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MI Risk with 5-Fluorouracil GI Cancers is Significant, but moderate

Recent research has shown that patients who are treated with 5-fluorouracil (5FU) for stomach cancers have a greater risk of myocardial Infarction (MI) however, the numbers per se are not high.

“The topline is that we found tiny differences, but there’s such a large competing death signal that the differences are small , and there are only a few patients who suffer from myocardial infarction” the study’s leader Jan Walter Dhillon Shanmuganathan, MD, Aalborg University Hospital, Aalborg, Denmark, said in an interview. According to our research 5-FU isn’t dangerous.

Published online on December 21st, in JACC, this is the most comprehensive study ever published on the prevalence of MI in patients who have received 5-FU to treat intestinal cancers.

“The significant advancement in our understanding of the cardiotoxicity of 5-FU is highlighted by the work of Shanmuganathan and colleagues. 5-FU isn’t easy to understand and there is a lot to be done to refine patient- and treatment-related determinants of what is a relatively low risk for MI,” Giorgio Minotti (MD, PhD), University Campus Bio-Medico Rome, Italy, and Massimiliano Camilli (MD, Catholic University of the Sacred Heart Rome) are quoted in an accompanying editorial.

Competing Risques

5-FU is widely believed to be associated with angina or acute coronary syndromes including MI However, information on adverse events is varied and are often based on small case series or observational studies.

The current nationwide study utilized data from the Danish National Patient Registry 2004-2016 to identify 10,290 patients suffering from GI cancer. They also matched them according gender to 20,580 healthy patients.

The median age of patients was 65, and 53.6 percent of them were male. Only 20 patients were lost to follow-up of 6 months and 35 patients were lost to follow-up after one year.

Results show that the cumulative rate of MI after 6 months was 0.7 percent for patients treated with 5-FU and 0.3% for controls ( P < .001) and an additional risk of death of 12.1 percent against 0.6%.

The cumulative incidences for the first year of 5-FU-treated patients were 0.9% and 0.6%, respectively ( P=.051), with a death risk of 26.5% and. 1.4%.

Fine and Gray models that considered competing risks showed that MI rates were higher for patients with 5-FU at 6 months (2.10; 95% CI, 1.50 – 2.95; P.001) and 1 year (1.39 (95% CI: 1.051.39 – 1.84; P =.022).

Additional analyses revealed that 55.4% of patients diagnosed with MI suffered MI within 5 days after 5-FU administration, and 75.4 percent had an event within one month.

“Previous small-scale case series showed a median duration of chest pain of about 12 hours following infusion initiation, with a time period of between 1 and 2 days that is circumscribed by the five-day MI incidence reported in this study.” Minotti and Camilli report.

Notably, 23 out of the 65 patients diagnosed with MI continued 5-FU treatment without hospital admission for re-infarction. All were alive at the time of MI’s diagnosis.

Shanmuganathan said 5-FU is widely used in Denmark for solid tumors , including breast, gastrointestinal, as well as neck and head tumors, however, treatment is usually removed when there is cardiotoxicity.

“So we’d like to re-challenge and understand why they aren’t choosing 5-FU even if they’ve had an infarction of the myocardium because the risk] is very low,” he said. “But, we want to see the baseline cardiac score before giving it.”

A subgroup analysis also demonstrated a significantly higher risk of MI in patients who have 5-FU no preexisting ischemic heart disease — both at 6 months (risk ratio [RRof 2.45 95% CI, 1.15 – 3.76) and 1 year (RR, 2.07; 95% 95% CI, 1.09 – 3.06).

The editorialists say that this analysis is an additional strength of the study and “sheds light” on unresolved issues about CV risk factors that contribute to 5-FU cardiotoxicity (or not). They refer to an earlier study published earlier in the year that found that 2.6 percent of patients with 5-FU had vasospasm. Those who did developed it were younger and less likely to have cardiovascular risk factors.

The editorialists say that “on the whole, studies with large sample sizes seem to show multifaceted effects of CV complications on increasing risk for a relatively rare and serious event like MI but not the chance for a more common and benign event like chest discomfort that is uncomplicated.” This needs to be further investigated.

Shanmuganathan pointed out that cancer may increase the risk of MI due to inflammation and other common mechanisms. As such, the 5-FU group’s risk for MI could be misinterpreted.

The study did not include details on the stages of cancer, or the precise doses for 5-FU. The study also looked at intravenous 5-FU only, and not the oral capecitabine (Xeloda). The study did not include other cardiovascular-related events or patient groups that were treated with 5-FU. “This paper provides us with an indication of the future studies.”

The editorialists argue that “mode of administration is even more important” than dose because the cardiotoxicity of 5-FU is determined by the plasma exposure over time, not plasma peak which makes slow infusions more dangerous than bolus infusions.

“Most common colorectal regimens like FOLFOX, FOLFIRI, and FOLFOXIRI have seen changes over the years, and variability across cancer centers in relation to the use of 5-FU infusions is more than plausible,” Minotti and Camilli declare. It is unclear how this affected these analyses at the moment. Another mystery is the role that concomitant chemotherapy drugs may have played.”

Tarec ChristofferEl-Galaly, MD and DSc was previously employed by Roche. He also received speaker fees from AbbVie. All other authors, Minotti, and Camilli have not disclosed any financial relationships .

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

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