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.