Cardio-Oncology for Pediatric and Adult Cancer Patients

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances at Cleveland Clinic podcast for medical professionals, exploring the latest innovative research in clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today, I'm happy to be joined by Dr. Shahn Amdani pediatric cardiologist, specializing in heart failure and transplant at Cleveland Clinic Children's. He is here today to talk to us about cardio oncology. So welcome.

Shahnawaz Amdani, MD: Hi, Dr. Shepard. Thank you so much for having me on this podcast and it's an honor and privilege, and I look forward to discussing with you something that I'm extremely passionate about.

Dale Shepard, MD, PhD: Yeah. Well, thanks for of joining. We're going to talk a little bit about the cardio-oncology program. But maybe just to fill in our listeners, what's your role here at Cleveland Clinic?

Shahnawaz Amdani, MD: Sure. So I've been here for just about three years and I wear various hats within the Cleveland Clinic Children's Institution also circling around my passion for taking care of heart muscle disease. And in that role, I've been fortunate to take care of patients with inherited heart muscle diseases, genetic cardiomyopathies as they call it. Patients with different kinds of heart muscle diseases, such as those with dilated cardiomyopathies, hypertrophic cardiomyopathies, restrictive cardiomyopathies, and left ventricular non-compasionate cardiomyopathies. I also co-lead the Fontan or the single vental congenital heart disease clinic here. One of the main focuses that I have sort of had, and fortunate to have had that was to build the pediatric cardio-oncology program or the cardiac surveillance program for children who are undergoing care chemotherapy or have completed their chemotherapy and are now long term survivors.

Dale Shepard, MD, PhD: Perfect. So let's take a step back, because there's a lot of listeners from a lot of different backgrounds. What exactly is cardio oncology?

Shahnawaz Amdani, MD: Yeah, that's a great question. So up until 15 or 20 years ago, we really didn't have an understanding that people who undergo chemotherapy or radiotherapy or any treatment to eliminate their cancer had any long term effects to the heart and vascular system. It's really kudos to people like you, Dr. Shepard and everyone else here at Taussig and here at Cleveland Clinic Children's in our oncology department that the success of cancer chemotherapy has unfortunately, or fortunately brought our cardiologist to realize that there are long term consequences of the therapies that you give. And both to the heart and to the vascular system. So the cardio-oncology is essentially a field that's born more recently. And the prime focus here is to make sure that we are collaborators and partners trying to help mitigate and prevent some of the cardiac complications that may arise when somebody's on chemotherapy radiotherapy.

Dale Shepard, MD, PhD: So give us a little bit of an idea. Now I certainly use a lot of doxorubicin. That's a key player here causing trouble, and it's just fascinating that someone can have had doxorubicin decades before and it still puts them at risk. Tell us a little bit about how that toxicity develops. What do we know at this point about toxicity?

Shahnawaz Amdani, MD: So the anthracyclines are the whole class in which you have doxorubicin and daunorubicin, they're a very effective tool for treating various childhood malignancies. But one of the things that it does is it causes free radical production and iron chelation and whatnot. And it's essentially... It boils down to causing in many cases, irreversible myocardial damage that's persistent and progressive. So there are two spectrums that we see in patients who get anthracyclines, like doxorubicin and daunorubicin. One is the acute cardiotoxicity where you have an acute decline in heart function and heart failure symptomatology that need IV inotropic or IV heart medications. And then the flip side is many of these patients actually don't have anything early on. But over time, the stress to the heart builds up and they add on cardiovascular risk factors. As we all age, one of the things that unfortunately happens is you add on certain cardiometabolic risk factors, such as obesity and hypertension and diabetes. And along with already that... Already with the damage that's happened early on it tags on and then causes long term decline in heart function, which often presents as cardiomyopathy or heart muscle disease.

Dale Shepard, MD, PhD: So tell me a little bit about the pediatric program that you have and how patients get involved and what does it look like?

Shahnawaz Amdani, MD: Yeah, it's certainly a labor of love. I think as you may have appreciate from the oncology perspective is a diagnosis of cancer is really devastating for a family. And especially for a child it's life altering both for the child and more so for the family. And what ends up happening is I think over the last three years, we've been very fortunate. I've been fortunate to work with some of my oncology college weeks here, Dr. Seth Rotz who heads the pediatric cancer survivorship program and Dr. Rabi Hanna, who's the head of the pediatric hematology oncology division. Who's really a fierce advocate for understanding and trying to help make sure that these kids have the highest quality of life. So what we do now is we over three years develop a big... A systematic way in which we screen these patients early on.

And it depends, I always have this laundry list of questions for our oncologist is, what kind of malignancy is this? How much radiation is the child going to receive? How much of this radiation is going to be directed towards the chest, how much chemotherapy the patients going to receive, what kind of chemotherapy as you're realizing. And it's not only anthracyclines you have other kinds of chemotherapeutic agents that cause arrhythmias, that cause coronary artery disease that cause hypertension that cause myocarditis or heart inflammation. So I try to understand that and then tailor what kind of preventative and therapeutic strategies could be applied to prevent and mitigate some of the complications.

So it's very involved, we get involved in many cases from the get go and we think it's a higher situation. So as to help make sure that the chemotherapy regimen stays on track and some of the other ones, we try to allow the family to process the oncologic diagnosis. And once they get discharged from their initial chemotherapeutic regimen, then they see me in the clinic. And then we go over sort of the long term goal where I'm really the supporting player, making sure that these kids have fulfilling lives.

Dale Shepard, MD, PhD: And then is this something where you continue follow up for a long period of time as part of their survivorship plan?

Shahnawaz Amdani, MD: Yeah, absolutely. And so what ends up happening is we are testing out two things. One is sort of making them understand that the cardiac surveillance is going to be lifelong. The duration and the frequency is going to change over time as they get further off from the malignancy. And it also depends on two things the dose of anthracyclines that they received. The cumulative dose of anthracyclines that they received and the cumulative radiation that they have received in particular to the chest. And then the second thing is help making sure that they're active. They understand that they're... You cannot change some of the cardiac risk factors that you've already received, but you could change the metabolic risk factors. So not being obese, making sure you don't get hypertension or diabetes. Being up and active could help mitigate some of the effects that have already gone into the heart.

Dale Shepard, MD, PhD: So the patients that develop acute problems, they oftentimes may need further therapies down the road. And those therapies could be harmful as well. How often can we get patients back to a point where they have a relatively normal function?

Shahnawaz Amdani, MD: Most of the patients... I'd say, 90% of the patients that have acute cardiotoxicity will have reversal. If you are treated at a center of excellence like ours, that you had at Cleveland Children's, early institution of cardiac therapies. And we are fortunate here at Cleveland Clinic to have the best cardiovascular providers. So we have the full gamut of supportive therapies that we could use from IV medications to mechanic of circulatory support. And we've utilized all sorts of things here to help prevent the patient having a catastrophic event. So we tend to have at least 90, 95% success in turning things around. Having said that we also have had patients from outside institutions who had irreversible myocardial damage that have gone to receive ventricular and heart transplantation. And now living successfully with that. So we are fortunate to be able to provide that kind of support to these patients.

Dale Shepard, MD, PhD: And I guess this follow up from the transplant setting. What's the gap that's required at this point from the time of a cancer diagnosis to a transplant? Seems like it's kind of a moving target at times. Where is that currently?

Shahnawaz Amdani, MD: Yeah. So that's a great question. Again, it depends on the type of malignancy and that's where I love to partner with smart oncologists like yourself and others at our institute. And it's really on a case by case basis. Some people say it's a hard for two years or three years, but for us, it's a case by case in modern discussion where you try to weigh the risks and benefits. Or what kind of malignancy, what are the chances of relapse, if it relapses, what are the chances of cure? Is bone marrow transplant applicable to this population? So we try to make sure that the patient gets the maximum benefit and maximum chance of survival. So it's a very complicated question and a very big discussion that takes place.

Dale Shepard, MD, PhD: From a cardiac toxicity the patients that don't get an acute problem, but we're going to be following long term, how good are the current risk models? How well can we predict, and is there work being done to improve the ability to do that?

Shahnawaz Amdani, MD: Yeah. So we've certainly gotten better at our imaging tools. So back when traditional cardiac surveillance was done, or somebody said 15 years ago that we got cardiac surveillance for somebody with cancer, you were essentially looking at echocardiogram derived ejection fraction. Or the amount of squeeze that the heart has with each peak. Nowadays we've gotten more sophisticated or especially over the last decade where we look at something called a myocardial strain or the amount of deformation that the heart goes through with each peak. And the estimate of that is called the Global longitudinal strain. And we certainly look at that and the change in the global longitudinal strain, which could proceed the decline in ejection fraction by a couple of months to a couple of years. So it allows us to get that lead time. I think what we all love is the lead time, because it allows us to modify some of the things that allows... That can then prevent overt cardiotoxicity.

On the other hand, it's brought a new set of challenges because what do you do with the subclinical cardiotoxicity in a pediatric patient? Do you start them on therapy? Do you wait for a little bit? And again, that's where the nuance of being at a center where you've seen hundreds of these and are managing them on a daily basis. There's still no award trials in the pediatric room that have determined which patients go on to have overt cardio toxicity. And that's where sort of the nuance of medicine comes in and experience comes in.

Dale Shepard, MD, PhD: What are some of those therapies that you discuss with patients and their families in terms of trying to minimize risk?

Shahnawaz Amdani, MD: Cardio preventative strategies that, especially this is some of the... This is an area where we derive a lot of expertise from our adult colleagues. And in particular, there are two medications that are used. One is called an ACE inhibitor or an angiotensin converting enzyme inhibitor, which essentially decreases the stress to your heart and avoids adverse remodeling. The other is called Carvedilol or a beta blocker, which again does something, in a similar fashion. And both of these could be used two ways. We either use them preventative or empiric. So you start them when you know somebody's a high risk and at high risk for decompensation even before, or during the first dose of chemotherapy. In some patients you may decide to do a troponin trigger, some sort of a trigger that would allow you to then say, "Okay, this is a point, whether it be a rise in troponin T, which is a marker of mycardial damage arise in anti troponin which is a marker of mycardial stress or a decline in global longitudinal strain or a decline in ejection fraction.

And then you could start it. The one thing that's important to note, and I always tell my family that is the benefit of having close cardiac surveillance with a cardiologist is that studies have shown that the sooner you start the heart failure medications after you develop heart failure, the more likely you are to reverse that heart damage. So if you wait for a longer period of time, the chances of having any sort of response goes on tremendously, and that's we're following up with us in a close fashion. Especially in a higher risk situation is extremely important.

Dale Shepard, MD, PhD: You're seeing primarily patients on the pediatric side. How do the things that you're doing on the pediatric side compared to what we're doing in adult side?

Shahnawaz Amdani, MD: Yeah, that's a great question. So one of my adult counterparts, Dr. Patrick Colia is in the adult side. But I see cancer survivors and there's an interesting contrast. So I do have a lot of adult cardio oncology colleagues, and I love collaborating with them. And there are certain nuances that I think people should understand. One is the pediatric patient does not usually have any additional comorbidities. So they're not usually having renal disease or diabetes or atherosclerosis or ischemic cardiomyopathy. The adult colleagues, unfortunately sometimes see patients who already have advanced atherosclerosis or peripheral arterial disease or hypertension that's uncontrolled or diabetes or renal disease. So it gets complicated because you already have cardiometabolic risk factors. And now you add on additional cardiotoxic agent. And so that's one challenge. Our challenge is trying to make our families understand that something may happen 10, 15, 20 years down the line.

And for that, you need to see us every six months to a year. And so that's the trade off. So we both have a unique set of challenges. The other is the adults are using a lot of newer medications and the kind of malignancies are different too. You have breast cancer, yes, you use certain medications that can cause cardiomyopathy. But they also use immune checkpoint inhibitors, they have colon cancer things that we don't see on the pediatric side and those medications can have other effects. So the immune checkpoint inhibitors, for example, can cause myocarditis and heart inflammation. So they need to be more aware of that. And you can have arrhythmias with inhibitors and whatnot. So there's certain different manifestations that can happen in the adults. And there are different kinds of connotations when you have a pediatric patient.

There is a lot of overlap. We often do trade patients who go on from being a pediatric to an adult provider. So that's where you having an established pediatric cardio-oncology program and an adult cardio-oncology program is extremely important. We are fortunate again, to have advanced cardiac MRI capabilities. Again, it's a more sophisticated way to look at ejection fraction and ventricular volumes. But also to look at myocardial fibrosis and inflammation, which can happen in certain chemotherapeutic agents.

Dale Shepard, MD, PhD: So we're blessed to have a robust program on the pediatric and adult side. But it's a relatively new area. How common is it that people that might be listening might be able to find a local program that they can participate in?

Shahnawaz Amdani, MD: Yeah, that's I think where it's a challenge because you need somebody who's a cardiologist who understands heart muscle disease. And that has special... Not really special interest in taking care of kids with malignancies or adults with malignancies. But at the same time is now nuance and expert enough to have seen enough. So you need to see a certain amount of volume because this kind of cardiotoxicity and cardiac manifestations and master manifestations are slightly different than what you'd see with other heart conditions and whatnot. So there are certain experience centers around the country and so certainly we are one of them. And I think that's where you have to be at that kind of center where you're seeing certain amount of volume like our center. So it's hard. I think if you try to find it, there are probably few institutions around the country that are doing it in a way that is advancing care.

Dale Shepard, MD, PhD: What are the gaps? What's going to have to happen to make the next big steps to help out either preventing children from getting problems in the first place, fixing problems that might develop minimizing risk? What do you think are the biggest gaps right now?

Shahnawaz Amdani, MD: Yeah, I think if I... Again, this is... It's hard because in pediatrics, we don't have randomized controlled trials to guide our decision making from who is going to develop cardiotoxicity. I think if we had the precisions, medicine, or genotypic, phenotypic manifestation, not everybody... What I've been fascinated by is not everybody who receives the same chemotherapeutic agent or even the same dose of chemotherapy or radiotherapy develops the same amount of cardiotoxicity. So why does one person get more than the other or the other less than the first one? And I think that's where an understanding if there are genetic correlates that we can understand that could help risk stratify and personalize the prediction modeling for that particular patient is one area that I think will be developed in the coming decade.

Obviously, you're trying to understand what kind of diagnostic procedures are going to predict overt cardio toxicity and what will be that lead time. I think global longitudal strain is great and it's one, it's hard because you need to have good images. You need to have a patient cooperation. And I think those are some challenges on the pediatric side. So how do you develop a surrogate marker, whether it's a lab marker, an imaging marker that could predict who's going to have cardiotoxicity. So I think those are some of the unique challenges that will hopefully come in the next decade, but genomic medicine, precision sort of personalized risk prediction. Those are some of the areas that I think have big gaps, understanding medications. We are talking about Enalapril, ACE inhibitors and beta blockers, to be honest with you, there's only one randomized control trial in pediatric heart failure to date that has looked at the efficacy of beta blockers and that wasn't in cardio-oncology.

And then the new trial that we are looking at is the Entresto trial or the adult heart failure medication that we are now looking at in pediatrics. But that's again, not specific to cardio-oncology, they're looking at an order of pediatric heart failure population. So doing randomized trials that are specific to pediatric heart failure is important. Again, mechanistic studies are extremely insightful that have not been done with such robustness. I think understanding why certain manifestations happen will allow us to sort of get to what therapies are needed to reverse them.

Dale Shepard, MD, PhD: Well, certainly I appreciate you joining today because you're helping spread the word. But from an education standpoint, families that might be looking for this sort of thing, doctors that might be needing to be made aware that that this is a really important area. How do we spread the word? How do we educate people?

Shahnawaz Amdani, MD: I think the one thing I want to emphasize for our families and for our physicians and amazing hematology and oncology physicians who are caring for patients with cancer, who survived cancer, is that cardiac complications are real. Cardiac complic complications happen. They happen more often than we appreciate. And I think partnering up with a cardio-oncology specialist or a person who specialized to understand cardiac manifestations of chemotherapeutic and radio therapeutic agents is extremely important. Because cancer survivors, the most common cause of longterm mobility and mortality is cardiovascular diseases. And I think that's where, I think understanding that such patients require regular cardiac surveillance by a specialist who's trained to look at this as extremely important.

Dale Shepard, MD, PhD: Shahn you've given us some great insights today and I'd like to thank you for being with us.

Shahnawaz Amdani, MD: Absolutely Shepherd. It was a pleasure. And I appreciate the opportunity.

Dale Shepard, MD, PhD: This concludes this up episode of Cancer Advances. You'll find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget you can access realtime updates from Cleveland Clinics Cancer Center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.