Page 188 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 6
Discussion
The cost analysis performed in this study showed that prospective DPYD screening for these four variants and dose individualization is cost-saving. This confirms that upfront DPYD screening does not result in an increase in healthcare 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 screening strategy is unlikely to result in an increase in costs.
However, the net saving for the screening strategy in our cost analysis was with €51 relatively small. One of the determinants for this finding is that in our clinical study patients carrying a DPYD variant were still at increased risk of developing severe treatment-related toxicity, compared to wild-type patients (39% versus 23%, p=0.001).11 The higher incidence of toxicity in DPYD variant allele carriers was mainly driven by carriers of the variants c.1236G>A and c.2846A>T. For these two variants a 25% dose reduction was applied in the study, which was concluded to be probably insufficient to reduce the incidence of toxicity to the background incidence in wild-type patients.
Our results are in line with four previous studies investigating costs of DPYD genotyping and toxicity.10,17 Deenen et al. previously confirmed that upfront screening for one DPYD variant (DPYD*2A) is cost-saving.10 Another study, by Cortejoso et al. investigated screening for three variants (DPYD*2A, c.2846A>T, c.1679T>G) and compared genotyping costs and costs for treating severe neutropenia in a retrospective analysis. Occurrence of severe neutropenia resulted in average costs for treatment for this side effect of €3,044 per patient (drug and hospitalization costs). Genotyping costs for the three DPYD variants were only €6.40 per patient (approximately 16 times less expensive than in our study). The authors calculated that DPYD genotyping would be cost-effective, provided that at least 2.1 cases of severe neutropenia per 1,000 treated patients are prevented by upfront genotyping of the three variants.17 This was, however, not validated in a prospective setting.
The third study, by Murphy et al., investigated the cost implications for reactive DPYD screening (i.e. screening patients for DPYD variants after experiencing severe toxicity) versus prospective screening.18 In a period of three years, all patients experiencing severe (grade ≥3) fluoropyrimidine-related toxicity in an Irish hospital were screened for four DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G and c.1601G>A). Genotyping costs if prospective DPYD screening for all patients would have been performed were calculated. Total costs of hospitalization for five DPYD variant allele carriers (identified after experiencing severe toxicity) were €232,061, while prospectively testing would have cost in total €23,718 for the 134 included patients (€177 per patient), showing that hospitalization costs are significantly higher than costs for prospective DPYD screening.18 The main difference between their study and our study was that the study by Murphy et al. did not collect data on the prospective DPYD screening strategy, but only on reactive DPYD screening.
The fourth study was a retrospective study as well, performed by Toffoli et al.19 Toxicity- related costs on 550 colorectal cancer patients were investigated and genotyping of the same four variants as in our study was performed, but this was done retrospectively and not used for dose adjustments. This showed that average costs for treatment of toxicity were
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