Dihydropyrimidine Dehydrogenase Deficiency Testing for Patients Treated With 5-Fluorouracil and Capecitabine

Key Message

What Is the Issue?

• Fluoropyrimidines, such as 5-fluorouracil and capecitabine, are drugs used for the treatment of solid tumour cancers. Deficiency in the enzyme dihydropyrimidine dehydrogenase (DPD), which breaks down these drugs, can significantly increase the risk of severe toxicity and death.
• Pretreatment DPD deficiency testing, via genotyping, or phenotyping, followed by dose adjustments is recommended in several countries to reduce adverse drug reactions. However, most evidence is based on genetic variants identified in individuals from European countries such as the Czech Republic, Denmark, France, Ireland, Italy, the Netherlands, Spain, and the UK. This raises uncertainties about the transferability of the safety and effectiveness of these approaches to patients from diverse ethnic origins.
• In Canada, access to DPD deficiency testing is inconsistent and varies widely across provinces and territories.

What Did We Do?

• We conducted a national survey on the current state of DPD deficiency testing and a rapid review to identify and summarize evidence comparing the clinical and cost-effectiveness of DPD deficiency testing and test-guided dose adjustments versus usual care.
• We searched key resources, including journal citation databases, and conducted a focused internet search for relevant evidence published since 2015. One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings.

What Did We Find?

• The survey results suggest that DPYD genotyping is conducted in 5 Canadian provinces, and 2 more are set to start testing later this year. One province indicated that they conduct both DPYD genotyping and DPD phenotyping, as required. The cost of testing ranged from CA$50 to CA$500 and was dependent on the testing platform and required turnaround time.
• The evidence suggests that DPYD variant carriers are at a higher risk of severe toxicities, hospitalization, and death compared to patients with the wild-type gene and that genotype-guided dose adjustments may improve these clinical outcomes in variant carriers.
• The data for the clinical utility of genotype-guided dosing is based largely on study populations from European countries, decreasing the utility of genotype testing in Canada, where the target population includes numerous ethnic origins. Further research and guideline development is required to support the validity and utility of variants more common in these groups.
• Phenotype testing provides an appealing complementary or alternative test that is independent of ethnic origin; however, evidence supporting its clinical validity and utility is minimal.
• Evidence suggests that DPYD testing with subsequent genotype-guide dose adjustments is cost-effective compared to usual care. No evidence was found on the cost-effectiveness of an extended DPYD genetic panel or of DPD phenotyping.

What Does This Mean?

• Based on the evidence identified in this report, DPYD genotyping may be clinically valid and cost-effective to improve the safety of fluoropyrimidine use in Canada for patients of European descent.
• Clinicians and decision-makers can use the evidence summarized in this review to inform decisions regarding the implementation of DPD deficiency testing.