Capecitabine-based treatment of a patient with a novel DPYD genotype and complete dihydropyrimidine dehydrogenase deficiency

Linda M. Henricks, Ester J. M. Siemerink, Hilde Rosing, Judith Meijer, Susan M. I. Goorden, Abeltje M. Polstra, Lida Zoetekouw, Annemieke Cats, Jan H. M. Schellens, André B. P. van Kuilenburg

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Fluoropyrimidines are frequently used anti-cancer drugs. It is known that patients with reduced activity of dihydropyrimidine dehydrogenase (DPD), the key metabolic enzyme in fluoropyrimidine inactivation, are at increased risk of developing severe fluoropyrimidine-related toxicity. Upfront screening for DPD deficiency and dose reduction in patients with partial DPD deficiency is recommended and improves patient safety. For patients with complete DPD deficiency, fluoropyrimidine-treatment has generally been discouraged. During routine pretreatment screening, we identified a 59-year-old patient with a sigmoid adenocarcinoma who proved to have a complete DPD deficiency. Genetic analyses showed that this complete absence of DPD activity was likely to be caused by a novel DPYD genotype, consisting of a combination of amplification of exons 17 and 18 of DPYD and heterozygosity for DPYD*2A. Despite absence of DPD activity, the patient was treated with capecitabine-based chemotherapy, but capecitabine dose was drastically reduced to 150 mg once every 5 days (0.8% of original dose). Pharmacokinetic analyses showed that the area under the concentration-time curve (AUC) and half-life of 5-fluorouracil were respectively tenfold and fourfold higher than control values of patients receiving capecitabine 850 mg/m2. When extrapolating from the dosing schedule of once every 5 days to twice daily, the AUC of 5-fluorouracil was comparable to controls. Treatment was tolerated well for eight cycles by the patient without occurrence of capecitabine-related toxicity. This case report demonstrates that a more comprehensive genotyping and phenotyping approach, combined with pharmacokinetically-guided dose administration, enables save fluoropyrimidine-treatment with adequate drug exposure in completely DPD deficient patients.
Original languageEnglish
Pages (from-to)424-430
JournalInternational Journal of Cancer
Volume142
Issue number2
DOIs
Publication statusPublished - 2018

Cite this

Henricks, L. M., Siemerink, E. J. M., Rosing, H., Meijer, J., Goorden, S. M. I., Polstra, A. M., ... van Kuilenburg, A. B. P. (2018). Capecitabine-based treatment of a patient with a novel DPYD genotype and complete dihydropyrimidine dehydrogenase deficiency. International Journal of Cancer, 142(2), 424-430. https://doi.org/10.1002/ijc.31065