The Impact of Upfront DihydroPyrimidine Dehydrogenase (DPD) Testing on the Therapeutic Management of Patients Scheduled for 5-FU.

PURPOSE: 5-fluorouracil (5-FU) is catabolized by dihydropyrimidine dehydrogenase (DPD). DPD deficiency can trigger life-threatening toxicities, and pretesting DPD is increasingly recommended. Here, we investigated the impact of upfront DPD testing on treatment strategy, that is, whether DPD status influences physicians' choice to use 5-FU or not, and if so, whether to maintain standard dosage or reduce it. METHODS: This is a non-interventional, observational study of 525 adult patients likely to be treated with 5-FU. Upfront DPD status was determined by measuring plasma uracil. Multivariate logistic regression was then used to investigate the factors influencing treatment strategies. A further analysis was then performed on a subset of 419 fit patients eligible for 5-FU. Finally, we studied the impact of adaptive dosing on clinical outcomes (efficacy and toxicity) in the 374 patients who received 5-FU eventually. RESULTS: DPD testing identified 392 extensive (EM; 74.7%), 78 poor (PM; 14.8%), and 55 ultra-rapid metabolizers (UM; 10.5%). Multivariate analyses identified performance status (p = 0.001), DPD status (p = 0.006), age (p = 0.004), metastatic stage (p = 0.04) and history of prior 5-FU treatment (p = 0.002) as factors influencing treatment strategy. PM were more likely to be treated without 5-FU (22%) than EM (3%) or UM (10%) patients (p = 0.002). Similarly, of those treated with 5-FU, 100% of PM had a dose reduction, compared to 9% and 25% of EM and UM patients, respectively (p < 0.001). No difference in efficacy (response rate: 51.6%, progression-free survival: 14.7 months) and safety (severe toxicities: 4.3%) was found, regardless of the DPD status and subsequent dose adaptation, but reduced survival was observed in patients for whom 5-FU was excluded. CONCLUSION: Upfront DPD testing has a strong impact on treatment strategies, and subsequent adaptive dosing limits the risk for severe toxicities without compromising efficacy in real-world patients.