[Dihydropyrimidine déhydrogenase (DPD) Deficiency Screening and Securing of Fluoropyrimidine-Based Chemotherapies: Update and Recommendations of the French GPCO-Unicancer and RNPGx Networks]

Bull Cancer. 2018 Apr;105(4):397-407. doi: 10.1016/j.bulcan.2018.02.001. Epub 2018 Feb 24.
[Article in French]

Abstract

Fluoropyrimidines (FU) are still the most prescribed anticancer drugs for the treatment of solid cancers. However, fluoropyrimidines cause severe toxicities in 10 to 40% of patients and toxic deaths in 0.2 to 0.8% of patients, resulting in a real public health problem. The main origin of FU-related toxicities is a deficiency of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme of 5-FU catabolism. DPD deficiency may be identified through pharmacogenetics testing including phenotyping (direct or indirect measurement of enzyme activity) or genotyping (detection of inactivating polymorphisms on the DPYD gene). Approximately 3 to 15% of patients exhibit a partial deficiency and 0.1 to 0.5% a complete DPD deficiency. Currently, there is no regulatory obligation for DPD deficiency screening in patients scheduled to receive a fluoropyrimidine-based chemotherapy. Based on the levels of evidence from the literature data and considering current French practices, the Group of Clinical Pharmacology in Oncology (GPCO)-UNICANCER and the French Network of Pharmacogenetics (RNPGx) recommend the following: (1) to screen DPD deficiency before initiating any chemotherapy containing 5-FU or capecitabine; (2) to perform DPD phenotyping by measuring plasma uracil (U) concentrations (possibly associated with dihydrouracil/U ratio), and DPYD genotyping (variants *2A, *13, p.D949V, HapB3); (3) to reduce the initial FU dose (first cycle) according to DPD status, if needed, and further, to consider increasing the dose at subsequent cycles according to treatment tolerance. In France, 17 public laboratories currently undertake routine screening of DPD deficiency.

Keywords: 5-Fluorouracile; 5Fluorouracil; Capecitabine; Capécitabine; DPYD; Dihydropyrimidine dehydrogenase; Dihydropyrimidine déshydrogénase; Dépistage; Fluoropyrimidine; Pharmacogenetics; Pharmacogénétique; Recommandation; Recommendation; Screening; Toxicity; Toxicité.

Publication types

  • Review

MeSH terms

  • Antimetabolites, Antineoplastic / administration & dosage
  • Antimetabolites, Antineoplastic / adverse effects
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Capecitabine / administration & dosage
  • Capecitabine / adverse effects
  • Capecitabine / therapeutic use*
  • Dihydropyrimidine Dehydrogenase Deficiency / complications*
  • Dihydropyrimidine Dehydrogenase Deficiency / diagnosis
  • Dihydrouracil Dehydrogenase (NADP) / analysis
  • Dihydrouracil Dehydrogenase (NADP) / genetics
  • Fluorouracil / administration & dosage
  • Fluorouracil / adverse effects
  • Fluorouracil / therapeutic use*
  • France
  • Humans
  • Neoplasms / drug therapy
  • Phenotype
  • Practice Guidelines as Topic
  • Pyrimidines / administration & dosage
  • Pyrimidines / adverse effects
  • Pyrimidines / therapeutic use
  • Uracil / blood

Substances

  • Antimetabolites, Antineoplastic
  • Pyrimidines
  • Uracil
  • Capecitabine
  • Dihydrouracil Dehydrogenase (NADP)
  • Fluorouracil