Treatment Algorithm of Neuroendocrine Tumors (NET) in 2025 - Dr. Thor Halfdanarson

Laying the Foundation for Neuroendocrine Tumor Diagnosis Hello again and welcome back to the Oncology Brothers Podcast. I'm Rohit Gosain here as always with my younger brother and Co host, Rahul Gosain. Today we are diving into the world of neuroendocrine tumors. And to bridge the gap between data in hand and our daily community practice, we are joined by world renowned expert doctor Thou Haft Anderson from Mayo Clinic. Thor, thanks so much for joining us. Speaker 2 It's a pleasure to be here, Thor. Welcome. Let's start with laying the foundation. When it comes to patients with neuroendocrine, we have to keep a few things in mind. The origin grade, histological features, TI 67, Thor. Can you touch on how these features play a role in stratifying the disease and what's your initial work up, including what type of scans? Absolutely. The most important part if you're faced with a neuroendocrineoplasm is to figure out is it a portly differentiated neuronscarcinoma which takes you down a different path or is it a well differentiated neuron tumor. And if it's a well differentiated neuron tumor, you have to put it in tumor grade bucket either 1-2 or three based on the case it's 7. Also try your best to figure out where it started from because the pancreatic Nets and the lung Nets call for slightly different approaches than the more common small bowel Net's. So at diagnosis, especially for metastatic disease, we would like good quality concerts and hand cross-sectional imaging, ideally a dual or triple face CT because some of those liver metastases are remarkably good at hiding in the venous phase. So we need the arterial phase as well. And then we need a Somerset and receptor or SSTR or Duratate or Gallium or copper PET scan, whatever you call it. That is something I like to do early on to see if there is metastatic disease not detected by cross section limiting and then you do it at regular intervals during the disease course as things go on. Functional vs. Non-functional NETs and Somatostatin Analogs Thor, thanks so much for laying that foundation in our clinic. As you stated, differentiation and grade helps us decide how which route we're going to take. And of course with neuroendocrine tumor, the important aspect is are they functional versus non functional and are we targeting tumor growth or our? Speaker 3 Goal is rather. Speaker 1 To target tumor growth as well as the functional aspects, in some cases one can rather even observe these patients and that too even in metastatic space. Speaker 3 So, Thor, could you please walk us through your? Speaker 1 Treatment paradigm. How do you decide which one to go for when you have these differentiation and great information available at hand? Speaker 2 Excellent question. So a functional neuron tumor is essentially 8 neuron tumor that produces chemicals, hormones typically like serotonin, that cause symptoms. Some neuron tumors, especially the pancreas, can produce hormones that don't cause symptoms. We would call them non functional even though the hormone levels are elevated. It's not until they actually have symptoms from the hormone that we call them functional. That's a critical aspect because the goals of the treatments are essentially twofold #1 would be to treat symptoms, including the syndrome symptoms from tumor bulk, and try to maintain or improve quality of life as best you can. And then the other aspect is to control tumor growth, shrink or at least maintain tumors. Of all of the treatment cards that we have, we have deck of treatment cards, maybe 8 or 10 cards in the deck. Some of the cards will work on tumor growth and symptoms. Some of the cards only work on tumor growth. They all work on tumor growth, but not all on symptoms, so you have to really play your cards based on the clinical presentation. So symptomatic, I think a good start is almost always so much as an analog therapy. Although now with the publication of the letter to study, the use of radioligand therapy with Lutecium is actually quite appropriate for those with KS 7, more than 10% and less than 55%, which falls into the high grade 2 and the grade three well diff category. The radioligand therapy also works great for central control. Not everyone realizes how good that is for symptoms. Here with the Netter study, we have PFS. We don't have OS yet. That is absolutely correct for the Netter studies, Netter 1 and Netter 2, we have OS for Netter 1, so we can go into that later if needed. For Netter 2, we only have PFS as you may recall from that publication last year. So Netter 2 was essentially looking at radio ligand therapy with lutetium Dota tape in previously untreated patients with high grade 2 or grade 3, comparing it to double dose arctriotide long acting 60 milligrams, which is twice the usual dose. And there was a striking and impressive improvement in PFS. But we haven't seen the OS data yet while we were talking about somatostatin analogs and the dose. Can I take a deeper dive on this around the practical nuances to better control function symptoms? Do you consider a higher dose? Can we give this more frequently and then we were dividing these patients in functional or nonfunctional. Is there any role of somatostatin analogs for nonfunctional Nats? So we addressed the second part first. So as long as these tumors light up on somostatin receptor imaging or dilatate them and saying they the target is there whether or not they have a functional syndrome. So we would expect a somoset and analog to control that tumor growth. And indeed we have two clinical trials from like way back, both clarinet and Pro Med to comparing or either land Rea tetractyreotide with placebo showing improved progression free survival. So yes, it does control tumor growth regardless of having syndrome. And the first part, So what I do when I start someone, and this mostly applies to patients with carcinoma syndrome, the classic, the diarrhea and the flushing. We have other manifestations including occasional wheezing, which I don't see very often but does happen. And then obviously, of course with heart disease that sneaks up on you over time. So you start with the standard dose. And then I talked to my patients and surrassed them so well I gave you that the line rheotide drug, trheotide shot 4 weeks ago. Tell me what happened and they will say, well, great diarrhea is gone. Where they will say, well, I saw that like in week 4, the diarrhea started coming back. You may have to shorten the dose. We do have data, not the greatest, but the small prospective study that looked at the above label or double dose line reotype called Clarinet Forte and that showed that there were some benefit in controlling tumor. It was uncontrolled. There wasn't the reference armor, but we've been doing this for a long time. Either you can go up on the dose or shorten the interval. Imaging and Tumor Markers for Neuroendocrine Tumor Monitoring That can work. Speaker 1 Well, and now it's the word where you've decided to initiate somatostatin analog because somatostatin receptor were positive on the initial scan that was gallium dotatate. But in terms of monitoring these patients, are you repeating gallium dotatate or you're relying on conventional CT and also any role of tumor markers like 5 HIAA and chromogranin? Speaker 2 So these are great questions and this comes up all the time. I personally rely on cross-sectional imaging. So you will face ET or MRI and if you really want to look at the liver, getting like a liver contrast sometimes helps call out those liver lesions. So for the metastatic patients, I typically don't repeat a daughter take path more than every one year or every other year because I don't think it really adds much. Well, the exception to that would be patients with bone only or bone predominant disease. So there's just no other way to monitor them. I have a handful or more of such patients in my clinic where Dota tape path is really the only good study that I have. Sometimes you have to combine a quality cross-sectional contrast enhanced imaging with a Dota tape, be it on the same scanner or different scanners. But I don't like them for monitoring. Here's one of the reasons. Intensity changes on path imaging for receptor path are very different from metabolic FGP. But things go bright and things go less bright, and I have no idea what that means. You can't measure size under these scans. So all of a sudden there's a big red ball there and then it's smaller next time, but then it's bigger again. So that's why I like the cross section limits. I know that when you're talking about monitoring these patients, if there's local progression, things like surgery, radiation ablation is so important as well. And shout out to my colleagues in radiology. I think with the new fancy drugs and radio ligands, we sometimes forget the things that actually work really well. For example, for syndrome, big liver, bulky liver, math bad carcinoid syndrome, embolization with whatever method you prefer and you have excellent syndrome control, which I think we sometimes forget that we have great regional therapies. Sequencing Radioligand, Targeted, and Other NET Treatments Indeed, multidisciplinary plays such an important role here based on conventional imaging, Thor, you've seen that the disease is progressing. From the treatment options standpoint, we have radioligand therapy, which we have taken a deeper dive with Doctor Suarez and Doctor Ken Herman in our another episode. Speaker 3 However, the other. Speaker 1 Important treatment options that are available are Everlimus, Cape Tem, PRT is mentioned and also now we have Cabozantinet based off of cabinet study Thor. With these options available, how do you decide on sequencing and do you continue with somatistatin analog here while you're switching the therapy? Speaker 2 With somatistatin analog, if there is a functional syndrome, I would almost always continue that to control the syndrome. For nonfunctional tumors, there is probably very little if any role of continuing the SSA. We don't even know if it works after radio like on therapy with PRT, even though we're targeting that receptor. So do I need tumor shrink goods? So if so, then, and I have a pancreatic NET, well, K cetabine tematolomide has a good tumor strength. Do I need to control syndrome? And then I'll try something that also shrinks tumor volume, for example, in patients with small bowel neuron tumors and carcinoid syndrome with everolimus may not be as effective. So there was that the radiant two study that compared deveralamus with with the placebo and patients with syndromic carcinotic syndrome and show a non static statistical improvement with most may not work as well there. Also look at comorbidities. So someone who has pretty bad type 2 diabetes, you may want to stay away from everolamus and use something else. Someone who has bad hypertension, you may want to stay away from Cabo. Dentative, I will say that of those targeted agents, say Cabo is probably the only one that has randomized phase level data post PR tape. That is not to say that almost doesn't work in that situation. It's just that we have that level of data for Cabo. And so we have all of these treatment cards and now you have to play them based on whether you want to control tumor growth, which we typically want to do the syndrome and then be mindful of comorbidities. Role of NGS and Immunotherapy in Neuroendocrine Tumors Or for the last few minutes, can we go through some rapid fire questions and pick your brain on these particular scenarios starting with is there any role of NGS and neuroendocrine tumors? So for grade one, grade 2, these are genomically dull tumors, at least the ones in a small bowel. So we don't have anything that we can target. If we go to the other extreme spectrum for high grade ported death, we may thank actionable alterations and up to 1/4 of them according to the literature, I'd say probably in reality less than 5% or less than 10%. We've seen all career maintenance, we've seen fusions, we've seen her to overexpression. So yes, in the the big thing in the middle of the Weld diff G3, especially pancreatic one said we should probably test more than we do. We may find actionable alterations. We do find alterations in the pancreatic entities like ATRX and DAX and that sort of stuff. And these are pathogenic mutations, but not yet targetable. So yes, there's a limited role. It was a long answer to that question and then a common scenario that we run into as a community oncologist. We're also seeing lung cancer. So for small cell lung cancer, we're often using immunotherapy. With chemotherapy we have lobinectidin now we also have torlactamab, which is a bispecific. Is there any role of any of these drugs including immunotherapy for high grade neuroendocrine carcinoma of GI origin? There is an evolving role. So if we start with the portal diff, so we have the the SWAG trial as 2012 is looking at the platinum and taupe side plus minus a tieselizumab. It's a three arm randomized phase three study. We have two retrospective studies, one from Taiwan and one from Mayo looking at the addition of ICIS or immunotherapy to platinum and taupe side and both of them were negative. But these were retrospective studies. So take that with a great result beyond progression combination Epinivo has about 15 to 20% response rates and poorly differentiated NEC's. ICIS have very little role in, in, in mismatch repair proficient well differentiated entities, but definitely worth the considering in those that are rapidly proliferating. Lerpy has been shown to have some activity both from us and and then it's been studied in in the prostate, there's definitely some activity there. And then lastly with DLL 3 Tarlata map has been reported in case reports because DLL 3 is expressed in about sixty 7080% of 40 differentiated NEC. So carcinomas and maybe up to like 1/4 to 1/2 of pancreatic Nets. So terladimab has been used off label and then we have now the darium studies with obrixtamic, which is another bispecific T cell engager. So those studies are opening around. So if you have a DL3 positive patient or patient with DL3 positive NEC, consider that absolutely. Cabozantinib Dosing and Challenging Tumor Marker Interpretation And before we close the starting toes of cabozantinib, do you rely on 40 milligrams or is it 60 milligrams? Speaker 2 Yeah. So as a part of the cabinet team, I was on that the study I'm very comfortable with starting with 60. I'm quick to adjust, but I realized not everyone is. And if you look at the cabinet trial, the average dose, it was about 40 milligrams and 60 to 70% of patients need a dose reduction. You need to look at the patient in front of you. If it's someone with less perfect performance that is starting with 40 is fine. We have some retrospective data not on this, but on Everolimus, but from Brazil and some from suggesting a lower. Those may be similarly effective with less toxicities, let's say starting with 40 if you're a little questionable performance that is. Starting with 60 if you're very comfortable with capo is also very reasonable. Speaker 1 And the Thor with regards to role of five HIA and chromogranin, if they are elevated, how are you managing these patients when they don't have any particular symptoms? Speaker 2 Yeah. So the chromogranin is a challenging marker. So it is incredibly unreliable and it does have some have some role in monitoring patients with established disease. So meaning that if chromogramin is stable and somewhat metastatic disease, the tumor is probably not progressing. The sensitivity is not great for diagnostic purposes. Chromogramin is near as as close to useless. So it goes up in PPI therapy. I've seen it go as high as 5000, more than 100 times the upper limit of normal that we have on a PPI totally disappeared when we when we tip the PPI off. Chronic atrophic gastritis, very, very common among the elderly, CKD, all of these things raise chromogram and so chromogram on its own. Look at the PPI and maybe do a rapid GI look for chronic gastritis. As for the five HA, that indicates there is serotonin production because this is the end product of serotonin metabolism. So then you have to be a little bit more careful. But there are definitely these patients with diarrhea and with elevated 5H A. I've been looking for a net for months or even years and haven't been able to find it. So there's something else going on in them. Speaker 1 As we wrap up, any final message for the community, unity and colleges tuning in. Expert Advice and Episode Recap for Neuroendocrine Tumors Yeah. So I think my final message would be that the guidelines out there because of the data as it is not having nearly as much for a face like level 1 randomized data, there are some good resources and bias. So I've been very involved in the North American American Society. We have some good guidelines there. They are open to the to providers. We have the the European Society that has really detailed guidelines. I'm not sure if they are open, but then just want to put a word out for all of those resources out there. And it's always good if you have someone especially with potentially resectable metastatic disease or challenging primary tumor to refer to a high volume multi D center just to talk about it. And I like to Co manage with community. There's no reason for me to the patients every time, but if needed, I'm there. Speaker 1 Oncology is a team sport, so certainly multidisciplinary in reaching out to tertiary or coordinary centers is extremely important and not forgetting the role of clinical trials because that's again what's taking this field and the science ahead. Thor, thank you for sharing your thoughts on this particular evolving space in neuroendocrine tumors. For our listeners, let us go or a quick recap. In today's conversation with Doctor Thor Haft Anderson, we focused on the initial workup and treatment options for neuroendocrine tumors. Speaker 2 We started off by appreciating the origin in grade Ki 67 and functional symptoms of this disease in making treatment decisions. Then we also had a chance to touch on how to monitor this disease through conventional imaging and when to rely on something like Dota Tate scans. Speaker 1 To close, we address few common questions that we often see. Is there a role of NGS here? What about the use of immunotherapy? And what's the preferred dose of cabozantinib? We have covered a lot here and we hope you enjoyed this discussion. Make sure to tune back for a discussion around Radio Lichens with Doctor Suarez and Dr. Herman. In neuroendocrine tumor world, we are the oncology brothers.