Subject: Dihydropyrimidine Dehydrogenase (DPD) Deficiency Puts Patients at Grave Risk When Treated with Fluoropyrimidines
Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and
neurotoxicity) associated with 5-fluorouracil has been attributed to deficiency of
dihydropyrimidine dehydrogenase activity. A few patients have been rechallenged with 5-
fluorouracil and despite 5-fluorouracil dose lowering, toxicity recurred and
progressed with worse morbidity. Absence of this catabolic enzyme appears to
result in prolonged clearance of 5-fluorouracil.
1 Zhu, A X., et al, Dihydropyrimidine Dehydrogenase and Thymidylate Synthase Polymorphisms and Their Association with 5-Fluorouracil/Leucovorin Chemotherapy in Colorectal Cancer, Clinical ColorectalVol 3, No. 4 (2004), 225:235.
2 Ma, Wen Wee, Uridine Triacetate: An Antidote to Life Threatening 5-Fluorouracil and Capecitabine Toxicity, Journal of Hematology Oncology Pharmacy, 2017.
3 Caudle, K Eet al, Clinical Phamacogenetics Implementation Consortium Guidelines for Dihydropyrimidine Dehydrogenase Genotype and Fluoroupyrimidine Dosing, Clinical Phamacogenetics Implementation Consortium, posted online Oct 2013.
4 Ciccolini, J, et al, Routine Dihydropyrimidine Dehydrogenase Testing for Anticipating 5-Fluorouracil Related Severe Toxicities: Hype or Hope?, Clinical Colorectal Cancer, Vol 9, No. 4 (2010), 224:228.
5Saif, W M, Pharmacokinetically Guided Dose Adjustment of 5-Fluorouracil: A Rational Approach to Improving Therapeutic Outcomes, Journal National Cancer Institute, (2009);101: 1543-1552.
6 Tsalic M, et al. Severe toxicity related to the 5-fluorouracil/leucovorin combination (the Mayo Clinic regimen): a prospective study in colorectal cancer patients. Am J Clin Oncol. 2003 Feb;26(1):103-6.
7 Piper, M., et al, Pharmacogenetic Testing to Predict Serious Toxicity From 5-Fluorouracil (5-FU) for Patients Administered 5-FU Based Chemotherapy for Cancer, Technology Evaluation Center (Blue Cross Blue Shield), Assessment Program (2010) Vol 24, No. 13.
8 Mercier C, et al. Profiling dihydropyrimidine dehydrogenase deficiency in patients with cancer undergoing 5-fluorouracil/capecitabine therapy. Clin Colorectal Cancer. 2006 Nov;6(4):288-96.
9 Gamelin, E, et al, Individual Fluorouracil Dose Adjustment Based on Pharmacokinetic Follow-up Compared With Conventional Dosage: Results of a Multi-Center Randomized Trial of Patients With Metastatic Colorectal Cancer, Journal of Clinical Oncology, Vol 26, No. 13 (2008), 2099:2105.
10 Ciccolini J, et al. A rapid and inexpensive method for anticipating severe toxicity to fluorouracil and fluorouracil-based chemotherapy. Ther Drug Monit. 2006 Oct;28(5):678-85.
11 Woloch, C, et al, Population Pharmacokinetic Analysis of 5-FU and 5-FDHU in Colorectal Cancer Patients: Search for Biomarkers Associated with Gastro-Intestinal Toxicity, Current Topics in Medicinal Chemistry, (2012), Vol 12, No. 15, 1713:1719.
12 Yang CG, et al. DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity. Cancer Chemother Pharmacol. 2011 Jan;67(1):49-56.
13 Mercier, C. Et al. Pharmacoeconomic Study In Head And Neck Cancer Patients: Impact Of Prospective Dpd Deficiency Screening With 5-Fluorouracil (5-Fu) Dose Tailoring On Toxicities-Related Costs. ASCO annual meeting proceedings, June 2008, Orlando, USA. Abstract in J Clin Oncol No. 21S (June Supplement), 2009.