Cardiotoxicity Rare With Common GI Chemotherapy

In patients with gastrointestinal cancers treated with fluoropyrimidine-based chemotherapy agents, better overall survival at 1 year offsets a small increase in their risk of CV events, new data suggest.

In the observational study of more than 100,000 patients, there was a 0.9% increase in absolute risk of acute CV events in those treated with fluoropyrimidines versus alternative cancer therapies. The difference was driven primarily by the occurrence of arrhythmias. In a subgroup of patients with preexisting CAD, treatment with fluoropyrimidines did not increase the risk of ACS.

“Fluoropyrimidine chemotherapy remains the mainstay of systemic treatment for gastrointestinal malignancies. However, we have previously shown that patients at high cardiovascular risk or with prior cardiovascular disease are 27% less likely to receive this group of chemotherapy drugs due to perceived concerns regarding potential cardiovascular complications,” senior author Charlotte Manisty, MD, PhD (University College London, England), told TCTMD.

Reporting the results in JACC: CardioOncology, the researchers say many clinicians err on the site of caution in prescribing these agents for patients with established CVD due to concerns about the potential for arrhythmias, ischemia, and myocarditis, even though the literature around fluoropyrimidine-associated cardiotoxicity has been inconsistent.

“We therefore propose that clinicians should consider this new evidence when balancing the risks of chemotherapy, and should avoid withholding this effective anticancer treatment due to inappropriate concerns of toxicity,” Manisty added in an email. “Better understanding of the relative risks and benefits of fluoropyrimidine, supported by better communication between cardiology and oncology, may improve outcomes for patients with gastrointestinal cancers.”

Clinicians should . . . avoid withholding this effective anticancer treatment due to inappropriate concerns of toxicity. Charlotte Manisty

In an editorial accompanying the paper, Mohamad Bassam Sonbol, MD (Mayo Clinic Cancer Center, Phoenix, AZ), and colleagues say the study contributes important and reassuring real-world evidence on the CV risks associated with fluoropyrimidine.

They note that these data add to a recent single-center study of more than 4,000 patients treated with the fluoropyrimidine 5-fluorouracil (5-FU), which found that patients who developed coronary vasospasm as a complication of therapy were actually less likely to have CV risk factors than those who did not.

“These findings taken together suggest that it may not be in the patient’s best interest to withhold fluoropyrimidine therapy based on preexisting heart disease alone,” they write.

Consistently Lower All-Cause Mortality

For the study, Manisty and colleagues led by Aderonke T. Abiodun, MBChB (University College London), conducted an observational cohort study of 103,110 GI cancer patients (mean age 69.7 years; 41% female). To mimic a pragmatic trial, they applied a target trial emulation framework to linked national cancer, cardiac, and hospitalization registry data from the Virtual Cardio-Oncology Research Initiative. This resulted in a comparison of 25,401 patients who received fluoropyrimidine as first-line therapy and 64,589 patients who did not.

The diagnoses were esophageal cancer in 20.8%, gastric in 12.9%, and colorectal in 66.3%. Compared with those who did not receive fluoropyrimidines, patients who did were younger, had fewer comorbidities, and were more likely to have esophageal and stage IV cancers. Nearly 12% of patients had preexisting CAD.

At 1 year, the absolute risk of death was 41.9% in the fluoropyrimidine group and 49.6% in the control group (RR 0.85; 95% CI 0.83-0.86).

Hospitalization for CV events (including ACS, heart failure and cardiomyopathy, coronary interventions, cardiac arrhythmia, and cardiac arrest/CV death) occurred in 15.8% of the fluoropyrimidine group versus 14.9% of the control group (RR 1.07; 95% CI 1.00-1.13). This risk difference was due to 0.8% more cardiac arrhythmias and 0.3% more cardiac arrests.

In subgroup analyses, lower risk of all-cause mortality was consistent for fluoropyrimidine across all patient subgroups, including advanced-stage cancers and those with preexisting CAD.

An extended analysis that followed patients to 5 years still showed a consistent survival benefit, plus no increased risk of CV events, with fluoropyrimidine versus no fluoropyrimidine therapy.

What Happens After Cardiotoxicity?

The editorialists note that the study didn’t look at the safety of continuing fluoropyrimidine therapy after an initial CV event.

“The decision to continue, modify, or discontinue treatment after a cardiac event depends on factors such as treatment intent and the severity of the event,” they write. “In a curative intent setting, risk-mitigation strategies may allow continuation, whereas in a palliative setting, quality-of-life considerations may justify discontinuation.”

Several alternative therapies have been used in this situation, including an oral fluoropyrimidine consisting of tegafur and metabolic inhibitors that slow 5-FU metabolism, they add. However, this strategy has not been widely adopted outside of Asia and Europe.

To TCTMD, Manisty said restarting chemotherapy should be considered on an individual patient basis, although emerging data support rechallenge and careful monitoring in patients with prophylaxis against coronary vasospasm (with nitrates and/or calcium channel blocking agents).

“For patients who develop atrial arrhythmias, fluoropyrimidines can be continued, but decision-making regarding anticoagulation should balance the risk of gastrointestinal bleeding,” she added.

Sonbol and colleagues suggest that future studies should look at better ways to “identify patients at heightened risk of cardiotoxicity and developing effective cardioprotective strategies to optimize treatment safety.”