COMMENTARY

Cardio-oncology Not Just for Subspecialists

Melissa K. Walton-Shirley, MD; Ana Barac, MD, PhD; Laxmi S. Mehta, MD

Disclosures

May 07, 2018

Melissa K. Walton-Shirley, MD: Hello. I'm Melissa Walton-Shirley for the heart.org | Medscape Cardiology, and I'm joined today by Laxmi Mehta, section director of prevention and Women's Cardiovascular Health Program and associate professor of internal medicine at the Ohio State University Medical Center. Welcome, Laxmi.

We have to recognize that we all take care of cancer patients.

Laxmi S. Mehta, MD: Thank you. It's great to be here.

Walton-Shirley: Ana Barac, director of the cardio-oncology program at MedStar Heart and Vascular Institute and associate professor of medicine at Georgetown University in Washington, DC. is joining us as well.

Ana Barac, MD, PhD: Thank you, Melissa; great to be here.

Cancer and Cardiac Injury

Walton-Shirley: Thank you. These are the perfect panelists for a discussion on cardio-oncology.

When I think of cardio-oncology, I think of the cardiotoxicity of chemotherapy. We already know that radiation can worsen coronary heart disease[1] and that cancer itself can damage heart muscle,[2] but, Ana, you noted that it is much broader than that. Can you give a brief overview of what cardio-oncology encompasses today?

Barac: It is a field that has grown tremendously because of two primary reasons: Patients with cancer are living much longer, and the treatments are getting better. There are the two large populations that cardio-oncology addresses: patients who are currently undergoing treatment, and patients who are survivors, who received treatment. Both cardiovascular disease and cancer increase with age, so we have synergy between two competing causes of death, and an ageing population.

The field is evolving as cancer and cardiovascular therapies are evolving. For every new therapy, we start asking, is this good for this patient? We have entire populations of patients for whom therapies were not tested. Take, for example, transcatheter aortic valve replacement (TAVR). Is it better for some cancer survivors than traditional surgery? We could not have asked that 15 years ago. The field is really increasing with the number of patients and with the number of cancer treatments.

More Complex Than Anthracyclines

Walton-Shirley: Back in the day when I first started in cardiology, we were concerned about anthracyclines. Now, we have immunotherapy and proteasome inhibitors, et cetera, and we were just talking earlier about how we used to only see systolic dysfunction, but now we see diastolic dysfunction. Do you think there are differences in the outcomes that are produced by these types of cancer therapies with regard to cardiovascular health?

Barac: I think that in the space of anthracyclines, that is an excellent point. We are learning more about subclinical features of toxicity. It is not only toxicity of the drug. In the example of diastolic dysfunction, when we image patients serially after anthracyclines, there is a linear progression of diastolic dysfunction. There is a signal but also some noise, because of existing risk factors. If I see diastolic dysfunction, it could be because of the drug, but it could be because of untreated hypertension.

When I see diastolic dysfunction in a patient getting anthracyclines, I ask myself: Am I treating all cardiovascular risk factors? Diastolic dysfunction per se does not always lead to systolic dysfunction, but when I see it, it's a red flag that I need to pay more attention to these patients.

Mehta: Also, as an echocardiographer, there is so much disparity in how we diagnose diastolic dysfunction. Sure, we have the American Society of Echocardiography (ASE) guidelines,[3] but many people do not necessarily follow them to the letter. They are really unclear—should I follow this pattern or this pattern? Is it a grade 1, is it not? There are discrepancies between different readers as well as intrareader observability, and that makes it challenging as well.

Barac: That was one of the reasons why the ASE developed guidelines[4] specifically for cancer patients, and a big part of that guideline was to send a clear message that you should follow the recommendations of ASE on how to perform an echo, but be cognizant that in these patients, oncologists are ordering the echo. As a cardiologist, I'm going to look at the images even if my colleague is reading it. I will take your message very differently than if you send a message to the oncology community.

Another important area is that there are currently at least two classes of oncology agents that are linked to decreases in cardiac function. This weighs into the decision-making on choice of drugs, and particular attention is needed in comparing changes on the echocardiogram and knowing what number is going to drive the oncology decision.

It takes team care in the most complex way you can imagine, because the decision needs to take into account the benefit of the cancer drug and the risk for cardiac dysfunction—what if the ejection fraction (EF) decreases, or what if diastolic function improved within the perspective of the cancer efficacy. It is an ongoing balance. We are continually getting new data.

For example, if the cancer drug is not very efficacious, the oncologist may say, "I can pass on this drug and use something else." Or you can have a situation where an oncologist says, "This is a very aggressive tumor biology; I really would like to consider using this agent."

There are also cases where we see subclinical evidence of toxicity, but that doesn't always mean that we have to stop the drug. We could try to treat and follow the patient as they are on the cancer treatment and decide what to do along the way.

Echo Image Quality

Walton-Shirley: We have to also highlight the danger of the phraseology, "This is a technically difficult study," because the problem that I deal with is that I see some images on multimodality machines that are not dedicated cardiac echocardiography machines. I have to read images that are not just from one period to another, but also from one machine to another with different acquisition protocols. Oftentimes, I have to back up, reframe it, and hand-measure the left ventricular (LV) and diastolic dimension, because that is a life-threatening thing if I report out that the ventricle has gotten larger or the EF has dropped.

Mehta: The other thing, Melissa, is that when patients get their follow-up echocardiograms during cancer treatment, the echocardiographer and the sonographer largely focus on systolic dysfunction. They're not doing a full study, and that can be quite limiting, so we may not pick up the early signs.

Your center and my center may be focused on that, but across the country, the world, is that really what's being done on an everyday practice? A bit different.

Barac: It's an evolving practice. There is need for education on both sides of the aisle—the oncology and cardiology communities. The patient is in the middle, and we are both taking care of the patient. What I foresee is collaboration on the trials that are going to focus on both cardiovascular outcomes and oncology outcomes.

Comprehensive echocardiograms are extremely important, but the reaction to findings of comprehensive echocardiography cannot be "Let's change management." We really need studies that are going to incorporate cardiovascular outcomes in oncology trials, that are going to allow the continuation of treatment until symptoms occur or include those symptoms in outcome assessments; that's how we're going to move forward.

Cardiac Consult for the Cancer Patient

Walton-Shirley: Absolutely. Laxmi, you wrote the recent American Heart Association (AHA) statement on breast cancer,[5] and you're a prevention expert. Tell me, should cardiologists see patients before or after they undergo treatment, or both?

Even though they are undergoing oncology treatment, they still need to be worried about their heart, and do the same preventive things they should be doing regardless.

Mehta: That's a great question. It really depends on the patient. If a patient has underlying heart disease, they definitely should see their cardiologist beforehand, to make sure their cardiologist is aware. They can discuss the treatments that are going to happen. It doesn't necessarily mean that treatment should be affected by their underlying heart disease, but it's a conversation that should occur.

Certainly, if they end up having some sort of therapy that does affect their heart, they need to see their cardiologist and have those collaborative discussions between the cardiologist and the oncologist. Some centers are fortunate to have a cardio-oncology program like we do. We collaborate on certain patients that have side effects from treatment. The outcomes of the patient, how the patient is feeling, determines whether they need to see a cardiologist or not.

It is imperative, also, to have a conversation about prevention for these patients. We know that cardiovascular disease is the number one killer of men and women. We need to understand that, even though they are undergoing oncology treatment, they still need to be worried about their heart, and do the same preventative things they should be doing regardless of whether they have cancer or heart disease: diet, exercise, having their blood pressure under control. Those are just key things that we all should be doing.

Data From ACC

Walton-Shirley: Absolutely. Then, Ana, were there any takeaways from the clinical trials presented at this ACC 2018?

Barac: There were two late-breaking clinical trials; both focused on an interesting area that has grown in recent years, and that's primary prevention. They were addressing the subpopulations of women with breast cancer. The CECCY trial from Brazil[5] touched the audience in many ways. First, it addressed patients who need to receive anthracycline treatment. Most of these women had triple-negative breast cancer (no HER2-targeted therapy; those patients were excluded).

I was privileged to serve as a panelist, and I asked Dr Avila to comment on how she screened 1100 women to enroll 200 and randomize them. She pointed to major difficulties in being accepted by the oncology community. They were turned down by three centers who did not want to participate in the trial.

The trial tested whether LV function would be better if carvedilol is started at the time of anthracycline treatment. They randomized patients to placebo versus carvedilol.

When you do a trial, you need to follow the guidelines. For example, anthracyclines are not given to patients with low EF, so those patients were excluded them from the trial, because you cannot randomize them. The patients started with EFs of roughly 65% and ended up with EFs that were not significantly different at the end of the 6-month trial when they imaged them again.

You can say it's a negative trial, but there are a lot of positives in the trial. Dr Avila commented that by the end of the trial, they created wonderful partnerships with the oncologists. They're going to continue follow-up of these patients for at least 2 years. There is still a chance we may see a signal, because we learned that from other studies that you don't see the effect immediately.

I contrasted that trial with a similar trial that was presented 2 years ago at the AHA, the PRADA trial,[6] from Norway. The PRADA trial was slightly smaller; it randomized women to metoprolol and candesartan in a 2 × 2 factorial design, and showed that candesartan attenuated LV dysfunction by a small percent. You're talking from 64% to 61%, very small signal from the angiotensin receptor blocker. I think that the difference was because the PRADA trial used MRI to assess EF. It's a more accurate test if you're going to follow LVEF over time. Echo has lower accuracy.

They found that after receiving anthracycline, all of the patients had elevations in troponin that was attenuated with metoprolol. It was small but statistically significant across the board.

Yesterday, the Brazilian group showed that the same thing happens with carvedilol. There was a very nice clear signal: Troponin goes up [with anthracyclines] and goes down with carvedilol. I think this provides some mechanistic look into it. We know that anthracyclines cause injury. It's very important to mention that all of these patients are getting low-dose anthracyclines. It was a total cumulative dose of 240 mg/m² of doxorubicin. I don't think that these data mean we should give carvedilol to everybody in the future, but I think it's a very nice start.

We need to be patient, gather data in a very systematic and organized way and partner with oncologists. In my institution and around the country, there is far more interest in primary prevention or cardiac dysfunction.

Mehta: We need more long-term data; 6 months is not enough to make definitive decisions.

Cardio-oncology As a Recognized Subspeciality?

Walton-Shirley: You can tell by the complexity of our conversation that we could talk about this topic for a long time. I just want to hear a brief yes or no: Should we take cardio-oncology and make that a recognized subspecialty?

Mehta: It is a great subspecialty to have, and I am fortunate to be in a large center that has that availability, but we have to recognize that we all take care of cancer patients, whether they came to us with a history of cancer or they develop cancer afterward. Monitoring them and understanding the side effects of chemotherapy or radiation therapy, or targeted therapies, is key.

The burden of this doesn't just fall on the oncologist or the cardiologist; the primary care physician needs to be aware of this, [as does] the emergency department physician.

Many people don't have access to a large cardio-oncology presence in their region. We have to be cognizant enough and that is why we need to educate all, and that's also why we came out with that scientific statement on breast cancer and heart disease, so that the burden of this doesn't just fall on the oncologist or the cardiologist. The primary care physician needs to be aware of this. The emergency department physician who sees this patient acutely needs to be aware of it, and also the patient needs to be aware of this potential overlap.

Walton-Shirley: Ana, what do you say to that?

Barac: I would say that we need different levels of certification. I think education 101 is needed across the board for cardiology and oncology. For the more complicated cases, we obviously need clinical trials. Some of these patients become eligible for cardiology trials in the space.

When you need experts, you need layers of education. I was privileged to lead the cardio-oncology section within the American College of Cardiology (ACC) and we recently held the first Heart House Roundtable that brought together representatives of the American Society of Clinical Oncology; the American Society of Hematology; the National Cancer Institute (NCI); the National Heart, Lung, and Blood Institute (NHLBI); the Centers for Medicare & Medicaid Services (CMS); the US Food and Drug Administration (FDA) oncology representative; and the FDA cardiology representative, and we laid out a number of items. Individual practitioners want to collaborate, but it becomes really difficult on a day-to-day basis when you have a number of things to take care of. Help from the professional organizations, from regulatory bodies, from government agencies, really goes a long way. I am very optimistic.

Mehta: It is also important to recognize that we're not just talking about patients during their cancer treatment, but also their long-term effects—so 20 years later. That's where it gets challenging in terms of whom do they see and what is the diagnosis. And that's where education 101 comes in. Cardiologists, oncologists, primary care, emergency department, all—it should be a med school discussion.

Walton-Shirley: I couldn't agree more. I'd like to thank Ana and Laxmi for chatting with me. I really enjoyed it. I learned a lot, and I hope our viewers did too. Until next time, this is Melissa Walton-Shirley for the heart.org | Medscape Cardiology. Thanks for joining us.

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