Field of cardio-oncology opens new pathways for consultation, collaboration

Survival rates of patients with cancer have increased steadily over time, but that has led to a quandary that — until recently — had not been well characterized.

Many oncology treatments are cardiotoxic and, as a result, cancer survivors often develop and eventually die of some form of heart disease.

During the last few years, cardiologists and oncologists have intensified efforts to learn more about how certain cancer therapies affect the heart and cardiovascular system.

Researchers are trying to identify patients with cancer — prior to treatment initiation — who may be at risk for cardiovascular disease. They also hope to identify cardioprotective therapies that could mitigate cardiovascular risks of oncology treatments, and refine treatment of cardiovascular disease after cancer therapy.

Some institutions have developed cardio-oncology programs to enable better collaboration between cardiologists and oncologists in these endeavors.

“The paradigm is changing,” Ana Barac, MD, PhD, FACC, director of the cardio-oncology program at MedStar Heart & Vascular Instituteand assistant professor of medicine and oncology at Georgetown University, told HemOnc Today. “The idea is: Let’s identify cardiovascular effects. Can we modify them? Can we make the treatments better and learn more through them?”

Photo credit: Gary Landsman/MedStar Washington Hospital Center; printed with permission.

With the field of cardio-oncology in its infancy, there is still much to be learned, and there are few definitive trials or guidelines to show the way.

However, the ultimate goal for patients with cancer is to prolong OS and, to optimize that, cardiovascular effects must be taken into account.

“We have recognized together that emerging chemotherapeutics in the oncology world, although very effective, have an undeniable cardiovascular risk,” Gagan Sahni, MD, FACC, FACP, director of cardio-oncology and cardiology consult services at The Mount Sinai Hospital, told HemOnc Today. “Unless we tackle both so-called ‘evils’ in a collaborative way, we cannot ensure the best results for our patients.”

Evidence of cardiotoxicity

The American Cancer Society estimates there are more than 15.5 million cancer survivors in the United States, and that number is expected to exceed 20 million by 2026. More than two-thirds of people diagnosed with cancer live at least 5 years after their diagnosis.

“This means that they have time for potential cardiovascular side effects of chemotherapy agents to manifest,” Sahni said. “Also, these patients are becoming older and, as they get older, their risk for cardiovascular disease also becomes greater.”

Analyses of cohorts of patients with cancer have determined that cardio-related morbidity and mortality is a great risk in this population.

For example, an analysis of more than 63,000 women with breast cancer included in the Medicare–SEER database revealed cardiovascular disease was a greater cause of death than breast cancer (15.9% vs. 15.1%).

“What’s very interesting is that, at the time of breast cancer diagnosis, only one-quarter of individuals had any cardiovascular risk factors,” W. Gregory Hundley, MD, FACC, FAHA, professor in internal medicine and radiology and medical director of cardiovascular imaging at Wake Forest Health Services, said in an interview. “That tells us two things. First, cardiovascular events are very important in individuals treated for cancer. Second, because the cardiovascular events occur after someone’s been treated for cancer, it implies that the cancer treatments are somehow related to the subsequent cardiovascular event.”

Armenian and colleagues conducted a retrospective cohort study that matched 36,232 2-year survivors of adult-onset cancer with 73,545 controls without cancer. The results, published in Journal of Clinical Oncology, showed survivors of multiple myeloma (incidence rate ratio [IRR] = 1.7; P < .01), lung/bronchus carcinoma (IRR = 1.41; P < .01), non-Hodgkin lymphoma (IRR = 1.13; P < .01) and breast cancer (IRR = 1.13; P < .01) had higher risk for cardiovascular disease than controls, particularly if they had at least two risk factors. Among those with cancer, 8-year OS was worse in those with cardiovascular disease than in those without it (60% vs. 81%; P < .01).

Adverse cardiovascular effects from cancer treatments tend to occur more often in patients with pre-existing risk factors, such as older age, hypertension and existing coronary artery disease, Sahni said.

Research on Medicare and private-insurance databases has showed hospital admissions for heart failure and other cardiovascular conditions “are more predominant after patients have started receiving treatments for cancer, implying that there’s something going on,” Hundley said.

Although some cardiovascular effects may happen immediately, most happen long after cancer treatment is finished. That could be 2 years, 5 years or even 10 years later.

“Because we do so much better at getting many people cured of their cancer, they often have late-term cardiac side effects while they’re being followed during survivorship,” Randall Holcombe, MD, MBA, director of University of Hawaii Cancer Center and previous chief medical officer — cancer at Mount Sinai Medical Center, told HemOnc Today. “It’s very important to understand what the long-term consequences of chemotherapy may be so that patients are followed appropriately and any cardiac issues are addressed.”

The evidence is not limited to cardiovascular events. Using serum biomarkers and noninvasive imaging, such as echocardiography and cardiac MRI, researchers have identified onset of subclinical cardiovascular disease during and after cancer treatment with cardiotoxic agents.

“The markers of subclinical disease that have been identified are associated downstream with future cardiovascular events,” Hundley said.

There also is evidence that childhood cancer survivors are more likely to develop metabolic health risk factors — including elevated BMI, hypertension and hypertransaminasemia — that can lead to premature adverse cardiovascular events.

Mechanisms and culprits

The harmful effects of cancer therapies on the cardiovascular system manifest in a variety of ways, experts told HemOnc Today.

The effects appear to occur in two general compartments, Hundley said.

“One, the heart muscle structure itself, involving the myocytes and the extracellular matrix that supports those myocytes, and, two, the areas of the body responsible for fatigue or vascular events — the blood vessels, the microcirculation and also the skeletal muscle,” he said.

Many cancer treatments are designed to attack cells with a high rate of metabolism. Thus, they may have an effect on the heart muscle cells, which have a very high rate of metabolism to enable the heart to beat. This effect could cause heart failure or cardiomyopathy.

In addition, some cancer treatments are designed to attack the vascular structure of tumors, which can have the unintended consequence of also attacking native vascular structures — such as the cardiovascular system — and could lead to coronary artery disease or myocardial infarction.

The classes of drugs known to be related to adverse cardiovascular events include anthracyclines, HER-2–targeted therapies and tyrosine kinase inhibitors.

Anthracyclines — used to treat breast cancer, leukemia, lymphoma and solid tumors — have been associated with congestive heart failure. Women treated with anthracyclines for breast cancer “are often young when they present with cancer, and we see a significant late-term toxicity from the anthracycline treatment,” Holcombe said.

HER-2–targeted therapies for breast cancer, such as trastuzumab (Herceptin, Genentech), “are mechanistically associated with reversible or predominantly reversible effects on cardiac muscle,” Barac said. “They may not be associated with high frequency of heart failure per se, but they are still recommended to be used only in patients with normal ejection fraction.”

Some research has suggested the agents are associated with as much as a fivefold increased risk for heart failure.

Some TKIs “operate by increasing hypertension and, therefore, exposing the individual to increased risk for hypertension, cardiomyopathy and heart failure,” Barac said.

Douxfils and colleagues assessed the impact of new-generation TKIs on risk for vascular occlusive events in patients with chronic myeloid leukemia.

Results, published in February in JAMA Oncology, showed that — compared with imatinib (Gleevec, Novartis) — the TKIs dasatinib (Sprycel, Bristol-Myers Squibb), nilotinib (Tasigna, Novartis) and ponatinib (Iclusig, Ariad) appeared associated with elevated risks for vascular occlusive events at 1 year (OR for dasatinib = 3.86; 95% CI, 1.33-11.18; OR for nilotinib = 3.42; 95% CI, 2.07-5.63; OR for ponatinib = 3.47; 95% CI, 1.23-9.78) without any improvement in OS.

Other anticancer agents linked to adverse cardiovascular effects include the antimetabolite 5-FU, which accelerates coronary artery disease; the selective proteasome inhibitor carfilzomib (Kyprolis, Onyx), which has been associated with congestive heart failure, cardiac arrest and arrhythmias; the angiogenesis inhibitor bevacizumab (Avastin, Genentech), which — like some of TKIs — blocks vascular endothelial growth, increasing risk for hypertension and bleeding; and thalidomide (Thalomid, Celgene) and its derivative lenalidomide (Revlimid, Celgene), which are associated with increased risk for thromboembolism (see Table).

Radiation therapy “can cause accelerated coronary artery disease, valvular disease and pericardial diseases, and these usually manifest themselves a decade after initial exposure,” Sahni said, noting that risks are particularly elevated in patients who receive both radiation and a chemotherapy drug known to have adverse cardiovascular effects.

It is important to continue researching how cancer treatments, particularly new ones, might adversely affect the heart and the vascular system, Barac said.

“Any new drug that touches the pathways that are important for cardiovascular homeostasis is a potential cardiovascular hazard,” she said. “But we can’t blow this out of proportion. For example, the risk in young patients without risk factors if they are given anthracyclines is very small.”

Collaborative efforts

The mounting evidence of cancer treatment–related cardiotoxicity has made collaboration between cardiologists and oncologists essential, experts said.

In September, the FDA held a public workshop on cardiovascular toxicity assessment in oncology trials in collaboration with the American Association for Cancer Research, American College of Cardiology (ACC), the American Heart Association and ASCO. Because new targeted therapies have introduced additional cardiovascular complications, goals of the session included to discuss best practices for identifying cardiovascular safety signals within trials, identify cardiovascular risk factors that need to be captured at baseline and throughout the study, and evaluate the role of imaging and biomarkers to predict and monitor cardiovascular toxicities.

“This was organized in collaboration with cardiology and oncology professional societies and was a true step forward,” said Barac, who co-chaired the workshop.

However, even though some cancer centers have set up cardio-oncology programs to facilitate this collaboration, others have been slower to embrace a formal partnership.

“Cardio-oncology is new and is not on the radar of many practicing oncologists around the country,” Holcombe said. “Oncologists understand that there are some cardiac ramifications of cancer and of cancer treatment, and they often refer patients to cardiologists, but [they] are not really aware of the emerging specialty of cardio-oncology. A lot of places in [the United States] don’t have a cardiologist who specializes in that.”

Cardiologists also must understand the need for their expertise to benefit patients with cancer.

“It is important that the next generation of cardiologists is trained to recognize the harmful cardiovascular effects of chemotherapeutic agents and how to best manage this growing patient population,” said Anita D. Szady, MD, director of cardio-oncology in the division of cardiovascular medicine at University of Florida.

To characterize the landscape and raise awareness, Barac and colleagues — on behalf of the ACC — in June 2015 published an assessment of cardio-oncology clinical care delivery and education, including the results of a survey of chiefs of cardiology and program directors.

“The survey respondents recognized clinical relevance but emphasized lack of national guidelines, lack of funds, and limited awareness and infrastructure as the main challenges for development and growth of cardio-oncology,” Barac and colleagues wrote.

Shortly before publication, the ACC created a member section in cardio-oncology, which the authors characterized as “a major step forward.”

“The best way to mitigate the cardiovascular risk is to get a cardiologist to understand the oncologic treatments that patients are receiving and get them involved early on so that you can get some baseline study and then compare later studies to what was obtained at baseline,” Holcombe said.

The process needs to begin with patient education about the potential cardiotoxicity of their cancer treatments, as well as the signs and symptoms of heart disease, Sahni said.

“Once a patient reports to you that they are feeling different from these drugs, which could be attributed to heart disease, we can intervene and detect earlier,” Sahni said.

Oncology physicians and nurse practitioners should be trained how to use tools like the Cardiac Risk Score Index, and how to recognize patients who have abnormalities on electrocardiogram and echocardiography, so they can quickly refer a patient to a cardiologist, she said.

“Patients undergoing potentially cardiotoxic chemotherapy should be monitored by incorporating techniques such as global longitudinal strain (GLS) in their surveillance echocardiograms, because the latest studies have suggested that a decline in GLS may predict cardiotoxicity even before the left ventricular ejection fraction declines,” Sahni said.

Testing for certain biomarkers, such as troponin I and myeloperoxidase, also could be useful adjunctive tools to predict which patients are at greater risk for developing cardiotoxicity, she added.

Once a patient’s cardiovascular risk is known, cardiologists and oncologists can weigh that against the cancer risks and “tailor-make the patient’s therapy to his or her cardiovascular risk profile,” Sahni said.

In addition to consultation, cardiologists and oncologists need to collaborate on research to help develop best practices for detection and treatment of cancer treatment-related cardiovascular conditions, Hundley said.

“There are not many primary or secondary prevention algorithms for preventing cardiovascular disease [after cancer treatment], although that looks like the primary cause of morbidity and mortality for these patients,” he said. “That’s why linking these two groups together to perform this research is important, so that we can design these preventive measures. The problem is, we don’t have the data or the know-how to implement guidelines because our management strategy is basically 30 years old.”

Earlier this month, ASCO released a clinical practice guideline on recommendations for the prevention and monitoring of cardiac dysfunction in survivors of adult-onset cancers. Key recommendations included to discuss risk for cardiac dysfunction with patients prior to starting therapy, implementing prevention and screening strategies in select higher-risk populations, and continuing cardiac imaging surveillance in high-risk survivors.

“In children with cancer, the short- and long-term risk of cardiac dysfunction associated with therapeutic exposures, such as anthracycline chemotherapy or use of chest-directed radiotherapy is well described,” the guideline authors wrote. “This led to the development of evidence-based guidelines to direct surveillance and prevention of cardiac dysfunction in survivors of childhood cancer. The need for comparable screening guidelines in survivors of adult-onset cancers is paramount, so that proper interventions can be implemented to avert the risk of cardiac dysfunction during and after completion of therapy.”

Primary prevention

One of the next major steps in the evolution of cardio-oncology is determining whether patients can be started on medications before or during cancer treatment to protect their heart and vascular system.

“Early detection is important, but prevention of cardiotoxicity is of even greater importance,” Szady said. “Early involvement of the cardiologist is key to not missing this opportunity.”

In the OVERCOME trial, published in 2013 in Journal of the American College of Cardiology, Bosch and colleagues found that patients with acute leukemia or malignant hemopathies assigned enalapril and carvedilol had no change in left ventricular ejection fraction (LVEF). However, those assigned no cardiovascular treatment experienced a decline in LVEF at 6 months (absolute difference on echocardiography, –3.1%; P = .035; absolute difference on cardiac MR, –3.4%; P = .09). In addition, at 6 months, patients in the intervention group had a lower rate of death or heart failure (6.7% vs. 22%; P = .036) and death, heart failure or final LVEF less than 45% (6.7% vs. 24.4%; P = .02) than controls.

Gulati and colleagues presented results of the PRADA trial, conducted in women with breast cancer, at the American Heart Association Scientific Sessions in 2015. Candesartan — an angiotensin receptor blocker — prevented LVEF decline, but the beta-blocker metoprolol was not protective in women treated for breast cancer with anthracycline or taxanes, trastuzumab if they were HER-2 positive, as well as radiation in some cases.

During a follow-up of 10 to 61 weeks, LVEF declined 2.6% (95% CI, 1.5-3.8) in those assigned candesartan and 0.8% in those assigned placebo (95% CI, –0.4 to 1.9; P for between-group difference = .026). A similar difference was not observed between metoprolol and placebo.

Pituskin and colleagues conducted the MANTICORE trial — published this year in Journal of Clinical Oncology — to test whether taking bisoprolol, a beta-blocker, or perindopril, an angiotensin-converting enzyme (ACE) inhibitor, for 1 year was cardioprotective in women assigned trastuzumab for HER-2–overexpressing early-stage breast cancer.

After 17 trastuzumab cycles, compared with placebo, those assigned bisoprolol had a lower decline in LVEF (–1% vs. –5%; P = .001). However, neither intervention had a significant effect on trastuzumab-induced left ventricular remodeling, which was the study’s primary endpoint. In addition, the bisoprolol and perindopril groups each had three patients interrupt trastuzumab due to left ventricular dysfunction, compared with nine in the placebo group (P = .03).

“It’s not the same whether you start someone on a beta-blocker or an ACE inhibitor,” Barac said. “There is nothing set in stone. That is one reason why it is important to get the cardiologist involved early.”

Studies such as these are “the mainstay of emerging research in this field,” Sahni said, because “even before the advent of heart failure from cardiotoxic chemotherapy, we can actually mitigate the cardiovascular risk and reduce the development of heart failure with these drugs.”

Future heart problems

Another aspect of cardiovascular care in patients who have undergone cancer treatment is that the longer they survive, the more likely they are to need cardiac intervention later in life.

With that in mind, the Society for Cardiovascular Angiography and Interventions published an expert consensus statement on management and treatment of patients with cancer presenting in the catheterization laboratory with cardiovascular disease.

“What [the society] realized was that, in the community, there was an obstacle to tackling patients with both cancer and heart disease because of the complexity of them, as well as factors such as anemia and thrombocytopenia,” consensus statement author Cezar A. Iliescu, MD, FACC, FSCAI, director of the cardiac catheterization laboratory at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “[The society] looked at centers and operators that had experience in doing these procedures and saw how they did them safely. The beauty of the document is that it encourages interventionalists throughout the country to help patients who have cancer in the effort to overcome cardiovascular problems.”

The document lists 20 chemotherapeutic agents associated with myocardial ischemia and posits an algorithm for screening people for percutaneous coronary intervention based on prior chemotherapy and radiation exposure.

It also shows that using fractional flow reserve to assess plaque vulnerability can defer intervention in more than 40% of patients with cancer and offers guidance on how to properly perform cardiac catheterization in patients with cancer, who — because of thrombocytopenia — are at increased risk for clotting and bleeding.

“We’re trying not to intervene and interfere with cancer therapy as much as we can,” Iliescu said. “But on the other hand, [the document] gives interventional cardiologists the tools in such a situation. ... Percutaneous coronary intervention is a little more meticulous in such a situation because of the increased frailty of the patient population and the added comorbidities.”

Further research needed

The field of cardio-oncology is on its way to being established, and much more is known today than just 5 years ago. However, several research gaps remain.

Following in the footsteps of the OVERCOME, PRADA and MANTICORE trials are more studies of cardioprotective therapies administered before or during cancer treatment.

Although these studies analyzed patients with normal heart function before cancer therapy, the SAFE-HEaRt study will evaluate whether treatment of breast cancer with HER-2–targeted therapies is feasible in patients with slightly reduced LVEF if they take beta-blockers or ACE inhibitors beforehand.

“SAFE-HEaRt is a cardiac safety trial in patients who otherwise wouldn’t be eligible for their therapies because their ejection fraction is lower,” said Barac, an investigator for that study.

There also should be more assessment of cardiovascular outcomes in phase 3 trials of new cancer treatments because “we would have more understanding of why the drugs have certain effects,” Barac said. “By the time the FDA announces that there might be a signal, it may be very late and represent a lost opportunity.”

More studies that would help in the development of risk prediction also are necessary, she said. For example, it would be useful to be able to combine a risk-prediction tool for cardiomyopathy with risk-prediction tools used by oncologists, she said.

Sahni said she would like to see more study of the long-term effects of cardioprotective agents in this population, now that patients with cancer are surviving longer than before.

In particular, she said, members of the field need to know whether lessons learned from studies of childhood cancer survivors — such as the ability of dexrazoxane (Zinecard, Pfizer) to reduce cardiovascular risks in survivors of childhood leukemia and lymphoma — can be applied to adult survivors.

Recognizing the importance of the issue, the NHLBI and NCI have issued a joint program announcement calling for research proposals for improving outcomes in cancer treatment–related cardiotoxicity.

Hundley said funds should be appropriated in three areas: basic science research to identify who is most at risk; population-based studies to identify risk factors and whether changing them because of cancer therapy boosts the development of cardiovascular disease and other heart diseases; and clinical trials of therapeutic interventions that could prevent cardiovascular conditions and events after cancer treatment.

A changed dynamic

Much more research needs to be done, but enough has been learned that the dynamic between cardiologists and oncologists has forever changed.

“The threshold to get cardiology involved has decreased,” Iliescu said. “It used to be that patients were referred to cardiology when they were extremely symptomatic and when they were showing signs of having heart failure, myocardial infarction or cardiac tamponade. The collaboration is moving from where we were treating people who were decompensating that — in many cases — the battle was lost, to where we are preventing, screening, detecting and facing these problems. In a way, it brings more complex decisions, but in the long run, it will definitely translate to better outcomes for the patients.”

Some institutions have adopted this attitude and created cardio-oncology programs or structured relationships between cardiology and oncology. However, many others have not yet caught on.

But the question remains: At what cost?

“You don’t want to trade cancer, which is a manageable disease, for ... cardiovascular disease,” Hundley said. “Working together will become the way to solve this.” – by Erik Swain

References:

American Cancer Society. ACS report: Number of US cancer survivors expected to exceed 20 million by 2026. 2016. Available at: www.cancer.org/cancer/news/news/report-number-of-cancer-survivors-continues-to-grow. Accessed on Nov. 27, 2016.

Armenian SH, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2015.64.0409.

Armenian SH, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.70.5400.

Barac A, et al. J Am Coll Cardiol. 2015;doi:10.1016/j.jacc.2015.04.059.

Bosch X, et al. J Am Coll Cardiol. 2013;doi:10.1016/j.jacc.2013.02.072.

Gulati G, et al. Late-Breaking Clinical Trials 4. Presented at: American Heart Association Scientific Sessions; Nov. 7-11, 2015; Orlando, Fla.

Gunn HM, et al. J Adolesc Young Adult Oncol. 2015;doi:10.1089/jayao.2015.0036.

Iliescu CA, et al. Catheter Cardiovasc Interv. 2016;doi:10.1002/ccd.26379.

Patnaik JL, et al. Breast Cancer Res. 2011;doi:10.1186/bcr2901.

Pituskin E, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.68.7830.

For more information:

Ana Barac, MD, PhD, FACC, can be reached at MedStar Washington Hospital Center, 110 Irving St. NW, Suite 1F12 18, Washington, DC 20010; email: ana.barac@medstar.net.

Randall Holcombe, MD, MBA, can be reached at University of Hawaii Cancer Center, 701 Ilalo St., Honolulu, HI 96813; email: rholcombe@cc.hawaii.edu.

W. Gregory Hundley, MD, FACC, FAHA, can be reached at Cardiovascular Medicine Division, Wake Forest Health Sciences, 1 Medical Center Blvd., Winston-Salem, NC 27157; email: ghundley@wakehealth.edu.

Cezar A. Iliescu, MD, FACC, FSCAI, can be reached at 17400 Red Oak Drive, Houston, TX 77090; email: ciliescu@mdanderson.org.

Gagan Sahni, MD, FACC, FACP, can be reached at The Mount Sinai Hospital, 1 Gustave L. Levy Place, Box 1030, New York, NY 10029; email: gagan.sahni@mountsinai.org.

Anita D. Szady, MD, can be reached at 1600 SW Archer Road, Gainesville, FL 32608; email: anita.szady@medicine.ufl.edu.

Disclosures: Barac, Holcombe, Hundley, Iliescu, Sahni and Szady report no relevant financial disclosures.