Original ResearchA cost analysis of upfront DPYD genotype–guided dose individualisation in fluoropyrimidine-based anticancer therapy
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 tumour types, including colorectal, breast, gastric and head and neck cancers. 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 hospitalisation, 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 interindividual 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 80% of 5-FU [4]. DPD enzyme activity varies widely between patients, with an estimated 3–8% 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 €2772 per patient and therefore lower than the non-screening arm, for which the average total medical costs were €2817 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 individualisation in heterozygous carriers of a DPYD variant, therefore evaluating the net cost effects of this expanded DPYD genotyping strategy.
Section snippets
Study design and participants
The cost analysis was performed as part of a recently published clinical trial [11]. This was a multicentre study in which 17 hospitals in the Netherlands participated (NCT02324452). The study approval was obtained from 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 centres. All patients provided written informed consent before inclusion in the
Patient characteristics and toxicity incidence
The study was open for inclusion between April 30th, 2015 and December 21st, 2017. In this period, a total of 1103 evaluable patients were enrolled in this study, of whom 85 were heterozygous DPYD variant allele carriers (7.7%) and 1018 wild-type patients (92.3%). The group of DPYD variant allele carriers included 51 c.1236G>A carriers, 17 c.2846A>T carriers, 16 DPYD*2A carriers and one c.1679T>G carrier. Details on patient characteristics, treatment and toxicity incidence are published
Discussion
The cost analysis performed in this study showed that prospective DPYD screening for these four variants and dose individualisation is cost saving. This confirms that upfront DPYD screening does not result in an increase in health-care costs, while it can significantly improve patient safety and prevent toxicity-related deaths, as shown previously [11]. Results of the probabilistic sensitivity analysis and one-way sensitivity demonstrated that even when varying parameters in the model, the
Role of the funding source
LMH, CATCL and the NCT02324452 study were sponsored by the Dutch Cancer Society (Alpe-d′HuZes/KWF-fund, NKI2013-6249). CATCL was previously supported by an unrestricted grant from Roche Pharmaceuticals. There was no involvement in the study design, data collection, analysis, interpretation, writing of the report or decision to submit for publication by any of the funding sources.
Conflict of interest statement
J.H.M.S. is shareholder of Modra Pharmaceuticals bv, inventor of patents on oral taxanes and consultant to Debiopharm. All other authors have declared no conflicts of interest.
Acknowledgements
All 17 participating centres are acknowledged for their contribution to patient inclusion. The authors thank Dr. Maarten Deenen for providing his previously developed cost model (Deenen et al. J Clin Oncol 2016) and his input to the study.
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2023, Biomedicine and PharmacotherapyCurrent diagnostic and clinical issues of screening for dihydropyrimidine dehydrogenase deficiency
2023, European Journal of CancerCitation Excerpt :Although toxicity-related costs may depend on national health systems, these Irish, English and Dutch studies concluded that targeted DPYD genotyping is cost-effective. For instance, the cost-efficiency study by Henricks et al. conducted on 1103 patients prospectively enrolled in the ALPE trial, showed that upfront genotyping of the 4 DPYD variants followed by FP dose reduction according to CPIC guidelines improves patient safety and quality of life, without additional costs (author’s conclusion is “cost-saving or cost-neutral”) [82]. Cost-effectiveness of phenotyping-guided dosing remains to be evaluated so as to provide a comprehensive comparison of both genotyping, phenotyping, and combined approaches.
Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer
2022, Clinical Colorectal CancerCitation Excerpt :A number of prior studies have evaluated the cost and outcomes of DPYD genotyping from European and Canadian perspectives. Henricks and colleagues performed a cost analysis31 of DPYD genotyping from a Dutch perspective, using data from their pivotal prospective trial (NCT02324452).13 Their analysis did not formally assess the effectiveness of DPYD genotyping (did not estimate incremental QALYs), but concluded that DPYD genotyping was likely cost-saving due to reduced costs of toxicity management in the context of the trial's patient population.31
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Authors contributed equally.