Page 181 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Cost analysis on DPYD genotype-guided dosing
Introduction
The class of fluoropyrimidine anticancer drugs includes 5-fluorouracil (5-FU) and its oral prodrug capecitabine. These drugs are used by approximately two million patients yearly worldwide,1 and are the cornerstone of chemotherapeutic treatment for several solid tumor types, including colorectal, breast, gastric and head- and neck cancer. While fluoropyrimidine drugs are highly valuable treatment options, severe and potential fatal fluoropyrimidine- related toxicity remains a major clinical limitation. Around 15─30% of the patients develop severe treatment-related toxicity,2,3 usually associated with interruption or discontinuation of therapy and often hospitalization, resulting in increased health care costs.
During the last decades it has become clear that safety of patients treated with fluoropyrimidine-based anticancer therapy is strongly affected by inter-individual variability
in the enzyme dihydropyrimidine dehydrogenase (DPD), which is the main metabolic enzyme of fluoropyrimidines. The DPD enzyme is present in the liver and inactivates over 6 80% of 5-FU.4 DPD enzyme activity varies widely between patients, with an estimated 3 to
8% of the population having a reduced DPD activity.5,6 DPD deficiency results in reduced 5-FU clearance, and as a direct consequence, highly increased risk of severe treatment-related toxicity when DPD-deficient patients are treated with standard doses of a fluoropyrimidine drug.7
DPD deficiency can be caused by genetic polymorphisms in DPYD, the gene encoding DPD. Currently, four DPYD variants are considered as being clinically relevant and dosing recommendations are provided for these variants: DPYD*2A, c.1679T>G, c.2846A>T and c.1236G>A).8,9 Upfront genotyping followed by a fluoropyrimidine dose reduction in carriers in any of these four variants has proven a useful strategy to improve patient safety.10,11 However, this strategy has not yet been universally implemented in daily clinical care.
One of the potential barriers that can make physicians reluctant to implement upfront DPYD screening as a routine test, is uncertainty on the cost-effectiveness of a DPYD screening strategy.12 Deenen et al. previously showed that upfront screening for one DPYD variant, DPYD*2A, is cost-saving, as average total medical costs in the screening arm were €2,772 per patient and therefore lower than the non-screening arm, for which the average total medical costs were €2,817 per patient. This shows that the reduction in toxicity- related costs outweighs the screening costs.10 In our current study, we aimed to investigate the medical costs associated with upfront screening for the four DPYD variants currently considered clinically relevant and dose individualization in heterozygous carriers of a DPYD variant, therefore evaluating the net cost effects of this expanded DPYD genotyping strategy.
Patients and methods
Study design and participants
The cost analysis was performed as part of a recently published clinical trial.11 This was a multicenter study in which 17 hospitals in the Netherlands participated (NCT02324452). Study approval was obtained by the institutional review board of The Netherlands Cancer Institute, Amsterdam, the Netherlands, and approval from the board of directors of each individual hospital was obtained for all participating centers. All patients provided written informed consent before inclusion in the study.
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