Purpose of DPD Lab Testing in Patients Undergoing Fluorouracil Chemotherapy
The Dihydropyrimidine Dehydrogenase (DPD) lab test is essential before initiating fluorouracil-based chemotherapy to identify patients with DPD deficiency who are at high risk of potentially lethal toxicity, as DPD is the main enzyme responsible for fluoropyrimidine metabolism. 1
Importance of DPD Testing
- DPD is the primary enzyme involved in fluoropyrimidine metabolism, responsible for catabolizing approximately 80% of 5-fluorouracil (5-FU) in the liver 1
- Approximately 3-5% of patients have deficiencies in DPD function due to genetic polymorphisms, which can lead to increased and potentially lethal fluoropyrimidine toxicity 1
- The European Medicines Agency (EMA) recommends mandatory DPD testing before initiating any fluoropyrimidine-based chemotherapy to prevent severe toxicity 1, 2
- Fluorouracil is explicitly contraindicated in patients with DPD enzyme deficiency according to FDA labeling 3
Testing Methods for DPD Deficiency
Two main approaches are used to assess DPD functionality:
1. Genotyping
- Identifies pathologic polymorphisms in the DPYD gene, primarily DPYD*2A, c.1679T>G, c.2846A>T, and c.1236G>A 1, 4
- Less sensitive than phenotyping but can identify specific genetic variants 2
- Recommended to test for the four most common DPYD variants before treatment 4
2. Phenotyping
- Directly measures DPD enzyme activity in peripheral blood mononuclear cells (PBMC-DPD activity) 2
- Indirectly assesses DPD function by measuring uracil levels or UH2/U ratio in blood 1, 5
- More comprehensive assessment of actual enzyme function 2
Clinical Implications of Test Results
- For patients with heterozygous polymorphisms, fluoropyrimidine dose should be reduced by 50% 1
- For patients with homozygous polymorphisms or uracil levels >150 ng/ml, fluoropyrimidines are contraindicated due to high risk of complications 1
- For uracil levels >16 ng/ml, the dose should be reduced by 50% 1
- Alternative treatments like raltitrexed may be considered for patients with complete DPD deficiency who have high risk of recurrence 1
Toxicity Profile in DPD-Deficient Patients
- Severe toxicity occurs in approximately 13% of patients receiving fluoropyrimidines, with fatal outcomes in 0.8% 5
- Women appear more susceptible to DPD deficiency (79% of deficient patients in one study) 6
- Toxicity is often severe in DPD-deficient patients, with high frequency of neurotoxic syndromes (37%) 6
- The toxicity score is twice as high in patients with marked DPD deficiency compared to those with moderate deficiency 6
Regional Differences in Testing Recommendations
- In European populations, DPD testing is strongly recommended before initiating fluoropyrimidine therapy 1, 4
- In Asian populations, the incidence of DPD deficiency is significantly lower (approximately 0.6%), so routine testing is not always performed 1
- For Asian patients, testing may be considered based on the anticipated genetic profile of the specific population, with mandatory testing for those who experience severe fluoropyrimidine toxicity 1
Clinical Pitfalls and Caveats
- DPD testing should be conducted before initiating treatment, not after toxicity has occurred 1
- Relying solely on genotyping may miss some cases of DPD deficiency, as not all genetic variants are routinely tested 2
- The canonical IVS14+1G>A mutation is not found in all patients with severe or lethal toxicities, highlighting the need for comprehensive testing 5
- Uracil concentration is a continuous variable, and the relationship between levels and DPD activity is not always clear-cut, potentially leading to under-treatment if dose reductions are applied too liberally 2
In summary, DPD testing is a critical safety measure before administering fluorouracil-based chemotherapy to identify patients at risk of severe toxicity and to guide appropriate dosing or alternative treatment selection.