title: [Prevention of severe toxicity from capecitabine, 5-fluorouracil and tegafur by screening for DPD-deficiency].
abstract: Capecitabine, 5-fluorouracil and tegafur form the group called the fluoropyrimidines, which is one of the most frequently prescribed group of anti-cancer drugs for the treatment of (metastatic) colorectal, gastric and breast cancer. The primary enzyme responsible for the inactivation of the fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD). Consequently, patients with an inborn partial DPD deficiency, induced, for example by the polymorphism DPYD*2A, are highly prone to severe, potentially lethal toxicity following a standard dose of fluoropyrimidines. In this article, based on three representative case reports and our prospective study in patients with cancer, we demonstrate the clinical value of prospective screening for DPD deficiency in patients being treated with fluoropyrimidine-based anti-cancer therapy. The results show that upfront genotyping for DPYD*2A followed by a fluoropyrimidine dose reduction of 50% (on average) in patients heterozygous polymorphic for DPYD*2A, significantly reduces the incidence of severe to potentially lethal toxicity compared to historical control patients given full-dose therapy.
authors.affiliation: Divisie Klinische Farmacologie, Nederlands Kanker Instituut, Amsterdam, the Netherlands.
authors.forename: Maarten J
authors.initials: MJ
authors.lastname: Deenen
authors.forename: Annemieke
authors.initials: A
authors.lastname: Cats
authors.forename: Caroline M P W
authors.initials: CM
authors.lastname: Mandigers
authors.forename: Marcel
authors.initials: M
authors.lastname: Soesan
authors.forename: Wim E
authors.initials: WE
authors.lastname: Terpstra
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000031:analogs & derivatives; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D018570:Risk Assessment; D005641:Tegafur / Q000009:adverse effects
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D005641:Tegafur; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil