How to Diagnose, Treat, and Follow Neuroendocrine Tumors (NETs)

Intro Hello again and welcome back to Oncology Brothers podcast. I'm Rohed Ghosain and here as always with my brother and Co host Rahul Ghosain. Today we are going to dive into the world of neuroendocrine tumors to cover the current landscape and recent advances in this disease. We are joined by world renowned medical oncologist in this field, Doctor Pamela Coons from Yale Cancer Center. Pamela, thanks so much for joining us. Speaker 2 Thank you for having me. Speaker 3 Pamela, welcome. Congratulations on your recent promotion as a professor. Now, all right, getting back to the neuroendocrine story, can we start off by laying the foundation on different grades, histological features Ki 67 that we have to keep in mind when we talk about neuroendocrine tumor and what is that work up in your clinic? Different grades of neuroendocrine tumors Do you get gallium pet CT for all your patients? Can we start here and keep that patient in mind in front of us in the clinic? Speaker 2 Thanks so much. And this is complicated even for those of us who who do it frequently. You know and I I really try to involve my patients in describing shared terminology. I think that's actually something I do from the get go. So as we think about evaluating a patient, I first talk about primary site, so Nets being categorized in multiple different ways. So where do they start? Pancreas, small intestine, lung, other unknown primary. Then we think about greed and differentiation. So is it. And those are really with the help of our pathology team and we rely very heavily on them. The Who classification criteria have really changed considerably over the last 10 to 15 years, which is why we're all so confused because the terminology keeps shifting. At present, we're using well differentiated grade 1-2 and three neuroendocrine tumor. So if it says tumor on a pathology report, it generally implies that it's going to be well differentiated and then we're calling it poorly differentiated neurochrine carcinoma. The Ki 67 plays in because the that determines the grade 1-2 and three. So Grade 1 is going to be Ki 67 one to two, Grade 2 is 3 to 20 and grade 3 is greater than 20. And in general this is not part of The Who criteria, but the poorly differentiated under carcinomas in general are going to be greater than Ki 67 of about 55%. It's there's you know some exceptions to that, but you're generally going to see that Ki 67 be quite a bit higher. And then we talked about well differentiated and poorly differentiated in the pathologist. Help us look at that and then we think about stage and you guys nicely here on your slide are thinking about localized and metastatic disease and that's absolutely critical as we think about tailoring a treatment to the patient. So and I definitely use a gallon 68 PET CT, some institutions will use copper 64, they're really interchangeable. But a somatostatin receptor imaging, a PET SSRI imaging is something that we will use. Octreotide scans have really fallen out of favor given that our pets have much better resolution. The way I describe that why that matters for patients is that it really helps us determine extent of disease. It complements our cross-sectional imaging. It doesn't replace it. So our primary tool for evaluating patients with Nets will still forever be either a multi phase CT or an MRI. The pets will do a time of diagnosis and intermittently to ask answer specific questions. Speaker 1 Perfect. Well, thanks so much for summarizing and laying that foundation, Pamela. Now when it comes to this particular disease, we have to make a treatment decision saying not every localized treatment or metastatic patient has to be treated with something. Treatment Decisions We can in fact observe these patients. So the treatment decision really depends on the extent of the disease symptoms or versus no symptoms, which is functional versus non functional diarrhea, flushing or carcinite type symptoms. The great status in terms of how you decide your treatment, what is your discussion with the patients and when do you consider treatment modality itself? Speaker 2 Yeah, it may be. I totally agree. All of those, all of those factors are come into play. So for a patient with localized disease that is a patient that we assuming that they don't have medical comorbidities that preclude a surgery, we generally will recommend surgery and then most of those patients don't need subsequent treatment. So I think that's true for the well differentiated grade 1-2 and threes. We're a little bit more cautious with the high grade, with the poorly differentiated neutercron carcinomas and thinking about surgery even for localized disease. But that's a very nuanced conversation. So we'll we'll set that aside for now. For patients with metastatic disease, this is where it gets complicated. I would say for patients who have grade one or two well diff neuroendocrine tumors who are asymptomatic and non functional, we might consider observation. Those are the patients that get incidentally diagnosed, maybe they go into the emergency room for some unrelated issue. They're found to have perhaps low volume disease, get the diagnosis. I will comment that the kind of funk, so functional neuron tumors really are defined as patients who have a measurable hormone in the urine or the blood and symptoms of hormone access that's a reason for symptoms. But some of our patients with Nets will have symptoms from tumor bulk. So if they have large liver lesions. So either of those two sets of symptoms may push me into thinking this patient needs treatment sooner. So if it's a patient with symptoms from tumor bulk, we really need to think about what treatment options do we have that will yield tumor shrinkage. There honestly aren't that many in nuts. For pancreatic nuts, we have capecitabine, temazolamide, we have Lutathera. Both actually have a chance of tumor shrinkage. For small bowel Nets, our options are even further limited, but we have Lutathera that has about a one in five chance or 20% shrinkage rate. Our somatostatin analogs biologic therapies generally yield stability and don't usually yield tumor shrinkage. So it's sort of what you think about what agents do you have available, what, what outcomes do those treatment options yield? So is it shrinkage or stability? And that helps me think about how to tailor those treatments. Speaker 3 And Pamela, you touched on it in these settings, debunking surgery can also be one option. Again, this is not with curative intent, but just to help with those symptoms. And you brought up somatosatin a log analogs. Somatostatin analogs Can we take a little deeper dive here because we have oxytide, linreotide, different doses, how frequently we can give this and do you give test those when we're using somatostatin analog, something that we worry about and something these agents can actually mimic the underlying disease? Can you touch on this how you tailor when it comes to somatostatin analogs? Speaker 2 Yes, definitely. So, so Somatosan analogs do kind of mimic naturally occurring somatostatin. So the history is that that is a very short acting hormones. So it was not a practical treatment to give in its natural form and so long. So somaticine analogs are there are a number, but the ones that are FDA approved for Nets include short acting octreotide that's for control of carcinoid syndrome specifically long acting octreotide, which is a monthly intramuscular injection that is approved both for hormone control. Well, actually it's formally FDA approved for hormone control. I'll get to the FDA approval for sort of tumor control. There's lanreotide that's approved for both hormone control and tumor control, long acting lanreotide and octreotide, they are essentially the same drug. They have the same mechanism of action in terms of affinity for somatostatin receptor type 2, and they're used very interchangeably. The difference is in how they're administered. So octreotide long acting is intramuscular, lanreotide long acting is deep subcutaneous. There are some conflicting data on patient reported outcomes in terms of how they feel as they're being administered. Most patients have told me there's not a significant difference. There's some studies that suggest that the deep sub Q may be less painful for patients, but really they they are felt to have the same mechanism of action. They're used very similarly. Your question about testos, So I would say there used to be a sort of a, a philosophy that you needed to give a short acting arctria type testos prior to giving long acting. I think that's now fallen out of favor. These are very safe medications for patients that need somatosan analogs for relief of carcinoid syndrome. Flushing diarrhea. I may start with a short acting, but purely because I want quick relief I will start that simultaneous with a long acting dose and then once that long acting kicks in they may not need the short acting as much for initiation of Ssas. For tumor control, you do not need to even use short acting octreotide. You would just start from the GACA with either octreotide or lanreotide. Speaker 1 OK. For localized disease, we've established we rely on local therapy that is surgery, even sometimes radiation or ablation for metastatic disease. Somatostatin analogs for non-functional NSCLC If it is somatostatin receptor positive and rather functional, we could utilize them for hormone control or rather sorry tumor control or symptoms control. Any scenario where you would utilize somatostatin analogs for non functional Nets at all? Speaker 2 Yeah, absolutely. I often will use somatostatin analogs as a first line tumor control agent for patients with well differentiated Nets, especially Grade 1 and 2, and especially if they are fairly low volume disease. That's often our first go to. Again, because it is so well tolerated. I tell patients in clinic I don't want the fix to be worse than the problem. Like if you're asymptomatic, I don't want to make you feel sick. Speaker 1 And with regards to utilizing gallium Dotatate scans, how often do you get it? Gallium dotatate scans Because do you get it at the time of progression and every three to four months or even six months? Do you rely on CTCAP in those settings? And also, do you have a washout period from the Somat statin analog before considering gallium Dotatate? Speaker 2 All good questions. So I still rely on standard cross-sectional imaging whether it's CT and and a key take away is that it has to be ordered as a multi phasic CT. That arterial phase imaging is really important for the Weldef Nets. So either contrast CT or an MRI for patients with metastatic disease. Typically every three to four months I will get a gallium Dota PET scan every like at time of diagnosis, at time of progression, especially if I'm considering luticium dilatate as a treatment and I will use it to answer a specific question that may arise on a CT or MRI. For example, let's say patient has had sort of cytoreductive surgery, they've been sort of they are radio graphically free of disease, but let's say something pops up in six months or in a year that due to pet can actually be very helpful in distinguishing between inflammation or true recurrence and and can help clarify a lot. Speaker 3 All right, now let's switch gears. Is Dota Tate scan still sensitive enough for hybrid disease? Sticking with well differentiated but Grade 3 disease Pamela upfront treatment here is Dota Tate scan still sensitive enough for hybrid disease. Speaker 2 So this is the newest category in The Who classification criteria within the last few years. So well differentiate grade 3 means phenotypically the cells look well differentiated, yet the Ki 67 is greater than 20%. I worry about these patients. I think that the clinical behavior can be very variable. We don't know enough yet about this entity to have a good sense of kind of prognosis and pace of growth. So I tell patients that really the first year or so teaches us a lot about their individual biology. These are patients I might worry about putting up observation. I probably would not observe these patients. I might worry about starting with an A Somatosan analog, although it's not, you know, not a wrong decision, but I would I would still worry about it. And I do in fact get gallium Dota tape pets. I might actually also get an FDG pet on these patients. So what's interesting is that if patients with well death grade three are avid on Dota PET scan, that generally tells me that they have a more favorable biology. If they are negative on Dota PET but positive on FDG PET, that tells me they will have a more aggressive biology. It is sometimes tricky to get both of those FDA approved, but it can sometimes be very helpful if you have this question. Speaker 1 Now with regards to the initial treatment, we are comfortable with somatostatin receptor positive disease relying on somatostatin analogues. The optimal chemotherapy sequence for metastatic neoplasms The confusion comes after especially with the sequencing of it. We have everolimus, PRRT, Cape TEM and awaiting cabozetinib approval based off of cabinet study. Now Pamela, please help us out. How do you dissect this population? Speaker 2 Yeah, this is complicated. I think that you know we are in a sort of the silver silver lining is that we are in an era where we have a lot of approved therapies for metastatic Nets, yet we don't have high level evidence telling us what the optimal sequence is. We do have some clinical trials that are ongoing and in the works that are finally now comparing active agent to active agent. You know it's only recently and it affect the cabinet study that you just mentioned was still a placebo-controlled chart trial because at the time it was designed we still didn't have sort of the standard and guideline based therapies appropriate in that second and third line setting. So I think this really comes down to some of the factors we talked about earlier and really tailoring to the patient. I tell patients I was in clinic all day yesterday, so I gave the spiel in clinic yesterday. We have lots of tools in the toolbox. That's the good news. And we really tailor each next step based on where the progression is, the pace of growth and how you're doing. And another medical comorbidities, a very standard approach that I'd say many of us have converged on is after progression on Somatosan analog nutrition. Dota Tate is often being used as a second line treatment. It's one of our most effective treatments. It has a median progression free survival of about 2 1/2 years and small intestine net about a 20% shrinkage rate and in pancreatic that probably closer to 40%. So that's often as a second line treatment for pancreatic NET. What's interesting is I think there's real equipoise between captain and latrician Dota Tate as a second line treatment and especially for peanuts that for which you need tumor shrinkage. So patients really symptomatic and there's actually an alliance clinical trial studying those to head to head as a one to one randomization. So we will have information on that in the near future hopefully. Speaker 3 That's perfect. And again, the other thing when it comes to lutetium dictate as a treatment option, we have to keep their renal dysfunction in mind. Pamela, as a community oncologist, when I'm seeing lung cancer, breast cancer, I'm getting NGS day in, day out for these patients. Role of NGS testing in lung cancer Is there any role of NGS testing for this disease, be it upfront or at the time of progression? Speaker 2 I, I think there still is, I think that a key take away is that tumor mutation burden and in general somatic mutation rate is low in patients with well def Nets poorly differentiated urnican carcinoma may actually have higher tumor mutation burden and higher somatic mutations. So the way I think about these is really for the well diff. I don't generally get somatic profiling early in the disease course, but as I am running out of standard treatment options, I will often get it whether it's circulating tumor DNA or tissue based. I would say that given that many of these patients may live for years, I would caution against using a 5 year old tissue sample on which to do that, which is great that we now have liquid based assays for poorly differentiated Nordic and carcinomas. I will consider getting earlier somatic profiling including tumor mutation burden. I think that the chances of finding an actionable actionable mutation are still pretty low for both net and neck. So I don't know if I'm just treating myself. I still, I still, I still will do it. I was actually very excited this week. I found a VHL somatic mutation and may consider using belzodafan for that patient. So we get lucky occasionally and it just adds a tool to the toolbox. Speaker 3 Absolutely, and we've seen some bucket approvals nowadays. Be a for her too and Trek. Again, similar story, needle in a haystack. So at least in my practice, this still ends up being something that we go for. And then before we start to close for high grade or poorly differentiated neuroendocrine tumors, do you combine chemotherapy with immunotherapy or any role of fluorbonectin at the time of progression like what we tend to do for our small cell lung cancer patients? Speaker 2 That is a great question. I actually just got an e-mail about that from a community oncologist like today. So I will say I tend to be a bit of a purist when it comes to clinical trials and than patient outpatient eligibility. So in general, I will not extrapolate the small cell lung cancer data to GI Nerdegan carcinomas. So at first line, I'll usually start with platinum metopicide. We have a little like small trials that are looking at IPPY Nevo. Those are the DART trials. I will occasionally think about using IPPY Nevo, but and I we have some data from a number of smaller phase two studies with that are using Irinotecan based therapies that I will use. There is an open clinical trial through SWAG that is actually looking at sort of platinum atopicide plus or minus atizo, plus or minus Atizo maintenance based on the small cell lung cancer data that's actively enrolling. I really hope that we have, you know, hopefully that fully accrues and we'll get information on that. But I think that GI necks are just different than small cell lung cancer and we probably need to have formal data in the GI neurocrine carcinomas. Speaker 1 Well, certainly an unmet need and we'll have to wait until these clinical trials result out. Well, Pamela, thank you so much for covering the current landscape of neuroendocrine tumors for our listeners. Conclusion Let us go for a quick recap. In today's discussion with Doctor Pamela Koons from Yale Cancer Center, we had a chance to focus on treatment options for neuroendocrine tumors, categorizing the disease based. On its grade, histological features and symptoms plays an important role in deciding appropriate treatment options. Speaker 3 In this conversation, we also had a chance to focus on current imaging modalities to monitor this disease and then we touched on first line treatment options including somatosatin analogs and also had a chance to talk about subsequent treatment options if the disease was to progress to upfront treatment. We all eagerly await after your approval of cabozantinib in this space. Thank you so much for joining us. Make sure to check out our other discussions around crunch, standard of care, treatment options, conference highlights, and new drug approvals. We also look forward to seeing you in person at GI ASCO in January 2025. We are the oncology brothers.