Fluoropyrimidine toxicity in patients with dihydropyrimidine dehydrogenase splice site variant: the need for further revision of dose and schedule.

Abstract

Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolic catabolism of 5-fluorouracil (5-FU) and its derivatives (capecitabine and tegafur). Complete or partial deficiency of DPD activity has been demonstrated to induce severe toxicities in cancer patients treated with fluoropyrimidine therapy. We analyzed 180 individuals that were candidates for a treatment with 5-FU class drugs for the most common DPD mutation, IVS14+1G>A, and detected four heterozygous patients. We recorded the toxicities for all 180 individuals after the first two chemotherapy cycles and found that three of the four patients, although they were treated with a dose reduction in 50 % on the basis of the genetic analysis, all showed severe toxicities that resulted in hospitalization of patient and premature discontinuation of treatment. One patient with mutated DPD was not treated with chemotherapy upon the clinician's decision because of his DPD mutated genotype and the presence of microsatellite instability. Our data suggest that greater dose reductions or alternative therapies are needed for patients with DPD IVS14+1G>A mutations.

• Authors: Elena Magnani, Enrico Farnetti, Davide Nicoli, Bruno Casali, Luisa Savoldi, Chiara Focaccetti, Corrado Boni, Adriana Albini, Maria Banzi
• Journal: Internal and emergency medicine (Intern Emerg Med) Vol. 8 Issue 5 Pg. 417-23 (Aug 2013) ISSN: 1970-9366 [Electronic] Italy
• PMID: 23585145 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Antineoplastic Agents
• Deoxycytidine
• Capecitabine
• Fluorouracil

Topics

• Adult
• Aged
• Antimetabolites, Antineoplastic (administration & dosage, adverse effects, metabolism)
• Antineoplastic Agents (administration & dosage, adverse effects, metabolism)
• Capecitabine
• Colonic Neoplasms (drug therapy)
• Deoxycytidine (administration & dosage, adverse effects, analogs & derivatives, metabolism)
• Dihydropyrimidine Dehydrogenase Deficiency (genetics)
• Dose-Response Relationship, Drug
• Fluorouracil (administration & dosage, adverse effects, analogs & derivatives, metabolism)
• Head and Neck Neoplasms (drug therapy)
• Heterozygote
• Humans
• Male
• Mutation
• Patient Selection
• Polymerase Chain Reaction