BTK_JournalReview_NET_11May

Hi everyone, and welcome back to another journal article review with your surgical oncology team. I'm Elizabeth Barbera. I'm a six year resident at Bergie Medical Center. I'm Connor Chick. I'm a surgical oncology fellow at Ohio State. I'm Lexie Adams. I'm a surgical oncology fellow at MD Anderson. I'm Tim Lin.

I'm a surgical oncology staff at Brook Army Medical Center. Unfortunately, Dr. Nelson couldn't make it this time around, but we're excited to have him back for our next episode. We're also thrilled to be signing on again with the BTKA team for an additional two years of great surgical oncology content.

So keep an ear out for new episodes with some new members as well. Anyway, let's get started with today's episode, which we're all pretty excited about. We highly recommend you guys check out our most recent Clinical Challenges episode, which was published on February 17th. This episode gives great context for the work of a management of small bowel neuroendocrine tumors, and gives a great introduction into what we'll be discussing today.

One of our former faculty jokes that our team's less behind the knife and more behind the

chemo. But today we're not gonna talk about chemotherapy at all. We're gonna talk about two other great trials. The first is another two trial investigating lu Dotatate plus long acting octreotide versus octreotide alone for the treatment of gastroenter pancreatic neuroendocrine tumors.

Published by seeing in colleagues in the Lancet of June last year in 2024. The second is a retrospective study published in surgery in 2016 by Dr. Maxwell Etal, and this study investigates what the optimal surgical strategy is for managing neuroendocrine metastases. Yeah, I'm sure listeners are excited to learn more about medical therapy for cancer diagnoses, but it is an important thing to be aware of when you're treating these diseases, mainly because, you know, as surgeons we're often asked to sort of decide, what's next for the patient? And that can be a decision between surgery versus medical therapy. And I think, you know, being aware of the array of medical therapies and how they should be applied is extremely

important. 'cause it helps you decide when to go to the operating room and apply surgical resection instead of medical therapy.

So, you know, these are difficult. It's a difficult disease to study because of a couple things. One. You look at the word that Lexi had to pronounce there, gastroenter pancreatic. And that sums up some of the problem is that there's, you know, a myriad of these neuroendocrine tumors. They're small bowel, they're pancreatic, you know, there are some that come from the, you know, upper and lower parts of the GI tract from the four gut, hind gut.

Those are less common and tend to to be worse actors, but they're kind of mid gut. Small bowel, pancreatic, we sort of treat them the same, but then there are some subtleties to it. And then it's also, you know, we sort of clump all these together, but they're really vastly different diseases based on their grade and differentiation.

And we'll get into that somewhat, but you know, when you try to talk about neuroendocrine tumors as one entity, it's really the wrong way to approach it, and you really

have to think a lot about. You know, the clinical scenario, the imaging, and, and very importantly, the pathology report, specifically the grade and differentiation before you can make any real decisions.

So we'll get into some of that tonight. Awesome. So I do think we need a little bit of a setup here because some of this starts to get kind of complicated very quickly, as Dr. Rein just alluded to. Connor, do you mind giving the listeners some background and context for Lutetium Dotatate and why this therapy is such an important tool in our treatment armamentarium for neuroendocrine disease?

Yeah, absolutely. So we talked about in our previous previous episode about dotatate. Which is a type of PET scan that's used for evaluating neuroendocrine tumors. What a dotatate scan actually is, is a PET scan using instead of FDG, it uses Gallium 68 dota, which is a radio labeled somatostatin analog, the bind somatostatin receptors.

And this works in neuroendocrine tumors 'cause those are usually over expressed. The DOTATATE scan has largely replaced OC

TRIO scan, which some of you may have read about in textbooks or learned about earlier on in residency. May still be lingering around in ab site books here and there. But because of better sensitivity, lower radiation and a shorter duration, DOTATATE is really replaced.

OCT scan. So then now that we've talked about the imaging technique, we can talk about the therapy that's based on that imaging technique. So PRRT or peptide re receptor radionuclide therapy is a treatment that uses radio labeled somatostatin analogs, such as LUTETIUM 1 77 dotatate. And so that binds the same somatostatin receptors, but delivers cytotoxic radiation directly to tumor cells.

So we can combine these two principles. So PRRT can be considered when Dotatate shows high uptake of Gallium 68 dotatate, which indicates strong expression of somatostatin receptors on the tumor cells. Okay, great. So now that we've jogged everyone's memory about what we talked about in February about Lutetium Dotatate and why it works do you mind

giving us Lexie some context for what our first trial was trying to investigate?

Definitely. So, up until this point, we had the clarinet and pro trials and these established somatostatin analogs as the standard of care for grade one and grade two neuroendocrine tumors. However, higher grade tumors have originally been classified with poorly differentiated carcinomas and therefore treated with platinum-based chemotherapy.

These were recognized as distinct entities in 2017, but there was really a gap in guidance of how to manage the higher grade two and three tumors. L Dotatate plus octreotide was the therapy given to treat patients with advanced somatostatin receptor positive grade one or two neuroendocrine tumors who had progressed on somatostatin analogs.

And that was established by the Netter one trial. But netter two sought to investigate whether the L dotatate plus octreotide. Specifically the 30 milligrams long acting at the same dose and schedule as established in the nether one trial would prolong

progression-free survival compared to octreotide alone for patients with higher grade well differentiated neuroendocrine tumors.

And do you mind pausing for a second, Lexi, because I think this can be kind of confusing. Dr. Rein, do you mind explaining how a neuroendocrine tumor can be both high grade but well differentiated? Yeah, there is a fair amount of confusion around these terms and. The easy breakdown here is that grade is basically based on the KI 67, the KI 67, also known as a proliferation index.

So there are certain cutoffs that we call, or grade one, grade two, grade three. So three and 20 are the numbers to keep in mind. So grade one raise less than three. Grade two is three to 20, grade three is over 20. Those are all within well differentiated tumors. The differentiation is really a call by the pathologist.

It's not based on any specific number. And you know what I was taught in Fellowship by Dan Halprin, which always stuck in my mind, is if a pathologist calls something poorly differentiated,

I. Neuroendocrine tumor and doesn't use the word neuroendocrine carcinoma, then you need a new pathologist. So that's another distinction here, is that if you have a high grade neuroendocrine, now it's a carcinoma neuroendocrine tumor of sorts, sort of.

So if it has neuroendocrine features, but it's high grade now, they should really be thinking about calling it a neuroendocrine carcinoma, which again, as of 2017, is a totally different entity. The other thing that he taught was if you as a surgeon go to operate on a patient with a neuroendocrine carcinoma, I believe what he told us is, I will find you.

Which was, you know, a threatening way to tell us, do not operate on. Endocrine carcinoma. So the key thing here is that it's all very confusing because there's a lot of different mixed terminologies that have been used over time. The other term that you're gonna use all the time that we've been very careful not to use so far in this conversation is a carcinoid, right?

So carcinoid is sort of the old term

for a endocrine tumor. You really shouldn't use that word anymore. It's sort of fallen out of favor. And now we call these all neuroendocrine tumors. Once it becomes high grade and kind of ugly under the microscope, then typically we were talking about a neuroendocrine carcinoma, which is treated more like a small cell lung cancer than like any sort of GI cancer whatsoever.

So it's, you know, chemotherapy, you know, whether it be a topside or platinum based or, you know, they're gonna use small bi small cell neuroendocrine. Is gonna be treated like small cell lung cancer. It should be chemo only. Essentially, there may be some rare circumstances where you might operate, but as a basic rule, don't op operate on the neuroendocrine carcinomas.

When you have a well differentiated tumor, it's a neuroendocrine tumor. Those can be graded differently based on the KI 67. And again, the numbers that you should have in your mind are the cutoffs of three and 20, and the more confusing thing about all this. As that you guys talked about the clarinet and permit trials.

A lot of those trials used a KI

67 of 10% as the cutoff. Why it wasn't three or 20, you know, so it, it becomes a little confusing here, but a lot of people will use the number 10 as a cutoff for sort of somatostatin analog will work. So that's not gonna be the same cutoff as your grade one, grade two, but it'll be the cutoff that was used for a number of the trials to look at this class of drugs, which are called somatostatin analogs because they are analogs that utilize the expression of the somatostatin receptor, much like our, our dotatate pets and our lutathera, but they're gonna sort of turn that receptor off, and that's how those medical therapies work.

So that sets us up well to talk about the Netter two trial. So this was an international multicenter open label randomized trial, and that this was conducted across North America, Europe, and Asia. Eligible patients had metastasized or locally advanced higher grade two or grade three tumors. And like you alluded to their Q 60 sevens

were between 10 and 20% in that higher grade two category and between 20 and 55% for that grade three category.

These were well differentiated castero pancreatic nets that were considered inoperable and had they had been diagnosed within six months. So just real quick, Beth, why do you think they set that KI 67 at 10%? They didn't include patients with KI six sevens below 10% for this net or two trial. I imagine maybe a few things.

One is, lower grade potentially already had effective treatments or they were looking for patients who were gonna show a treatment effect sooner as opposed to people with more indolent disease. Yeah. Yeah. So I think that's definitely part of Indo indolent disease is hard to study, especially indot disease that already has an effective therapy that will prevent progression for a long time.

Also, you know, one of the key aspects of Neter two versus, you know, the way that Lutathera was used before that is it was really not used as a FirstLine

therapy before Neter two. So Neter two was the first big study that looked at Lutathera for FirstLine therapy. And so they wanted to, you know, find a population that needed a new first line therapy, whereas patients with the lower KI six seven already have the somatostatin analogs and maybe weren't as, you know, desperate for a new therapy.

But also, like you said, you know, trying to get a result quicker. Is it, you know, what you look for when you're designing a trial. Sorry, Lexi, we interrupted. No problem. So these patients were assigned two to one to the study group. So the study group being lu Dotatate plus 30 mgs of octreotide, LAR versus high dose octreotide, LAR 60 milligrams.

Four cycles were administered every eight weeks. Tumors were assessed at regular intervals until progression of disease or death, and their primary endpoint was progression-free survival. Beth, do you mind taking us through the results? Yeah, definitely. So between January, 2020 and October, 2022

approximately 226 patients were assigned to treatment groups.

The primary disease site was the pancreas. In 54% of patients followed by small bowel, 65% had grade two, and 35% had grade three disease. The authors found median progression-free survival to be about 23 months in the L Dotatate group versus 8.5 months in the control group. And these results were consistent across subgroups.

That's a reduction in risk of disease progression or death by about 72%. So Lew Dotatate was well tolerated with similar toxicity observed to the control arm. Connor, do you mind summarizing some key takeaways for us from this trial? So one of the first points that the authors make in their discussion actually is that this is the first study to investigate radioligand therapy as first line therapy given to patients with any cancer, which is really exciting.

And as you mentioned, Beth, this study not only met its primary endpoint, but it also showed a significant benefit in patients receiving the radio labeled ligand therapy, which was fairly well tolerated compared to the control group. And then a key takeaway we should go

over is the toxicity, because you know, when you're comparing it to somatostatin analogs, which are extremely well tolerated, you do have to be aware of the toxicity, particularly as we talk about moving this into the first line.

And so, Lexi, do you have the, the results about toxicity from this trial? So toxicity was pretty similar between the two groups. There were six deaths throughout the randomized period, but these were all attributed to disease progression, not to therapy itself. Adverse events were low in all arms.

There were two discontinuations attributed to the. Octreotide, LAR in the control group. And then there were three discontinued for side effects due to the lu Dotatate itself in the experimental group. And then in the experimental group, an additional. Five discontinued for the octreotide, LAR.

Few patients required dose reduction and there were the dose interruptions were the same in both groups. Yeah. And then the other thing, you know that I think there was some concern about here is

hematologic toxicities, and they did see. You know, 14% greater than or equal to grade three hematologic toxicities with lutathera versus basically none in the somatostatin analog, which makes sense.

So, but I, I do think that is one thing to keep in mind is that when you. Make a transition from somatostatin analog as first line to luta therapy as first line. There is some real toxicity, not dramatic, but there is some real toxicity. And that's just something to keep in mind. When we talk about how to kind of incorporate this into practice.

And I think that, you know, before net or two, I think a lot of people were using. After somatostatin analogs had failed. So they would start that. And inevitably, particularly in a patient who has a grade two tumor with a higher KI six seven, you knew it was gonna fail and then you would try this after it failed.

But now, particularly in those patients with KI 60 sevens in the teens or twenties where you're not confident that a somatostatin analog is gonna do a whole lot,

people are moving lutathera into the first line. Okay, great. Well, I think these are all really good points, and I think everyone on the podcast is gonna walk away with a better understanding of radiolabeled leg and therapy moving forward.

We ready to transition to our next article? Let's do it. This is a little bit of an older study published in 2016. That is the next article we're gonna discuss. But we think there's some really important points to make here about surgical debulking of neuroendocrine tumors for the listener to take away.

I think this really requires a shift in mindset from the traditional strategy applied to metastatic disease to the liver from say, adenocarcinoma. Dr. Verlin, do you mind setting the stage here? I mean, I think hopefully we beat this horse pretty good in the last episode. You know, where we talked about what are our goals, right?

What's our, what's our goal in going to the operating room? So we operate in the primaries, particularly for small bowel, because they often cause bowel obstruction and symptoms. So we're trying to get rid of the symptoms, but why are we operating on metastatic disease and a

indolent disease? You know, we'll go through the paper.

The only. I do wanna put out there before we, we go through these results, is that essentially any retrospective study of surgery. Is going to show that it's associated with better survival. It's, it's a very low bar to get over. And the reason of course is because who are you gonna operate on? You're gonna operate on the younger, healthy patients with less disease.

You know, and so those patients are gonna do better, whereas the 90-year-old with 40 liver mets, you're not gonna operate on. So, and those patients will inevitably succumb to either the disease you're studying or just their baseline. Comorbidities or other diseases quicker and so their survival will be lower.

So we always have to be careful when talking about any retrospective study of surgery versus not surgery. It's always gonna favor surgery. So with that in mind, we'll get into the paper. So, Connor, do you mind now giving us some context for the upcoming study?

Sure. So, metastatic disease in neuroendocrin tumors is actually pretty common.

In fact, up to 60% of patients initially present with metastatic disease, and this is primarily in the liver long-term, this is a problem because patients can die from liver replacement with tumor and subsequent liver failure. This can, in theory, be aggressively managed with surgery to improve survival and quality of life.

However, recurrence is the rule rather than the exception with a five year recurrence rate of up to 94%. So that leaves us with the question of how much liver surgery is appropriate and who needs liver surgery and who are we actually helping? One of the major issues of course, is that once you resect normal liver, they're not necessarily gonna get that back.

And if the recurrence rate is that high, then doing a formal, you know, major liver resection for neuroendocrine liver metastasis probably doesn't make much sense. So where does that leave us? You know, oftentimes these patients have

many tumors scattered throughout the liver. And so the question we have to ask is what to what degree do we have to actually resect these liver metastases?

And we end up talking about debulking, which is something we rarely talk about in surgical oncology and most other diseases. So this target was previously suggested to be somewhere around 90%, but this would leave relatively few candidates suitable for liberty debulking. So, Beth, why don't you summarize the study methods for us.

Definitely. So this was a retrospective review of patients treated at a single center between 1999 and 2015 with details maintained in a prospectively maintained surgical database. The degree of resection was determined by the senior surgeon per the authors and techniques included both paral sparing approaches with ablation, wedge resection, enucleation, or radiofrequency, as well as anatomic resection.

Estimations of hepatic debulking were made from pre and postoperative CAT scans and progression-free survival and overall survival were assessed by the

Kaplan-Meier method. Lexie, do you mind taking us through the study results? So 108 patients were ultimately included in the study and underwent liver directed therapy for both pancreatic nuts and small bowel nets.

63.9% achieved at least a 70% reduction in their tumor burden, whereas only 39% of the cohort achieved that 90% benchmark. Patients tolerated surgery pretty well. There was a 0% 30 day mortality mortality rate, and generally a low complication profile. The median pro progression-free survival, the cohort was 2.2 years.

Median overall survival in the cohort was 10.2 years. And while degree of debulking was associated with improved survival, there was not a consistent stepwise increase. When you compared the group's at 70% debulking versus 90% debulking. And ultimately the author suggests that the 90% threshold is too strict.

And lowering

that threshold will probably benefit more patients that would then be considered eligible for surgery with still quite significant survival benefit. And while this is a retrospective study with inherent limitations and it has a small sample from a single institution this.

I think still gives us some important clinical takeaways. What do you think Dr. Gland? Yeah, I think, you know, this is an important paper kind of in line with other previous papers that have shown very similar results. One key distinction, I think is that. We're, you know, there can be two different goals for debulking.

So a hormonally active tumor, you know, just to keep in mind then I think you should be even more aggressive about debulking because you can potentially improve the patient's quality of life even if you're not improving their overall survival. But I do think that. As we be, you know, as we get more effective medical therapies, there's sort of two ways to look at it, right?

So you could say, well, we have such effective medical therapy. We don't need to do, we don't need to do surgery anymore. We don't need to

bulk anymore. And that's a very open question because nobody's done this study in the modern era where we have more effective therapies. What is PRRT gonna do to this question?

I don't think anybody knows. I think it's an open question. You could say, well, why are we operating on liver mets when we have PRRT? We can just give PRT really interesting. Point though is that PRRT seems to be somewhat dose dependent on how much tumor you have. And so potentially if you debulk and follow it with PRRT, maybe the PRRT is more effective 'cause it can hit those smaller spots when, when it's not, we're not, you're not utilizing a large dose.

So to speak on the large liver met, but now you can hit the microscopic spots in the liver. That's all kind of theoretical at this point, but I think that's probably where the field is headed in the next 10 years is maybe we need to combine these therapies. So yeah. What, what do we do with this paper? I think the dogma has always been.

If you can operate on endocrine tumors, you probably should. This paper is sort of in line with that. It doesn't refute that. There's been very

little data that has refuted that. The problem, of course, is that all the data that says we should be debulking is retrospective, and so, you know, unless somebody's gonna do a randomized.

Controlled trial of surgery versus no surgery, which, you know, difficult to do. There's lots of problems with randomized surgical trials, but maybe that would be something on the horizon, like PRRT versus surgery that would help answer these questions. But I'm not confident that that's gonna happen anytime soon.

So for now, I think, you know, you try to get out what you can get out, try to do it in a low morbidity fashion. That's where, you know, as you guys kind of alluded to, ablation and. More minimally invasive techniques are certainly being used very widely, and I think those are those are very helpful in these situations.

But if you can get, you know, if you can clear most of the liver. You can do it in a low morbidity fashion. The answer right now is, yes, you should do that. Inevitably when you go to the operating room on these patients, you will find more than

you think. Is there, you know, I just did one of these, I think it was this week or last week, I can't remember, but you know, went for two, found four.

Right? But you just. You take 'em out and you reset the clock, you get, you know, you resect something so that you can get good pathologic information, both from the primary and from the metastatic site, unless again, it's increasing morbidity dramatically. And then you have the information on what medicines to give next.

And I do think there's an argument, and I think we talked about this last time before, you know, kind of kicking the can down the road. Sort of in the same vein as like a well d lipos sarcoma or these tumors that you know are gonna come back. But if you can just sort of kick the can down the road and extend their life, it becomes more of a chronic disease than an acute disease.

And I think there's a real argument to be made for that. We also know that. The medical therapies, particularly somatostatin analogs and even the everolimus and, and other things. We won't get too crazy here, but they, they all have a

shelf life, so to speak, for each patient. Like eventually the patient will progress through those.

So there's also an argument to be made for sort of delaying the start of those therapies as long as you can. The, the only other caveat I'll give here is that a lot of these arguments I'm making are in the sort of grade one or low KI 67 group where you have a lot of options. It's harder to make that argument if the KI 67 is 40% and they have four liver mets.

Right. Yeah. That's a, again, a different disease. So you know, a lot of what we've talked about today is sort of, I would say grade two or grade one. So KI 67 of 20% or below 10% or below. Then I think. Very, very long disease course, chronic illness. Kick the can down the road as much as you can in those cases.

Be aggressive surgically so that you can save this somatostatin analog for later, particularly if they're young. And, you know, give them 5, 6, 10 years without being on medicine every day. Which I think is, is very

beneficial. For younger, healthier patients who don't want to be constantly reminded that they're sick by taking medicine all the time.

All those I think, are real arguments. This 10 to 20 range I think is really interesting right now because that's where kind of lutathera is probably becoming first line and changing a lot of the way that we've been managing this disease. And then over 20, I think you're back into kinda the grab bag.

We haven't talked at all about actual chemotherapy for neuroendocrin tumors. But I think that's a real option. When the KI 67 starts creeping up towards 20 that's where like Cape 10 becomes maybe first line depending on what you're doing. And so the, again, kind of bracketing these different KI 60 sevens and almost treating them like totally different diseases, I think is the right way to approach this.

Do not treat all neuroendocrine tumors as the same thing. Yeah. One other thing I would probably add too is it's, I mean it's, it's unfortunate that it's so hard to study these. Questions because something I'm starting to see too and I'm sure y'all are as well, is this

concept of converting someone to liver only so that you can treat with lutathera.

And that probably applies more to the patients that have truly ary liver metastases where there's, you know, a hundred tiny lesions and where resection may not make a lot of sense. So for those patients, the reason I should back up to the reason to sort of cut, quote, unquote convert them to liver only is if you give lutathera with the small bowel primary and especially lymph nodes, mesenteric lymph nodes in place, it'll cause this dense desmoplastic reaction that can actually cause a small bowel obstruction.

And so that patient may actually be in trouble. So most medical oncologists will not want to give lutathera if mesenteric lymph nodes in particular are still in place. It's not that, it's not an absolute contraindication by any means and they didn't even mention that in the net or two paper that that we talked about in this podcast.

But definitely an important cons consideration 'cause that would be an interesting question. Is for those, for patients in that situation that have many liver mets

and their primary's been resected, should we do more surgery or, or should we focus more on lutathera? So yeah, like Dr. Lan said, probably not gonna have a, a large prospective trial to answer that question, but situation that we're probably gonna find ourselves in.

Yeah, I think most of what we've talked about tonight has been. You know, really applies to liver mets. I think, you know, again, going back to our, our first episode, the, the small bowel primary should almost always come out. You know, there's, there's very few scenarios where I would leave that intact because they're gonna develop a bowel obstruction and die of that before anything else.

So, you know, getting that symptomatic primary out is extremely important. And I think, you know, again, you think about the morbidity of the operation here. So, you know, there are scenarios where you have so much disease in the small bowel or in the mesentery that it is a very highly morbid operation to take it out.

And that does change things quite a bit. But the. Vast majority of these, you can take 30 or

40 centimeters of small bowel. You, you do a good mesenteric resection and you'll clear their symptomatic primary for good. And then you're dealing with the, the metastatic disease and trying to turn that into a chronic thing and, and treat that as long as you can.

But I think it's a very good point Connor, to, you know, take the primary out first and then deal with all this other stuff. But if you're in there and there's a big mat in the liver, it's pretty hard not to take it out or do something about it. Okay, great. Well, I think that wraps up our journal discussion for neuroendocrine disease.

Hopefully everyone listening has a better understanding of some of the more nuanced treatment strategies and decision making for advanced disease. We're really excited to kick off another two year season with you all in a few months with some new fresh team members. So until then, dominate the day.