Talking Tall Rounds®: Cardiovascular Oncology Center

Podcast Transcript

Announcer:

Welcome to the Talking Tall Rounds series, brought to you by the Sydell and Arnold Miller Family Heart Vascular and Thoracic Institute at Cleveland Clinic.

Patrick Collier, MD, PhD:

Welcome to Tall Rounds and the topic today is Cardiovascular Oncology Center, a multidisciplinary approach. So just by way of introduction, and my name is Dr. Patrick Collier. I'm a staff here in cardiovascular medicine and one of the hats I wear is co-director of the Cardio-Oncology Center. Because cardio-oncology isn't a specific disease, I thought it would be worthwhile just to have a few introductory slides and give a little background.

Patrick Collier, MD, PhD:

So what is a cardio-oncology? I would say it's the newly organized subspecialty that covers the broad intersection between heart disease and cancer. Cardio-oncology patients tend to be cancer survivors who get cardiovascular disease or cardiovascular disease survivors who get cancer. And this subspecialty has emerged because of increased survivorship in both cohorts and recognition of very impressive epidemiology. So there are currently 21 million people living in the US who have ever been diagnosed with cancer and about 28 million living US people with diagnosed heart disease. And these are growing cohorts with 2 million new cancer diagnoses per year in the US and over 50 percent of our population with risk factors for cardiovascular disease. Now because of an aging population and shared risk factors, this is a growing epidemiology and recognizing that this is a big overlap cohort and it's growing and it includes some patients with complex and unmet needs. There's been a rapid growth in dedicated cardio-oncology services.

Patrick Collier, MD, PhD:

And just to give a roadmap for how such a center works, we see that a very important link is this consult service between oncology and the center. But also now there are subspecialist referrals from other cardiologists dealing with challenging cases. These days, patients are also self-referring and we also get patients from pediatric survivorship clinics. Now you can see these two-way spokes to many other subspecialty services. So the cardio oncology center certainly acts as a triage service. So we interact quite a lot with cardiothoracic surgery and structural intervention dealing with cardiac masses and radiation heart disease. A very important link is with prevention, dealing with uncontrolled cardiovascular risk factors in our cancer population. Cancer-related thrombosis, we interact with vascular medicine. Arrhythmia, we link with electrophysiology and heart failure, really any form of heart failure, myocarditis, for example.

Patrick Collier, MD, PhD:

The oncology teams often directly interact with imaging labs, but the Cardio-Oncology Center helps with that interaction also. So today at Tall Rounds, it starts with a case report of a rare and challenging diagnosis. Really in order to highlight the importance of our multidisciplinary approach and where I'm going to follow with specific talks, we've got specialists in imaging, oncology, cardiology, electrophysiology, heart failure and cardiothoracic surgery. And at the Cleveland Clinic we truly pride ourselves on our team of teams approach and I think our Cardio-Oncology Center serves as a great template of this. So I'd like to welcome to the podium Dr. Erika Hutt, and Erika is our great imaging fellow and she's going to present a case report as discussed.

Erika Hutt, MD:

Thank you Dr. Collier, and good morning everyone. As Dr. Collier said, I'll be presenting this case. It's a challenging and rare case of a patient that I had the opportunity of caring for in my month during the Cardiac Intensive Care Unit. So this was a 20 year old male with no significant past medical history. He presented with chest pain for four months, initially to an outside hospital and was found to have a large mediastinal mass on an initial CT test that he had done for actual ruling out of PE. It showed that there was right atrial invasion, and I'll show you the image here. So you start seeing the mass there, it's invading the right atrium. We're going to come back and you can see it starts in a mediastinal and it invades into the right atrium. So very large mass. These are the echocardiogram pictures. This is an RV inflow view and as you can see, the valve act sort of like a ball in cage and causes obstruction of the tricuspid valve inflow, very large. And here you can see the color and you see acceleration of low through that valve. So very minimal amount of blood flows coming to the RV. Again, this is just a short axis to show the size of the mass. Here they measured at 5.3 times 5.4 centimeters. And here's again, just a different image just to show how big the mass is, and it's really just invading the entire right atrium. And this is just a profile through the tricuspid valve, a doppler profile where you can see that there is tricuspid valve stenosis or at least functional tricuspid valve stenosis with a mean gradient of eight. This is his EKG, so you can see he's in atrial flutter. You can see that more clear here in lead one where you can see that these flutter waves there. And he was going at around 120 beats per minute on admission. So this was his hospital course on that's day negative six, presented to the outside hospital. Day negative seven they did a CT guided biopsy at the outside hospital, which was non-diagnostic. They decided to transfer him to us. Day zero, he's admitted to Cleveland Clinic. Again, we try an IR guided biopsy and it's again, unfortunately non-diagnostic. Day nine, he comes to the CICU with atrial flutter with rapid ventricular response. He was going at 150 and developed cardiogenic shock from that. In day 10, just a day after coming to our unit, he was placed on VA ECMO for management of cardiogenic shock, which was obstructive plus cardiogenic. He also had IV dysfunction. And then on day 12 he was taken to the OR for mass removal. We still didn't have a diagnosis, which was a very, very challenging situation. But he was obviously very young, no comorbidities, so we really wanted to give him a chance. And on day 26, he was discharged home. And this are the surgical images that Dr. Unai provided to us. So as you can see, this is a right atrial view. And you can see this is the large right atrial mass. This is the resected right atrial tumor. And this is just the final how it looked with a pericardial patch over here. And it ended up being an angiosarcoma on biopsy.

Erika Hutt, MD:

So this is the follow up event, so he was discharged home one month postop. He was start on adjuvant chemotherapy with gemcitabine and docetaxel. Two months postop, he unfortunately had the first relapse and developed long nodules. So we knew it was metastatic and he was enrolled in the first trial, six months postop, he had brain metastasis, chemo was changed, he was treated with Gamma Knife. 12 months postop, he was enrolled in another trial and 13 postop, his brain meds actually really improved, but unfortunately 19 months postop he passed away. And the reason why I wanted to bring him up is because despite the fact that we have a negative outcome, I do think that on a 20 year old, giving him those 19 months of life after the surgery I think is a good thing because otherwise he probably would've passed on the first admission. Thank you.

Patrick Collier, MD, PhD:

My talk is in seven minutes or so, and I talk about the role of imaging and biomarkers in cardio-oncology. So I'm going to try and address a couple of questions. So what are the typical cardio-oncology scenarios? What are the risk benefits that we need to think about? What are the types of kind of toxic therapy cut points that define cardiotoxicity? How often should we do imaging and what are the limits of such surveillance? So there are many scenarios, but the most typical are dealing with patients with cancer that have established cardiovascular disease, new cardiovascular symptoms, or are undergoing cardio toxic therapy and require baseline and serial valuation of heart function. So what about chemotherapy related cardiotoxicity? What is it? Well, really 40 years ago or so, it started out as anthracycline related heart failure. But now it's fair to say really with the huge range of new chemotherapeutics, cancer therapeutics, much more complex range of cardiovascular pathologies are in this area and more of it because of increased survivorship and the term cancer therapeutics related cardiac dysfunction, you'll see CT or CD in the literature. And this term is being coined to try and encompass all the potential cardio toxic effects. That includes left vent systolic dysfunction, hypertension, myocardial infarction, myocarditis, electrical disturbances, and it's a long list.

Patrick Collier, MD, PhD:

Now just to start, it's important to state that most patients tolerate chemotherapy without cardiac toxic effects, but it's an important minority and they can suffer a wide range of serious cardiac problems, either acutely during treatment or thereafter. Not all of it is preventable and not all of it is actually related to chemotherapy, could be common disease. I think, again, when we're thinking about our decision making, it always centers on net benefit of therapy and we have to consider the toxicity and we have to think about the cancer prognosis and existing therapies. So two sort of extreme scenarios. If you have a poor prognosis cancer with few existing treatment possibilities, you may be forced to accept toxicity for a new therapy. But alternatively and hopefully more commonly with treatment advances, toxicity may be unacceptable for later generation drugs in a cancer with multiple existing therapies that has a generally good prognosis.

Patrick Collier, MD, PhD:

So this slide tries to highlight the very large variation of different types of therapies and cardiotoxicities. This again, by no means is exhaustive. You can see anthracyclines, HER2 new targeted therapies, fluoropyrimidines, anti-antimicrobial therapies, VEGF inhibitors, radiotherapy, and the list goes on. Again, the bottom shows a list of the pathologies that are most common that we have to deal with. But heart failure, left ventricular dysfunction is probably the one that creates the most referral. So with regard to heart failure, left ventricular dysfunction, which imaging test to use? We would say echo is preferable because it's widely available, it's accurate reproducible, there's no ionizing radiation. We know that cardiac MRI can be hugely helpful in selected cases as it remains a gold standard test in many of the parameters that we measure cardiology. MAGA testing has fallen out of favor. It's certainly not first line now because of the radiation, but also cross modality error.

I would note that many of these patients have already had staging CT scans and this may be already available and can be certainly very helpful from a cardiologist's perspective because it can inform about anatomy, heart chamber size, atherosclerotic burden, et cetera.

Patrick Collier, MD, PhD:

When we're talking about echo ejection fraction still is the parameter of choice strain we find to be supportive and sometimes very helpful, particularly when it's concordant with ejection fraction. The cut points to define cardiotoxicity really have varied a lot because of the different sources of truth. So from the FDA approved labeling to clinical trial protocols to cut points to adjust therapy and guidelines, you can see different definitions in the literature. There has been attempt just last week, the European Society of Cardiology at their Barcelona meeting did produce this guideline document and in it mentioned essentially hopefully an internationally agreed definition for cancer therapeutics related cardiac dysfunction. And again, somewhat complicated and again subdivided into asymptomatic and symptomatic and then through grades of severity.

Patrick Collier, MD, PhD:

So who should get what test? In this document they highlighted their recommended baseline and serial testing and they did this for various different types of treatment. And when you review their suggested protocols, you can see it's quite testing intense. And I suppose when you get enthusiastic cardiologists together, it's probably no surprise that this is their initial recommendations. But I guess this is a template document and this is a first draft so to speak. I think in clinical practice you would find that such testing is not necessary as frequently performed. Our approach with regard to anthracyclines is typically to get assessment of baseline after therapy and for patients that are getting higher doses, certainly above 300 milligrams per meter squared, we can consider imaging at those points or of course if patients develop symptoms or particular concerns.

Patrick Collier, MD, PhD:

Similarly, for HER2-targeted therapies, where I would say over time we've seen less cardiotoxicity. Our approach has been to image patients with commandant cycling therapy at baseline post and cycle three monthly and try and identify higher risk patients such as those with longstanding hypertension, reduced ejection fraction and in those patients do baseline and maybe three monthly testing, certainly while on treatment. If you look at their document, however, they're even suggesting that three monthly therapy is indicated for low risk patients during treatment with follow-up studies. So that's certainly quite, I think we could agree that that's fairly intensive testing. They went through more than just anthracyclines and HER2 new therapies. They gave some instruction on VEGF inhibitors at tyrosine kinase inhibitors, proteasome inhibitors, and indeed immune checkpoint inhibitors. Which certainly have had a lot of media attention with concern for rare but potentially myocarditis. They also included stem cell transplant patients and they tried to also deal with how should you follow up these patients in terms of remote testing, once they get past their treatments.

Patrick Collier, MD, PhD:

They dealt with special cases such as pregnant women, carcinoid heart disease, and AL amyloid. So I think it's very certainly a very comprehensive document and I think it will probably serve as a good template for which we can try and modify and optimize over time. So with all this testing, there are certainly limitations and it's certainly worth considering those. I would say certainly high on the list is limited cost effectiveness data. In clinical practice we certainly have seen the consequence of high measurement variability. These patients are difficult to image and we've certainly seen that false positives aren't without concern. Identification of false positive cardiotoxicity risk can prohibit and can limit patients from accessing life-saving therapies. And that's a very important concern. I think it's also to be aware that these patients are going through a very challenging scenario where the heartrate blood pressure medications and fluids status can often vary quite a lot. There's often confounding variables in terms of ejection fraction assessment. And we also need to consider that there's other causes other than just the chemotherapy. The chemotherapy always gets blamed, but we also have to think about concomitant ischemia, stress cardiomyopathy, myocarditis or infiltration in this higher risk population.

Patrick Collier, MD, PhD:

A slide on biomarkers now troponin as a marker of cardiovascular toxicity, particularly in the setting of antipsych induced myocyte death and cardiotoxicity has been studied also with regard to trastuzumab or HER2 new targeted related loss of myocyte contractility. And these have been markers that have been shown to be able to predict risk for events such as heart failure. Perhaps the most studied biomarker remains NT-proBNP as a marker to confirm the presence of heart failure, but also to identify a specific heart failure phenotype that is a higher risk for adverse outcome. But just like imaging, biomarkers have disadvantages. So we haven't a fully established sampling strategy. We have a problem with non-specificity in these highly sensitive markers, especially in the presence of multiple confounders. There's a challenge of interpreting surrogate endpoints. We don't treat biomarkers, we treat patients and a lack of clinically meaningful cutoffs.

Patrick Collier, MD, PhD:

So certainly quite a lot of challenges in this area, but something that we're working towards. And I think with the sheer numbers of people involved in this area, I think we'll come up with some better solutions over time. So following on, and most important, that was a cardiology perspective, but this is cardio-oncology.

Rohit Moudgil, MD, PhD:

Today I'm going to talk about the management and cardiac issues during and after treatment. Once they have detected there is some kind of cardiac issues going on related to the treatment itself. How do we manage those patients during the treatment and after the treatment? So what are the possibilities? When we start some kind of medication, there's wide variety of things that can happen between the chemotherapy initiation at the end of it as well as other things. So, cardiomyopathies are one ischemia, hypertension, pulmonary hypertension, myocarditis, pericardial disease, radiation, thromboembolism, QD prolongation, as well as arrhythmia. There's lot of things that can happen between the start and the finish of the actual chemotherapy and each and every one of them carries a specific nuance in terms of how to manage it. So Dr Tang will be talking about the heart failure aspect and just quickly going over and reverberating what Dr. Shepard said. The therapy strategies for dox-cardiotoxicity where we can prolong the continuous infusion or we can use the liposomal dox and again, there's a concept of efficacy on this as well as the use of dexrazoxane has been known to cause a little bit of decrease in cardiotoxicity but has some oncological implication in addition to GDMT. But there are other strategies we can use in conjunction with what we have for cardiomyopathies and it's also drug specific also. For example, for trastuzumab, if we are able to improve the cardiac outcome, we would like the patient go back on trastuzumab because we know from clinical trials that the benefit is quite huge. And this is a small hazard ratio determined. So, if you stop the trastuzumab for only four weeks, the chance of cardiovascular outcome increases by 15 percent in just four weeks.

Rohit Moudgil, MD, PhD:

So trastuzumab is a very powerful medication. Our goal is to liaison with the actual oncologist and see how we can optimize their cardiac function so they can get these lifesaving cancer medications. That's where the cooperation comes in. Not only that, there's other aspect of cardiomyopathy. So, 5-FU has known to cause different kind of cardiomyopathy. About 20 to 30 percent of patients on 5-FU can develop cardiomyopathies and using nitrous calcium channel blockers and use of other therapies such as the oral medication capecitabine could be a possibility. So this is where we liaison. Same with VEGF inhibitors. So AC inhibitor tends to be first choice, but the blood pressure can be as high as 250 systolic. So you need some of the stronger medications such as nifedipine to aggressively manage these patient, the newer medications coming out, for example, CAR T-cell therapy, and we are going to see a lot of inflammatory disease secondary to that. And what we are going to find is that the use steroids and other IL-6 antagonist, the inflammatory aspect that we haven't explored too much in cardiology. We might be delving into it because as more and more medications are coming out, chemotherapy is immune checkpoint inhibitors which are looking directly at the inflammation. And certainly radiation is a big part of the therapy. When we look at the oncology patient and management of that is also becoming more and more prominent in how to do it.

Rohit Moudgil, MD, PhD:

So as mentioned, immune checkpoint inhibitors are here to stay about roughly 50 percent of the cancer have some form of immune checkpoint inhibitors. And this is currently the clinical trials going on in checkpoint inhibitors, the phase one, phase two, phase three. And each dart represented clinical trials. So you can see how much of the patients we are going to be start seeing, who will be treated with immune checkpoint inhibitors and on the peripheries all the different kind of cancers that you can see.

And just to give you an idea of what has happened, if you look at the top left hand corner in 2014, 2015, those are the numbers of fatal and non-fatal myocarditis. Just in 2016 and 17, there's a massive increase in myocarditis patients. And thing is we are going to keep seeing increase on these myocarditis patient and we are going to see more and more of it. And thing is again, as I mentioned before, the management just also becomes trickier in terms of, for example, this is a journey of one of the patient with myocarditis. As you can see the troponins are going up and kinase, but the way we treated it, first we tried with prednisone in this patient and then there was plasma exchange and there was a use of a abatacept, which is an inhibitor of one of the CTLA-4, which is an immune checkpoint inhibitor use of a abatacept to prevent severe form myocarditis.

Rohit Moudgil, MD, PhD:

So there are certain nuances which is more specific to cardio-oncology rather than just a cardiac patient that we have to be aware of. Abatacept is a really good medication. And right now there's a multi-center trial going on called Atrium, which is actually run by my good friend Dr. Neilan from MGH. And we are the part of that clinical trial also. So there's a lot of nuances that goes on into this. Other things that I'm going to briefly touch about is security prolongation. So some of the medications, some of the chemotherapy, for example the arsenic trioxide or the hdac inhibitors, they tend to cause QT prolongation and we have to be aware of that medication because if these patient are on that medication. So we have to make sure that we are doing ECGs and the specific guidelines associated with it in terms of how we look at the QT.

Rohit Moudgil, MD, PhD:

So one of the best formulas to use is published in 2004 for the QT measurement, but you have to be careful and when we look at the FDA guidelines for each and every medication, there's a specific guideline how to manage the QT prolongation in terms of looking at the electrolytes. As well as adjusting the dosages based on the QT. So we have to be cognizant about that. Last but not the least, atrial fibrillation is a big part of it. And we know that patient who get diagnosed with atrial fibrillation has more propensity to detect cancer. And a patient who have cancer has within the first three months they have more propensity of daring atrial fibrillation. So they go hand in hand and the management of atrial fibrillation becomes tricky. For example, this medication called Ibrutinib, which is being used quite a lot in CML and CLL patients and hairy cell leukemia, about 25 percent of the patients in the real population can develop atrial fibrillation. And the problem with that is that if you give anticoagulation these reports anywhere from 60 to 56 percent of these patients can develop IDC.

Rohit Moudgil, MD, PhD:

So it becomes very finicky, in terms of how to manage this patient. But at the end of the day, what the tolerance is all about and all what we are trying to reverberate is the cooperation. It is a teamwork. Cardio-oncology, as Dr. Collier said, is based on this teamwork. So we are coming together in the beginning but is keeping together is a progress. And now including clinic, we are working together and it's going to be success. And as Dr. Collier mentioned then ESC guidelines just came up over the weekend and that's a platform. It is an expert opinion in terms of what we should do. We here, including clinic, are actually starting registry, which is a global registry, about 130 institutions, 24 different countries. And we are actually liaisoning with all the cardio oncologists all across the world to actually do the research, and to have a really good evidence based guidelines that will come down the road. But at least CSC guidelines does provide a very good template to start with. Thank you very much for your time.

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