Chair of the Department of Gastroenterology, Hepatology, and Nutrition, Michelle Kang Kim, MD, PhD, joins the Cancer Advances podcast to discuss neuroendocrine tumors. Listen as Dr. Kim talks about creating a database of biomarker studies, the use of DOTATATE PET CT imaging, and the collaborative, multi-disciplinary approach taken at Cleveland Clinic to treat neuroendocrine tumors.
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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 overseeing our Taussig phase one and sarcoma programs. Today I'm happy to be joined by Dr. Michelle Kim, Chair of the Department of Gastroenterology, Hepatology and Nutrition. She's here today to talk to us about the Neuroendocrine Tumor Clinical Care and Research Program. So welcome Michelle.
Michelle Kang Kim, MD, PhD: Thank you so much for having me, Dale.
Dale Shepard, MD, PhD: Absolutely. So maybe start off, give us an idea of what your role here is at the Cleveland Clinic.
Michelle Kang Kim, MD, PhD: So I joined the Cleveland Clinic about six months ago now, and very pleased to have been asked to chair the Department of Gastroenterology, Hepatology Nutrition. And in that role really asked to take what is already a terrific, very solid department and to increase some of the academic output and also to develop a neuroendocrine tumor program here.
Dale Shepard, MD, PhD: Excellent. So what were some of the big drivers that brought you to Cleveland?
Michelle Kang Kim, MD, PhD: I just thought it was the perfect next step. I had been at New York City at Mount Sinai for 17 years and had held a variety of roles there, and here at Cleveland Clinic I thought there was such an opportunity to really take what is a tremendous patient-centric department and to be able to not only continue to provide quality care and streamline the care of those patients, but also to be able to do research with all of the data that comes from seeing those patients. And also potentially to build registries and data banks to be able to advance the science of what we know of gastrointestinal health.
Dale Shepard, MD, PhD: Excellent. We're going to focus on neuroendocrine tumors. I think it's fair to say these are not particularly well understood tumors. Would you agree?
Michelle Kang Kim, MD, PhD: I think that's very fair. And certainly this is not something that anyone sets out to specialize in in medical school or in training, but I was very fortunate to have been in exposed to it as a junior attending at Mount Sinai, and to be mentored generously by Dick Warner, who was really one of the grandfathers, godfathers of the neuroendocrine field.
Dale Shepard, MD, PhD: Yeah, excellent. So can we maybe start, as we talk about neuroendocrine tumors, just kind of from an educational standpoint, lots of terms get thrown around, including one that's a little cringey, which is benign neuroendocrine tumors, malignant neuroendocrine tumors, carcinoid tumors. Can you just give us a really quick backdrop? What does that mean? What are we talking about?
Michelle Kang Kim, MD, PhD: That's a great question and one that frequently comes up actually with patients.
So neuroendocrine tumors of course start out in the cells of the enterochromaffin cell, and really are widely distributed throughout the body. About one third is in the lung, about two thirds in the gastrointestinal tract.
And I would say another thing that's very important to say is that actually the incidence is increasing over the past few decades. And so while the chances might not have been very high that you would see one maybe 30, 40 years ago, the incidence is now risen so that it's much more likely that you actually will see it. And I think, therefore more important for everyone to know.
Regarding your question about nomenclature and classification, so I think the biggest question that comes up is what's a neuroendocrine tumor, what's a carcinoid tumor, and are they the same thing?
And generally speaking, in terms of nomenclature, we've been going more towards calling these tumors neuroendocrine tumors and really reserving the term carcinoid for things like carcinoid syndrome that we specifically see in the mid-gut, and let's say carcinoid heart disease that we also see with the mid-gut patients.
And then in terms of benign versus malignant, as you know, of course all of these have the potential to be cancerous. Some of them though are found very early, where actually there is a very limited malignant potential. And so I think that it actually behooves all of us to be able to understand the biology and then to be able to understand ultimately what to tell our patients.
Dale Shepard, MD, PhD: And so we're going to shift gears here in a second to some of your research in the past and the program you're developing. But just so we understand scope, you mentioned instances going up. Is this from more imaging studies, more surgeries we find them? And what is that instance? How common are they?
Michelle Kang Kim, MD, PhD: So I would say several decades ago it was about one per 100,000, and now going up to about seven per 100,000. We don't quite understand why this is. I suspect that a lot of it is a detection bias and that it's related to the increase in cross-sectional imaging and also in the endoscopies and colonoscopies that we're performing for other reasons. So many times these are found incidentally, but of course many times these are also causing significant morbidity, mortality.
Dale Shepard, MD, PhD: And then tell us a little bit about some of your major research interests in neuroendocrine.
Michelle Kang Kim, MD, PhD: So I think what has been really fascinating about this field is that this is a very heterogeneous group of tumors. As I mentioned before, you can have them in different areas of the body and even within the GI tract. Let's say an neuroendocrine tumor from the stomach is very different from an neuroendocrine tumor in the small bowel or the rectum. And so I think the first is sort of just understanding what to expect depending on where the primary site is.
But in addition to that, we've got very limited ability to be able to predict how patients will do. So for instance, stage and grade, something that is used very commonly in cancers, is certainly some of our leading biomarkers for this condition, but that even within the same stage and the same grade, that you can have a tremendous amount of heterogeneity in how patients do.
So for instance, for a metastatic patient with mid-gut carcinoid, with carcinoid syndrome, someone can have a survival of six to 12 months or a survival over 30 years. And that's within the same stage in grade. And I find that biologically very interesting, but perhaps for patients, very disturbing, just not being able to say when you walk in the door, which one you're going to be.
Dale Shepard, MD, PhD: Interesting. So tell us a little bit about the programs being set up.
Michelle Kang Kim, MD, PhD: So this I think is a really fascinating opportunity and certainly one of the reasons that I came here. There's already a very strong robust program with endocrine oncology, with the surgeons, that have already been established here. And there's actually an neuroendocrine board that meets about once monthly.
I think what we would love to see is to continue to grow that existing program and to also add to it now the GI presence. And so gastroenterologists are among the first to see these tumors. They often will be, as I said, diagnosed on endoscopy or perhaps seeing a gastroenterologist because of non-specific symptoms.
And so I think having a strong GI presence really adds a level to it that is not anywhere else in the country, to be frank, that you can have patients come in with any type of neuroendocrine tumor from any area with any kind of biology, and they will receive outstanding care here because you have the right team to be able to see them.
Dale Shepard, MD, PhD: And we've had previous episodes of the podcast, we've talked about things like endoscopic resections and things. Is that something that's being incorporated with neuroendocrine tumors?
Michelle Kang Kim, MD, PhD: Yeah, absolutely. So this is definitely something that becomes very important. We see a lot of these in the stomach, the duodenum, and the rectum, and those are particularly amenable to advanced endoscopic resections. And so my colleagues, Ahmed Boht and others who do a lot of the submucosal and mucosal resections are invaluable partners to be able to ensure that these patients can have their tumors removed, not necessarily need a surgical procedure, and then to have an excellent outcome long term.
Dale Shepard, MD, PhD: And then just from a programmatic standpoint, you mentioned previously things like databases and things like that. What is the program doing in terms of collection of data and being able to understand more about the natural history of these?
Michelle Kang Kim, MD, PhD: So that's where, yes, I think that there are certainly external sources of larger populations of patients, but that it's very important to be able to also get very granular data in these patients. And so we are starting up a neuroendocrine tumor registry that includes a prospective enrollment of every patient with neuroendocrine tumors or with a family history of neuroendocrine tumors. And that will include collection not only of data via questionnaire, but also of plasma serum and DNA to be able to do biomarker studies in other studies in the future.
And so I'm pleased to say that actually I think we just recently got IRB approved and so that we will be able to start this prospective collection very soon.
Dale Shepard, MD, PhD: That's great. From a research standpoint, what are some of the interesting research questions that are being raised?
Michelle Kang Kim, MD, PhD: So as I said before, I think one of the great interesting things and perhaps the great opportunities in neuroendocrine tumors is to be able to predict outcomes from the start. And this is where there's just a tremendous amount of heterogeneity and we just don't have a lot of good answers.
And so the places where I have been before and where I plan to be in the future are essentially looking at different approaches to be able to predict outcomes. And so whether it's for instance, more basic level data in terms of race, ethnicity and comorbidities. And I think here one thing that's important that might not be important in more aggressive cancers is survivorship and understanding is the neuroendocrine tumor the dominant issue or is the cardiovascular disease going to be the dominant issue, and sort of understanding that balance.
But then I think also currently involved in some other studies including digital image analysis and artificial intelligence to look more objectively at existing pathology slides, and again, to be able to perhaps delve more deeply into potentially other predictive biomarkers that might be able to help us in our prediction of patient outcomes.
Dale Shepard, MD, PhD: And I guess you can only really treat patients when you know that they have a neuroendocrine tumor, and you talked about increased incidents and detection and things. But historically just having patients show up with symptoms and things and even identifying these as neuroendocrine tumors has been a problem. Is that getting better?
Michelle Kang Kim, MD, PhD: That's a great question. So I think that this is actually a real opportunity for some folks, and I think there's a lot of information out there in the internet, and patients are come in and sometimes very savvy and having had a really extensive workup. This is where actually I think gastroenterologists are very primely placed to be able to make that diagnosis or to exclude it, and honestly to maybe end the madness so that the extensive testing can stop.
Because certainly if you have, I would say the most common thing I see is if you see flushing and diarrhea and there's a suspicion for carcinoid syndrome, and perhaps you do a 24-hour urine collection for FHIAA, those symptoms and that, let's say abnormal test does not in itself create a diagnosis of neuroendocrine tumor. You have to have a tumor localized, you have to have a biopsy that confirms that.
And so there are a lot of patients out there who may have flushing or diarrhea or both and perhaps also have an elevated urine collection that then you have to sort of understand, well, why is this and why are they flushing? And it's probably something different that's not related to the endocrine tumor.
And one thing I will say is that there are an awful lot of reasons why tumor markers can be abnormal and falsely positive. And one of them, I'll say for the 24-hour urine collection is that diet is a prime reason why I see that these are often elevated. So an understanding of what the symptoms are, what you might be looking for related to those symptoms and how best to find that I think is really the ticket.
Dale Shepard, MD, PhD: Do you think we'll come up with better biomarkers? You mentioned things about biomarkers and so it's always been an area of frustration, I got to tell you, in patients that I've seen, that there's such fixation on their chromogranin level and what's going up and down. And some people measure numerous things, and well quite honestly doesn't normally do much other than aggravate the patients.
Is there anything in the future that might either help us use what we have better or sort of replace those measures?
Michelle Kang Kim, MD, PhD: Yeah, so I think you described really perfectly the imperfection of these biomarkers, and none of these were meant to be screening biomarkers for neuroendocrine tumors and particularly chromogranin A, which is used very frequently.
One thing I'll say is that our imaging has really gotten much better, leaps and bounds better. And so the gallium or copper DOTOTATE PET CTs are now able to image with incredible sensitivity and specificity. And that has been, I think, a game changer.
And then I think a better understanding that these biomarkers are imperfect, that checking a panel of eight to 10 biomarkers in understanding, well, what are you looking for, what is this going to mean if one of them comes back elevated, because at least one of them will come back elevated, and you've got to know then what you're going to do and what you're going to tell the patient.
In terms of better markers, I think that there are some on the horizon, but none that are ready for prime time. And I think in the meantime, this increased sensitivity with our DOTATATE PET CTs is actually a really great advance.
Dale Shepard, MD, PhD: And I guess just on that imaging standpoint, within neuroendocrine tumors, is there much of a risk of over-treating patients because we find things we never knew about in the past?
Michelle Kang Kim, MD, PhD: Yeah, I think that's exactly right. So this is where you have to understand what is this tumor going to do in this patient's lifetime, and sort of understanding that this is really the long game, this is not some short marathon sprint.
So often I will see, for instance, in our DOTATATE PET CTs, that they're picking up many more tumors than what we're seeing on cross-sectional imaging. And I think really being able to advise our patients like, listen, this is not tumor progression, your tumor's not out of control. It's just an increased sensitivity that we're seeing here. And then understanding that you need to understand the pace of the disease and balance that with the other comorbidities, which as we are all getting older and our patients are getting older and more frail, that this may not be something that is clinically relevant to you now or perhaps ever.
Dale Shepard, MD, PhD: I guess a lot of this we've been discussing is about education and how much is engagement with advocacy groups, and certainly within this disease they have some pretty robust advocacy groups. And how is that relationship with your program?
Michelle Kang Kim, MD, PhD: Yeah. No, I think that advocacy groups were really born out of not having enough information, especially before the internet and having all these different groups, and having just a limited number of providers who could advise patients. And so they've been a really key partner in many ways, creating patient educational forums, in creating, honestly, foundations that fund research.
And so the patients that are affiliated with these groups or that go to the sessions that are organized by these groups are inevitably better educated and have a much better understanding of their disease.
Dale Shepard, MD, PhD: I mean, I think probably because there are such a large number of patients with relatively indolent disease, there's certainly a handful of people around the country that many, many people go around and visit and get opinions and things. So that being the case, do you see there being an ideal patient type that should come to a specialty center? I mean, who should come to Cleveland Clinic or a specialty neuroendocrine program?
Michelle Kang Kim, MD, PhD: I think there are a few different types of patients who could really benefit from being seen here. And I will say that some of them I've actually even seen in the last several weeks, and I can attest to perhaps their satisfaction.
So the first is certainly patients who have not been diagnosed and perhaps have abnormal markers and have had a really million dollar workup and are just confused about whether they have one or they don't. To be frank, many times if the neuroendocrine tumor can't be found, many times it's not there, just given that it's fairly rare and that other conditions are more frequent and common.
But I will say that I've been able to give peace of mind to some people who don't know and don't understand why their markers are elevated. And sometimes we don't know either, but at least just with the decades of experience that I and others have, we can be reassuring and sort of exclude the diagnosis fairly firmly. So that's, I think, the first set of patients.
The second set of patients is certainly anybody who is newly diagnosed. There are a lot of questions here. People don't understand how they're going to do long-term. There can be a lot of anxiety and quality of life issues around this, and so I think when they're first diagnosis a really great time to come and see us. And whether it's a first opinion or a second opinion, I think that's a really great time.
And then I would say finally, anyone perhaps who is getting very different opinions from other institutions. And this happens very frequently in very high profile institutions, that you can get different opinions just because of the experience of the doctors and the institutional biases that you have in any given place. And it's not to say that one is better than the other, but that the experience is different and that sometimes there are different ways that you can treat someone first line and they're actually all acceptable, even though they're all very different.
And so anyone I think who has questions about this or who is not sure in the current management, I think is a perfect patient to be seen here.
Dale Shepard, MD, PhD: What are some of the things that we have offer here in terms of ablations or novel therapies or from a diagnostic standpoint, what are the things that are some of the big highlights?
Michelle Kang Kim, MD, PhD: So we certainly have the DOTOTATE imaging that I was talking about before, and this is of course a must at any high volume, neuroendocrine tumor center. I think what we have here that distinguishes us from perhaps other institutions is a really collaborative, robust group of people who are dedicated to the care of these patients. Because it is one thing to see this a few times a year and somebody who sees us every week. And so you need to go to a place that has a high volume of these kinds of patients.
And what I love about our group in the last six months is that it truly is a very collaborative group, that we're always thinking creatively. We want to see if this therapy is an option, why that might be maybe a better option than a different option. And it's a very thoughtful group that I think is really considering the patient and personalizing their treatment for that particular person.
And then finally, I think that what I've seen so far again has been just for people who have come in, not just from the local area, but also people who come in from out of town, out of state, and even out of the country, that the care can be just really seamlessly coordinated for a visit here, such that everything can be done sort of in a very time compressed kind of way.
Dale Shepard, MD, PhD: Well, that's great. So certainly not a common tumor, but more common tumor over time, misunderstood. And you're doing great work to put together a really cohesive group, so appreciate your insights.
Michelle Kang Kim, MD, PhD: Thank you so much.
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