Dr. Daniel Halperin:
Welcome to the ASCO Post Roundtable Series on Evolving Treatment Paradigms for Neuroendocrine Tumors. I'm Dr. Daniel Halperin, Associate Professor and Vice Chair in Hematology and Medical Oncology at Emory University. And joining me today are two of my wonderful colleagues.
Dr. Jess Maxwell:
I'm Jess Maxwell. I'm an Assistant Professor and surgical oncologist at MD Anderson Cancer Center in Houston, and I subspecialize in the surgical care of GI NET patients.
Dr. Virginia Corbett:
Hi, my name is Virginia Corbett. I'm Assistant Professor at the Icahn School of Medicine at Mount Sinai in New York City and I'm a specialist in neuroendocrine tumors.
Dr. Daniel Halperin:
And today we'll be discussing the treatment and management of neuroendocrine tumors with three patient case studies. Our second installment will focus on a patient with a well-differentiated grade 3 small bowel neuroendocrine tumor. This is K.L., a 55-year-old man with well-controlled diabetes and hypertension and he presents with about 20 lb of weight loss and this mild vague abdominal discomfort after eating. Both over the past 18 months or so. He undergoes a right upper quadrant ultrasound that unfortunately shows some hepatic lesions, but the gallbladder is totally unremarkable. And then he has a CT scan with hepatic metastasis in segments VII and VIII, and then a mesenteric mass is revealed right along the ileocolic artery with some edematous bowel wall in the associated territory, but no frank obstruction. So he undergoes a liver biopsy that shows a well-differentiated neuroendocrine tumor with a Ki-67 of 30%. So let's turn to our panelists and ask what we do next. I think this is a particularly fun case to think through. Dr. Maxwell, why don't we start with you? How would you approach this patient in this setting?
Dr. Jess Maxwell:
Well, I think from a surgical perspective, I'm thinking about two things, the primary and the hepatic disease burden that we can see at least on this CT scan. I'm a little worried about this primary tumor. I can't see the imaging myself, but you've got a patient who even though perhaps they're vague symptoms, they're certainly presenting with symptoms and weight loss and it's postprandial, which is always concerning for some amount of vascular issue. Usually drainage at an early stage, right? Not necessarily arterial supply. And you have reports that there's edema in that bowel wall. So you're going to see thickening and potentially depending on where that mesenteric mass is or the extent of the adenopathy, you may have a more proximal mesenteric mass that's causing vascular issues with supply or drainage.
But often there can be lymphadenopathy near the bowel itself, that mesenteric side, and it can cause, I describe it to patients as a Gordian knot, it just sort of grabs the bowel and it sucks it in and causes it to be really difficult for waste and air to move around, which can be really uncomfortable for the patient.
So my first thought is that this is a primary tumor that needs to come out no matter what we decide about the rest of the patient's disease. And I think that symptoms drive us to that point. But I often think about resecting the primary tumor in metastatic patients, even if I'm not planning on doing anything with the metastases later and the patient is asymptomatic, because of the Bennett paper that was published in 2020 that suggests that patients that have an asymptomatic primary resected upfront, meaning within the 6 months of being diagnosed, have a lower 3-year rate of unplanned admissions and bowel surgery compared to those patients who do not undergo upfront surgery. So I think in this patient's case it's pretty clear, but I will put in that plug for patients in which it may not be quite as clear as you're sort of gaming out how you expect this to go.
Dr. Daniel Halperin:
Dr. Corbett, what are your thoughts?
Dr. Virginia Corbett:
I think I agree with surgery. The other data, the recent data we have from NETTER-2 shows that in patients with higher grade neuroendocrine tumors benefit from early PRRT. However, in the situation where the patient has a highly symptomatic primary tumor, I think surgery is the best option. I know at our tumor board we probably discussed the elevated Ki-67 of 30%. With a more aggressive tumor, you worry about rapid recurrence. But given the symptoms and given the patient's situation with the weight loss, I really do think surgery is the best option. I think it's also important to know if they have elevated serotonin 5-HIAA, I think we get a few more tumor markers as well, but not included in the case. Maybe they have some other symptomatic disease.
Dr. Daniel Halperin:
Yeah. And I'll tell you in this context, I mean we really have the mechanical symptoms, but no evidence for carcinoid syndrome or other hormonal symptomatology intended to drive us really towards the mechanical issue and symptoms and management thereof. I did my best, Dr. Maxwell, to describe localized single-sided two-segment disease to make this as much of a chip shot as possible. While you're clearing the bowel disease, assuming it's fairly limited, pros and cons of going after low-volume liver disease.
Dr. Jess Maxwell:
I think it's reasonable as long as you have a healthy patient and you think you can enucleate these and for all of the things that you're trying to describe, you're offering me a fairly straightforward hepatic cytoreduction, the Ki-67 of 30%, I have a harder time interpreting in small bowel patients when we're talking about the liver metastases. I would have a lot of other things to say if this is a pancreas neuroendocrine patient, but I think the cons are that we do not have multiple imaging studies to suggest how stable these have been over time.
This is our first time meeting this tumor. And so I love a little bit of foot dragging if it's going to be an extensive operation, but I think, get in, know that you're going to do the primary tumor. If I am going to do the liver, then I would start with an intraoperative ultrasound. I would do the liver first so that we keep the fluids low. As long as the ultrasound doesn't uncover a tremendous amount of surprise tumors that are scattered about and were just occult on our imaging, I think it's reasonable to go, let anesthesia give their fluids, do the bowel and get out. And I think you've probably done something helpful for that patient.
Dr. Daniel Halperin:
And now is a perfect time to move to the next slide and say that yes, after the primary tumor and those couple of visible metastases are removed, you have done something good for the patient, they immediately start regaining weight. I know all of us have had this experience in our clinic where the patient is eating again and feels substantially better and it's what one of my colleagues always used to call a very satisfying operation to see the patient improve.
Unfortunately, as I think you both alluded to, it's not that long until we see disease again. And at the 9-month re-staging, we now start to see those multifocal small-volume disseminated metastases. And it's only about, again, 10% of the parenchyma, not threatening, but diffuse and relatively rapid after the surgery. And so now, let's consider our options again, because we have that opportunity here. Dr. Maxwell, why don't I ask you. How enthusiastic are you for surgery in this situation?
Jess Maxwell:
I don't love a 9-month disease-free interval or I should really say progression-free interval. Because the reality is, right, we knew those little spots were there. If we look back at the Fossmark paper that was published in 2019, they did that really nice study on metastatic small bowel neuroendocrine patients where they took a look at the surgical specimens when these patients went to the operating room. And what they found was that in addition, of course, to the targeted metastasis, when they looked at all of the normal liver parenchyma within that surgical specimen in 100% of patients and 100% of targeted specimens, there were tiny little neuroendocrine cells scattered all over and they ranged anywhere from just a couple of millimeters away to a few centimeters away. And so we know that those exist for all of these patients. It's just a matter of when they're going to rear their ugly heads. And I'm afraid despite it being low volume and potentially targetable, I'm worried that I would just end up playing whack-a-mole with this patient's liver. So at least at this time point, I don't think that a knife is probably the right tool.
Dr. Daniel Halperin:
Yeah, and I can imagine how painful it is to say that, but I would tend to agree.
Jess Maxwell:
Indeed.
Dr. Daniel Halperin:
Any other thoughts, Dr. Corbett, on the existing evidence around this and recurrence after a metastasectomy, for example?
Dr. Virginia Corbett:
I think proceeding with some somatostatin analogs therapy is the best choice in this situation. I think that in some situations you can consider a local regional liver-directed treatments if there's only progression of disease in the liver itself. And I think another important thing to consider is this patient had the debulking procedure and then they had this kind of interval following up. In some situations like this, I would even consider talking to patients about doing adjuvant lanreotide, not a lot of data for it, but in some patients with a faster growing tumor, you know that the tumor is there and maybe you could prevent it from coming back sooner.
Dr. Daniel Halperin:
And then if we could just refine the treatment decision that you just brought up there about starting somatosatin analog. Now earlier you'd mentioned NETTER-2 and the evidence sort of another relatively recent study in this space. How do you weigh out those data in this context in low-volume liver disease?
Dr. Virginia Corbett:
Yeah, so NETTER-2's data is very exciting. I feel like we're always looking for better treatments for patients with faster growing disease, NETTER-2 led to improve median progression-free survival and impressive overall response rate in patients with higher grade neuroendocrine tumors undergoing PRRT. I think in the situation I would save PRRT though for a higher volume disease when you really need it. Fortunately, the patient had a really large benefit from their surgical resection and I don't think we quite need PRRT yet in this context.
Dr. Daniel Halperin:
And I think it just brings back that individualization of management strategy and the nuance of the progression-free vs overall survival. It's sort of permissive but not necessarily mandated. And so fortunately for me, I agreed with you and started lanreotide in this case, but unfortunately after about a year we saw significant progression that sort of plumping up of disease. I'd quantitated it here as 10% to 30% really over the short interval between a couple of scans, not that slow creep that we sometimes see, but really that step change that tends to cause more concern, at least in my practice. I've tried to lay out as many options as I could possibly think of. What do we want to do next? We have this step change in well-differentiated grade 3 disease. Why don't we start with you Dr. Corbett? How would you think about making this decision?
Dr. Virginia Corbett:
I think given the growth of the tumor and the tempo of the disease, I think we need something that's going to have a good response rate. In a disease like this, if we don't get it under control, we're going to see it may cause problems for the patient, maybe they become symptomatic again. And so in this situation, I would favor starting PRRT. PRRT is well tolerated. It has, based on NETTER-2, a good response rate in higher grade disease and I think it would lead to the most powerful tumor modality for the patient in this context.
Dr. Daniel Halperin:
Dr. Maxwell, any thoughts on that choice next?
Dr. Jess Maxwell:
It's hard to argue with that given the progression that we saw before or that was mentioned at 12 months, it's not a great amount of time and now it's really starting to pick up the pace. So choosing something where we're fingers crossed, going to see a response rather than just static disease or static stable disease is ideal I think.
Dr. Daniel Halperin:
And then just to make things interesting because you both agreed, if the patient were, for example, to say that they weren't that interested in radioactive therapy right now or were to take PRRT off the table for you based on whatever reason, then how would we think about the current evidence in this situation, either prospective or retrospective to think about what we could offer the patient next?
Dr. Virginia Corbett:
I think that if the patient declined PRRT I’d go with cabozantinib. I think cabozantinib is as an excellent drug, especially based on the recent data, improving median progression-free survival. However, cabozantinib is associated with toxicities. There's a lot of side effects on these patient profiles. So again, I would have to really have a careful risk and benefit discussion with the patient about each agent and the risk and benefits of each, PRRT vs cabozantinib.
Dr. Daniel Halperin:
Totally, as I think we always try to do, think through the risks and benefits of all of our therapies. Anything else, Dr. Maxwell, you would add to that thinking?
Dr. Jess Maxwell:
I don't have a ton to add other than to echo Dr. Corbett's point. Cabo can have quite a few side effects and what I've noticed since obviously more patients are being put on this since the CABINET trial was released, a lot of patients will have abdominal pain and just abdominal discomfort when they take this. And I've had a lot of patients, I get calls on call about concerns in these sorts of situations. And so it's actually, I feel a lot better about cabo once the primary tumor has been resected because it's a little bit more clear about what's an AE vs what's attributable to the tumor itself. So that has been sort of an interesting and evolving issue that as surgeons we've had to sort out as it relates to this medicine being used more frequently in this patient population.
Dr. Daniel Halperin:
But I think certainly these are complex decisions with patients thinking through their preferences. But I do, I think the take-home here that we have prospective randomized evidence with both PRRT and cabozantinib in different patient settings that includes this well-differentiated grade 3 population is what I think I wanted to tease out in this case for us to think about as we're all making decisions and as the evidence comes out. So with that, we had a few more takeaways from this case. One which we touched on, I think conceptually with the way we got out of the gate is that well-differentiated grade 3 neuroendocrine tumors are very distinct from poorly differentiated neuroendocrine carcinomas and the evidence base is just a little bit thinner than what we're used to in grade 1/2 disease. I think that was really exemplified by the surgical conversation we had out of the gate, which we might've felt differently with a poorly differentiated carcinoma.
We also heard about the NETTER-2 data, demonstrating PFS superiority with PRRT over SSA for patients with Grade 2-3 GEP-NETs. And we didn't actually touch on it, but we have some retrospective evidence with CAPTEM for grade 3 small bowel neuroendocrine tumors out of Florida. And then CABINET, another prospective randomized trial showing the benefit of cabozantinib in patients with advanced pancreatic or extrapancreatic neuroendocrine tumors, including those with well-differentiated grade 3 disease, and then the others that we sometimes will individualize as needed based on the patient, as we started to get at with the discussion about PRRT vs cabozantinib, some of the nuance.
That brings us to the end of the case and we hope everyone will see the other segments for further discussion about the latest evidence in neuroendocrine tumors or visit ascopost.com.
