Discussion
5-FU is a commonly used pyrimidine analog and antimetabolite in adult patients with solid tumors and has significant cardiotoxicity. There are currently only two cases of reported cardiotoxic effects of 5-FU in a pediatric setting. One author described a 14-year-old male with NPC who developed severe dilated cardiomyopathy after 5-FU infusion with reversal of cardiotoxicity after completion of treatment [4]. The other case was that of a 14-year-old male who experienced sudden death during the infusion of his fifth cycle of 5-FU, which was postulated to be due to arrhythmia and cardiomyopathy, though no autopsy was available. Interestingly, the patient in this case had experienced dilated cardiomyopathy with his first cycle of 5-FU that resolved. He tolerated cycles 2, 3 and 4 without issue, but experienced irreversible circulatory collapse during his fifth cycle [5]. Both of these case reports were published prior to the FDA approval of uridine triacetate.
Our case is the first to describe a female pediatric patient with 5-FU-mediated cardiotoxicity treated with uridine triacetate. She tolerated the antidote well and completed a 5-day course with mild diarrhea as the only adverse effect. Based on literature reports of potential adverse outcomes with repeated exposure to 5-FU, the treatment team elected to eliminate subsequent doses and instead proceeded with Cisplatin monotherapy. In addition, the patient received standard doses of external beam radiotherapy. Despite these necessary modifications to the treatment regimen, the patient has had continued reduction in the size of the residual mass on MRI and remains PET-negative >1-year post-therapy.
Uridine triacetate is FDA approved as a 5-FU reversal agent for the emergency treatment of patients with life-threatening toxicity. Uridine triacetate is converted to uridine in circulation which competitively inhibits cell damage and cell death caused by 5-FU [6]. 5-FU-mediated cardiotoxicity may have a variety of presentations such as myocardial infarction, coronary vasospasm, arrhythmias or cardiomyopathy. The mechanism of 5-FU-mediated cardiotoxicity is not fully understood; however, it may be due to a combination of ischemia related to coronary vasospasm and direct myocardial cell toxicity. Based on reports in the literature, cardiotoxicity appears to be more frequently associated with continuous infusion rather than bolus infusion, presumably due to a higher incidence of vasoconstrictive events with continuous infusion. Several cases of successful re-challenge with bolus 5-FU, utilizing calcium channel blockers (CCBs) and nitrates to prophylaxis against coronary vasospasm recurrence, have been reported in the literature [7]. However, since there is increased variability of time to symptom onset with the infusion of 5-FU, re-challenge with infusion of 5-FU has not been widely studied. Our patient’s cardiotoxicity was fully reversed with the use of uridine triacetate due to prompt recognition of the condition as an adverse effect of 5-FU.