Pediatric cancer survivors and cardiovascular toxicity, disease risk | Image Credit: © appledesign - © appledesign - stock.adobe.com.

The American Heart Association (AHA) has released a new scientific statement that focuses on pediatric patients treated for cancer and cardiovascular toxicity.¹

Titled "Cardiovascular Toxicity in Patients Treated for Childhood Cancer: A Scientific Statement From the American Heart Association" and published in the Association's Circulation journal, the scientific statement recognizes that the field of cardio-oncology has expanded over the last 20 years to highlight issues of cardiovascular diseases in patients with cancers.

"There is increasing recognition that nearly all cancer treatments pose some short- or long-term risk for development of cardiovascular disease and that pediatric patients with cancer may be especially vulnerable to cardiovascular disease because of young age at treatment and expected long life span afterward," stated the authors of the statement in an abstract.

The statement was chaired by Thomas D. Ryan, M.D., Ph.D., FAHA, director of the cardio-oncology program and associate director of the heart failure & cardiomyopathy program at Cincinnati Children’s Hospital Medical Center in Ohio.

Ryan and co-authors noted that of new cancer diagnoses each year, approximately 5% occur in children, who have a 5-year survival rate of more than 85%. In the age group, that is approximately 500,000 survivors of pediatric cancer, which has resulted in an increasing and aging population at risk for therapy-related cardiovascular disease.

Over the years, an increasing recognition that chemotherapeutic agents can pose short- or longer-term risks such as "systolic ventricular dysfunction, diastolic ventricular dysfunction, coronary artery disease (CAD), arrhythmias, valvular disease, autonomic dysfunction, endothelial dysfunction, and pericardial disease," wrote the statement authors.

The statement highlights that anthracycline chemotherapy and chest-directed radiotherapy have been well-studied cardiotoxic therapies and that modern radiotherapy, dose reductions, and use of cardioprotection for anthracyclines have helped improve cardiovascular outcomes for survivors.

Additionally, statement authors noted that small-molecule inhibitors, antibody-based cytotoxic therapy, and immunotherapy have expanded treatment options for difficult-to-treat cancers, though have revealed new cardiotoxic profiles.

Anthracycline cardiotoxicity

According to the statement, anthracyclines are "highly effective and commonly used" as pediatric cancer therapies. With them though, come a risk of dose-dependent cardiotoxicity, which can vary by anthracycline analog.

"Recent international multicohort efforts have shown that, compared with the same dose of doxorubicin, daunorubicin confers half the risk of heart failure, and mitoxantrone confers a 10-fold increased risk," wrote the authors.

Cardiotoxicty from anthracycline can manifest as a reduction in left ventricular (LV) mass, relative wall thickness, and cardiac function. A pediatric acute myeloid leukemia trial highlighted in the AHA scientific statement documented a more than 20% increase of grade II cardiotoxicity (LV ejection fraction [LVEF] <50% or fractional shortening <24%) during and shortly after treatment completion.

Changes in cardiac size and function can progress during survivorship. High-dose (≥250 mg/m²) doxorubicin equivalent exposure is associated with a 7.2% 30-year cumulative incidence of heart failure, which is a 7-fold higher rate than in survivors who did not receive anthracycline therapy, compared to siblings of survivors, who have an estimated heart failure incidence of 0.3% by 45 years of age.

"Recent data suggest that some long-term survivors may develop an alternative remodeling phenotype that includes reduced LV cavity size with preserved or increased relative wall thickness, although this phenotype may be driven more by radiotherapy than chemotherapy," stated the authors, though they noted that clinical implications of these findings have not been established.

The authors also stated that early clinical studies of the anthracycline derivatives aclarubicin and diMe-doxorubicin demonstrated how anthracycline selection of a narrow mechanism of action, specific to chromatin damage and without the characteristic topoisomerase II–mediated DNA damage, could lead to comparable comparable antitumor efficacy without cardiotoxicity.

The authors stated this approach is "promising" for future study.

Other highlights from the statement include:

Radiotherapy and Long-Term Cardiovascular Risk
Chest-directed radiotherapy increases the risk of late-onset cardiovascular disease (CVD), including coronary artery disease (CAD), heart failure, and valvular disease in childhood cancer survivors. Recent data show a dose-dependent relationship, with each 1-Gy increase to the right coronary artery raising CAD risk by 28.7%, though modern techniques like proton therapy may help reduce exposure.

Impact on Cerebrovascular Health
Radiation exposure to the mediastinum and neck elevates stroke risk due to endothelial dysfunction, as seen in both pediatric and adult cancer survivors. While newer radiotherapy methods aim to limit cardiac and vascular damage, their long-term effects in childhood cancer survivors remain uncertain.

Cardiotoxicity of Targeted Cancer Therapies
Small-molecule kinase inhibitors, used in pediatric cancers like Ph+ leukemias and gliomas, can lead to cardiovascular side effects such as QTc prolongation, hypertension, and heart failure. While some effects, like left ventricular (LV) dysfunction, may be reversible, the long-term cardiovascular risks of these therapies remain unclear.

Immunotherapy-Related Cardiac Risks
Immunotherapies, including immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapies, can cause arrhythmias, myocarditis, and cardiomyopathy, with up to one-third of pediatric patients experiencing cardiotoxicity due to cytokine release syndrome. The incidence and severity of these effects in children require further study.

The scientific statement also highlights surveillance and survivorship, cardiometaboic considerations, exercise and cardiac rehabilitation, clinical management of cardiotoxicity, and future directions, outlined by the authors.

For additional details on these sections and for the full scientific statement, click here.

Reference:

Ryan TD. Bates JE, Kinahan KE, et al. Cardiovascular Toxicity in Patients Treated for Childhood Cancer: A Scientific Statement From the American Heart Association. Circulation. Published online March 19, 2025. Accessed March 21, 2025.