Please use this identifier to cite or link to this item:
Scopus Web of Science® Altmetric
Full metadata record
DC FieldValueLanguage
dc.contributor.authorSchwab, M.en
dc.contributor.authorZanger, U.en
dc.contributor.authorMarx, C.en
dc.contributor.authorSchaeffeler, E.en
dc.contributor.authorKlein, K.en
dc.contributor.authorDippon, J.en
dc.contributor.authorKerb, R.en
dc.contributor.authorBlievernicht, J.en
dc.contributor.authorFischer, J.en
dc.contributor.authorHofmann, U.en
dc.contributor.authorBokemeyer, C.en
dc.contributor.authorEichelbaum, M.en
dc.identifier.citationJournal of Clinical Oncology, 2008; 26(13):2131-2138en
dc.description.abstractPURPOSE: 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.en
dc.description.statementofresponsibilityMatthias Schwab, Ulrich M. Zanger, Claudia Marx, Elke Schaeffeler, Kathrin Klein, Jürgen Dippon, Reinhold Kerb, Julia Blievernicht, Joachim Fischer, Ute Hofmann, Carsten Bokemeyer, Michel Eichelbaumen
dc.publisherAmer Soc Clinical Oncologyen
dc.subjectGerman 5-FU Toxicity Study Group; Humans; Leukopenia; Genetic Predisposition to Disease; Diarrhea; Fluorouracil; Leucovorin; Methylenetetrahydrofolate Reductase (NADPH2); Dihydrouracil Dehydrogenase (NADP); Thymidylate Synthase; Vitamin B Complex; Antimetabolites, Antineoplastic; Severity of Illness Index; Logistic Models; Odds Ratio; Risk Assessment; Risk Factors; Prospective Studies; Predictive Value of Tests; DNA Methylation; Gene Frequency; Homozygote; Polymorphism, Genetic; Patient Selection; Germany; Female; Male; Mucositis; Promoter Regions, Genetic; Genetic Testingen
dc.titleRole of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Groupen
dc.typeJournal articleen
pubs.library.collectionPharmacology publicationsen
Appears in Collections:Pharmacology publications

Files in This Item:
There are no files associated with this item.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.