Heart of the Matter: Cardiac Toxicity

In 2002, Katharine Ray, a 27-year survivor of Hodgkin lymphoma, wanted work "that mattered" when she joined the staff of The Minnie Pearl Cancer Foundation (now PearlPoint Cancer Support) in Nashville, Tenn. A year later, at age 42, she received a diagnosis of stage 1 breast cancer, probably a result of radiation treatments she received when she was 14.

The diagnosis served as an important point of demarcation for Ray, who had never really processed what happened to her as a teenager.

"I had been there a year and was just beginning to understand my chances for a second cancer, and then it happens, and it's reality," she says. "I began looking past the breast cancer treatment & began gathering all the information I could find for late effects from the Hodgkin treatment going forward."

Ray took her research on possible late effects and, with her oncologist, made a plan for how she should be followed in the areas where she could be at risk.

She had noticed that at times her heart beat rapidly, and she was getting easily winded while climbing stairs or taking walks that involved any kind of incline. All her test results were normal, but in 2012 she decided to see a cardiologist who would understand what to look for when considering her medical history. She didn’t have to look far.

Across town from PearlPoint, cardiologist Daniel Lenihan directed the clinical research program at Vanderbilt University Medical Center in the division of cardiovascular medicine. In 2009, he cofounded the International Cardioncology Society (ICOS) with a goal to promote training and study in the field of cardiac implications of cancer treatments.

Lenihan is one of a growing number of cardiologists who focuses on cancer patients. This partnership of cardiologists and oncologists combines their knowledge to protect the hearts of people undergoing cancer treatment—patients such as Katharine Ray.

Heart Hazards

People who have survived cancer are at risk for a number of cardiac long-term and late effects linked to radiation and chemotherapy treatments, ranging from high blood pressure on one end of the spectrum to congestive heart failure on the other.

Radiation treatment can cause a thickening of the inner lining of the artery, known as atherosclerosis, which can cause blood clots and other problems associated with narrowed arteries and reduced blood flow. Chemotherapy and radiation may also cause structural heart problems, such as cardiomyopathy (weakening of the heart muscle), valvular heart disease and valvular degeneration, as well as pericardial effusion (a buildup of fluid around the heart) or pericardial constriction (an abnormal thickening of the lining enclosing the heart).

In addition, not only is radiation for Hodgkin lymphoma at a young age now recognized as a risk factor for later heart problems but also for breast cancer. In the past two decades, as these issues have come to light, patients with Hodgkin disease, as well as others receiving radiation treatments, now receive lower total doses of radiation, smaller doses given more often (hyperfractionation), cardiac shielding and education about following a heart-healthy lifestyle.

While changes in procedures and reductions in the amount of radiation have, presumably, reduced radiation’s toxic effects, a recent study of 2,168 women treated between 1958 and 2001 in Sweden and Denmark confirmed that "exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease." The study, which appeared in a March issue of The New England Journal of Medicine, found the increase was proportional to the average dose to the heart, that it began a few years after exposure and continued for at least 20 years.

In an accompanying editorial, Javid Moslehi, co-director of the cardio-oncology program at Brigham and Women's Hospital and Dana-Farber Cancer Institute in Boston, pointed to radiation as one of the effective treatment strategies that has led to the decrease in breast cancer mortality since 1990. He also called for preventive cardiovascular medicine before treatment to reduce atherosclerosis.

"The current study points to radiation therapy as a significant risk factor for coronary disease in patients with breast cancer," he wrote. "This 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."

Of the chemotherapy agents with cardiac toxicities, anthracyclines (particularly doxorubicin) have been studied most, and it appears that 1 percent of all cardiomyopathy cases (a weakening of the heart muscle, which can lead to heart failure) are linked to their use.

While anthracyclines, as well as the alkylating agent cyclophosphamide, have been known to carry the risk of cardiac toxicity, newer targeted therapies have also been shown to cause heart damage. In a study appearing in The Breast in fall 2010, researchers reviewed trials that demonstrated cardiotoxicity in patients who had received a number of targeted therapies, particularly Herceptin (trastuzumab), although in contrast to anthracylines, recovery is seen in most cases with Herceptin. The study also examined those who had received the vascular endothelial growth factor (VEGF) inhibitor Avastin (bevacizumab), as well as tyrosine kinase inhibitors, such as Nexavar (sorafenib), Tykerb (lapatinib) and Sutent (sunitinib). The researchers concluded that more effective screening methods were needed, as well as strategies to identify patients, before beginning treatment, who are at high risk for developing cardiac complications.

A standard measure of the heart’s function, the left ventricular ejection fraction (LVEF) shows how well the heart is pumping and can indicate cardiomyopathy (also called cardiac dysfunction) if it drops below a certain level. Significant declines can indicate congestive heart failure, which exhibits symptoms of tiredness, shortness of breath due to fluid (pulmonary edema) and leg swelling.

Lenihan refers to a specific clinical trial, in which 19 percent of patients experienced a reduction in the LVEF, 8 percent developed clinical signs of heart failure, and hypertension occurred in up to 47 percent.

The introduction of Herceptin was widely considered one of the greatest advances in breast cancer treatment, but studies have shown that patients with early-stage breast cancer demonstrated symptomatic heart failure in as many as 4 percent of cases and asymptomatic LVEF in as many as 14 percent of cases when treated sequentially with an anthracycline and Herceptin. Due to known cardiotoxicity of Herceptin, current label guidelines recommend a baseline LVEF assessment and regular reassessment.

Who's at Risk

In some instances, cardiac problems become immediately apparent when treatment begins, allowing for the offending drug to be halted until other options can be considered. For other patients, lingering effects remain that may or may not become apparent unless specifically tested for, ultimately becoming a long-term effect.

Patients who are older, have a history of hypertension or have an LVEF that is below normal following chemo-therapy or during Herceptin treatment, appear to be at higher risk for Herceptin-related cardiomyopathy.

For some patients, however, the effects of treatment become late effects, not appearing until years after treatment has ended, when patients may not connect heart problems with cancer treatment received in the distant past. These cardiac problems may also appear subtly and may be compounded by other risks, such as smoking and obesity.

"Patients who were treated five or 10 years before are at a higher risk for the development of heart failure than a patient population that did not get chemo," Lenihan says. "It doesn't mean every person is going to get heart failure, which is why I think you need to look at all the things that may contribute."

For example, he says, patients who have no cardiac risk factors, who exercise, don't smoke and don’t have high blood pressure, may have cause to suspect their heart problems are the result of prior cancer treatment. "But if you smoke and your blood pressure remains 160 over 90 for years, that’s probably what contributed mainly to heart failure."

In addition, with the exception of a few of the new targeted therapies, clinical trials have traditionally not included end points that allow for a careful study of cardiac side effects, meaning most previous studies either didn’t follow patients long enough or in enough detail to know exactly how common the problem is.

What's Being Done

Lenihan says these consistently inconsistent findings on cardiac toxicity have left the cancer community to determine who should be followed for a problem that has yet to be identified in its magnitude, while at the same time exploring ways to prevent cardiac toxicity and identify those patients at risk for cardiac problems.

Indeed, in 2006, the American Society of Clinical Oncology (ASCO) board of directors rejected proposed guidelines about cardiac follow-up due to lack of evidence on the benefits and harms of screening for cardiac and pulmonary late effects. At the same time, it directed a panel, consisting of experts in numerous clinical and research fields relevant to cancer survivorship, to complete a clinical evidence review as the basis for a future research agenda on the late effects of cancer treatment.

The panel reviewed studies on cardiovascular and pulmonary disease after treatment with radiation and chemotherapy. It found the estimated incidence of radiation-induced cardiac disease is 10 to 30 percent by five to 10 years after treatment. In addition, the panel found anatomic or functional abnormalities of the heart with all anthracyclines now in use.

Patients who were treated five or 10 years before are at a higher risk for the development of heart failure than a patient population that did not get chemo.

The report also said that, while Herceptin-related cardiac dysfunction has been recognized, it rarely causes death, and, in most cases, is reversible with improvement in cardiac function following drug discontinuation or treatment with cardiac medications.

The panel's conclusion: "An increased incidence of cardiac and/or pulmonary dysfunction is observed in cancer survivors. Research is needed to identify high-risk patients, and to determine the optimal screening strategies and subsequent treatment."

What's Next?

Gregory Cote, an oncologist at Massachusetts General Hospital in Boston, specializes in treating sarcoma and oversees phase 1 clinical trials, the first level of investigating a new drug in research subjects.

"We determine which patients are high-risk for cardiac issues from family history and clinical and diagnostic exams, and, for anthracyclines, we limit the dose of drugs and don’t go over it," he says. "But if a patient is not curable, we may break that rule occasionally or switch to less cardiotoxic formulations, such as liposomal anthracyclines. We need to remember that, despite the known cardiac risk, these are some of our best drugs, and we have to accept some risk to help cure or make patients' lives longer."

Cote says Massachusetts General also has cardiologists on staff who specialize in oncology, and, if a patient is high-risk, Cote will get them involved from the beginning to help with cardiac toxicity issues. In that way, he says, the cardiologist knows the patient from the start if issues arise.

He is concerned about younger patients who have sarcoma, because many will be treated with anthracyclines and, if cured, have years of life ahead of them. As a phase 1 researcher, he says he wants to be sure that cardiac late effects of new agents are determined early.

"From the early history of Herceptin, we learned that there could be cardiac side effects not initially apparent in the animal models," Cote says. "To help recognize problems, we see these clinical trial patients quite frequently and are always looking for side effects we weren't expecting to see."

Patients ending treatment without a survivorship care plan should make note of how much radiation (measured in grays, or Gys) they were given, how often they received the radiation and the exact field of radiation. (Women receiving radiation to the left breast are at greater risk of cardiac toxicity than those receiving it to the right.) They should also note the names of the chemotherapy drugs they were given, the dosages and how the drugs were administered.

If their primary care physician isn't aware of long-term and late effects of cancer treatment, patients may need to provide that information or look for a primary care doctor who is.

Those with symptoms or functional limitations should have a cardiac evaluation, Lenihan says. "Whenever possible, risk factors should be modified or reduced by treating elevated blood pressure, normalizing lipids, encouraging weight reduction and smoking cessation."

Lenihan says that future research on late cardiac effects in cancer survivors needs to include advanced cardiac imaging techniques such as 3-D echocardiography, strain rate imaging and magnetic resonance imaging (MRI), as well as novel cardiac biomarkers and genetic determinants of response to cancer treatment. "We think that if you detect the problem in its earliest stage, you can prevent and improve the damage that may have occurred," he adds.

He points to one study of patients with left ventri-cular dysfunction related to anthracycline exposure who were treated with contemporary heart failure therapy. "In those patients treated within two months of the completion of chemotherapy, 64 percent achieved complete recovery of LVEF."

More important than just following up after treatment, Lenihan adds, is implementing pre-emptive plans before treatment begins to identify which patients are more prone to cardiac problems, and providing easily accessible drugs to prevent or diminish the damage these drugs do to the heart.

Cote agrees that optimizing a patient's cardiac status prior to receiving known cardiotoxic drugs is preferred—but in some cases, the urgent need to begin treatment takes precedence.

When Katharine Ray began seeing Lenihan, she had a standard echocardiogram and stress test. He also performed a cardiac catheterization.

She says she had developed an aortic valve insufficiency, which means her heart valve didn’t close tightly, resulting in a backward flow of blood into the left ventricle—a condition that could lead to widening of the left lower heart chamber. She also had stenosis, a narrowing or obstruction of the heart valve, which required monitoring.

Ray, who now serves as the director of communications and marketing at PearlPoint, says Lenihan encourages her to stay active and to exercise "just short of exhaustion."

"I am also on a beta blocker, even though my blood pressure is not problematic, because it helps with the tachycardia [fast heartbeat]," Ray says. "And I am on a statin for cholesterol, even though the number is not alarming."

Lenihan compares a patient with a cancer treatment-related cardiac issue to a runner with a bruised thigh. "If you keep running on it, it becomes a major problem, but if you take meds or [do] exercises that protect your leg muscle, it will repair itself back to normal," he says. "The key is early detection."