Autopsy and Case Reports
https://autopsyandcasereports.org/article/doi/10.4322/acr.2018.049
Autopsy and Case Reports
Article / Autopsy Case Report

Dihydropyrimidine dehydrogenase deficiency as a cause of fatal 5-Fluorouracil toxicity

Shiraz S. Fidai; Aarti E. Sharma; Daniel N. Johnson; Jeremy P. Segal; Ricardo R. Lastra

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Abstract

5-Fluorouracil (5-FU), in combination with other cytotoxic drugs, is commonly used to treat a variety of cancers. Dihydropyrimidine dehydrogenase (DPD) catalyzes the first catabolic step of the 5-FU degradation pathway, converting 80% of 5-FU to its inactive metabolite. Approximately 0.3% of the population demonstrate complete DPD deficiency, translating to extreme toxicity of 5-FU. Here we present a case of a patient who had a fatal outcome after treatment with 5-FU who was found to have an unknown DPD deficiency discovered at autopsy.

Keywords

Dihydropyrimidine Dehydrogenase Deficiency, Drug-Related Side Effects and Adverse Reactions, Genetic Testing, Fluorouracil, Pancytopenia

References

Ashfaq R. Molecular profiling for personalized cancer care. Clin Exp Metastasis. 2012;29(7):653-5. [https://doi.org/10.1007/s10585-012-9483-3]. [PMID:22678423]

Bertholee D, Maring JG, van Kuilenburg ABP. Genotypes affecting the pharmacokinetics of anticancer drugs. Clin Pharmacokinet. 2017;56(4):317-37. [https://doi.org/10.1007/s40262-016-0450-z]. [PMID:27641154]

Lamb DC, Waterman MR, Kelly SL, Guengerich FP. Cytochromes P450 and drug discovery. Curr Opin Biotechnol. 2007;18(6):504-12. [https://doi.org/10.1016/j.copbio.2007.09.010]. [PMID:18006294]

Jancova P, Anzenbacher P, Anzenbacherova E. Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010;154(2):103-16. [https://doi.org/10.5507/bp.2010.017]. [PMID:20668491]

Peyrade F, Cupissol D, Geoffrois L, et al. Systemic treatment and medical management of metastatic squamous cell carcinoma of the head and neck: Review of the literature and proposal for management changes. Oral Oncol. 2013;49(6):482-91. [https://doi.org/10.1016/j.oraloncology.2013.01.005]. [PMID:23415727]

Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med. 2005;352(5):476. [PMID:15689586]

van Kuilenburg AB. Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur J Cancer. 2004;40(7):939-50. [https://doi.org/10.1016/j.ejca.2003.12.004]. [PMID:15093568]

Falvella FS, Caporale M, Cheli S, et al. Undetected toxicity risk in pharmacogenetic testing for Dihydropyrimidine Dehydrogenase. Int J Mol Sci. 2015;16(4):8884-95. [https://doi.org/10.3390/ijms16048884]. [PMID:25906475]

Meulendijks D, Cats A, Beijnen JH, Schellens JH. Improving safety of fluoropyrimidine chemotherapy by individualizing treatment based on dihydropyrimidine dehydrogenase activity – Ready for clinical practice? Cancer Treat Rev. 2016;50:23-34. [https://doi.org/10.1016/j.ctrv.2016.08.002]. [PMID:27589829]

van Kuilenburg ABP, Häusler P, Schalhorn A, et al. Evaluation of 5-Fluorouracil pharmacokinetics in cancer patients with a C.1905+1G>A Mutation in DPYD by means of a bayesian limited sampling strategy. Clin Pharmacokinet. 2012;51(3):163-74. [https://doi.org/10.1007/BF03257473]. [PMID:22339448]

Etienne-Grimaldi M-C, Boyer J-C, Beroud C, et al. New advances in DPYD genotype and risk of severe toxicity under capecitabine. Plos One. 2017;12;(5)1-19.

Meulendijks D, Henricks LM, Sonke GS, et al. Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015;16(16):1639-50. [https://doi.org/10.1016/S1470-2045(15)00286-7]. [PMID:26603945]

Deenen MJ, Meulendijks D, Cats A, et al. Upfront Genotyping of DPYD * 2A to individualize fluoropyrimidine therapy: a safety and cost analysis. J Clin Oncol. 2016;34(3):227-34. [https://doi.org/10.1200/JCO.2015.63.1325]. [PMID:26573078]

 

 

 


Publication date:
11/30/2018

5c01785a0e8825455ae94204 autopsy Articles
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