Screening for dihydropyrimidine dehydrogenase deficiency to prevent severe 5-fluorouracil and capecitabine-associated toxicity

5-Fluorouracil (5FU) and capecitabine are the cornerstones of all currently applied regimens for the treatment of patients with cancers of the gastrointestinal tract, breast, head and neck. Dihydropyrimidine dehydrogenase (DPD) plays a pivotal role in the metabolism of 5FU and as such, a deficiency of DPD has been recognised as an important risk factor, predisposing patients to develop severe 5FU-associated toxicity. In this manuscript, we discuss a wide range of methods that have been established to assess the genetic and functional status of DPD. Genotyping of DPYD is used to identify DPD deficient patients. However, its suitability for pre-treatment testing is under debate, not least due to conflicting genotype-phenotype relations in mutation carriers and relatively low positive predictive values. In addition to genetic screening, a number of phenotype-based methods have been introduced which appear to be well suited for clinical laboratories and which are an attractive option for monitoring of the DPD status. These phenotype-based screening approaches to detect DPD-deficient patients warrant further clinical validation.