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Melanie: Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And today, in this round table panel, we have a thought leader conversation as we discuss neuroendocrine tumor management, the state-of-the-art in 2021, including PRRT.

Joining me in this panel is Dr. Ali Zarrinpar, he's an Associate Professor in the Division of Transplantation and Hepatobiliary Surgery; Dr. Brian Ramnaraign, he's an Assistant Professor in Hematology and Oncology; Dr. Steven Hughes is the Chief of Surgical Oncology; and Dr. Kathryn Hitchcock, she's an Assistant Professor in the Department of Radiation Oncology, and they're all at the University of Florida College of Medicine. Thank you, doctors, for taking part in this today and for joining us.

Dr. Hughes, I'd like to start with you. Can you tell us a little bit about the incidence and prevalence of neuroendocrine neoplasms and what you're seeing in the trends?

Dr. Steven Hughes: Good morning. It's my pleasure to be with everybody today. These are actually very rare tumors affecting far less than 1% of the overall population. They are fairly common for us at the University of Florida as a tertiary referral center. Majority of them are incidentally noted and found because of other reasons, rather than actually causing symptoms. And if one actually performs autopsies, the number of patients that have microscopic neuroendocrine tumors is actually greater than 10%. So the majority of these tumors are silent, small, and very slow-growing.

Melanie: Dr. Ramnaraign, can you please give us an overview of the current management of neuroendocrine tumors if they're found whether incidentally or not? And how has treatment evolved over the years?

Dr. Brian Ramnaraign: Certainly, Melanie. The treatment of neuroendocrine tumors really should involve a multidisciplinary approach with radiation-oncology, medical-oncology and surgical-oncology. And the most important question to ask is the extent of the patient's disease. Is there a single lesion? Are there a few lesions or is it metastatic cancer?

A patient with a single neuroendocrine tumor or what we would call as oligometastatic, few metastatic lesions, may actually have a potentially curable disease. And that would usually involve a combination of a surgery, medical oncology, and radiation oncology, a patient with diffusely metastatic disease that's found later on in their disease course, we only have palliative options for. And that would involve systemic therapy options, including somatostatin analogs or even localized radiation therapy with a treatment called PRRT.

Melanie: So Dr. Hitchcock, on to you, how have advances in radiologic imaging significantly augmented your diagnostic and therapeutic capabilities? Can you speak about any that have really changed the landscape of treatment for you that helped to ensure superior staging and prognostication of neuroendocrine neoplasms?

Dr. Kathryn Hitchcock: Absolutely. This is an exciting topic where a lot has changed just in the time that I've been involved in medicine. Just like all cancers, imaging of this type of tumor has improved a lot since the late 1980s. We've got CT scan, MRI and PET now, all of which work for these tumors. But in addition to that, for these low-grade neuroendocrine tumors, we have a molecule called Dotatate that really likes to stick to this somatostatin receptor, which is very common on cells of these tumors. We're able to attach to that atom of gallium and then do a PET-type scan in order to see where the tumor is. The advantage of that over a regular PET scan is it's more specific to these types of cells so that you get a lot less confusing highlighting of things like inflamed hair follicles, for example.

Melanie: Dr. Zarrinpar, this one is for you. Do you have any specific recommendations for other providers as to if their patients are presenting with a neuroendocrine tumor? What should they be scrutinizing that could impair survival, might require dedicated therapy or help their mortality rate?

Dr. Ali Zarrinpar: So neuroendocrine tumors are rare. of that, partly because of that, the systemic therapies for neuroendocrine tumors are not really well established. So what providers need to know and what patients need to know is that for this kind of rare disease, they need to go to centers, regional centers, that are specialized in this kind of care.

These centers will be able to provide the latest in systemic therapy, physicians that have more experience than the local area physicians just because they see more of these patients. And they'll be able to provide more options like PRRT for example. And this multidisciplinary care that these regional specialized centers can provide are really absolutely necessary for these rare tumors.

Dr. Steven Hughes: Yeah. It's Dr. Hughes here. I was going to add to what Dr. Zarrinpar said, which is that, you know, one of the things that our center has value to add is that a number of these tumors actually can be safely followed by serial imaging over time. They don't all necessarily have to be removed at the time that they're identified. Some of these, the surgical treatment is more dangerous than observation is what I'm trying to say. But understanding which ones can be safely observed versus which ones need to be removed or treated more aggressively in a multidisciplinary care fashion really requires a high volume of these very rare tumors and that's the benefit we have at the tertiary referral center.

Melanie: Dr. Hughes, following up on what you just said, what are some of the considerations that go into knowing whether these cancers are resectable?

Dr. Steven Hughes: That's a great question. And to be honest with you, there's a variety of factors. Size of the lesion is one of the most important features, the location and where it arose. The biology of neuroendocrine tumors is actually dependent on the organ in which it arose. And so these tumors can arise in the stomach, in the small intestine, in the pancreas, in the colon, even in the esophagus. So anywhere in the gastrointestinal tract, one can develop a neuroendocrine tumor. And so the location of where it arose sometimes leads to just safely knowing that it can be observed for a period of time, sometimes leads to a recommendation for a biopsy to get an understanding of what's called the grade of the tumor, which is basically a measurement of how fast it's growing.

And then finally, of course, like what Dr. Hitchcock mentioned, some advanced imaging may give us some insight into whether the tumor has the capacity to break free of words started in spread to lymph nodes or the liver or even other areas. And so all of those things can come together to put together a comprehensive plan for a patient. Oftentimes this can mean let's just look at it again in six months.

Melanie: And we're going to get to PRRT, which is really what our topic is centered around. However, Dr. Zarrinpar, before we get to that, is liver transplant ever used to cure these patients? And when liver resection is used? Is it appropriate to remove a small area? Do you have to take out an entire lobe of the liver?

Dr. Ali Zarrinpar: So for patients with liver metastases and the very, very rare patient with a liver primary neuroendocrine tumor, when the tumors are well-differentiated, low grades and there is not diffused liver involvement or compromised liver function or really disease outside of the liver, resection or transplantation is a great option.

And the reason for that is that these tumors are generally indolent and systemic therapies are limited. And so if we can remove all the tumor or, you know, the vast majority of the tumor to get the patients either disease-free or deal with a lot of the side effects or the results of the tumor being there, then resection or transplantation would be an option.

Now, this is going to come back for the vast majority of the time. The question is, how do we decide which of these tumors is least likely to come back. For transplantation, there are a number of factors that patients will need to meet before being eligible for transplantation. And these are set out by the National Review Board.

Generally, you know, the tumors need to be just in the liver. They need to have scans that demonstrate the lack of metastasis outside of the liver. This needs to happen every three months. There needs to be a biopsy that shows lower grades. And they can't ever have any solid organ metastases outside of the liver. Those are the reasons for these things coming back very quickly. And the immunosuppression that liver transplantation needs makes these tumors actually grow faster. And so that's why patient selection is a big deal.

For liver resection, and I'd like to include local regional therapy like arterial embolization or ablation as a part of that liver resection modality. You know, that depends on how many tumors there are, whether there are tumors outside of the liver or not. And whether these tumors can be removed without really affecting liver function. And patients with liver tumors, I think surgery should be part of the armamentarium.

Melanie: Well, thank you so much, Dr. Zarrinpar, for discussing patient selection and considerations for surgical treatments. So Dr. Hitchcock, onto you, describe for the listeners the use of peptide receptor radionuclide therapy or PRRT for treatment of neuroendocrine tumors. Explain when in the course of the disease PRRT is best given.

Dr. Kathryn Hitchcock: That is a really important point because I think that as a community, we're not very good at getting these patients into PRRT at the right time quite yet. It's a very new technology and we're all learning. If there's one thing that I would like our listeners to remember today, it's that it's never too early to refer one of these patients to come just to have a discussion about PRRT. It may not necessarily be time to give it yet when the patient first comes to us, but just to talk about it upfront.

I would guess that 70% of my new consults for this disease end up in me saying, you know, "You, the patient, of course, are in charge of deciding what happens, but I would recommend that we wait on giving you PRRT for right now. In the meantime, let's talk about what that experience will be like when it comes down the road."

Unfortunately, another 15% or 20% of my new consults end up in me saying, "I think this treatment would probably hurt you more than help you. Let's instead talk to your medical oncologist about what we can do instead." And of course, what I'm not saying to those patients is that PRRT probably would have helped them if they had just come to me sooner. But now, that opportunity is lost, which is a terrible feeling.

So as far as optimal timing, there's a lot of complicated things that go into that, just like everything in cancer. But the best answer is that it's time to use PRRT when the neuroendocrine cancer is metastatic and showing signs that it's going to grow out of control despite the use of octreotide. But there's not yet such a huge volume of the tumor that if I use the PRRT, it will end up damaging the patient's normal organ. So, fairly early in the course of the disease, and there's a lot of research that is being proposed right now to use it even earlier before the disease gets very widespread, but the jury is still out as to whether that's a good idea.

Melanie: Dr. Ramnaraig, can you expand on Dr. Hitchcock's answer then for us? When you treat patients with octreotide, do you give it forever or is it a finite course? Are there situations where it can't be used?

Dr. Brian Ramnaraign: Yeah, I think that's a great question. when we start off octreotide or lanreotide, and those are the two somatostatin analogs which are our typical first-line treatment for someone with an unresectable or metastatic neuroendocrine tumor that's well-differentiated. It's usually lifelong and we sometimes can take treatment holidays or treatment breaks. But this somatostatin analog class of treatment was the first treatment that really was shown to slow the growth of the tumor as well as improve the symptoms of the carcinoid tumor, symptoms such as diarrhea, flushing, and palpitations.

And to pick up on where Dr. Hitchcock led off, the Lutathera PRRT treatment is a really effective treatment. And typically, we have given that as a second-line treatment after patients have progressed on a somatostatin analog. And that's based on the FDA approval, which was of course based on the large phase III trial called the NETTER-1 study, where patients after progressing on octreotide at 30 milligrams given every four weeks, they were either randomized to PRRT or to doubling of the dose of octreotide. And then what we've seen is that patients who received PRRT actually lived longer. So, I agree. We want to get these patients into PRRT as soon as we can, but patients just on octreotide or lanreotide can do very well for a long time.

Melanie: And I'd like to give you all an opportunity for a final thought. So, Dr. Hughes, starting with you, as we've discussed that this is a second line therapy. Tell us about any other analogs that might be widely used to treat metastatic neuroendocrine tumors that have been shown to slow progression. Do you have any other therapies that you'd like to discuss?

Dr. Steven Hughes: Well, I think as far as second line therapy, Dr. Ramnaraign is probably in a better position to talk about what's coming down the investigational pipeline, so to speak. I think a combination of systemic therapy, whether it's something like Lutathera that Dr. Hitchcock provides or a more conventional chemotherapy that Dr. Ramnaraign provides, typically what we see are certain spots of tumor that are not responding to those treatments and that's where Dr. Zarrinpar and I can kind of still fit in. And those smaller areas that are not responding to systemic therapy can be surgically removed and we can literally keep these patients disease under control for a long time. And so it's a nice notion that your disease is under control and you're going to have a long life. And that's very typical for many patients with neuroendocrine tumors. And surgery plays a role for those certain areas that systemic therapies are not keeping under control. I think that answers your question.

Melanie: Well then, Dr. Ramnaraign, would you like to respond to Dr. Hughes?

Dr. Brian Ramnaraign: Absolutely. Just to pick up where doctors use left off, I think we still have a long way to go in neuroendocrine tumors. You know, there's two factors that we still need to improve on. And one is reducing the chance of the neuroendocrine tumor coming back for patients with early stage who have had it resected.

You know, last week in clinic, I saw a woman who had a pancreatic neuroendocrine tumor diagnosed 15 years ago, had it resected and was doing well for those 15 years and, you know, all of a sudden it came back. So I think we need better treatments to reduce the risk and cure these patients and to prevent the cancer from coming back. And there are studies, you know, looking at giving a treatment after surgery, it's called adjuvant chemotherapy. There is a large phase III trial. coming out through the national cooperative groups. So I'm looking at giving these patients adjuvant chemotherapy. And, you know, we'll see if that pans out. And if that is actually going to work. But currently, that's not part of the standard of care.

And then the second point is with our metastatic cancers, we want our patients to live longer and healthier and have more fruitful lives. We need better treatments and PRRT definitely has allowed us to help our patients live longer. And I think a couple of questions that we need to answer are, can we make PRRT a first-line therapy now? Which, you know, it's not currently, it's a second line treatment. But maybe patients will do better if we give it first-line and there are trials looking at that. And there also are trials looking at combining PRRT with immunotherapy and other treatments and other chemotherapies. And, you know, in general, you know, we need better treatments and we've come a long way, but there's still a long ways to go.

Melanie: Dr. Zarrinpar, next word to you. We mentioned a few times, but can you expand for referring physicians that the program has this focus in engaging multidisciplinary teams to best treat patients. Can you tell us how you all work together and how you communicate with the referring physicians?

Dr. Ali Zarrinpar: So we're really a team and not just we have regular meetings. We have a regular, very organized meeting where we present patients. Radiologists are there. The medical oncologists are there. The surgical oncologists are there. The interventional radiologists and the transplant surgeons are there. The research folks are there. You know, this is something where every patient goes through that discussion with everyone present.

But also we work next to each other. We run into each other in the hospital and in the hallways between our offices and we talk about patients and we call each other regularly. So if there's a question or if there's a quick update or we're in the operating room and we find something either pleasantly or unpleasantly surprising, we'll call each other and ask each other their opinions. And so this really allows us to come together and provide what, you know, the best options are for each patient. I think it's really important to not just have one mind looking at a problem, but multiple ones from different angles with different set of tools and different viewpoints.

Melanie: And Dr. Hitchcock, last word to you. Can you tell referring physicians when and reiterate for us when to refer patients to UF Health Shands Hospital for PRRT? Can you wrap it up for us as to when and what you'd like the takeaway message to be for other providers on this topic?

Dr. Kathryn Hitchcock: Sure. So I think that, because this is a rare cancer, it's never a bad idea to get patients in contact with a group of people who, as Dr. Hughes described at the beginning of the program, see a lot of this particular disease in order to understand what the best program is going to be for that patient.

Of course, if every patient and every neuroendocrine tumor were the same, it would be a lot simpler and that wouldn't be necessary. But the number of variables here is huge. And so getting these patients in to see a group of people who, as Dr. Zarrinpar described, talk frequently, have formal meetings where we all review the data together, but also we're in constant contact with one another is so important in these complex cancer situations.

And although referring oncologists might want to continue the care of that patient at home, it doesn't hurt to very early on have a consultation at a tertiary care center like ours in order to help sort of lay out a plan for when something like PRRT or when a surgery is going to come into play for that patient. So early referral is really the answer.

Melanie: Thank you all so much for taking part in this panel today. What a fascinating topic. And to refer your patient or to listen to more podcasts from our experts, please visit ufhealth.org/medmatters. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole. Thanks so much for listening.