Implementation of dihydropyrimidine dehydrogenase deficiency testing in Europe

ESMO Open. 2023 Apr;8(2):101197. doi: 10.1016/j.esmoop.2023.101197. Epub 2023 Mar 28.


Background: The main cause for fluoropyrimidine-related toxicity is deficiency of the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). In 2020, the European Medicines Agency (EMA) recommended two methods for pre-treatment DPD deficiency testing in clinical practice: phenotyping using endogenous uracil concentration or genotyping for DPYD risk variant alleles. This study assessed the DPD testing implementation status in Europe before (2019) and after (2021) the release of the EMA recommendations.

Methods: The survey was conducted from 16 March 2022 to 31 July 2022. An electronic form with seven closed and three open questions was e-mailed to 251 professionals with DPD testing expertise of 34 European countries. A descriptive analysis was conducted.

Results: We received 79 responses (31%) from 23 countries. Following publication of the EMA recommendations, 87% and 75% of the countries reported an increase in the amount of genotype and phenotype testing, respectively. Implementation of novel local guidelines was reported by 21 responders (27%). Countries reporting reimbursement of both tests increased in 2021, and only four (18%) countries reported no coverage for any testing type. In 2019, major implementation drivers were 'retrospective assessment of fluoropyrimidine-related toxicity' (39%), and in 2021, testing was driven by 'publication of guidelines' (40%). Although the major hurdles remained the same after EMA recommendations-'lack of reimbursement' (26%; 2019 versus 15%; 2021) and 'lack of recognizing the clinical relevance by medical oncologists' (25%; 2019 versus 8%; 2021)-the percentage of specialists citing these decreased. Following EMA recommendations, 25% of responders reported no hurdles at all in the adoption of the new testing practice in the clinics.

Conclusions: The EMA recommendations have supported the implementation of DPD deficiency testing in Europe. Key factors for successful implementation were test reimbursement and clear clinical guidelines. Further efforts to improve the oncologists' awareness of the clinical relevance of DPD testing in clinical practice are needed.

Keywords: DPD deficiency; DPYD; fluoropyrimidine; implementation survey; pre-therapeutic testing; toxicity.

MeSH terms

  • Antimetabolites, Antineoplastic / therapeutic use
  • Dihydropyrimidine Dehydrogenase Deficiency* / diagnosis
  • Dihydropyrimidine Dehydrogenase Deficiency* / drug therapy
  • Dihydropyrimidine Dehydrogenase Deficiency* / genetics
  • Dihydrouracil Dehydrogenase (NADP) / genetics
  • Europe
  • Fluorouracil / therapeutic use
  • Humans
  • Retrospective Studies


  • Fluorouracil
  • Antimetabolites, Antineoplastic
  • Dihydrouracil Dehydrogenase (NADP)