Good afternoon, everybody, and welcome to sunny San Diego. It's my pleasure to welcome Dr. Hedera del Rivero, who will be discussing today an important topic of watching and waiting versus chemotherapy for GI and pancreatic neuroendocrine tumors. Dr. del Rivero is a dear colleague and a physician scientist from the National Institute of Health. She's one of the few in the world that obtained an endocrine and a medical genetics board certification so she can provide medical oncology so she could provide exceptional care to individuals with medical onc-related care, including endocrine neoplasias. She had several exciting programs and research studies at the National Institute of Health focusing on neuroendocrine tumors. And today, she's going to share with us some important information about therapies for these conditions. So Dr. del Rivero, welcome and thanks for your time. Hello, everyone, and thank you so much for the introduction, Dr. Hannes Ramouni. It is my pleasure to be with you all today, and I really wanted to thank the organizer committee for inviting me to give this talk to you all today. And yes, I wish I can be also medical genetics as well. OK, what we're going to discuss today is about the management of GI and pancreas neuroendocrine tumors, when we're going to decide about watch and waiting, and when we're going to decide about given systemic therapies. So first, I'm just going to give you a little bit of background about neuroendocrine tumors. As we all know, neuroendocrine tumors has increased in incidence exponentially over the last few decades. We can see here that all the other solid cancers, like prostate cancer, breast cancer, has plateaued. However, the incidence of neuroendocrine tumors, as we can see here, has increased certainly exponentially over the last few decades. Moreover, there is also an increase in incidence of neuroendocrine tumors of different sites. For example, the lung, the pancreas, the rectum, the small bowel. So we can also see that there is an increase in incidence of neuroendocrine tumors based on sites of disease. So you may question why we're having an increase in incidence of neuroendocrine tumors. And one of the reasons is because we have better diagnostic modalities with the data that they scanned, which has really helped us understand more about the biology of these neuroendocrine tumors. And also, we do more colonoscopies, endoscopies. And could this be an epigenetic factor related to the increase in incidence? It's possible, but that's a research question. Now, in terms of the classification of gradient of neuroendocrine tumors, it could be quite complex. So we know that these neuroendocrine tumors are an heterogeneous group of neoplasm. And at the same time, they have a complex gradient, as well as classifying the gradient progression. So we divide the neuroendocrine tumors or neuroendocrine neoplasia into two groups, neuroendocrine tumors, which are well differentiated from grade one to grade three. And then we have neuroendocrine carcinoma. Neuroendocrine carcinoma is a more aggressive tumor. It has a decimal prognosis. You only treat this type of neuroendocrine carcinoma with chemotherapy. However, the neuroendocrine, the well-differentiated neuroendocrine tumors, they're more indolent growth. This patient may live for a decade. And then different treatment options that we can definitely indicate patients that have an advanced or metastatic neuroendocrine tumors. Another important point about this is, and Dr. Parisi will discuss more about it, is that neuroendocrine tumors express somatostatin receptors in the surface of the cell. And because of that, DOTATATE scan is a good imaging modality. As the grade of neuroendocrine tumors become from well-differentiated to poorly-differentiated, these tumors start losing the somatostatin receptors. And they become more FDG PET-avid compared to DOTATATE scan. But as Dr. Parisi will discuss more about the concept of teranostics, this has been changed, the management of neuroendocrine tumors, the way we diagnose and treat using the same modality in terms of the radioisotopes that targets neuroendocrine tumors. So let's discuss a little bit more about what neuroendocrine tumors are and hormones. And since most of us are endocrinologists here, and in terms of consult service, you may see a patient that have this excess of hormones and they may call you about it. But neuroendocrine tumors arise from any neuroendocrine cells, and it could be anywhere in the body. Depending on the site, they can produce a specific type of hormone. But for the purpose of our talk today, we're only going to discuss about pancreas and GI neuroendocrine tumors. And also, if you want to learn more about pheochromocytomas and parathyroid encephalomas, I will advise you to go to Dr. Carl Spaksak's talk on Saturday. I know it's going to be very good. Now, let's discuss a little bit about how do we manage these patients with functional neuroendocrine tumors and the incidence as well of functional neuroendocrine tumors. Carcinoid used to be an old term. We're trying to get away from the carcinoid terminology. We now wanted to call it neuroendocrine tumor of the GI tract, or a small bowel neuroendocrine tumors, with carcinoid syndrome. And the reason why is because these tumors may produce excess serotonin, and that's why we measure that in the urine in the form of hydroxyindole acetic acid. But this excess of hormones can produce a series of symptoms. But an important point to remember here is that when the symptoms occur is when they are usually metastasized and it's in the liver. When they're localized, they usually don't have that many symptoms. However, when they metastasize and it's in the liver, that's when they have a series of symptoms related to the hormone excess. Insulinoma, so in terms of now we're going to talk about pancreas neuroendocrine tumors. Most pancreas neuroendocrine tumors are non-functional. Approximately, in the literature, you will say 10%, maybe 20%, up to 35% of patients with pancreas neuroendocrine tumors may produce a type of hormones. One of them is insulinoma. Usually, when insulinoma is diagnosed in early stages, and the reason why is because they're localized. And when they're localized, they can cause a lot of symptoms. And because of that, insulinoma usually can be diagnosed in early stages compared to the other neuroendocrine tumors, like the GI tract or the VIPOMA. Gastrinoma, we often see gastrinomas associated with MEN1 syndrome. It's associated with Salinger-Ellison syndrome with ulcers, diarrhea, sometimes perforation based on the increase in the acid gastrin levels as well. Now, in terms of the VIPOMA, this is very rare. And when it's diagnosed, it's usually metastasized. This causes Werner-Morrison syndrome, which is associated with severe diarrhea, which can be anywhere from 700 CCs, anywhere from three liters a day of diarrhea. It also has associated with low potassium as well with chlorhydria. This is very rare, but I do have a few patients with VIPOMA in the metastasized setting. And usually what we do in this situation is how do we manage the symptoms associated with this hormone excess. Glucagonoma is another one. It's very rare as well. It's associated with diabetes, a classic rash associated with glucagonoma and cachexia, and somatosatinomas, which is also rare, but something to keep in mind here and also because we have Dr. Karol Patza here in the audience is that there is a syndrome called Patzak-Swan syndrome, which is associated with polycythemia, paragangliomas, and somatosatinomas. And Dr. Patza discovered the HIF-2-alpha mutation associated with this tumor type. And this is something that has helped us understand a lot more about the biology of pheochromocytomas and paragangliomas. Now, once we have a functional neuroendocrine tumor, what do we need to do? And that's when we need to then understand how we can manage the symptoms associated with this hormone excess, and then in the metastatic study, how we can control tumor growth. And for that, we have different modalities of treatments for these neuroendocrine tumors. I have to say that in terms of the treatment for this tumor type, it's not like one size fits all. It's a very personalized type of therapy for these neuroendocrine tumors because you need to keep many factors in mind. For example, the volume of disease, whether it's low volume, large volume, whether it's only in the liver, whether it's everywhere besides the liver, whether the specimen starting receptors of no, whether they're functional or no, the rate of growth as well, whether they're more indolent versus more rapidly growing disease. So those are the type of things that you need to look whenever you wanted to personalize the management of these neuroendocrine tumors. And because of that, these tumors usually needs to be discussed in a multidisciplinary team. That way we can then understand what will be the management and with that, the best outcome of patients. Surgery is an option. Even in the metastatic setting, surgery can be an option. This is the only, maybe other solely tumor types, but neuroendocrine tumors are one of the few that even in the metastatic setting, surgery can be indicated. We'll discuss a little bit about somatostatin agonist, but the function of somatostatin agonist is control of symptoms due to hormone excess, but also it can control the growth of the tumor. It has anti-proliferative activity. Telotristat is a newer medication that blocks serotonin excess. It blocks the tryptophan hydroxylate, which is the rate limiting enzyme for serotonin synthesis. Liver-directed therapies. If the patient has a liver dominant disease or only has a few lesions, maybe you can consider discussing liver ablation, embolization, PRT with Lutathera or pectide receptor radionucleotide therapy, and Dr. Parisi will discuss more about that, so I will not go into detail on this. And other systemic therapies that we could consider on these patients is the virulimus, sunitinib, or capsidivine temosolomide. However, something that I want to mention here is that we still don't know what is the sequencing of treatments. And that's why there is still a lot of ongoing research to understand not only more about the biology of these neuroendocrine tumors, but to also understand what will be some of the sequences of this treatment to then provide the best outcomes for these patients. Now, based on what I just discussed, I'm just going to discuss a few cases with you. And with this, I feel like we can then differentiate what treatments needs to be given in a certain time in the course of the neuroendocrine tumors. And first, we're going to discuss this gentleman. He's a 68-year-old patient who underwent a CT scan of the chest in the context of work for suspected pulmonary embolism. Incidentally, the CT scan shows multiple intrapartic lesions. Further workup includes a dedicated CT scan of the abdomen and pelvis that confirmed the presence of six enhancing lesions. In addition, there was a three-centimeter mass that was found in the body of the pancreas. An ultrasound guide biopsy was done, and the pathology was consistent with well-differentiated neuroendocrine tumor. K67 was less than 2%. That is, the patient doesn't report any tumor-related symptoms, doesn't have any symptoms related to hormone excess. So what are you going to recommend to this patient? And in this situation, you need to keep in mind, as I discussed earlier, well-differentiated neuroendocrine tumors has a very indolent course. So this is a patient that, for CU, has a relatively low-volume disease, K67 less than 2%. So the K67 is also used as a prognostic tool. It tells me how the patients, in terms of grading, what is grade one, when the K67 is less than 3%, whether it's grade two, the K67 is anywhere from two to 20%, and grade three, when the K67 is greater than 20%, and usually when it's grade three, it's more aggressive behavior. But in this situation, we have a well-differentiated neuroendocrine tumor with a K67 less than 2% indicating this is a grade one. So in these situations, what do we do? So do you want to start landreotype or octreotype? So we know that these are certain agonists can have some anti-tumor activity. However, I need to understand the progression of these tumors. It's the first time I'm seeing these patients. I need to understand what is the progression of disease. I will not necessarily use sunitinib in this situation. Sunitinib now, we use it more as a third or fourth line of treatment. We can consider the bulk in surgery. If the patient has liver disease, we could. But at the same time, I personally don't want to expose the patients to a type of treatment without understanding what is the biology of these tumors. And in this situation, yes. I mean, this is one of those cases that I can watch and wait. I can continue surveillance scans. I could bring the patient in the next three to six months. I can understand what is the disease progression. These patients may not have any evidence of disease progression for a few years, and that's okay, even without treatment. And that's something that we need to keep in mind. Sometimes when we see a patient with metastatic disease, the first impulse is that we need to do something, and the patient feels that we need to do something. But at the same time, I feel that we need first to understand what is the growth rate and also the biology of these tumors to then personalize the treatment that can provide the best outcomes for these patients. So in this, my answer. Now, we have a different case. We have a 65-year-old female that complains with left-sided abdominal pain and persistent diarrhea. She underwent an exploratory laparotomy for persistent left-sided abdominal pain that was consistent with a small bowel obstruction. That's what it was found initially, and the reason why she underwent exploratory laparotomy and multiple liver lesions. She also underwent a small bowel resection and which resection of the liver. Pathology was consistent with a small bowel, well-differentiated neuroendocrine tumor with a KS67 less than 1%. So these scans was after the surgery, because again, she was complaining of abdominal pain, was diagnosed that she has a small bowel obstruction, and then after the diagnosis of a neuroendocrine tumor, she had an endodontic scan, and Dr. Parisa will discuss more about the endodontic scan and the difference between endodontic scans and corporate scans and so forth. And then we see the MRI that have also liver metastasis. So what would you do next? So this is a patient that also have well-differentiated neuroendocrine tumors of the small bowel, low KS67. However, she's symptomatic because she has diarrhea. She has persistent diarrhea, and that's because of the excess of serotonin due to the small bowel neuroendocrine tumors. So what do we do in those situations? Even though she has low volume disease, and I told you earlier that sometimes we can just watch and wait for these patients that have very slow growth disease, but in this intuition, because of the symptoms associated with the neuroendocrine tumor, I think it makes sense to start somatostatin agonist, such as Landreotide or Octreotide, because as I say earlier, this somatostatin agonist has two functions. One is antiproliferative activity, and the other one to control the symptoms related to the hormone excess. We will not give ephedralimus. Even this could be more as a third option for these patients. Lutathera could be considered, especially if we can see that the tumor is avid and that the scan is something that we can concede that I just don't feel that this is the time to give lutathera. Could ablation of the liver be done? Yes, I think it could be done. She has, we can see only one liver lesion. I think it could be done. And it can help with the diarrhea, but in this situation, first, I need to control the symptoms with Landreotide and somatostatin, because that can also have antiproliferative activity where the liver, direct therapies only address the liver, but not any extrepathic disease. In this situation, I will not do watchful waiting, as I say, because she's symptomatic. We need to do something for this patient. So this data came also from the two different studies. Those studies were randomized placebo control, double-blind study of Landreotide. That was the clarinase study, or the somatostatin, which that was the PROCMED study. And in this study, the primary endpoint was time to tumor progression, so stabilization of the disease. And as we can see here from this Kaplan-Meier curves, we can see that there is efficacy related to the sandostatin where we can see that there is a prolongation of the survival. So that being said, as we can see on the yellow line, this is the patients that were treated with octreotide on the blue, where the patients were on placebo. And the wider it is, these curves, the longer will be the time to tumor progression. So in this situation, we can see that there is a benefit of giving landreotide or sandostatin as we can see here in patients with neuroendocrine tumors. One other thing to keep in mind is that on this study, they also saw that they have benefit in terms of the hormone excess symptoms. They have less diarrhea episodes, they have less flushing. So that was something that the study also noticed as well when they published this data. So that's where the data comes why we need to give landreotide or sandostatin as a first line for these patients. One other thing to keep is toxicity. As a medical oncologist, we always look at toxicity of these different agents, but from the, since most of us are endocrinologists here, something that you need to keep in mind from this sandostatin agonist is it can cause hypothyroidism as well as hyperglycemia. Now, in terms of the carcinoid syndrome, it's a series of signs and symptoms associated with the serotonin excess. Likely associated with a small bowel or with the long neuroendocrine tumors in certain locations as well, sometimes with appendiceal neuroendocrine tumors. And the most common symptoms associated with the carcinoid syndrome is flushing as well as diarrhea. We also see some of these patients because the excess serotonin can also cause fibrosis in the valves of the heart, and they can also have, as a consequence, heart failure because of this excess serotonin. They can also have dyspnea in certain locations. So these are the signs or symptoms associated with carcinoid syndrome. And sometimes when we see a patient, we educate the patients about the five Es because these five Es can also be associated with exacerbation of these symptoms, mainly with flushing, like eating bananas, tomatoes, avocados, also certain emotions as well. Ethanol cause more flushing, exercise, and as well as epinephrine. So those are the things that we need to counsel our patients to make sure that they're keeping in mind or there are certain things that may exacerbate the symptoms related to carcinoid syndrome. Now, just continuing with this case. So this patient experienced worsening diarrhea. So she has now 12 times per day, despite getting Landria Tye, and as well as Landria Tye every three weeks. Usually the dose of Landria Tye is every four weeks, but the decision was made to give it every three weeks to see if maybe that helps control some of the symptoms, as well as she was receiving rescue shots of Landria Tye short-acting just because of the flushing. So what we're going to do next? So we have this patient that despite being on so much satin agonist, she's still very symptomatic from the excess serotonin. So in these situations, we can either, and maybe I can just ask our audience here, I don't know if that makes sense, but who would increase the dose of Landria Tye? Just raise your hand. Nobody? How about Telotristat? Okay, how about PRRT with Lutathera? Okay, Everolimus? Ablation or embolization? Yeah. So that's good. So actually, yes, you selected, thank you so much for participating with me, and you're right. So we need to give something in these patients to control the diarrhea. In this situation, Telotristat is a good agent to start with. Ablation, embolization, yes, it can be given. It can definitely control the symptoms of the diarrhea. I usually personally like to see if the medication works for the symptoms of that, and then consider ablation, embolization. And another reason why in this patient, if they wanna consider ablation, embolization first is because she still have disease outside the liver. So even if you address the liver lesions, she still have disease outside the liver, and she may still have symptoms related to serotonin excess. So that's the reason why Telotristat is the right answer for in this patient. So the data came from this study where it was also a randomized placebo-controlled double-blind study where they give Telotristat, and those patients that received Telotristat, they see a decrease on the 5-hydroxyindoleacetic acid as well as the decrease in the number of bowel movements per day. And that was proven like two years ago for the management of carcinoid syndrome. So, and just continue with this case, we have this, the other test can follow up. We see more disease, not only on the liver, but we also disease outside the liver. Involving other organs like wall of the sigmoid colus, there's areas of hypermetabolic activity in the abdomen pelvis, some implants in the tumor. So in those situations, what would we do? And maybe that would be more of a straightforward answer, but who wants to give a virulimus? How about sunitinib? Yeah, how about PRRT with Lutathera? Serofatinib, that's a newer TKI, and levavatinib. So and I agree with you, in this situation, maybe Dr. Aparici may comment more about that, but absolutely correct. This is a patient that will benefit from Lutathera. We know that this is a patient that have AVID disease. We know that this patient has not only atheropathic disease, but liver and atheropathic disease. So this is a type of patient that will benefit from Lutathera. And I just wanted to ask Dr. Parici, what do you think about this case? Well, I definitely agree with Dr. Aparici. 30% of the cases, the TKI, we don't know why, so it's definitely furthering the community, and furthering Lutathera. We will keep on doing research. So I think it's very over-expanding. It's not very over-expanding, but it might go out to a different kind of community, so I'm sorry that you're not making that. Right. Great, thank you so much. And we have Dr. Parici, so I wanted to also ask her expertise, as she is our nuclear medicine physician. And you're correct, this is a decision that we made with this patient to give Lutathera for the treatment of her metastatic disease. And also, just to remind you, where does the data come from? This comes from the NETHER study, which is a randomized study of high-dose sandostatin versus Lutathera. And the patients that receive Lutathera, as I discussed earlier, with a couple of myocarbs, they have much benefit. There is a tremendous benefit on progression-free survival, or time-to-tumor progression of the patients that receive Lutathera. And Dr. Parici will discuss more about that. Earlier, when the paper was published in the New England Journal of Medicine, there was some data that maybe benefited in overall survival. And we were truly excited about that, because it was the first treatment in the neoendocrine tumors that has benefited in overall survival. But now, in the final analysis, it was not benefiting overall survival, to the surprise of the investigators who run the study. But one of the things that they argue, maybe why they didn't see any benefit, is because it wasn't power for overall survival. Patients that were receiving high-dose sandostatin, they cross over to receive Lutathera. And also, if you can see earlier in the separation, there is some benefit, maybe a one year of survival. But still, it was very difficult to conclude about the study. But at the end, the data showed that there was no benefit, but again, with the arguing of the factors that I just mentioned earlier. Now, let's just move to another different case. So we have a 66-year-old male with a history of MEN1, when he was, I know, 36 years old. Clinical manifestations, classic MEN1, primary hyperparathyroidism, status post-3-gland parathyroidectomy, gastroenoma, status post-distal pancreatectomy, splenectomy, and at age 15, this is her history of the MEN1. However, at age 15, he was diagnosed with insulinoma. He has the classic symptoms of hypoglycemia, the Whipple Triad that we discussed earlier with insulinoma. He came to the NIH. A 48-hour fast test was done. And as we can see, the levels of glucose here drops to 41, with the insulin levels to 126. And pro-insulin levels was also elevated at that point. So this gave the confirmation of insulinoma. Image and studies, we can see here there is a mass that was biopsy that was proven to be insulinoma. We also see some liver metastasis here. Dot at the skin, we can also see that there is now multiple liver metastasis for this. And just so that you know, this is a CT scan. The best scans to see liver metastasis is an MRI. Lutathera has high sensitivity as well, just something to keep in mind. So the patient was not a surgical candidate. You saw that he has a lot of his prior surgeries. Diaxocyte was given, and as we know in this patient, diaxocyte can also help control the symptoms of hypoglycemia. However, there is this progression on the follow-up scans, progression of disease on the follow-up scans. So let's just raise your hands. Who wants to give sunitinib? How about capsaicin and temosolomide? Sandostatin or lanreotide? Everolimus? And liver direct therapy? That's very good. Everolimus. So this is just to keep in mind, why Everolimus here? So we know Everolimus may not have a lot of cytotoxic activities, more cytostatic, meaning that it doesn't shrink the tumors, but it stabilizes the tumors, and that's how it was approved. But one of the side effects of Everolimus is hyperglycemia. So and because of that, it makes a good choice for a patient with insulinoma. So this is just the data from the Everolimus. This was based on the RADIAN-3 study. So we can see that there is a benefit on progression for survival, stabilize the tumor, prolong time tumor progression. But for other agents, we need endocrine tumors, we can see that there is no evidence of overall survival. So we still have a lot of work to do in terms of management in these patients with neuroendocrine tumors. Now, this is my last case. So let's discuss this case. This is a 56-year-old male that complained with left upper epigastric pain. CT scan of the abdomen, identify a mass in the head of the pancreas. This is the measurements. Pathology of the biopsy reported a grade two well-differentiated pancreas neuroendocrine tumor. KS67 is 15.5%, so this is a grade two. Hormonal evaluation was within normal limits. Follow CT scan of the abdomen, show an increase in the pancreatic mass and increase in size of the liver lesions. Now is 5.8 centimeters when it usually was four centimeters in size. And also, I'm sorry, my apologies, the pancreas. So prior, it was very difficult to characterize the liver lesion. So the patient began monolysandrostatin, risk stages cancer reported evidence of disease. So this is a patient just to summarize. This is a grade two, well-differentiated neuroendocrine tumor that has a large volume of disease, symptomatic from the disease, and also rapidly growing disease. So what would you do in this situation? So who wants to give Sunitinib? How about Kevcylavin temosolomide? How about Xantostatin or Landreotide? Everolimus? PRRT with Lutathera? Liver director therapy? Yes, I agree. Kevcylavin temosolomide, captain. And I'll explain to you why. But the reason why liver director therapy is not an option, the liver lesions are too large to be treated with either embolization in this situation. PRRT with Lutathera, it worked, it worked. We know it stabilized the tumor. And we can see that this patient has quite avid disease in the dot of the skin. But as I say earlier, it doesn't have cytotoxic activity, meaning it doesn't necessarily shrink the tumor. So even though there has been some cases with extraordinary response to Lutathera, and sometimes in combination with other agents, still there is, where the research is going on is to do combination, develop clinical trials in combinations with PRRT to enhance the activity of Lutathera. In this patient, we need something to shrink the tumors. So in this situation, yes, chemotherapy is the option. Everolimus also doesn't have much cytotoxic activity, the same with Xantostatin, the same with Zonitinib. So in this situation, the only one here that can provide some tumor, decrease in the tumor size is chemotherapy with Temozolomide and Capsaicin. And this was based on an eco-accurate study that was discussed at one of the ASCO meetings by Dr. Pamela Kunz. And this was a randomized study with a randomized patient either to get Temozolomide alone or Temozolomide in combination with Capsaicin. And this data showed that the response rate of patients that were enrolled in this study has up to 33.3% on the patients that received the combination. Compared to the other studies like Zonitinib, compared to Everolimus, compared to PRRT, that we don't see this type of response rate. It makes sense in a patient with endocrine tumors with large volume disease that is symptomatic that Kapton is the best option for this patient. Now, I just want to discuss briefly about Zonitinib. Zonitinib is approved for the management of pancreas neuroendocrine tumors, not for small bowel neuroendocrine tumors. The same with Capsaicin and Temozolomide. The activity is on pancreas neuroendocrine tumors, not with the small bowel neuroendocrine tumors. But something that I want to mention here, and the reason why I mention it here is because that's one of the most common consoles that you get when the oncologist calls you. The patient has either a bladder cancer or a kidney cancer or any other solid tumor cancer that is on TKIs, and they call you because of the hypothyroidism associated with Zonitinib. But just to mention a little bit about the study, this was for pancreas neuroendocrine tumors. How it was approved is because they originally saw a benefit as well on progression-free survival of type tumor progression, and that's the reason why it was approved for pancreas neuroendocrine tumors. The study was closed earlier because there were some issues with randomizations, but based on this data, the FDA felt it was enough to approve it for the management of pancreas neuroendocrine tumors. Now, in terms of the thyroid dysfunction associated with TKIs, what we have seen, and that's something that at least when a patient is receiving either Kawasantinib, Zonitinib, and Lemvatinib, is that we usually wanna assess thyroid function test at baseline, and then after that, every four to 12 weeks. And the reason why I wanted to do that, because a lot of these patients are frail, so we wanted also to improve their quality of life in a cancer patient by optimizing their management of hypothyroidism. Often, we see a thyrotoxicosis, and that may be seen preceding hypothyroidism. And usually, the treatment of thyrotoxicosis in this situation is conservative management of sometimes steroids, but I just wanna bring this, because that's one of the most common consoles that we get from our oncology colleagues. Now, in conclusion, 10 to 30% of patients with pancreas neuroendocrine tumors secrete hormones resulting in clinical syndromes. Midcut neuroendocrine tumor may develop carcinoma syndromes that we discussed earlier. Biochemical assessment in relation to the clinical presentation and adequate image studies is recommended for these patients. Surgery is a courtesan of treatments and can reduce the clinical symptoms, as well in occasion cytoreductive techniques. However, it has to be discussed with a multidisciplinary team. Not every patient may benefit from surgery. We just need to determine when is the best time for the specific treatments that we discussed earlier, or whether the patient may benefit from surgery. Those are the things that we definitely need to discuss in a multidisciplinary team. Grades one and two neuroendocrine tumors grow slowly, and regardless of the primary tumor, a watch-and-wait approach with a follow-up three to six months can be considered before giving any systemic therapy, or before surgery, or before ablation and mobilization. And in the advanced disease that we discussed, there are different options. We still don't know the sequence. We're learning about the sequence in the management of neuroendocrine tumors. We also need to understand and develop other treatments for these patients because as I discussed earlier, most of the treatments has a prolonged time to tumor progression. However, it doesn't have a benefit in overall survival, meaning that it doesn't help the patients live longer. So there is so much work that needs to be done in the management of neuroendocrine tumors. But as we can see, despite that, in the last decade or so, there has been advancement in various treatments that at least has helped us to stop the growth of these tumors, like PRT, with lithotherapy, chemotherapy, targeted therapies, and so forth. So this is my last slide, and I want to thank you all for your attention. Thank you so much, Dr. Del Rivero, for this excellent review and great questions. It's my absolute pleasure to introduce my colleague, Dr. Karina Aparici, who's a clinical professor in radiology at Stanford University. She's a nuclear physician with residencies in both Europe and the U.S., originally from Barcelona, Spain. She specializes in the care of neuroendocrine tumor from a radionutrasurgical perspective. She's a physician scientist in the development of molecular imaging and therapies and has over 20 years of experience and has published over 100 papers in this field. Please join me in welcoming her. She's going to be speaking about external beam radiotherapy of neuroendocrine tumors. Good afternoon, everybody. I have to say that I have to change the title a little bit. There was a mistake there. I'm actually going to talk about internal molecular targeted radiation of neuroendocrine tumors. And with that, I will move on to the next slide about my disclosures. I don't have any disclosures, and this is going to be our outline. The way we treat these patients from the inside out, from the inside of the cell out, is based on the concept of theranostics. So we are going to very briefly discuss the concept of theranostics, then how we specifically use the concept of theranostics for PRRT, peptide radionuclide receptor therapy. That's what we use to treat neuroendocrine malignancies, with lutetium-177-dotatate, which is going to be our therapeutic probe for PRRT. And then we will discuss the clinical significance, patient selection, preparation, and doses. So what is theranostics? Theranostics is a concept that has existed for a long time. It's just that now it's becoming more like a field. And the way to think theranostics is about thinking of the disease that we want to treat. Most of us, we treat malignancies, and we think of a molecule that can be very specific and unique of that disease, of that malignancy, and that is going to be our molecular target. Once we have figured out which one is going to be our molecular target, we are going to develop a probe. And when we introduce this probe inside a mammal, inside a human, we have to make sure that this probe is going to be provided in very tiny amounts, nanograms or picograms. There is not going to be any pharmacologic effect. And it's going to be looking for this molecular target and attached to it. If we are able to get the signal from this probe from inside of the body, and for us this is really easy with radionuclides that can emit positrons, for instance, and we can image with PET scans, right? We are going to get a map of the distribution of that molecular target, a.k.a. the disease that we are imaging, the malignant cells that we are imaging, and we are going to be able to diagnose, help with the staging, localize, assess the disease burden, and know if there is overexpression of that target. So now let's move to the right side. We have the right probe, and we know that if we introduce it, it's going to go to those malignant cells that we want to treat. What if I switch the isotope? And instead of introducing an isotope linked to this probe, that instead of providing a signal that gives me a very nice image, now I get rid of this cell with a cytotoxic effect by targeting the nucleus. Now we are going to get into the concept of theragnostics. If we can diagnose it molecularly, we are going to be able to treat it at the molecular level. So let's discuss that for our PRR team, because as you see, the way I see theragnostics is a triangle. At the vertex I have my molecular target, and the basis of my therapy is going to be I'm going to be driven by my molecular imaging, and then I'm going to deliver my molecular therapy. So for PRR-T, which one is our molecular target? Somatostatin receptors, right? There is such a unique overexpression of somatostatin receptors, usually in neuroendocrine malignancies. And as Dr. Del Rivero mentioned, that actually changes with the evolution of these malignancies grade 1 and grade 2. They tend to overexpress somatostatin receptors. And unfortunately, grade 3 carcinoids, they tend to not overexpress somatostatin receptors. And there is a evolution of these neuroendocrines. As they evolve genetically, actually sometimes they tend to de-differentiate and they flip. They decrease the overexpression of somatostatin receptors, and they increase the overexpression of GLUT3 transporters. That's why we switch at some point in time, and there is overlap at some point in time with the imaging that we can use to assess these malignancies and characterize them biologically. For instance, neuroendocrine malignancies that tend to be positive for increased glycolysis, they tend to develop a worse, or at the end of the day, they tend to have a worse prognosis than actually the same neuroendocrine malignancies that have the same KI67 that under the microscope look exactly the same. The prognosis will be better if they are not FDG-avid. So we already have the molecular target. What is going to be our probe? Somatostatin analog, right? We introduce a somatostatin analog inside the body. It's going to be looking for somatostatin receptors. We just need something that emits a signal, positron emitter, so that we can get a PET scan. What about gallium-68 dotatate, for instance? Dotatate is a somatostatin analog. I label it with gallium-68. I'm going to get a PET scan, where I am going to see the overexpression of all these receptors in these malignant cells. If I use the same somatostatin analog, and now I switch the isotope to an isotope that is going to be a different type of radiation, an alpha emitter or a beta emitter, I'm going to be able to deposit so much energy in a few millimeters. In this case, dotatate has been FDA-approved to be labeled with lutetium-177. The commercial name is Lutanthera. And we're going to deposit so much energy in that cell and in two, three, four layers of cell around it, so that we allow for crossfire, that the idea is to convince the nucleus to get exhausted and undergo apoptosis. That's going to be our goal at the molecular level and at the cellular level. So now you understand why in theranostics, we think of pairs. We think of a diagnostic pair that provides us with a lot of information, and then we try to treat at the molecular level what we see with our molecular imaging. So we know our therapeutic probe, right? FDA-approved, lutetium-177 dotatate. As a diagnostic probe, we have nowadays FDA-approved gallium-68 dotatate, also approved copper-64 dotatate, another PET probe. Indian-111 octreotide has been around for a long time, but it didn't have the same sensitivity and resolution as PET agents. And also another somatostatin analog dotatoc labeled with gallium-68 is FDA-approved. At the end of the day, what is going to do the job in PRRT is lutetium-177. So what is lutetium-177? It's another element of the periodic table. That's what we do for a living. It happens to be a lanthanide. So what is different from a lutetium point of view? Nothing different. Lutetium-175 is a great element. It's an angel. If you guys have kids, they are our angels. But oh boy, when they become unhappy, they are going to emit all this energy, right? They get into these tantrums, and at that point in time, you just hands up and try to use that energy the best you can and just wait for it to disappear. From a nuclear point of view, that's called decay. And in terms of using the energy the best we can, we use it for medical purposes. That's it. Once it decays, it becomes hafnium, which is a very stable element, and it becomes another angel. So the goal is to bring that tantrum inside the cell so that it convinces the nucleus to undergo apoptosis. Why are we going to convince the nucleus to undergo apoptosis? Well, because the nucleus gets exhausted at some point in time. But first, let's talk about bringing lutetium-177 inside the cell. What are we going to do then? Because if I put it IV, it's not going to be inside the malignant cells and only inside the malignant cells as soon as or as much as possible. That's why this is a targeted therapy. So we leave the benign tissues aside from the therapy as much as possible. We want to bring this just inside the malignant cells, the ones that are expressing the somatostatin receptors. We just need a taxi driver that brings it inside. That's going to be our somatostatin analog. We bring it inside the taxi, and it goes inside the cells. Once inside the cells, or once this is attached to the somatostatin receptor, this is going to be internalized. Lutetium is going to be inside the cell by the nucleus, and it's going to have a penetration of this beta radiation, a mean penetration of 0.67 millimeters. So you can see it's going to affect this cell or a few cells around it with a maximum penetration of 2.2 millimeters. And you're telling me, oh, so how is this going to convince the nucleus? The nucleus has been receiving radiation for a long time, and it knows how to repair, because this radiation is going to affect the DNA strands of this nucleus, and it's also going to be creating free radicals in the cytoplasm. The nucleus is going to receive that and say, I know how to repair. But believe me, this is inside the cell this second, and this second, and this second, and you keep counting seconds, because the half-life of lutetium-177 is about a week. So this is non-stop, basically, convincing this nucleus, you are exhausted repairing. You really have to undergo apoptosis. That means that the effects of PRRT are not going to happen in an hour, or in a day, or in a month, or in two months, or in three months. It's going to happen slowly, but I always say the same thing, slowly but steadily, because inside that cell, it's going to try to convince the nucleus as much as possible, and it's going to be there non-stop. So does this work? And as Dr. Del Rivero already presented, we have the clinical trial of the NETR1. We were all waiting for it to know if this concept was working or not. And the data at around 24 months was so exciting. We just couldn't wait to put this inside of our patients to get this response, because before our patients were going to Europe, right, to be able to get these therapies. So as Dr. Del Rivero already explained, there were two arms. One was receiving large 60 milligrams, and the other one was receiving Lutathera plus 30 milligrams. And these were the Kaplan-Meier curves that we were receiving. So exciting, right? I mean, to have a progression-free survival of about 80% was so exciting. And even now, the progression-free survival is really high. We were receiving these overall survivals that, as we know, now it doesn't show that difference. And the question is, are we going to need another clinical trial to specifically assess that? And maybe, yes, that will be the answer. But I mean, during all these months, look at the overall survival that the patients can be getting. And the objective response rate, I mean, 4% versus 13%, even without 1% of complete response. So this was very exciting. So what was the payback? What were the side effects of PRRT? Since this is targeted and it works so slowly, the side effects are so benign. These patients go through the therapy having a very good quality of life. So that was also a very important thing to have into account when we think of patient selection for PRRT. In fact, although here in the States, we're still trying to figure out where within the scheme, as Dr. Del Rivero, we are going to introduce PRRT. In Europe, when patients have systemic disease, usually it has been quite established that the second line after SSA, after somatostatin, allows. Here we are still trying to figure it out when is the right place to localize PRRT. So how do we select our patients? So as Dr. Del Rivero very well said, from a multidisciplinary approach. We present our patients in our Net Tumor Board. We meet weekly, actually. We have a specialist from all the disciplines. And we review everything, pathology, imaging. We're going to look at the K67, the grade, if there is overexpression or not of somatostatin receptor, if the patient is progressing by imaging clinically. We are going to look at the organ function. We're going to basically decide what is the best next line of therapy together as a group. Once we have decided that PRRT is the next line of therapy that can help these patients, patients are sent to us to the Theranostics Clinic, where we are going to basically assess if the patient is a good candidate for PRRT. We're going to explain the therapy, the radiation, how it works, how doesn't it work, basically the different measures. For us, very important is to be more proactive and less reactive, because patients are going to commit to an eight-month therapy. This is a four-cycle therapy, usually about 200 millicuries per cycle, so a total of 800 millicuries. Since this is provided every two months, so it's 800 millicuries within eight months. So that's a commitment that the patient has to make, to be with us for eight months as we organize this treatment. Very important for us that they can make an educated decision, that they know what they are basically committing to, and of course, basically discuss the side effects. We have also realized that it's very important to assess the comorbidities that these patients have so that we can minimize side effects from these comorbidities and maximize the outcome of PRRT beforehand. And then we schedule. We schedule and schedule. We schedule the hands-on therapies, visits, imaging. We coordinate with injection of cold somatostatin, analogs, and then we just go ahead once we have everything ready. So how do we prepare the patients for this therapy? Well, first of all, we make sure that the insurance has approved the treatment and that we have every single thing in the system. We obviously order the dose, and very important is to have a good access. We are going to introduce this therapy inside the body, IV, and we are going to use amino acids to be able to protect the kidneys from the radiation for these patients. So it ends up being a long day because amino acids are infused slowly, within usually four hours. The therapy itself is usually infused in only 30 minutes. Have really good IVs. We don't really need large IVs, actually. We don't like to use centrals, but have two peripheral IVs, ideally in two different terms, one for the amino acids and one for the Lutathione. Why? For us, it's very, very important not to have any extravasations from our therapies. So far, we have had zero, and we want to have it zero. And if that ever changes, we want to make sure that that's the right site and the right vein that received it so that we can act appropriately. If patients have not good peripheral access, sometimes we place the PICC line and we remove it before we discharge the patient for radiation safety purposes. So we have a checklist that we share with our colleagues in GI oncology. We work very closely. And a few of the most important inclusion criteria are going to be lab-based. Before we start, since this is radiation, that although we target the malignant cells, we still have it circulating for a while. We are going to be very careful with the bone marrow reserve. We are going to be very careful with the renal function and with the liver function. So there are specific cut-offs that come within the package insert that we like to make sure that the patients have before we are going to be able to introduce the therapy. And this is important in the sense that sometimes when patients have had to go through other therapies that have unfortunately affected the bone marrow and they come to us for PRT, it's a little bit heartbreaking to see that we cannot provide the therapy because we don't have a level of platelets or of red blood cells that we would like to see before we feel comfortable providing the therapy itself. So these cut-offs are very important for inclusion criteria. Also very important is going to be the timing of the injection of the cold octreotide, of the SSA. We like it to be provided four weeks before we provide DOTATATE, because remember, Lutetium 177 DOTATATE is a tiny amount, only picogram or a nanogram, which is different from 30 milligrams or 60 milligrams of somatostatin analog. So timing is key and that could actually delay the initiation of the therapy. Patients can receive short-acting octreotide as long as they stop it within 24 hours prior to the start of the infusion of PRRT. So they can manage the symptoms. And very important for us for inclusion criteria, as Dr. Del Rivero was showing, is to have DOTATATE PET images that show the overexpression of somatostatin receptors, because it doesn't matter if under the microscope we have a patient with a grade 1, with a KI 67 of 1%, if they show an image like this, I mean you can see this almost three centimeters right paratracheal lymph node, which is actually biopsy-proven to be neuroendocrine. If it doesn't overexpress somatostatin receptors, PRRT is not going to help here control anything. So we will say that this is not a good candidate for PRRT, even if everything else looked like this was a good candidate. And we use the Krenning score basically to assess the level of overexpression of somatostatin receptors by imaging. And that's it. Then we go ahead. If this is not cycle 1, cycle 1 is usually 200 millicuries, if cycle 2, 3, or 4, we may change the dose accordingly, according to prior symptoms or according to prior toxicities. And then we go ahead and we dose. So actually Lutathera comes in this tiny vial, a couple of 3 or 4 cc's. We are going to infuse it in one of our rooms. This is one of our rooms in our Theranostics Clinic. We opened it during COVID. That's before we had some things hanging on the wall. And we are going to infuse it over 30 minutes. But the patient is going to be most of the day with us. One can count five to six hours. Because the patient comes, we start basically finding the peripheral IBS. We start with anti-emetics so the patient is comfortable with us during the whole day. Then we allow the amino acids to run for about 30 minutes or about 250 mLs to protect the kidneys. And once there has been this level of protection, then it's when we go ahead and provide infusion of Lutathera. Kidneys are usually completely asymptomatic during diffusion. This is usually going to take about 30 minutes. And then the rest of the day is going to be basically receiving the amino acids. Whatever is not going to be going inside the malignant cells is going to be excreted through the kidneys. So we are going to be encouraging the patient to go to the bathroom frequently and void frequently. By the time they finish and they leave the hospital, the radiation levels have significantly decreased. We like to infuse through a pump so that we can control the rate. But we use the typical infusion of long needle and short needle for ventilation of the vial. And then we discharge the patient with the typical radiation safety measures. They are very routine and very easy to follow for Lutathera. Of course, we measure them to make sure that they are within limits. And before we discharge, we always image them. Why? Because we can. Because we can confirm before they leave that the therapy went to the malignant cells that we wanted to target. We know that there was no issue with the calendar of the colocterion tight injections that blocked the therapy. We also, as you can see, the image on the right is a DOTATATE PETA scan of the patient. This patient had a primary pancreatic malignancy, neuroendocrine tumor with metastatic disease to the liver. As you can see, the image on your right is the PETA. The image on the left is the post-therapy scan that we acquired, which is not bad. It's definitely not as diagnostic and doesn't have the resolution of PET. This is because Lutetium-177 can also emit gamma rays. And then we can obtain some images. As you can see, I can confirm with this image that there was absolutely no extravasation in this patient because I have the arms and I have the areas of the IVs that are going to confirm that I don't have to worry about any local radiation to the extremities or where we introduced the treatment through. So we tell the patient we targeted what we had to target. We haven't found anything outside the lesions that we had when we diagnosed with the PETA scan. It should work. Unless we hear from you, we will see you in two months and we will check again labs, we will check the liver function, we will check the renal function. And as we obtain these images every time that the patients have for this cycle, we can see this history of the response to the therapy during these eight months. And this is mentally very important for us too. Very important for the patient because this increases the commitment to the therapy. And instead of being completely blind to the effects of the therapy, they can see how little by little things start to respond or disappear. They may clinically also feel improved and that helps them go through these eight months of commitment through this therapy. And that's it. We then release them, as I mentioned, making sure that they meet the radiation safety requirements. And we will just do that three more times for a total of four cycles. And hopefully they go through these therapies very nicely. There are side effects, of course. It's not that it's completely innocuous, but usually very well tolerated. So hopefully we can help with this therapy. This is a group of us at the Theranostics Clinic that was doing Christmas, but there are more of us and we are all here to help our patients, of course, to help you as much as we can. And with this, I would like to finish and thank you for your attention. Thank you so much for the nice talk. Another round of applause for our great speakers. And we're going to open the floor for questions. We have about eight minutes to answer your questions. My question is regarding the uptake. What would you consider a significant uptake? I know there is classification and we'd love to have a much higher uptake than the rest of the body, but at what lower level would you say I still can give PRRT? Yeah, that's a very good question, right? So we use the Krenning score. According to Dr. Krenning, the idea is instead of having a quantitative method of assessing it, we use a qualitative method of assessing. And this is based on the fact that there is always a bio-distribution for every single agent that we introduce. We have learned that the bio-distribution in the liver for basically allium 68.8 or copper 64.8 is more or less stable. It's a very good reference. So when we see tissue that is giving us a signal above the liver and definitely above the blood pool, that basically is an indication of a good level of ovarian expression. But if you remember the case that I showed, the expression, the signal that we were getting from, for instance, a three-centimeter right parietracheal lymph node was slightly above blood pool, but definitely below the level of the liver. What that is telling us is that, yeah, molecularly there is that expression, but are we going to be able to help control that disease with that tiny level of ovarian expression? In that case, we would not be recommending it. So it's basically this level above the liver that give us a qualitative idea of this threshold. Great. Any more questions from the crowd? I wanted to ask about the Lutatera treatment and cold somatostatin analogs. At least in pure chromocytoma paraganglioma, there are some papers that are actually suggesting that you don't have to stop cold somatostatin analogs and actually increase the efficacy of Lutatera. How do you view it? So I know what you said and stopping it in a certain time, but what do you think from your expertise? That is a very good question that, of course, is coming from you. Yes. So I would say standard of care, we usually recommend stopping the somatostatin analogs for four weeks just because of competition, but there is this very good hypothesis with a very good theory behind it that actually having high levels of somatostatin analogs called somatostatin analogs could actually be beneficial for the final outcome of PRT because it will be blocking unnecessary somatostatin receptors and therefore we could concentrate the nanograms or picograms of the molecule of the probe just targeting the malignant cells. I think that if that is proven, that would be brilliant. Thank you so much. Dr. Del Rivero, I wanted to ask you, so you have a pancreatic neuroendocrine tumor growing pretty fast. So what would you suggest, you know, which one, sunitinib or, for example, mTOR inhibitor? And what would be actually your choice and how you would approach the patient? Because it would be, you know, growing pretty fast, so there is no treatment with radiotherapy because, you know, you both talk about it. So what would be your approach in that scenario? Which one would you use? Yeah. Thank you so much, Dr. Patsek, and great question. So I think one question I have, whether it's only localized disease or metastatic disease, so that's one of the things that I need to know to guide me what would be the next treatment modality. So in situations where we see that the neuroendocrine tumor was slow-growing and then after that changed behavior, a more rapidly aggressive disease, I sometimes like to re-biopsy just because these tumors tend to differentiate, and that can also guide me to determine what is a treatment for these patients. But let's say for still well-differentiated neuroendocrine tumors, localized disease is growing rapidly, KS67 15, 20 percent, but not to grade three, I would still choose kefsidavin temozolomide. Sunitinib has a lot of toxicity, it doesn't really shrink the tumors as much as kefsidavin temozolomide, the same with the virulimus. So that would be my approach. Thank you so much. Any other questions from the group? Have a follow-up question. It seems that somatostatin-based imaging is a standard of care for every individual with neuroendocrine tumors, but it's not readily available in different parts of North America and the world. How should a clinician approach getting this standard of care imaging for their patients before consideration for the therapies that you've outlined? Yeah. We are so lucky, right? We have access to so many things, and in this way we feel like we can help patients so much. As I mentioned, the most important thing is to get the pair right, the diagnostic pair together with the therapeutic pair. Indian-111 octreotide, it's a great agent, it's just that from an imaging point of view it doesn't have the sensitivity of the level of resolution of a PET, but it's still a great diagnostic pair that is more widely available than a copper-64 dotatate or a gallium-68 dotatate. I think that sometimes we have to work with what we have, and hopefully and eventually we will be able to have more access to all these diagnostic agents, to all the communities and all the clinics all over. But at least that is there, and that could help right there, provide an answer when needed. Thank you. Dr. Rivera, your thoughts about accessibility? Yeah, I mean, I'm originally from Mexico, and I can tell you that in Mexico there is no dotatate, there is no luthathera, and it's very difficult to get sandostatin injections. So a patient gets 20 milligrams of sandostatin and it's kind of like her month of salary, one month of salary for her. So it's very difficult. I think that is something that we need to advocate more and improve the ability of these studies in other part of the country. We know the luthathera work. We know that it has definitely a survival benefit. Now the research is going how we can make luthathera more effective, and now there are combination treatments. But it's true. I mean, the other part of the country, there is no accessibility to that, and that's a situation that we need to improve. Absolutely. And there are research studies out there that physicians can refer patients to, including NIH-sponsored studies, right? Right. Yeah. Yeah, that's correct. Yeah, that's correct. So in this situation, yes. I mean, we definitely have accessibility at the NIH as part of the protocol, as Dr. Patzack will suggest. And yes, accessibility is something that we can provide, I mean, for patients all over. Yeah. Great. Well, I really enjoyed your talk. Phenomenal. Thank you for spending this afternoon with us. Thank you for being very engaging today, and have a blessed afternoon. Thank you. Thank you.

neuroendocrine tumors

tumor classification

personalized therapy

treatment options

surgery

somatostatin agonists

Lutathera

PRRT

progression-free survival

patient selection

radiation delivery