Kate Johnson


September 26, 2016

Targeting Unintended Effects on the Heart

For decades, oncologists have carefully stepped around their cardiologist colleagues and aimed ever-increasing numbers of toxins at tumors. Oncologists then regretfully watched the unintended effects on the heart.

The oncologist's traditional goal was to make the patient cancer-free, leaving cardiologists to do the cardiac damage control. But the now-blossoming field of cardio-oncology is taking a different approach.

Recognizing that cardiotoxic drugs are essential in the fight against cancer—and even that adverse cardiac effects may sometimes be a favourable prognostic indicator in oncology—the field of cardio-oncology has emerged with a quest to collaborate.

The goal is to maintain the momentum against cancer while keeping the health of the heart in central focus.

"We are trying to understand the synergism between cardiovascular risk factors, cancer, and cancer-treatment cardiac effects," said Ana Barac, MD, PhD, director of cardio-oncology at Georgetown Hospital and current chair of the American College of Cardiology's cardio-oncology council, speaking at a special session at the American Society of Clinical Oncology (ASCO) annual meeting.[1]

That goal is a moving target, with new cancer drugs in new combinations and new regimens emerging almost daily. Adding to this challenge is the graying population of cancer survivors for whom the aging heart provides yet another layer of complexity in the management of cardiotoxic risk.

The growing patient need for cardio-oncology experts has created a professional need for better understanding between the fields.

When it comes to issues of the heart, cardiologists have a paradigm that "time is muscle," which could guide oncologists in the realm of cardiotoxicity, noted Daniel Lenihan, MD, of Vanderbilt University Medical Center and president of the International CardiOncology Society, North America.

"Can we apply cardiology principles to issues that are occurring in patients with cancer? The answer is yes, and it could make a really big difference," he said. "The key is to recognize the problem and initiate therapy—not just close your eyes."

But part of the problem is knowing what to look for. Heart failure is a well-understood risk of anthracycline-based chemotherapy, with evidence-based approaches to its management.

"If you recognize the problem early and you initiate appropriate heart failure therapy, the chance of improvement is quite substantial," said Dr Lenihan. "But if you wait 6 months or longer, the chance of any improvement is almost negligible."[2]

Even patients with substantial anthracycline-induced cardiac dysfunction do well when therapy is initiated early.[3]

But the modern era of cancer therapies has expanded the oncologist's need for a more sophisticated understanding of injuries to the heart.

Addressing a Wider Range of Cardiotoxicities

"Cardiovascular toxicity is no longer just heart failure or cardiomyopathy," explained Javid Moslehi, MD, director of the cardio-oncology program at the Vanderbilt-Ingram Cancer Center.

The explosion of new targeted cancer therapies has not only transformed the nature of cancer treatment but also lengthened the list of potential cardiotoxicities, ranging from myocardial, to vascular, to thrombotic, or metabolic. "We have to be smart about the nature of the toxicities," he said.

For example, vascular endothelial growth factor (VEGF) inhibitors cause "a myriad" of cardiac issues, which can vary from patient to patient.

Virtually any patient who gets a VEGF inhibitor has an increase in blood pressure within weeks of treatment, generally in the hypertensive range.

"About 10%-15% of patients get cardiomyopathy (admittedly this is often asymptomatic and often reversible), some get thrombosis, but really the 800-pound gorilla in the room is hypertension," said Dr Moslehi. "Virtually any patient who gets a VEGF inhibitor has an increase in blood pressure within weeks of treatment, generally in the hypertensive range."

Although anti-VEGF-induced hypertension is generally manageable, clinicians need to be on guard for potentially serious problems, said Dr Lenihan. In patients who are already hypertensive at baseline, blood pressure can shoot up dangerously fast, he said, citing a small study in which six of 224 patients on sunitinib developed symptomatic heart failure within a mean of 22 days from treatment initiation, and four of them died.[4]

"This is not your usual hypertension; it is not essential hypertension; it is a different category altogether, so we have to learn how to respond better to that."

But how to respond? Is there some strategy for blood pressure control that should be incorporated into anti-VEGF therapy?

"We don't know much about this," confessed Dr Lenihan. However, he said that the use of angiotensin system inhibitors (ASIs) can have "a big impact on overall survival."

In one study, patients treated for metastatic renal cell carcinoma with targeted therapies (sunitinib, sorafenib, axitinib, temsirolimus, bevacizumab, and interferon alpha) who also received ASIs had improved overall survival compared with those who received no anti-hypertensive therapy (adjusted HR [aHR], 0.810) or other types of anti-hypertensives (aHR, 0.838), including beta-blockers or calcium-channel blockers.[5]

"The choice of blood pressure medicine really did matter," Dr Lenihan said. The most frequently used ASIs in that study were enalapril, lisinopril, valsartan, and ramipril.

But what about tackling other chemotherapy-induced cardiotoxicities?

Vascular problems are another growing concern with new cancer therapies. A recent study[6] looking at the proteasome inhibitor carfilzomib in the treatment of relapsed multiple myeloma showed a "dramatic increase" in deep vein thrombosis and pulmonary embolisms among patients who had carfilzomib added to lenalidomide and dexamethasone therapy.

Although the study authors described "a favourable risk-benefit profile," the cardiac toxicity details were buried in a supplementary appendix "It's pretty clear that this was not a myocardial but a vascular issue," said Dr Moslehi.

"As cardiologists, our go-to for vascular problems is to pull out a statin," said Dr Lenihan, citing another recent paper[7] on renal cell cancer patients treated predominantly with anti-VEGF showing better overall survival if they were on statins versus not (aHR, 0.749).

A study of breast cancer patients receiving anthracycline-based chemotherapy showed that statins were protective against new-onset heart failure.[8]

Issue: How to Measure Cardiotoxic Risk?

Not everyone who takes a potentially cardiotoxic drug ends up with cardiovascular problems, so a "more sophisticated and knowledgeable" approach to risk assessment is needed to identify patients most at risk, said Dr Lenihan.

In a study presented at ASCO 2014,[9] Dr Lenihan's group showed that in anthracycline-treated patients, the strongest predictors of subsequent cardiotoxicity were baseline numbers of cardiovascular risk factors (OR, 1.27), cancer type other than breast cancer (ORs, 1.98 or 2.8 for lymphoma or "other" vs breast), and a baseline B-type natriuretic peptide (BNP) level above 100 pg/mL (OR, 2.6).

"Just as precision medicine has revolutionized cancer treatment, a personalized approach must be incorporated into toxicity assessment," added Dr Moslehi.

But what to do with that information about a patient's risk factors is a matter of debate. Would red-flagging patients at baseline compromise optimal oncologic dosing? Or would "it affect how soon we stop vital oncologic treatment?" asked Michael Ewer, MD, a cancer cardiotoxicity expert at the University of Texas MD Anderson Cancer Center.

Catching the early warning signs of cardiotoxicity is still an evolving science of imaging and biomarkers.

Patients with high cardiotoxic risk can potentially benefit from prompt interventions and enhanced monitoring, admitted Dr Ewer, but catching the early warning signs of cardiotoxicity is still an evolving science of imaging and biomarkers.

"We've heard that myocardial dysfunction is not the whole story, but when it comes to imaging, the myocardium is what we've focused on, and the test we seem to rely on is the left ventricular ejection fraction (LVEF)," he said.

However, LVEF is an "imperfect marker" for drug-induced myocardial dysfunction because decreases can be caused by other, nonpharmacologic insults, and their detection is often too late in the game, "You can have a whole bunch of damage before the EF goes down," Dr Ewer said.

Biomarkers, on the other hand, offer some sensitivity.

"With cell loss, as seen in infarction, troponin, creatine phosphokinase (CPK), and lactate dehydrogenase (LDH) are elevated, and in heart failure brain natriuretic peptide is up," he explained.

However, knowing how to interpret these biomarkers in the context of chemotherapy is less clear.

During anthracycline therapy, troponin is expected to be elevated, "reflecting the early lethal effect of therapy on the myocyte," Dr Ewer explained. "However, if it is unusually high, we may conclude that the heart is especially sensitive and cardioprotective strategies might be appropriate."

Similarly, after anthracycline treatment, elevated troponin would be unexpected because cell death has stopped and the heart has remodeled. "So if we see elevated troponin, and we sometimes do, then cell death is probably ongoing, the heart is experiencing oxidative stress, and the BNP might also be elevated. These patients should be managed "in the same way that we handle cardiac dysfunction in other settings—that is, preload and afterload reductions," he advised.

ASCO's forthcoming clinical practice guideline, "Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers," which is to be available soon, may help with many of these questions, commented Dr Barac.

Currently, different guidelines are talking to different groups of healthcare providers in different languages, she noted.

For example, the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) 2013 guidelines on heart failure[10] "are frequently read in depth by cardiologists, who would rarely know about the National Comprehensive Cancer Network (NCCN) clinical practice guidelines[11] or the Children's Oncology Group (COG) guidelines[12] that are frequently checked by oncologists. That's why we need to work on synchronizing them."

By addressing which cancer patients are at risk, preventive strategies before and during potentially cardiotoxic cancer therapy, and appropriate surveillance, Dr Barac said the ASCO guidelines should prove helpful to both oncologists and cardiologists.

Dr Barac disclosed research funding from Genentech/Roche (Inst).
Dr Moslehi disclosed a consulting or advisory role with Acceleron Pharma, Bristol-Myers Squibb, Millennium, Novartis, and Pfizer.
Dr Lenihan disclosed a consulting or advisory role with Bristol-Myers Squibb, OncoMed, Onyx, and Roche/Genentech, and research funding from Acorda Therapeutics and Millennium.
Dr Ewer disclosed honoraria from Roche; a consulting or advisory role with AstraZeneca, Pharmacyclics, and Roche Laboratories; and that he is the author of the book
Cancer and the Heart.


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