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

Elena Magnani, Enrico Farnetti, Davide Nicoli, Bruno Casali, Luisa Savoldi, Chiara Focaccetti, Corrado Boni, Adriana Albini, Maria Banzi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)417-423
Number of pages7
JournalInternal and Emergency Medicine
Volume8
Issue number5
DOIs
Publication statusPublished - Aug 2013

Fingerprint

Dihydrouracil Dehydrogenase (NADP)
Appointments and Schedules
Fluorouracil
Dihydropyrimidine Dehydrogenase Deficiency
Tegafur
Drug Therapy
Microsatellite Instability
Mutation
Complementary Therapies
Hospitalization
Therapeutics
Genotype
Enzymes
Pharmaceutical Preparations

Keywords

  • Dihydropyrimidine dehydrogenase (DPD)
  • Dose reduction
  • Fluoropyrimidine chemotherapy
  • Toxicity
  • Tumors

ASJC Scopus subject areas

  • Emergency Medicine
  • Internal Medicine

Cite this

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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.",
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AU - Magnani, Elena

AU - Farnetti, Enrico

AU - Nicoli, Davide

AU - Casali, Bruno

AU - Savoldi, Luisa

AU - Focaccetti, Chiara

AU - Boni, Corrado

AU - Albini, Adriana

AU - Banzi, Maria

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