Dihydropyrimidine Dehydrogenase (DPD) Testing for Topical Fluorouracil
Patients should be tested for dihydropyrimidine dehydrogenase (DPD) enzyme deficiency before starting treatment with topical fluorouracil. 1, 2
Rationale for DPD Testing
- DPD is the initial and rate-limiting enzyme in the metabolic catabolism of 5-fluorouracil (5-FU) and its derivatives 3
- Fluorouracil cream is contraindicated in patients with DPD enzyme deficiency as stated in the FDA drug label 2
- A large percentage of fluorouracil is catabolized by the DPD enzyme, and DPD deficiency can result in shunting of fluorouracil to the anabolic pathway, leading to cytotoxic activity and potential toxicities 2
- European Society for Medical Oncology (ESMO) guidelines explicitly recommend testing for DPD deficiency before initiating 5-FU-based chemotherapy 1
Clinical Significance of DPD Deficiency
- Complete or partial deficiency of DPD activity has been demonstrated to induce severe toxicities in cancer patients treated with fluoropyrimidine therapy 3
- Patients with DPD deficiency who receive systemic 5-FU are at risk for severe toxicity including:
- Women appear particularly prone to DPD deficiency (79% of deficient patients in one study) 4
DPD Deficiency and Topical 5-FU
- While systemic absorption of topical 5-FU is minimal in most cases, there have been documented cases of severe systemic toxicity from topical application 5
- A case report documented severe neutropenia on day 11 of topical 5-FU treatment in a patient who was later found to have DPD deficiency 5
- The most common clinically significant DPD mutation is IVS14+1G>A, detected in 24-28% of all patients suffering from severe 5-FU toxicity 6
Recent Evidence on Topical 5-FU in DPD Variant Carriers
- A 2024 retrospective cohort study found that patients carrying a single DPYD variant allele did not have a significantly higher risk of grade 1+ toxicity from topical 5-FU (21.4% vs. 10.2%) 7
- No patients in this study experienced grade 3+ toxicity, suggesting lower risk with topical application compared to systemic administration 7
- However, the risk of severe toxicity in patients with complete DPD deficiency remains unknown, and topical 5-FU should be avoided in these patients 7
Recommendations for Clinical Practice
- Test for DPD deficiency before initiating topical 5-FU treatment 1, 2
- Avoid topical 5-FU in patients with known complete DPD deficiency 2, 7
- For patients with partial DPD deficiency (heterozygous carriers):
- Consider alternative treatments for actinic keratosis such as cryotherapy, imiquimod, or photodynamic therapy 1
- If topical 5-FU must be used, consider treating smaller areas (less than the maximum 500 cm² recommended for 5-FU 5%) 1
- Monitor closely for signs of systemic toxicity including blood count abnormalities, neurological symptoms, or severe local reactions 4, 5
Caveats and Considerations
- The incidence of potentially severe 5-FU-induced toxicity associated with topical application may be greater than documented 5
- Evaluation for DPD deficiency is not routinely performed in all clinical settings, which may lead to underdiagnosis 5
- Patients with multiple DPYD variant alleles or complete DPD deficiency may be at higher risk than those with a single variant 7