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Tolerance-based capecitabine dose escalation after DPYD genotype-guided dosing in heterozygote DPYD variant carriers

a single-center observational study

Kleinjan, Jan P.a; Brinkman, Ithamarb; Bakema, Robbertd; van Zanden, Jelmer J.c; van Rooijen, Johan M.a

doi: 10.1097/CAD.0000000000000748

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.

Departments of aInternal Medicine

bHospital Pharmacy

cClinical Chemistry, Certe, Martini Hospital

dUniversity of Groningen, Groningen, The Netherlands

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:

Received August 12, 2018

Accepted December 27, 2018

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.