Originally published as JCO Early Release 10.1200/JCO.2006.10.4182 on February 25 2008

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Role of Genetic and Nongenetic Factors for Fluorouracil Treatment-Related Severe Toxicity: A Prospective Clinical Trial by the German 5-FU Toxicity Study Group

Matthias Schwab, Ulrich M. Zanger, Claudia Marx, Elke Schaeffeler, Kathrin Klein, Jürgen Dippon, Reinhold Kerb, Julia Blievernicht, Joachim Fischer, Ute Hofmann, Carsten Bokemeyer, Michel Eichelbaum

From the Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and Department of Mathematics, University of Stuttgart, Stuttgart; University of Tuebingen and Department of Internal Medicine II, University Medical Center, Tuebingen; Epidauros Biotechnology AG, Bernried; and Department of Internal Medicine II (Oncology, Hematology, Bone marrow transplantation, Pneumology), University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Corresponding author: Ulrich M. Zanger, PhD, Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstraβe 112, D-70376 Stuttgart, Germany; e-mail: uli.zanger{at}ikp-stuttgart.de and Carsten Bokemeyer, MD, Department of Internal Medicine II (Oncology, Hematology, Bone marrow transplantation, Pneumology), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany; e-mail: c.bokemeyer{at}uke.uni-hamburg.de

Purpose To assess the predictive value of polymorphisms in dihydropyrimidine dehydrogenase (DPYD ), thymidylate synthase (TYMS ), and methylene tetrahydrofolate reductase (MTHFR ) and of nongenetic factors for severe leukopenia, diarrhea, and mucositis related to fluorouracil (FU) treatment.

Patients and Methods A multicenter prospective clinical trial included 683 patients with cancer treated with FU monotherapy. Toxicity was documented according to World Health Organization grades. DPYD, TYMS, and MTHFR genotypes were determined, and DPYD was resequenced in patients with severe toxicity.

Results Grade 3 to 4 toxicity occurred in 16.1% of patients. The sensitivity of DPYD*2A genotyping for overall toxicity was 5.5% (95%CI, 0.02 to 0.11), with a positive predictive value of 0.46 (95% CI, 0.19 to 0.75; P = .01). Inclusion of additional DPYD variants improved prediction only marginally. Analysis according to toxicity type revealed significant association of DPYD with mucositis and leukopenia, whereas TYMS was associated with diarrhea. Genotype, female sex, mode of FU administration, and modulation by folinic acid were identified as independent risk factors by multivariable analysis. A previously unrecognized significant interaction was found between sex and DPYD, which resulted in an odds ratio for toxicity of 41.8 for male patients (95% CI, 9.2 to 190; P < .0001) but only 1.33 (95% CI, 0.34 to 5.2) in female patients. Homozygosity for the TYMS enhancer region double repeat allele increased risk for toxicity 1.6-fold (95% CI, 1.08 to 2.22; P = .02).

Conclusion DPYD, TYMS, and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients. Toxicity risk assessment should include sex, mode of administration, and folinic acid as additional predictive factors.

published online ahead of print at www.jco.org on February 25, 2008.

Supported by Grant No. 01 GG 9846 from the German Federal Ministry of Education and Science and by the Robert Bosch Foundation, Stuttgart, Germany.

Presented in part at the 1st Joint Cold Spring Harbor Laboratory/Wellcome Trust Conference on Pharmacogenomics, September 24-28, 2003, Hinxton, United Kingdom.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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