Intro: Welcome to UAB MedCast, a continuing education podcast for medical professionals, providing knowledge that is moving medicine forward. Here's Melanie Cole.

Melanie Cole, MS (Host): Welcome UAB MedCast. I'm Melanie Cole. And today, our discussion focuses on neuroendocrine tumors, treatment and their symptoms. Joining me is Dr. J Bart Rose. He's the Section Chief of HPB Surgery and the Director of UAB's Pancreatobiliary Disease Center, and an Associate Professor at UAB Medicine. Dr. Rose, it's such a pleasure to have you join us. What are the most common locations for neuroendocrine tumors that you see and how common are they in general?

Dr. J Bart Rose: Melanie, thank you so much for having me and letting me discuss this topic that's near dear to my heart. Most of the neuroendocrine tumors that I see are going to be those that start in the pancreas or the small bowel, but actually probably the most common place for neuroendocrine tumors developed in the United States is the rectal neuroendocrine tumors. Thankfully, those are usually very small and handled endoscopically with your colonoscopy.

Melanie Cole, MS: Well, thank you for that. So, the most common symptoms that primary care or first line physicians would know for neuroendocrine tumors, how do they differ based on tumor location? Give us a little bit of an overview for that.

Dr. J Bart Rose: Neuroendocrine tumors are a very rare cancer. There'll be many physicians who go their entire careers that never see one or maybe see one or two. And they can present very differently. If you think back to medical school, this was one of those conditions that mimicked a lot of different things, and that's because they can secrete a whole host of different hormones that their normal organ would produce.

So, the pancreas can produce hormones that stimulate blood sugar dysregulation, so glucagon, insulin. They can overproduce stomach acid and by over secreting gastrin. Small bowels can secrete things like serotonin and bradykinin that can cause carcinoid syndrome, flushing, palpitations, shortness of breath, wheezing, diarrhea. So, these can really mimic a lot of different things. And that is one of the reasons why the symbol for the Neuroendocrine Tumor Association is the zebra. And that goes back to our adage in medical school that when you hear hoof beats, think horses, not zebras. But for neuroendocrine tumors, it actually can be zebras.

Melanie Cole, MS: That's really interesting. So if they are more challenging to diagnose, what do you recommend? If they're thinking zebras and they have some of these symptoms, which you just mentioned, could really overlap with so many different things, then what are they looking for? And tell us about some of the imaging for detection and staging that they might be able to use, or once they've sent on for referral.

Dr. J Bart Rose: One of the most frequent starting places is getting a good quality CT scan of the abdomen and the pelvis. If this is something you're considering, you know, they have a longstanding issue that you haven't been able to figure out, you can check serum hormone levels and those can sometimes be helpful. They can also be very confusing because they can be influenced by diet, time of day, other medications. But starting with a CT scan with an arterial phase is a good place to start. Because most of these tumors are going to be hyperenhancing on an arterial phase of a CT scan, you'd be looking in the pancreas or the small bowel, at least those are the ones I'm looking at. And then, paying special attention to regional lymph nodes and the liver, which is one of the most common sites for metastasis.

Melanie Cole, MS: Now, explain the role, Dr. Rose, of the dotatate PET scan in monitoring neuroendocrine tumor progression. So once we've decided what's going on and discovered what's going on and patients start with you, where does the PET scan fit in?

Dr. J Bart Rose: So, the PET scan can be helpful, in more advanced disease generally, or in very rare cases in making the diagnosis where a biopsy is not obtainable. Now, there are a few things that can light up on these dototate PET scans that are not neuroendocrine tumors. But for those who are not familiar with this, this is a PET scan that identifies areas that have an overexpression of somatostatin receptors on their cell surface. So, this dotatate molecule will bind to somatostatin receptors and it will light up on PET imaging.

Now, those are usually neuroendocrine tumors, but they can be other things. Lymphomas, hemangiomas can also cause false positives. So, we're really using those in situations where we either know that people have metastatic disease and we're trying to get a better sense for what is the volume of their disease or for people who have a high potential and we're trying to adequately stage them. So, not everybody who has a small neuroendocrinetumor needs a dotatate PET scan. But there are definitely certain people that would benefit from that. And I think that's one of those things where waiting on getting a dotatate PET scan might be appropriate until you have the patient see somebody who specializes in this, because there's a lot of nuances to when and how to order these PET scans.

Melanie Cole, MS: That's good advice, Dr. Rose. And now speak about standard treatment options for these tumors and how do they vary by the grades, stage, location. Speak about what you're doing that's exciting.

Dr. J Bart Rose: Well, neuroendocrinetumors, again, are unique in that they can secrete hormones, but the vast majority of them are what we call non-functional, meaning they're not secreting a hormone that is causing a syndrome. Now, they can maybe be secreting them at subclinical levels, but we don't really consider those to be functional. They also have varying grades, according to the WHO grading system. They're either well-differentiated or poorly differentiated. The well-differentiated or subcategorized into grades 1, 2, and 3. And within each of those categories, we have different treatments that may be available for patients with poorly differentiated neuroendocrine carcinomas.

We typically treat those like other more advanced malignancies with chemotherapy, and very rarely surgery for those with the more well differentiated tumors, the lower grade tumors, then there's a whole host of options from hormonal therapy with somatostatin analogs to chemotherapy, with capecitabine, temozolomide to targeted therapies with everolimus and Sutent or even surgery in the metastatic setting. This is one of those rare cancers where cytoreductive, or debulking surgery can play a significant role even in people who have a large burden of metastatic disease. And that's just one of those things where it's really important for these patients, especially with advanced disease, to be seen large centers that see these very often because the treatment plans around these rare cancers can be very complex, depending on the grade, the functional status, the stage, it can get quite confusing.

Melanie Cole, MS: Well, thank you for that. Now, speak about PRRT and chemo. How they differ in their application to these type of tumors and when would you use which are they adjuvant?

Dr. J Bart Rose: So, PRRT stands for peptide receptor radionuclide therapy. And essentially, what we're doing is we're taking advantage of the fact that these tumors have this overexpression of somatostatin receptors on their cell surface. So, you take that same dotatate molecule that you used for your PET imaging and you swap out the positron emitter, and you put in something that's either a beta or an alpha emitter. And now, you've turned something that was a diagnostic agent into something that is a therapeutic agent. And that combination of a molecule that can be both diagnostic and therapeutic is called theragnostics. And this is a really exciting field for research and development of new targeted therapies. We've seen this first in neuroendocrine tumors and now most recently against PMSA and prostate cancer. And there's a number of other that are in the pipelines, including in breast cancer.

So, I think, you know, PRT is an exciting new therapy that is going to be useful for people who have progressed on first-line therapy. Generally, we don't give that as a first line. So, most well-differentiated tumors, we're going to start on hormonal therapy or surgery first, and then PRT may be down the line is either a second or a third line. The chemotherapy, we typically reserve for the more advanced grade neuroendocrine tumors, because most of these, thankfully, well-differentiated grade 1 neuroendocrine tumors are incredibly slow growing and indolent. And because of that, they don't really respond to traditional cytotoxic chemotherapy very well. We will use things like the hormonal therapy or targeted therapies like everolimus or Sutent in the case of pancreatic neuroendocrine tumors.

Melanie Cole, MS: Dr. Rose, you briefly mentioned surgical intervention. Speak about that when it might be appropriate or considered.

Dr. J Bart Rose: So, it varies a little bit based on which organ has the neuroendocrine tumor in it. But just in general, we'll often recommend resection if it's just the primary tumor so they haven't metastasized and there's a chance for cure. If they are functional and they're causing some sort of life-limiting symptom, if they're obstructing the bowel in the case of small bowel. And then sometimes, like I mentioned, even in the setting of metastatic disease, if they're either having symptoms from it or we think that we can get a significant reduction in the volume of tumor in the liver so that they, one, may live longer and then, two, potentially have a better response to future therapies like PRRT.

Melanie Cole, MS: Dr. Rose, this is so interesting and given the complexity of these patients. And with the increasingly advanced treatment algorithms available to you that really add new options to your armamentarium of available therapies, as you've spoken here today, how important is the multidisciplinary management because it would seem that there are many professionals involved.

Dr. J Bart Rose: It's incredibly important. I mean, like most cancers, it's an important concept to have a multidisciplinary team. But I think in this setting, it's especially important because you're bringing in expertise from surgeons from Nuclear Medicine or Radiation-Oncology, depending on who's delivering the PRT interventional radiology. Sometimes there's liver-directed therapies with TACE or Y90 with TACE, with endocrine and with genetics. In the case of inherited syndromes that this can be related to, like MEN1, Von Hippel-Lindau. And, you know, these are really complicated treatments and most of these patients are going to be on two, three, sometimes four different modalities or more through the course of their lifetime with some of these with small bowel neuroendocrine tumors and pancreatic neuroendocrine tumors. We're talking about median overall survivals in the eight to 10-year range. So, these are going to be things that are almost managed more like a chronic disease, thankfully, than like an acute malignancy.

Melanie Cole, MS: Isn't that interesting? Dr. Rose, as we wrap up, speak to other providers, the key takeaways that you would like them to know about these complex tumors, these neuroendocrine tumors, and what you're doing at UAB Medicine that's really exciting.

Dr. J Bart Rose: Well, I think, the key takeaway here is that. These are complicated, and I don't want people to feel like they're on an island. Please send them to a provider that sees a lot of these, so that you can get optimal treatment for your patients. I think we're doing some very exciting things here. We have a multidisciplinary clinic that we're seeing all these patients now we bring all the providers to that single patient. We have a number of basic science research projects that are involving. New treatment strategies, new imaging strategies. I think, hopefully, the things that are coming down the pipe will be even better than we have now. We've opened new trials to allow re-treatment with PRRT, so I think there's some very exciting things here, when we're trying to stay on the cutting edge of neuroendocrine research at UAB, and then contributing globally to the knowledge around that disease.

Melanie Cole, MS: Well, you certainly are. You have so much expertise to share, Dr. Rose. And I thank you again. You really are a great guest, and thank you so much for joining us. And for more information, you can always visit our website at uabmedicine.org/physician. That concludes this episode of UAB MedCast. I'm Melanie Cole. Thanks so much for joining us today.