Background
Fluoropyrimidines are a rationally developed class of anticancer agents that are widely prescribed in clinical use of cancer patients. Adverse events of fluoropyrimidines are prominent. This can be explained by the initial and rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD) what catabolizes 5-FU. Patients with partial deficiency of this enzyme are at risk of developing severe 5-FU associated toxicity. The polymorphism DPYD*2A in the DPYD gene is most described as cause of decreased DPD activity with serious clinical relevance. Frequency of DPYD*2A is estimated between 1.0-2.0%. No routinely screening for DPD deficiency is performed yet prior to start of fluoropyrimidine treatment. The main aim of this study was to show that fluoropyrimidine-induced toxicity can significantly be reduced by dose adaption prior to start of therapy in DPYD*2A mutant patients and to demonstrate that this screening strategy is cost-saving.
Methods
Screening for DPYD*2A was performed in 854 Dutch cancer patients who were considered for treatment with Capecitabine or 5-FU. DPYD*2A mutants received adaptive dose with at least 50 % reduction. DPYD*2A wild type patients received conventionally dose. Patient files were investigated on general patient- and treatment characteristics, the toxicity profile and hospitalization and noted in an electronic CRF. Toxicity outcome in the prospective determined DPYD*2A mutant patients was compared to retrospectively determined DPYD*2A mutants. The cost-effectiveness analysis was carried out by using a decision tree and a multiple-state decision analytical model.
Results
Frequency of the DPYD*2A polymorphism in this prospective Dutch cancer population was 1.5 %. Of the 13 found DPYD*2A heterozygous mutants, 7 patients received treatment in adaptive dose. There was a beneficial toxicity profile without hospitalization due to adaptive dosing in these DPYD*2A mutant patients. Comparison of toxicity outcome in prospective vs. retrospective determined DPYD*2A mutant patients showed a significant difference in toxicity (diarrhea, P = 0.012; hematological P = 0.004; mucositis P = 0.016; any grade ot toxicity P < 0.001). Cost-effectiveness analysis showed favorable economic perspective in expected costs for the screening strategy vs. usual care (non screening): €5,750.13 vs. €5,829.39. Saved costs are €79.26 per patient with 1 percent reduction in severe toxicity. Considering the yearly amount of fluoropyrimidine treatments the save-costing will be at least €554,820.
Discussion & Conclusions
The present study shows that screening for the DPYD*2A mutation prior to start of fluoropyrimidine therapy provides significant reduction in fluoropyrimidine-associated toxicity and hospitalization in DPYD*2A mutant patients treated in adaptive dose. In addition, the favorable economic perspective for screening in our cost-effectiveness analysis suggests that screening should become standard of care in the treatment with fluoropyrimidines. However, pharmacogenetic screening is just one approach, screening for just one coding mutation alone cannot identify all patients at risk.
