Exploring the Complexities of Neuroendocrine Tumors and Carcinoid Heart Disease

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and 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 directing the Taussig Early Cancer Therapeutics Program and Co-Director of the Cleveland Clinic Sarcoma Program. Today, I'm happy to be joined by Dr. Michelle Kim, Chair of Cleveland Clinic's, Department of Gastroenterology, Hepatology & Nutrition. She was previously a guest on this podcast to discuss neuroendocrine tumors, and that episode is still available for you to listen to. She's here today to talk to us about neuroendocrine tumors and carcinoid heart disease, so welcome back.

Michelle Kang Kim, MD, PhD: It's great to be here. Thanks for having me.

Dale Shepard, MD, PhD: Remind us what you do here at Cleveland Clinic. I gave your title, but what do you do here?

Michelle Kang Kim, MD, PhD: Foremost, I'm a clinician. I'm a gastroenterologist. I've always had an interest in gastrointestinal tumors and cancers, but the bulk of my career has really been focused around caring for patients with carcinoid and neuroendocrine tumors, as you know, a relatively rare tumor, but a tumor that's increasing in incidence and prevalence such that actually, it's as common as esophageal, gastric, and pancreatic cancers combined. Actually, it's more common than you think, and a lot of us are likely to diagnose and to be treating these patients, so I'm thrilled that you're dedicating another episode to these patients.

Dale Shepard, MD, PhD: Absolutely. We're going to talk about neuroendocrine tumors. We're going to talk about carcinoid heart disease. Just as a refresher because a lot of people listening in with different backgrounds, what exactly is a neuroendocrine tumor?

Michelle Kang Kim, MD, PhD: A neuroendocrine tumor is again, a relatively rare but increasingly prevalent cancer that occurs throughout the gastrointestinal tract and also throughout the lungs. The breakdown is approximately two-thirds GI, one-third lung, and so the folks who are likely to see these tumors are gastroenterologists and lung doctors.

The tumors are best known for secreting peptide hormones that can often be associated with a lot of clinical symptoms and specific clinical syndromes, and that's what they're known for. Having said that, there are also a lot of nonspecific presentations, and a lot of times these tumors are picked up incidentally.

Dale Shepard, MD, PhD: You've mentioned a couple times about increasing incidence and prevalence. Do we know why that there are more of these tumors?

Michelle Kang Kim, MD, PhD: Well, that's a million-dollar question. I think that a lot of us believe that there's a detection bias that we're seeing just because we're testing so much more. There's so much more awareness for these tumors and our imaging tests, our endoscopic tests are so good at detecting them, and so we are finding them at earlier stage, and we're finding them just in general, a lot more commonly than we did before.

Having said that, I do think that there is perhaps a thinking that there could be some association with other environmental factors or perhaps even medications. One such exposure could be proton pump inhibitors. While we've known for some time that proton pump inhibitors can be associated with neuroendocrine tumors in animal studies, this is not something that has typically been known to occur in humans. But I will say that in the field, there seems to be a growing recognition that there may be a correlation.

Dale Shepard, MD, PhD: This is something that is rare. Sometimes people don't think about it. I know there's late diagnosis sometimes, and that frustrates patients, but then we think about rare things like carcinoid heart disease. Again, maybe give us a little background about what is that.

Michelle Kang Kim, MD, PhD: I think the first thing to know about it is that this really is occurring in mostly patients with metastatic disease, so a pretty extensive disease, and particularly with those who have disease emanating from the mid-gut or the small intestine. For instance, for all of those patients who have, let's say, gastric neuroendocrine tumors, pancreas, rectal neuroendocrine tumors, these are typically not associated with carcinoid heart disease.

What happens with the mid-gut tumors is that you often will get an overproduction of serotonin, other peptide hormones, and when you've got that overproduction of serotonin and other hormones, you are "bathing" in it to a certain extent, often associated with quite a bit of tumor burden, and that is what puts you at risk for carcinoid heart disease.

Now, carcinoid heart disease in itself is an entity that's usually a right-sided valvular disease often again, associated with retraction and plaques around the valves. It's something that we see very often in patients who have extensive disease, and again, not so much in those who have more limited or local disease.

Dale Shepard, MD, PhD: So, is this something that maybe at presentation with metastatic disease we're likely to see, or is this something that our patients that sometimes we have these patients with neuroendocrine tumor or metastatic, we've been treating them for years, and that we're likely to see it over the course of time?

Michelle Kang Kim, MD, PhD: I've seen it both ways. I've certainly seen the first day they walk in the door, and it's a very dramatic presentation, often with right-sided heart failure, lower extremity edema, all the rest. That's an easy diagnosis to make. You can often just hear it on exam, the murmur, and then you will often get an echocardiogram afterwards to confirm the diagnosis.

But the other scenario that you presented is also very common, that someone who has, let's say, been under your follow-up for a long time, perhaps had stable disease at some point, then perhaps more recently starting to progress, they can start to develop the carcinoid heart disease at that time during your follow up.

Dale Shepard, MD, PhD: When we think about this carcinoid heart disease, how often do we see it? We think about within the neuroendocrine patient population, what percentage might be likely to get carcinoid heart disease?

Michelle Kang Kim, MD, PhD: It's really going to be a minority. Again, I think because we are diagnosing these tumors so much earlier now, often incidentally and without having the dramatic carcinoid syndrome that's often associated with the metastatic disease. So, I would say that that rate is dropping. It used to be much more common, but now it's quite a minority.

I would say obviously there will be a lot more common things that are responsible for valvular disease, and I would say carcinoid heart disease is probably going to be the rarest of the rare.

Dale Shepard, MD, PhD: I guess rare enough that even within neuroendocrine patients with neuroendocrine tumors too, is there a recommendation for screening of some sort?

Michelle Kang Kim, MD, PhD: Yeah, that's a great question. Again, you just need to know which patients are at risk of developing it. That means, again, we're excluding all of the tumors that might be coming from the lungs or from the rectum or from the foregut, let's say, in the pancreas or stomach, so these are only the midgut patients. I would say that there's not too much utility, I think, to screening them when they have more local or regional disease, but certainly when they have metastatic disease. Certainly, if you hear anything on exam that sounds like it could be a heart murmur, then it makes sense to get at least a screening echocardiogram and then to have surveillance afterwards.

I'd say that depending on the society guidelines that you look at, depending on the clinical scenario of the patient, that it could be anywhere from every few months to people who have existing carcinoid heart disease to every one to three years for those who don't and those who you're surveying for it.

Dale Shepard, MD, PhD: You've mentioned that this is predominantly patients with midgut tumors. Is that because they're the ones that are more likely to be functional, or if a patient that happened to have one somewhere else in the GI tract that's functional, does that put them at increased risk?

Michelle Kang Kim, MD, PhD: Not at all. There can be a lot of functional tumors, let's say gastrinomas or insulinomas coming from the duodenum or from the pancreas, and that's an overproduction of gastrin or insulin, which is a completely different clinical syndrome. Those patients, despite having functional tumors, will not be at risk for carcinoid heart disease. It's really, as I said, almost predominantly the midgut patients who have extensive metastatic disease, often in the liver as well as in other organs who are going to be the ones who are responsible for it.

So, it's not just a matter of functional, but it's really what exactly about it is making it functional and what is it overproducing? I would say almost invariably, the patients with carcinoid heart disease also have carcinoid syndrome, that very dramatic flushing, diarrhea, wheezing. Oftentimes, you'll see the patients who have syndrome, and then you're sort of keeping a closer eye on those folks knowing that those patients are at risk for having carcinogenic heart disease.

Dale Shepard, MD, PhD: So at a place like Cleveland Clinic, we oftentimes have multidisciplinary care. Tell us a little bit about how we work as a team to manage these patients.

Michelle Kang Kim, MD, PhD: Yeah, this is where I think the best of an academic medical center and a tertiary center like a Cleveland Clinic rises to the top. When you have a suspicion for carcinogenic heart disease, and that really starts a collaboration between the treating doctors, and the treating doctors may be gastroenterologists like me or oncologists, and then starts a collaboration with the cardiac team, so there's then of course, going to be more of a diagnostic cardiologist who's probably going to order the echocardiogram and assess the severity of the carcinogenic heart disease.

Depending on the severity, depending on the patient's particular scenario, they may be a candidate for valve replacement, and this is where there can be sometimes some differences in approach where, let's say, if you have right-sided heart disease, do you just replace one valve, do you replace both valves, depending on the severity of the carcinoid heart disease, and again, the patient's functional status and how they are as a surgical candidate.

Dale Shepard, MD, PhD: Certainly, valve replacement can be beneficial, but if patients still have that metastatic burden, does that put them at risk for that treated heart to then get carcinoid heart disease again?

Michelle Kang Kim, MD, PhD: Right. Great question. I think the way that we approach this is quite similar to how we approach a lot of disease, which is that especially when the heart is in failure or you have severe valvular disease like that, the heart comes first. We always say that we will manage the oncologic plan around the carcinoid heart disease, but oftentimes, the first thing that needs to happen is that needs to be assessed and treated.

Then what we're left with and largely because these are the mid-gut tumors, they often are what we call grade one, which is the more indolent tumors. Patients have often had symptoms for many months and sometimes years, and the tumor is often by its nature, quite indolent on its biology, and so you actually have time to be able to do things in sequence and to do things in the order that they should be done, which is why the heart comes first.

Then we consider what are we going to do about the rest of the disease, and that depends again on where it is. Oftentimes, patients are already on somatostatin analogs, let's say, octreotide or lanreotide. This will often be very helpful for the symptoms of the carcinoid syndrome, so at least the patients are feeling a little bit better, and they're not feeling quite so ill. But usually, when someone is going up for cardiac evaluation or surgery, the somatostatin analogs are the only things that the patients are on actively while under the cardiac evaluation team.

Dale Shepard, MD, PhD: Have there been differences in the ability to control carcinoid heart disease or incidents with the introduction of newer therapies like glutathione?

Michelle Kang Kim, MD, PhD: Yeah, so I think that we don't know yet if these other treatments, they're certainly effective for oncologic control, but I don't know. Because carcinoid heart disease is such a late manifestation of metastatic disease, I'm not sure that those treatments will necessarily affect outcomes related to the heart disease. So, it's really, I would say, two separate things. The valvular disease is best treated with medical treatment as we do with heart failure and with a surgical treatment, but again, the oncologic treatments are much more for the actual tumor.

Dale Shepard, MD, PhD: I guess if people might be listening in, they have patients they're treating with neuroendocrine tumors, what would be an ideal patient that should come to a specialty center to be evaluated?

Michelle Kang Kim, MD, PhD: Well, I think certainly because of the relative rarity of the disease, we see patients with all stages of disease, ranging from very local, controlled disease to inoperable, widely metastatic disease. We certainly see quite the range, but I will say that I think especially those patients with more regional and metastatic disease should certainly be seen, at least for our consultation with our center here and with specialty centers just because there are so many different available treatments. The treatments are constantly changing, and I think sometimes the sequencing, people are not sure which do you do first. Which is first line? How do you address a patient who has complex multidisciplinary disease such as this patient?

For that reason, I think certainly, as the complexity and the acuity of the disease goes up, they should all be seen. But I think it is, if possible, better to be seen a little bit earlier in the disease and to try to be preventative and try to advise the patient about what they can expect going forward.

Dale Shepard, MD, PhD: Excellent. I know one of your focuses was trying to build out further the multidisciplinary nature of how this disease is treated, so maybe just gives us a little bit of insight on how that's going and what we have in place here.

Michelle Kang Kim, MD, PhD: Yeah, no, I'm happy to. I think one of the greatly gratifying things about Cleveland Clinic and carcinoids is that there are so many people here who are interested in the field and so many people too who have clinical and research and other expertise. We are very fortunate to have a neuroendocrine tumor board. We're actually in the process of expanding that board to meet more frequently throughout the month to be able to accommodate our larger volume of patients and making sure that we're really doing the best that we can to identify an appropriate and optimal treatment plan. I am extremely happy with the collaboration of this group. I think, again, everyone presents their viewpoint, but we all come to consensus at the end of the day. Again, everybody's quite collaborative, and we treat patients from all over the country.

What's also been very exciting is we are continuing to develop our neuroendocrine tumor registry and biobank. This is something that I brought over from my previous institution, and we've been doing here, and again, collaborating with translational and other scientists to be able to identify biomarkers and to be able to personalize treatments and predict outcomes in patients. We also have some projects on digital image analysis and AI and looking to see if there are some features that we can ascertain from pathologic specimens that are more and above, beyond what we can do right now.

Dale Shepard, MD, PhD: That's fantastic. As we think about management of this disease, again in a multidisciplinary way, what sort of therapies are most exciting moving forward?

Michelle Kang Kim, MD, PhD: This has been really quite a journey to see what's happened in the last 10 to 20 years or so in the field, because in the beginning, we really had the level of evidence, the rigor of the studies was not ideal because everyone was operating in silos and reporting out institutional experiences that were somewhat anecdotal. Now with these much larger collaborative national, international studies, we've got high-level evidence now to show which agents should be first line and second line.

The good thing about neuroendocrine tumors, again, because so many of them do tend to be indolent, that oftentimes there is a lot of time for you to start with one treatment, and in the time that you're treating them with, let's say, somatostatin analogs, actually other treatments come along. So, you always stay ahead of the curve with some of our more indolent patients in terms of being able to offer them more and more treatment options.

So, there is some clarity on what should be first and second line, but then there's also definitely some patient preference, physician preference, some of our beliefs about what we think is best that play into the role as well.

Dale Shepard, MD, PhD: And partially that indolent nature you mentioned about treating patients all over the country, this is a tumor that allows that. Patients have relatively few symptoms, a fairly indolent disease, so they can actually travel to specialty centers.

Michelle Kang Kim, MD, PhD: Exactly.

Dale Shepard, MD, PhD: Well, you're doing great work. It's very, very nice to get your insight on neuroendocrine tumors and carcinoid heart disease, and appreciate you being with us.

Michelle Kang Kim, MD, PhD: Thank you so much for having me.

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