Tolerance-based capecitabine dose escalation after DPYD genotype-guided dosing in heterozygote DPYD variant carriers: a single-center observational study

Objective Certain polymorphisms of the DPYD gene encoding for the dihydropyrimidine dehydrogenase (DPD) enzyme are associated with fluoropyrimidine-induced toxicity. Dose reductions of the fluoropyrimidine prodrug capecitabine are recommended for patients carrying these DPYD variants to prevent toxicities. Capecitabine dose escalation after an initial genotype-guided dose reduction is advocated when treatment is well tolerated. However, practical guidelines on how to implement these dose escalations are lacking. We implemented a protocol for tolerance-guided capecitabine dosing in DPYD variant carriers and aimed to explore its effect on toxicity of treatment. Patients and methods Patients receiving capecitabine-based chemotherapy for different types of solid tumors were identified retrospectively. Capecitabine doses were reduced in case of a DPYD variant (DPYD*2A, c.2846A>T, DPYD*13, or c.1236G>A) and subsequently adjusted on the basis of tolerance. Outcome was evaluated by clinical chart review and dosing characteristics from the hospital pharmacy. Results were compared with a cohort of capecitabine-treated DPYD wild-type patients. Results Of 185 patients eligible for analysis, 11 patients were heterozygous for a DPYD variant. A median dose escalation of 8.5% was achieved using the prespecified protocol. One DPYD variant carrier experienced a grade 3 toxicity after a dose escalation. Overall, DPYD variant carriers did not experience more, or more severe toxicities than DPYD wild-type patients. The total prevalence of severe toxicities in the wild-type group was 43.1% and is comparable with the literature. Conclusion Tolerance-based capecitabine dose escalation did not lead to more toxicity in DPYD variant carriers compared with wild-type patients. Our results can guide future prospective research. Correspondence to Johan M. van Rooijen, MD, Department of Internal Medicine, Martini Hospital, van Swietenplein 1, 9728NT Groningen, The Netherlands Tel: +31 50 524 6283; fax: +31 50 524 5889; e-mail: j.vanrooijen@mzh.nl Received August 12, 2018 Accepted December 27, 2018 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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