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Uridine Triacetate for Severe Fluoropyrimidine Cardiotoxicity in a Patient With Thymidylate Synthase Gene Variants

A 56-year-old woman with history of hypertension, inadequately controlled on hydrochlorothiazide and nebivolol, presented with colorectal cancer with metastases to the liver in 2019. Genotypic testing revealed that her colorectal cancer was KRAS/NRAS wild-type and microsatellite stable. FOLFOX was

services were consulted and recommended treatment with uridine triacetate, as the timing of symptoms within 96 h of 5-FU administration were consistent with severe fluoropyrimidine cardiotoxicity. On day 2 of her hospitalization, she was initiated on standard dosing of uridine triacetate (10 g of uridine triacetate every 6 h for 20 doses) ( Figure 1A).
On day 3 of her hospitalization, her blood pressures normalized and she no longer required vasopressors, although she remained in atrial fibrillation. A transesophageal echocardiogram excluded the presence of an atrial thrombus and demonstrated mildly depressed ejection fraction (not quantified), following which electrical cardioversion was performed with restoration of sinus rhythm. She was initiated on intravenous diuresis, resulting in improvement in her kidney function to her baseline creatinine of 0.7 mg/dl as well as normalization of her lactate and liver enzymes. Prior to discharge, metoprolol, lisinopril, and spironolactone were initiated as guideline-directed medical therapy for heart failure. FOLFOX was discontinued with a plan for reassessment of her cancer treatment options as an outpatient.
A repeat echocardiogram 3 weeks after her hospitalization showed normalization of LV function (LV ejection fraction >55%), suggesting either direct myocardial injury from 5-FU that resolved upon discontinuation of the offending agent, or potentially a stress cardiomyopathy in the setting of systemic fluoropyrimidine toxicity.
Tachycardia-induced cardiomyopathy was also considered, but was felt to be less likely in the absence of any prior signs or symptoms of atrial fibrillation. Three weeks after discharge from the hospital, she underwent continuous-recording ambulatory ECG monitoring for 10 days, which demonstrated no further episodes of atrial fibrillation.
She underwent testing for gene mutations with the 5-FU Toxicity and Chemotherapeutic Response panel (ARUP Laboratories, Salt Lake City, Utah). Testing was performed to identify genetic variants in thymidylate synthase (TYMS), the target enzyme for 5-FU activity responsible for DNA synthesis, and dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme for 5-FU catabolism ( Figure 1B). She was found to have 2 variants in the TYMS gene associated with fluoropyrimidine hypersensitivity, specifically a 6 base-pair deletion at the 3ʹ untranslated region and a 28 base-pair tandem repeat in the 5ʹ-promoter enhancer region with a G>C Genetic variant testing is emerging as a potential strategy; however, it is not currently recommended for routine screening before treatment, given the variable penetrance and phenotypic variation that has been reported among gene carriers for chemotoxicity (4,5). Although there are insufficient data to recommend genetic testing in all patients with fluoropyrimidine cardiotoxicity, this strategy can be helpful in patients who present with cardiotoxicity early in the course of therapy (within the first 2 cycles) and also manifest other signs of systemic fluoropyrimidine toxicity, such as significant nausea and vomiting or early-onset cytopenias.
Our patient presented with concurrent cardiotoxicity and gastrointestinal symptoms shortly after her first exposure to 5-FU. In light of her TYMS variants, the decision was made to forego additional fluoropyrimidine treatment in favor of an alternative regimen.
Several nonfunctional alleles of DPD (rs55886062, rs3918290, and rs67376798) have been associated with an increased risk of cardiotoxicity (6). In a study of 258 healthy volunteers, decreased DPD activity affected approximately 8% of African Americans and 2.8% of Caucasians (7). Patients with 1 nonfunctional DPD allele are recommended to have an initial fluoropyrimidine dose reduction of 50%, and those with 2 nonfunctional DPD alleles are recommended to receive an alternate therapy (8). Similarly, polymorphisms in untranslated regions of TYMS have been associated with predisposition to fluoropyrimidine toxicity, although their incidence in the general population is not well described and they are not typically associated with severe cardiotoxicity (9). While the incidence of severe fluoropyrimidine toxicity ranges from 50% to 88% among heterozygote carriers of a nonfunctional DPD allele (6), the incidence of severe toxicity is lower (18% to 43%) among heterozygote or homozygote carriers of TYMS variants (9). A 6-base pair deletion in the 3ʹ untranslated region of TYMS has been shown to cause decreased mRNA stability and lower expression of TYMS (10). No specific guidelines exist for dose adjustments for patients with TYMS genetic variants.
In conclusion, the fluoropyrimidines 5-FU and capecitabine can be associated with a range of cardiotoxic phenotypes, including cardiomyopathy and arrhythmia. The present case demonstrates the use of uridine triacetate as an antidote for severe 5-FU cardiotoxicity. Rapid diagnosis of severe fluoropyrimidine toxicity is important to enable emergent administration of uridine triacetate within the 96-h time frame. The diagnosis of severe fluoropyrimidine toxicity is primarily based on clinical assessment. However, genetic variant testing for polymorphisms in the enzymes DPD and TYMS can support the diagnosis of severe fluoropyrimidine toxicity and guide further oncologic treatment. A multidisciplinary approach incorporating oncology and cardiooncology can facilitate both inpatient and outpatient management of fluoropyrimidine-associated cardiovascular toxicity.
ACKNOWLEDGMENT The authors would like to thank the patient for providing verbal consent to publish the case report.