware of these data and we by no means exclude the possibility that female carriers experience severe toxicity from FU treatment. However, it is important to emphasize again the difference between our prospective study on FU monotherapy and the retrospective nature of most previous studies. In a retrospective study with unclear inclusion criteria, multiple treatments, and inconsistent toxicity scales, it is difficult to prove a causal relationship between DPYD genotype and toxicity.3,4 In the prospective study on DPYD genetics and FU toxicity by Morel at al2, also cited by Deenen et al and already discussed, sex had unfortunately not been taken into account as a separate risk factor, and the sex of the patients experiencing toxicity had not been revealed. Importantly, the female patient alluded to by Deenen et al who experienced lethal toxicity was homozygous for DPYD*2. In conclusion, we thank Deenen et al for their detailed analysis of our data and for pointing out possible alternative explanations. The additional data presented here do not support their hypotheses but they provide additional support to our main findings of low positive predictive value for DPYD*2A genotyping and an intriguing interaction between DPYD genetics and sex for the development of FU-related toxicity. Together with our additional observation that the patient's genetic background determines to some extent the type of toxicity, value of detailed prospective studies is emphasized and warrants additional investigation into genome-wide determinants as well as nongenetic causes of toxicity. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
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. 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 3. Raida M, Schwabe W, Häusler 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 4. 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
Related Correspondence
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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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3 (presented in our Appendix Table A6
