DPD Testing and Medication Dosage Adjustments in mCRC Patients

Dihydropyrimidine dehydrogenase (DPD) deficiency testing represents an ongoing debate in colorectal cancer treatment, despite fluoropyrimidine-based chemotherapy being used for nearly 7 decades. DPD deficiency affects approximately 4% to 8% of patients depending on racial and ancestry factors, with nearly 1000 known genetic variants that can impact drug metabolism. The challenge lies in the lack of standardized assays and the complex relationship between genotype and phenotype, particularly for patients with heterozygous alterations who have intermediate metabolism.

Current institutional policies vary significantly regarding DPD testing implementation. Some major cancer centers have integrated testing requirements into their chemotherapy ordering systems, requiring documentation of testing discussions with patients or justification for omitting tests. However, many institutions maintain that testing remains optional due to concerns about treatment delays and the relatively low incidence of severe toxicity. The debate centers on whether universal testing is justified when homozygous deficiency occurs in only 1 in 1000 patients.

Clinical experience shows mixed results with DPD testing utility, as many intermediate metabolizers tolerate standard doses without issues, while some patients with normal DPD status still experience significant toxicity. The limited data on intermediate metabolizers receiving infused fluorouracil protocols (rather than bolus regimens) further complicates dosing decisions. Medical-legal considerations add another layer of complexity, as clinicians weigh the risks of missing rare but severe toxicities against the practical challenges of implementing universal testing programs.