Treating Cancer without Harming the Heart
More people are living longer after a diagnosis of cancer than at any time in the past. This is the result, in part, of new therapies and strategies for treating cancer. But some of the same treatments that help people survive cancer may also damage the heart and lead to cardiovascular problems, including hypertension, cardiac arrhythmia, and heart failure.
Compared with their siblings, adult survivors of childhood cancers are 10 times more likely to develop coronary disease and 15 times more likely to develop heart failure. Treatment-related cardiovascular side effects—known as cardiotoxicities—are also common among 5- to 10-year survivors of adult cancers.
Survivors of childhood cancer who have been exposed to radiation therapy to the chest and anthracycline chemotherapy are at the greatest risk of cardiac side effects. Newer agents, such as certain targeted therapies, may contribute to cardiovascular changes in some patients. More research is needed to define potential cardiotoxicities associated with all anticancer therapies for various doses and durations of exposure.
In recent years, as patients with cancer have been living longer, the evidence of cardiotoxicities has grown. Investigators from the fields of oncology and cardiology have come together to investigate the biology of these effects and search for ways to prevent, manage, and possibly reverse them. Out of these collaborations a new discipline, known as cardio-oncology, has emerged.
“Many different forms of cancer treatment—chemotherapy agents, radiation, immunotherapy agents, and targeted agents—alone and together can result in cardiac adverse effects,” said Lori Minasian, M.D., Deputy Director of NCI’s Division of Cancer Prevention (DCP). “NCI is working with the National Heart, Lung, and Blood Institute (NHLBI) to support research that will help us better understand the risk factors and ways to reduce or prevent both the short-term effects and the late effects that can compromise survivorship.”
Building a Research Agenda
To address the need for new research strategies on cardiotoxicity, NCI and NHLBI led a workshop in 2013 to identify gaps in knowledge, priorities for future research, and resources and collaborations needed to advance the field of cardio-oncology. The workshop addressed all types of cancer treatments but focused on two forms of cardiotoxicity: hypertension and heart failure.
A theme that emerged from the workshop was the need for standards in the collection of data on patient outcomes and cardiotoxicity. The use of standard terms and procedures to assess heart health at baseline and throughout treatment would allow researchers to track and compare cardiovascular side effects in different patient populations and across institutions.
Participants also agreed on the need for a better understanding of the biology of cardiotoxicity. “Understanding fundamental mechanisms underlying cancer treatment-related cardiotoxicity is essential to the development of new methods to monitor, treat, and prevent these toxicities,” wrote the authors of a report summarizing the 2013 meeting.
The workshop led to research recommendations by experts and the identification of resources and infrastructure that are needed to help to advance the field of cardio-oncology. The results of this meeting have helped to guide subsequent research agendas and conferences on cardiotoxicity.
In addition, the National Institutes of Health has announced funding opportunities on cancer treatment-related cardiotoxicity. For example, funding is available to support research on identifying patients with cancer at risk of developing cardiotoxicity and for research on managing treatment-related cardiotoxicty.
This past summer, DCP convened a group of medical oncologists and cardiology specialists to review echocardiogram results from patients participating in two NCI-supported cardiotoxicity studies. The studies, which are funded through the NCI community-based oncology program, are the:
- USF Study – A randomized phase II study evaluating the use of lisinopril and extended-release carvedilol phosphate to reduce trastuzumab (Herceptin®)-induced cardiotoxicity in patients with breast cancer receiving trastuzumab. (The trial is conducted by SunCoast community oncology program.)
- PREDICT Study – A prospective, observational study evaluating biomarkers of prediction for early cardiac dysfunction in patients with breast cancer receiving adriamycin or trastuzumab. (The trial is conducted by the University of Texas MD Anderson Cancer Center.)
Through an analysis of these two studies, the experts began to develop a framework for evaluating cardiotoxicity in future cancer clinical trials. There was general agreement that although an echocardiogram is an accepted and widely available tool for measuring heart function in general, more research was needed to assess the use of this technology as a diagnostic tool for cardiotoxicity endpoints in patients participating in cancer clinical trials.
The workshop also generated a discussion of broader questions for the field, including:
- How should cardiotoxicity be defined?
- What is a reasonable baseline definition of risk factors that could describe a patient’s underlying cardiovascular risk before treatment has begun?
- How can doctors predict which types of patients will develop cardiotoxicity, especially among those with metastatic disease?
Modifying Treatments for Childhood Cancers
A focus of cardiotoxicity research has been on reducing the cardiotoxic effects of childhood cancer treatments and on how to monitor and care for adult survivors of childhood cancers. In recent decades, there has been dramatic progress in the treatment of some of the most common childhood cancers. Overall, more than 80 percent of children who have access to current therapies are expected to survive their disease for at least 5 years, and many will become long-term survivors into adulthood.
But the same therapies that have led to this progress may cause serious side effects, including cardiovascular problems. The incidence of heart damage among survivors of childhood cancer increases over time. And for some young patients, exposure to certain therapies may prevent the heart from growing normally, resulting in serious heart problems in adulthood.
To reduce treatment-induced cardiac and other side effects, researchers and clinicians have gradually modified many treatments for childhood cancers over the last few decades. Clinical trials run by the NCI-funded Children’s Oncology Group have demonstrated that, in many cases, the intensity of a treatment could be reduced without compromising its effectiveness. For instance, treatments that decrease the amount of radiation given and use lower doses of chemotherapy may lessen the risk of heart and blood vessel late effects relative to older treatments.
Researchers are investigating ways to detect early signs of heart problems in people who received these treatments as children. If such early signs could be identified, doctors might be able to identify survivors at high risk of cardiac death who might benefit from monitoring and strategies to maintain cardiac health.
For instance, Gregory T. Armstrong, M.D., of St. Jude Children’s Research Hospital, and his colleagues recently found that assessing cardiac health using echocardiographic measures known as global longitudinal strain and diastolic function may help identify cancer survivors who are at high risk of treatment-induced cardiac disease. But the study authors cautioned that additional research is needed to characterize the cardiac changes that occur in adult survivors of childhood cancer over time that may predict the development of cardiac damage.
An editorial accompanying the study noted that although doctors can detect “subclinical” changes (changes that do not result in overt symptoms) in certain cardiac functions, “the benefit of early detection is still unknown.” More research is needed to determine whether early intervention in patients at risk for cardiotoxicity will lead to improvements in long-term clinical outcomes, noted the editorialists, Edward T.H. Yeh, M.D., and Pimprapa Vejpongsa, M.D., of MD Anderson Cancer Center.
The authors of the editorial added: “There is currently no proven treatment that will reverse cardiac injury that was already incurred after cancer treatment. It would be more desirable to prevent cardiovascular damage with primary prevention.”
Focusing on Breast Cancer
Cardiotoxicity researchers have also focused on breast cancer, in part because many breast cancer patients are exposed to treatments that can potentially damage the heart, such as chest radiation.
A 2013 study of cardiac problems in women who received radiation therapy for breast cancer found that any exposure of the heart to radiation leads to increases in the risk of ischemic heart disease. In this population-based analysis, the risk of a major coronary event increased in the first 5 years after exposure to radiation and remained elevated for at least two decades after the exposure, Sarah C. Darby, Ph.D., of the University of Oxford and her colleagues reported.
“Women with preexisting cardiac risk factors have greater absolute increases in risk from radiotherapy than other women,” the authors noted.
The findings on ischemic cardiac disease may represent just the tip of the iceberg, said Javid Moslehi, M.D., of the Brigham and Women’s Hospital and Dana-Farber Cancer Institute, in an accompanying editorial. Radiation therapy has been linked to other heart problems that were not part of the analysis, including cardiomyopathy and arrhythmias, he noted.
“The current study points to radiation therapy as a significant risk factor for coronary disease in patients with breast cancer,” Dr. Moslehi, who now directs the Cardio-Oncology Program at Vanderbilt-Ingram Cancer Center, wrote. “The finding suggests that cardiac risk factors should be assessed and aggressively managed—starting at the time of radiation treatment (or even before) and continuing throughout survivorship.”
Researchers are already collecting information about potential risk factors for cardiotoxicity and tracking cardiac side effects over time through cancer clinical trials. During a breast cancer trial called N9831, for instance, researchers evaluated a therapeutic regimen that included trastuzumab, which has been associated with cardiotoxicity in some studies.
Among the women in the trial, the incidence of trastuzumab-related cardiac events “is low and does not appear to be increasing over time,” Pooja P. Advani, M.D., of the Mayo Clinic in Jacksonville, FL, and her colleagues found. The treatment regimen “continues to have a favorable benefit–risk ratio,” the study authors noted.
Certain risk factors, such as older age, hypertension, and a low pretreatment measure of the percentage of blood leaving the heart each time it contracts, were associated with an increased risk of trastuzumab-related cardiac events, the authors noted. But they added that additional research is needed to establish biological markers of cardiovascular risk.
Exploring New Directions
Several clinical trials are exploring new strategies for preventing or reducing damaging cardiovascular changes induced by cancer treatments. An NCI-sponsored study, for instance, will investigate whether carvedilol, a type of drug known as a beta-blocker, can prevent, or possibly reverse, damage to the heart among young adults who received high-dose anthracyclines.
Anthracyclines can cause deterioration in heart muscle known as cardiomyopathy, and children may be more susceptible to this kind of damage than adults. The drugs “destroy the heart cells, and if you do that to a developing heart, the injury is going to be more significant,” said one of the lead investigators, Saro Armenian, D.O., M.P.H., of the City of Hope, in a news release.
Another clinical trial, sponsored by NHLBI and NCI, is under way to test whether a statin medication, which is commonly used to treat high cholesterol, can help prevent the cardiotoxic effects of some breast cancer treatments. The Preventing Anthracycline Cardiovascular Toxicity with Statins (PREVENT) trial will investigate whether the use of atorvastatin can help reduce or prevent cardiotoxicity among patients with breast cancer and lymphoma receiving anthracycline treatment.
“Observational studies have indicated that statin drugs can reduce these events in breast cancer patients, and we aim to find out exactly how effective atorvastatin is in this population,” W. Gregory Hundley, M.D., professor of cardiology at Wake Forest Baptist Medical Center and the study’s lead investigator, said in a news release. “It may be that the anti-inflammatory effects of statins, rather than their cholesterol-lowering effects, are helpful during cancer treatment.”
Asking Provocative Questions
Knowledge of the mechanisms by which various treatments induce cardiovascular toxicities may help researchers develop new strategies to minimize, manage, or reduce these side effects. NCI has invited researchers to help develop new insights into cardiotoxicity and other treatment-induced side effects through its Provocative Questions Initiative. Specifically, Provocative Question number 9 asks researchers to investigate the molecular and cellular mechanisms that underlie severe adverse side effects caused by cancer treatment.
NCI is also supporting researchers who are working on questions related to cardiotoxicities through a variety of funding mechanisms. In January 2014, DCP initiated the NCI Community Oncology Cardiotoxicity Task Force for the purpose of coordinating study designs and research activities across the NCI Community Oncology Research Program (NCORP). The task force, which is under the direction of Dr. Minasian, includes cardiologists, oncologists, and clinical trialists.
“Members of the task force have spoken regularly over the last 2 years. They will be meeting periodically to discuss the latest research findings and to identify priorities for new investigations in cardiotoxicity—and to challenge each other to create the best study designs,” said NCI’s Eileen Dimond, R.N., M.S., a nurse consultant in DCP's Community Oncology and Prevention Trials Research Group.
“It is encouraging to see so much energy around this area of research that so directly affects the lives of our patients,” she added.