Fluoropyrimidine-induced toxicity and DPD deficiency.. A case report of early onset, lethal capecitabine-induced toxicity and mini review of the literature. Uridine triacetate: Efficacy and safety as an antidote. Is it accessible outside USA?

Abstract

Fluoropyrimidine-based regimens are among the most commonly used chemotherapy combinations for the treatment of solid tumors. Several genetic polymorphisms that are implicated with fluoropyrimidine anabolism and catabolism have been associated with the development of life-threatening toxicities. Uridine triacetate is an FDA-approved antidote for 5-fluorouracil or capecitabine overdose and early-onset, life-threatening toxicity within 96 h of last chemotherapy dose. To date, it is not accessible for Greek patients as per the current summary of product characteristic's time restrictions. We report and discuss the course and outcome of capecitabine toxicity in a 66-year-old female colorectal cancer patient with heterozygous dihydropyrimidine dehydrogenase deficiency. This paper highlights the difficulty in timely access of this lifesaving medication for Greek and possibly other European patients.

Dihydropyrimidine dehydrogenase level and the redox status in patients with colorectal cancer are prognostic for adverse effects of fluoropyrimidines

“…The toxicity of fluoropyrimidines is well known to be associated with neutropenia and thrombocytopenia. Many research groups have suggested a relation between DPD enzyme concentration/activity and some toxic effects associated with the treatment [30,31]. Our experiment demonstrated that lower DPD values were associated with a decrease in the white blood cell count and the granulocyte count.…”

Elevated Risk of Fluoropyrimidine-Associated Toxicity in European Patients with DPYD Genetic Polymorphism: A Systematic Review and Meta-Analysis

“…The dihydropyrimidine dehydrogenase gene (DPYD) encodes the dihydropyrimidine dehydrogenase (DPD) enzyme, which plays a vital role in the metabolic catabolism of fluoropyrimidine [4]. Studies have already shown that DPD deficiency can cause severe toxicity in patients receiving fluoropyrimidine-based regimens; failure to degrade fluoropyrimidine may exacerbate side effects including myelosuppression or hand-foot syndrome [5,6]. Since genetic variants in the DPYD gene may cause DPD deficiency [7], researchers have previously proposed the usefulness of genetic screening for DPD deficiency in patients undergoing fluoropyrimidine-based therapy.…”

Transient Coma and Signs of Encephalopathy Related to 5-Fluorouracil and Carboplatin: A Case Report

“…Of note, 5FU-induced central neurotoxicity can present in various forms such as Wernicke encephalopathy [16], mimic stroke [17], or cause progressive dementia [18], suggesting both metabolic and direct 5FU toxicity as a possible mechanism. Some studies have reported the successful treatment of 5FU-related encephalopathies with the 5FU antagonist, uridine triacetate [19,20], which might be a therapeutic option for 5FU-associated acute central nervous system toxicities with and without elevated ammonium levels, but which is not yet broadly available [21]. Encephalopathies have also been reported during treatment with the 5FU prodrug, capecitabine, implying that a switch to capecitabine might not be a safer alternative [22][23][24].…”