Cardio-oncology booms but awareness lags

Cardio-oncology is expanding, fed by a steadily increasing population of cancer survivors at elevated risk for a range of cardiovascular diseases and complications because of the anticancer treatments they received. Cardio-oncology’s quick growth has also been driven by the rapidly expanding universe of cancer treatments with direct or indirect adverse effects on a diverse range of cardiovascular functions.

During the past year, the field’s rapid evolution has featured the first formal diagnostic and care standards in two iterations: A position paper on the cardiovascular toxicities of cancer treatment from the European Society of Cardiology (ESC), released in August 2016 (Eur Heart J. 2016 Sept 21;37[36]:2766-801); and a guideline for preventing and monitoring cardiac dysfunction in adult cancer survivors, issued last December by the American Society of Clinical Oncology (ASCO) and endorsed by the American Heart Association (J Clin Oncol. 2017 March 10;35[8]:893-913), but notably not endorsed by the American College of Cardiology, despite having an ACC representative on the guideline panel. In 2015, the ACC started a Cardio-Oncology Section, one of 20 special-interest sections it maintains, and by mid-2017 the section had some 500 members.

Despite these milestones and spread of the cardio-oncology concept, the cardiovascular consequences of cancer treatment remain underappreciated and incompletely understood by many cardiologists and primary care physicians, experts say. Other current limitations include the absence of a well defined cardio-oncology subspecialty and training infrastructure and significant gaps in the field’s evidence base, including no direct proof of the clinical value of screening for the earliest signs of cardiovascular adverse effects in cancer patients.

“I’ve had recent conversations with cardiologists who said ‘I’m not sure what cardio-oncology is,’ ” said Tomas G. Neilan, MD, director of the cardio-oncology program at Massachusetts General Hospital in Boston.

“The number one priority for cardio-oncology is to raise awareness about it at every level: patients, their support people, oncologists, cardiologists, and primary care physicians,” said Daniel J. Lenihan, MD, until recently professor of medicine and a cardio-oncologist at Vanderbilt University in Nashville, Tenn., who in September moved to Washington University in St. Louis to start a cardio-oncology program there.

More than just heart failure

A few decades ago, in the primordial days of cardio-oncology, the concept of cardiovascular damage during cancer therapy focused entirely on myocardial damage caused by anthracyclines and chest radiation, a concern that eventually expanded to include trastuzumab (Herceptin) and other agents that target the human epidermal growth factor receptor 2 (HER2). These treatments cause significantly reduced left ventricular ejection fractions and heart failure in a significant minority of treated patients. Patients who receive combined treatment with an anthracycline and trastuzumab are at the highest risk for developing heart failure with reduced ejection fraction, but even among patients treated with this combination, fewer than 5% develop outright heart failure.

While this parochial view of cardio-oncology has recently shifted, it remains true that myocardial damage from a relatively large cumulative anthracycline dose, or from radiation, causes some of the most extreme cases of cardiovascular adverse effects and remains an ongoing problem as these treatments stay front line for selected cancer patients.

But some of the recent burgeoning of cardio-oncology has followed the recognition that many other drugs and drug classes can cause a spectrum of adverse cardiovascular effects.

“Cardio-oncology has become more complicated, with hundreds of new cancer treatments, each one with an adverse effect profile. Many of the new drugs cause vascular or metabolic issues,” said Javid J. Moslehi, MD, director of cardio-oncology at Vanderbilt University. Heart failure and ejection fraction were the “easiest things to tackle” in the recent ASCO guidelines, but there are many other manifestations of cardiovascular toxicity from cancer treatments.

“There has been a significant focus on heart failure and cardiomyopathy due to anthracyclines and HER2-targeted therapies. I think the field will continue to evolve over the next 5 years to focus on other cardiovascular complications, including arrhythmias and vascular disease,” observed Michael Fradley, MD, director of cardio-oncology at Moffitt Cancer Center in Tampa. “In addition, there will be an increased focus on targeted drugs and immunotherapies,” agents that Dr. Fradley said “have many unique cardiovascular complications. We need additional guidelines regarding the management of a variety of cardiotoxicities as well as long-term monitoring strategies.”

In a review article Dr. Moslehi published toward the end of 2016, he fleshed out the wider scope of adverse cardiovascular effects from cancer therapies, noting that the vascular endothelial growth factor (VEGF) signaling pathway inhibitors, drugs such as bevacizumab (Avastin) and aflibercept (Zaltrap), have been documented to cause hypertension, arterial thromboembolic events, and cardiomyopathy; and that tyrosine kinase inhibitors have been shown to cause vascular events, QT interval prolongation, and cerebral and peripheral vascular events (N Engl J Med. 2016 Oct 13;375[15]:1457-67).

In his own recent review, Dr. Fradley highlighted adverse cardiovascular effects from additional anticancer drug classes, including proteasome inhibitors, which can trigger hypertension and cardiomyopathy; immunomodulators, implicated in causing both venous and arterial thromboembolism; and the immune checkpoint inhibitors, linked with myocarditis, arrhythmias, hypotension, and myocardial ischemia (Eur Heart J. 2016 Sept 21;37[36]:2740-2). A similarly broad spectrum of adverse cardiovascular effects linked with a wide range of anticancer treatments also appeared in the ESC 2016 position paper on cancer treatments.

But while the range of cancer treatments that can have some impact on the cardiovascular system is strikingly large, experts uniformly caution that far from every patient treated for cancer needs an immediate cardiology consult and work-up, especially when the cancers appear in young adults.

“We’re not quite at the point where every cancer patient needs to be seen by a cardiologist or cardio-oncologist,” Dr. Fradley noted in an interview.

The most common cardiology referrals made by Sandra M. Swain, MD, are for patients with either breast cancer or lymphoma who undergo treatment with an anthracycline. “If a patient receiving this treatment has a history of any cardiovascular disease, I’ll refer them. But if a patient is just undergoing adjuvant chemotherapy with another drug, and if everything looks fine and an echocardiogram shows everything is normal, then I don’t refer. I refer [to a cardiologist] any patient with a cardiac history just in case they experience toxicity, but that’s not every patient. It’s not feasible to refer every patient,” said Dr. Swain, a medical oncologist who is professor of medicine and associate dean for research development at Georgetown University in Washington.

“If a patient develops hypertension while on treatment I refer them to a PCP or cardiologist. I don’t treat hypertension myself. But if a patient is ‘normal’ they don’t need a cardiology assessment up front. It’s impossible to refer all patients, especially younger patients, with current resources. There are too many patients who receive cardiotoxic therapies to refer everyone. I involve the cardiologist once there is evidence of damage,”she explained.