title: Prospective DPYD genotyping to reduce the risk of fluoropyrimidine-induced severe toxicity: Ready for prime time.
abstract: 5-Fluorouracil (5-FU) and capecitabine (CAP) are among the most frequently prescribed anticancer drugs. They are inactivated in the liver by the enzyme dihydropyrimidine dehydrogenase (DPD). Up to 5% of the population is DPD deficient and these patients have a significantly increased risk of severe and potentially lethal toxicity when treated with regular doses of 5-FU or CAP. DPD is encoded by the gene DPYD and variants in DPYD can lead to a decreased DPD activity. Although prospective DPYD genotyping is a valuable tool to identify patients with DPD deficiency, and thus those at risk for severe and potential life-threatening toxicity, prospective genotyping has not yet been implemented in daily clinical care. Our goal was to present the available evidence in favour of prospective genotyping, including discussion of unjustified worries on cost-effectiveness, and potential underdosing. We conclude that there is convincing evidence to implement prospective DPYD genotyping with an upfront dose adjustment in DPD deficient patients. Immediate benefit in patient care can be expected through decreasing toxicity, while maintaining efficacy.
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Carin A T C
authors.initials: CATC
authors.lastname: Lunenburg
authors.affiliation: Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Henricks
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Swen
authors.affiliation: Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, The Netherlands.
authors.forename: Maarten J
authors.initials: MJ
authors.lastname: Deenen
authors.affiliation: Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jan H M
authors.initials: JHM
authors.lastname: Schellens
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: A.J.Gelderblom@lumc.nl.
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics; D000069287:Capecitabine / Q000009:adverse effects* / Q000493:pharmacokinetics; D003362:Cost-Benefit Analysis; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D005472:Fluorouracil / Q000009:adverse effects* / Q000493:pharmacokinetics; D005820:Genetic Testing; D005838:Genotype; D017048:Health Care Costs; D006801:Humans; D010597:Pharmacogenetics / Q000191:economics / Q000379:methods*; D010641:Phenotype; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil
keywords: 5-Fluorouracil; Capecitabine; DPYD; Dihydropyrimidine dehydrogenase; Fluoropyrimidines; Individualised medicine; Pharmacogenomics