Page 182 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 6
The study population consisted of patients treated with a fluoropyrimidine-based anticancer therapy, either as single agent or in combination with other chemotherapeutic agents and/ or radiotherapy. Prior chemotherapy was allowed, except for prior use of fluoropyrimidines. Before start of fluoropyrimidine therapy, patients were genotyped for four DPYD variants (DPYD*2A, c.1679T>G, c.2846A>T and c.1236G>A). Heterozygous DPYD variant allele carriers received an initial dose reduction of either 25% (for c.2846A>T and c.1236G>A) or 50% (for DPYD*2A and c.1679T>G), in line with current recommendations from Dutch and international pharmacogenomic guidelines.9,13 To achieve maximal safe exposure, dose escalation was allowed after the first two cycles, provided that treatment was well tolerated and was left at the discretion of the physician. The dose of other chemotherapeutic agents or radiotherapy was left unchanged at the start of treatment. Homozygous or compound heterozygous DPYD variant allele carriers were not included in the study. Non-carriers of the above mentioned DPYD variants were considered wild-type patients in this study, and were treated according to existing standard of care.
Toxicity was graded by participating centers according to the National Cancer Institute common terminology criteria for adverse events (CTC-AE),14 and severe toxicity was defined as grade 3 or higher. Patients were followed for toxicity during the entire treatment period. Toxicity defined as possibly, probably or definitely related to fluoropyrimidine-treatment was considered treatment-related toxicity. Toxicity-related hospitalization and treatment discontinuation due to adverse events were also investigated.
The primary end point of the prospective study was the frequency of severe overall fluoropyrimidine-related toxicity across the entire treatment duration. A comparison was made between DPYD variant allele carriers treated with reduced dose and wild-type patients treated with standard dose in this study, and also with DPYD variant allele carriers treated with full dose in a historical cohort derived from a previously published meta-analysis.8 Secondary endpoints of the prospective study included a cost analysis of individualized dosing based on upfront genotypic assessment, and pharmacokinetics of capecitabine and 5-FU in DPYD variant allele carriers.
Cost analysis
To compare the prospective screening for four DPYD variants (screening strategy) with no DPYD screening (non-screening strategy), a cost analysis model was composed. This analysis consisted of a cost-minimization analysis using a decision analytical model from a health care payer perspective.
A previously published model by Deenen et al.10 was used and updated with data from the current study and current prices. Estimated parameters incorporated in the model were derived from data of the present trial and relevant data from literature.15,16 Interventions for treatment-related toxicity were prospectively collected for all patients during the trial. An overview of the decision tree is depicted in Figure 1. In the model, a comparison between the screening strategy (prospective screening for four DPYD variants and dose adjustments in heterozygous DPYD variant allele carriers) and the non-screening strategy was made. Expected differences in costs of both strategies were calculated.
Costs included were restricted to direct medical costs only and included costs for 180