MI Risk With 5-Fluorouracil in GI Cancers Significant, but Modest

Patrice Wendling

December 22, 2021

Patients receiving 5-fluorouracil (5-FU) for gastrointestinal cancers have a significantly higher 6- and 12-month risk for myocardial infarction (MI) but the absolute numbers are low, new research suggests.

"The topline is that we detected small differences — but there's such a large competing death signal that the differences are very small and there's only a few people who get myocardial infarction," study leader Jan Walter Dhillon Shanmuganathan, MD, Aalborg University Hospital, Aalborg, Denmark, said in an interview. "Using 5-FU isn't that dangerous, from what we can see from our experience."

The study, published online December 21 in JACC: CardioOncology, is the largest published analysis of the incidence of MI in patients receiving 5-FU for the treatment of gastrointestinal cancers.

"The work by Shanmuganathan et al marks an important improvement of our understanding of 5-FU cardiotoxicity. However, 5-FU is difficult to decipher, and much remains to be done in terms of refining patient- and treatment-related determinants of what appears to be a relatively modest risk for MI," Giorgio Minotti, MD, PhD, University Campus Bio-Medico, Rome, Italy, and Massimiliano Camilli, MD, Catholic University of the Sacred Heart, Rome, say in an accompanying editorial.

Competing Risks

5-FU is known to be associated with angina or acute coronary syndromes including MI, but data on adverse events are variable and often based on small case series or observational studies.

For the current nationwide study, the researchers used data from 2004-2016 in the Danish National Patient Registry to identify 10,290 patients with GI cancer treated with up to six cycles of 5-FU regimens over 6 months and matched them by age and sex to 20,580 population control patients without cancer.

The median age was 65 years and 53.6% were male. Only 20 patients were lost to 6 months' follow-up and 35 were lost to follow-up at 1 year.

Results show the cumulative incidence of MI at 6 months was 0.7% for 5-FU-treated patients and 0.3% for controls (P < .001), with a competing risk for death of 12.1% vs 0.6%.

The corresponding 1-year cumulative incidences were 0.9% and 0.6% for 5-FU-treated patients and controls (P = .051), with a competing risk for death of 26.5% vs 1.4%.

In a Fine and Gray model that accounted for competing risks, the hazard ratios for MI were higher in 5-FU patients at 6 months (2.10; 95% CI, 1.50 - 2.95; P < .001) and 1 year (1.39; 95% CI, 1.05 - 1.84; P = .022).  

Additional analyses revealed that 55.4% of patients diagnosed with MI experienced MI within 5 days of 5-FU administration, and 75.4% had events within 1 month.

"Previous small case series reported a median time to chest pain of approximately 12 hours following infusion initiation, with a time window of 1 to 2 days that is well encircled by the 5-day MI incidence reported in this study," Minotti and Camilli observe.

Notably, 23 of the 65 patients diagnosed with MI continued 5-FU treatment without hospital admission for re-infarction, and all were alive 3 months post-MI.

Shanmuganathan said 5-FU is widely used in Denmark for solid tumors including gastrointestinal, breast, and head and neck tumors, but that treatment is typically stopped when there's cardiotoxicity.

"So, we would like to rechallenge and see why they're not choosing 5-FU, even if they have a myocardial infarction because [the risk] is very low," he said. "But we want to see the baseline cardiac calcium score before we give it."

A subgroup analysis also showed a significantly higher risk for MI in 5-FU patients with vs without preexisting ischemic heart disease — both at 6 months (risk ratio [RR], 2.45; 95% CI, 1.15 - 3.76) and 1 year (RR, 2.07; 95% CI, 1.09 - 3.06).

This analysis represents another strength of the study, the editorialists say, and "sheds light on unsettled issues about CV risk factors aggravating (or not) 5-FU cardiotoxicity." They point to a study published earlier this year, in which 2.6% of 5-FU patients developed vasospasm and those who did were younger and less likely to have any cardiovascular risk factors.

"On balance, studies with significant sample sizes seem to reveal multifaceted effects of CV comorbidities on aggravating the risk for a relatively infrequent and serious event such as MI but not the risk for perhaps a more frequent and benign event such as uncomplicated chest pain," the editorialists say. "This will require further investigation."

Shanmuganathan noted that cancer itself can increase the risk for MI because of inflammation and other shared mechanisms, and as such, the risk for MI in the 5-FU group may be subject to confounding.

The study also lacked information on cancer stages and the exact doses of 5-FU, and examined only intravenous 5-FU and not the oral formulation, capecitabine (Xeloda). Other cardiotoxic events and other patient populations treated with 5-FU were also outside the scope of the study. "This paper gives us a good idea about future studies."

The editorialists assert that "mode of administration is even more important" than dose because the cardiotoxicity induced by 5-FU is determined by plasma exposure over time rather than plasma peak, which makes slow infusions more cardiotoxic than bolus infusions.

"Most common colorectal regimens, such as FOLFOX, FOLFIRI, and FOLFOXIRI, have undergone modifications over the years, and variability across cancer centers with respect to 5-FU infusion modalities is more than plausible," Minotti and Camilli say. "How this influenced these analyses is not known at this point in time. Another black box pertains to the role concomitant cancer drugs may have played."

Co-author Tarec Christoffer El-Galaly, MD, DSc, was previously employed at Roche; and has received speaker fees from AbbVie. All other authors, Minotti, and Camilli have disclosed no relevant financial relationships .

J Am Coll Cardiol CardioOnc . Published online December 21, 2021. Full text, Editorial

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