Primary Prevention Strategies for Avoiding Cardiotoxicity in Patients With Cancer: A Growing Area of Research
Cancer is not for the faint of heart, and sometimes neither is the treatment, according to information presented during the ASCO20 Virtual Education Program.1 Approximately 30% of patients who receive cancer therapy will have cardiovascular complications.2 What’s more, in anthracycline-treated patients, the incidence of significant cardiotoxicity and heart failure is between 5% and 10%, depending on the cumulative dose and duration of exposure.
Primary prevention strategies could help reduce cardiovascular toxicity and improve patient outcomes, but prospective clinical validation is needed. During the ASCO20 Program, medical oncologist Susan Faye Dent, MD, FRCPC, Associate Director of Breast Cancer Clinical Trials and Co-Director of the Cardio-Oncology Program at Duke University, in Durham, North Carolina, discussed the current evidence supporting cardioprotective medication in patients with cancer and the knowledge gaps in this growing area of research.
Susan Faye Dent, MD, FRCPC
“Primary prevention strategies in cancer, especially with neurohormonal therapy, are not ready for prime time,” said Dr. Dent. “We need larger, multicenter, randomized controlled trials to answer these questions, and we need longer follow-up, too.”
Why Consider Prevention Strategies?
As Dr. Dent explained, the rationale for primary prevention strategies is to prevent cardiovascular toxicities while completing prescribed cancer therapy. Among trastuzumab-treated patients, 2% will develop symptomatic heart failure, and 34% will develop asymptomatic left-ventricular dysfunction.3
“In some cases, asymptomatic drops in left-ventricular ejection fraction have led to the early termination of therapy for patients, which we know may compromise cancer outcomes,” said Dr. Dent.
Cardioprotective medication in patients with cancer could also help prevent exacerbation of preexisting cardiovascular disease and promote long-term cardiovascular health in survivorship, said Dr. Dent. She noted that left-ventricular dysfunction is reported in up to 16% of adult breast cancer survivors.
As Dr. Dent reported, dexrazoxane is the only cardioprotective agent approved by the U.S. Food and Drug Administration for anthracycline-induced cardiotoxicity. It works by preventing anthracycline from binding to DNA topoisomerase II, which leads to cardiovascular toxicity and ultimately heart failure with anthracyclines.
Although dexrazoxane is widely used in pediatric malignancies and is approved in metastatic breast cancer, said Dr. Dent, there has been a reluctance to use this agent in breast cancer over concerns that it might negatively affect response to treatment.
However, a meta-analysis of seven randomized trials and two retrospective studies of patients with breast cancer treated with anthracyclines with or without trastuzumab in both early and metastatic settings showed a clear reduction in the risk of heart failure and cardiac events with the use of dexrazoxane.4 More importantly, said Dr. Dent, dexrazoxane showed no negative impact on cancer outcomes. Nevertheless, the authors of the study concluded that the quality of available evidence was low. “Further randomized trials are therefore warranted before systematic implementation of this therapy into clinical practice,” said Dr. Dent.
According to Dr. Dent, there are a number of medications on the market that are used in cardiovascular disease, such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and beta blockers, but the evidence supporting these drugs as a primary prevention strategy for patients with cancer is also limited.
Dr. Dent reported that five randomized controlled trials have been published in patients with early-stage breast cancer who received anthracyclines with or without trastuzumab. These studies randomly assigned patients to placebo vs cardiac medication (either single-agent interventions or a combination). There were a variety of clinical endpoints, but all five studies measured changes in left-ventricular ejection fraction in the experimental arm.
Although three of these studies were positive, showing attentuation in the reduction of left-ventricular ejection fraction of 3 % to 5 % in the experimental arms, she said, the other two studies found no significant difference between study arms. Dr. Dent also noted several limitations with these small studies: variable exposures to anthracyclines and trastuzumab, different clinical endpoints and definitions, short follow-up, and a young population with few cardiovascular risk factors.
A meta-analysis of 17 randomized controlled trials looking at the efficacy of neurohormonal therapies in preventing cardiotoxicity in patients with cancer undergoing chemotherapy identified a benefit in favor of cardioprotection with neurohormonal therapies.5 However, the absolute benefit was a prevention in drop of left-ventricular ejection fraction of only 3.96 %. The authors of the study also reported substantial heterogeneity and publication bias among the trials analyzed, which “limit the ability to recommend the routine use of these agents to reduce cardiotoxicity.”
Current Research and Future Directions
According to Dr. Dent, there are a number of ongoing randomized controlled trials looking at cardiovascular drugs such as statins as a primary prevention approach in breast cancer, non-Hodgkin lymphoma, and other cancers treated with anthracyclines. There are also studies exploring cardioprotection strategies from a lifestyle perspective, with physical activity and dietary interventions. The outcomes for these studies include weight loss and physiologic endpoints as well as changes in blood pressure, cholesterol, and glucose levels.
For primary prevention strategies to succeed in patients with cancer, however, Dr. Dent emphasized the need to include patients with comorbidities and to risk-stratify them according to those comorbidities. Standardization of definitions, such as drops in left-ventricular ejection fraction, and adjudicated cardiac imaging could also increase data quality and improve clinical research. Importantly, said Dr. Dent, investigators need to choose clinical endpoints that are clinically meaningful as well.
“Finally, I think it would be prudent to start incorporating cardiac biomarkers in risk prediction, and some current studies are looking at this approach,” Dr. Dent concluded.
DISCLOSURE: Dr. Dent has received research funding and honoraria from Novartis.
1. Dent SF: Primary prevention strategies for patients with cancer: Are they ready for prime time? ASCO20 Virtual Education Program. Presented August 9, 2020.
2. Hamo CE, et al: Cancer therapy-related cardiac dysfunction and heart failure. Part 2: Prevention, treatment, guidelines, and future directions. Circ Heart Fail 9:e002843, 2016.
3. Cardinale D, et al: Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 131:1981-1988, 2015.
4. Macedo AVS, et al: Efficacy of dexrazoxane in preventing anthracycline cardiotoxicity in breast cancer. J Am Coll Cardiol CardioOnc 1:68-79, 2019.
5. Vaduganathan M, et al: Efficacy of neurohormonal therapies in preventing cardiotoxicity in patients with cancer undergoing chemotherapy. J Am Coll Cardiol CardioOnc 1:54-56, 2019.