Dr. Daniel Halperin:
Welcome to The ASCO Post Roundtable Series on the Evolving Treatment Paradigms for Neuroendocrine Tumors. I'm Dr. Daniel Halperin, Associate Professor and Vice Chair of Clinical Affairs in the Department of Hematology and Oncology at Winship Cancer Institute at Emory. Joining me today are two fantastic colleagues.
Dr. Jess Maxwell:
Hi there. My name's Jess Maxwell. I'm a surgical oncologist at MD Anderson, and my practice is mostly comprised of patients with GI neuroendocrine tumors.
Dr. Virginia Corbett:
Hi, my name is Virginia Corbett. I'm a medical oncologist at the Icahn School of Medicine at Mount Sinai, and I'm focused on the treatment of neuroendocrine tumors.
Dr. Daniel Halperin:
Today the three of us are going to be discussing the treatment and management of neuroendocrine tumors with three patient case studies.
The first installment we'll focus on the treatment of a patient with a pancreatic neuroendocrine tumor. G.M. is a 40-year-old woman with no past medical history, and she presents to urgent care with right flank pain, nausea, and vomiting. Started all of a sudden this morning. Her laboratory studies are just notable for hypercalcemia to 12, and so she undergoes a noncontrast CT that shows nephrolithiasis. There's this subtle irregularity in the tail of the pancreas, about 1.6 cm in diameter. And so of course we get a contrast-enhanced pancreas protocol CT in the emergency room, and there we see four small hypervascular lesions throughout the pancreas, the largest of which is still about 1.6 cm.
And so the question for the panelists is, what tests would we like to order next to learn more about this patient? Dr. Corbett, why don't you kick us off?
Dr. Virginia Corbett:
So I think we start with staging. We start with either a CT chest, abdomen, and pelvis with contrast or a CT chest and an MRI abdomen and pelvis, possibly with Eovist contrast to evaluate the liver. The elevated calcium also deserves further evaluation, and I would start with a PTH.
Dr. Daniel Halperin:
As we learn more and find out that the patient has a primary hyperparathyroidism leading to the hypercalcemia and we see these multifocal hypervascular lesions in the pancreas, I wonder, Dr. Maxwell, if I could toss it over to you if there's other things you might be looking for or friends you might be phoning for help.
Dr. Jess Maxwell:
Yeah, I would be worried in this patient that perhaps they have MEN type 1 given the constellation of symptoms and the abnormalities that we're finding. I'm always a little bit concerned about that when I see multifocal disease in the pancreas. Basically every time I see a patient like this walk through my door, even if they're not quite as sick as this patient presented, I think a genetic consult is warranted. That'll guide a lot of what we do next.
Dr. Daniel Halperin:
Perfect, and so of course I feel the same way. In this situation, of course we would discover that the patient does in fact have MEN1, and that's the root cause of the issue. These are good old-fashioned grade 1 neuroendocrine tumors we would expect.
What sort of intervention do we think we would go after in this setting?
Dr. Virginia Corbett:
I think with all neuroendocrine tumor patients, you really have to have a multidisciplinary discussion before deciding about treatment options. That includes early involvement of surgical teams, interventional radiology nuclear medicine, and a review of targeted imaging, including gallium-68 DOTATATE PET-CT scan or a copper-64 DOTATATE PET-CT scan.
Also, we haven't really spoken about this, but I don't know if the patient has any functional hormonal syndrome. It doesn't sound like it, but we probably would send some additional tumor markers, possibly a gastrin, a glucagon, a VIP, maybe an insulin level, just to see is there anything else that would turn up on the testing.
You've already mentioned referral to endocrine and genetics, but I really do think genetics referral is so important even before sending the testing because with MEN1, this has such a huge impact on families. And so having the opportunity to have genetic counseling and a conversation with a genetic counselor about the impact on their loved ones is really, really important before proceeding with care.
Dr. Daniel Halperin:
Absolutely.
Dr. Maxwell, any additional thoughts?
Dr. Jess Maxwell:
When a patient with a tumor that is less than 2 cm, I have a conversation with them about indications for resection. Certainly if they presented with clinical symptoms that suggested a functional tumor, that could be a reason to intervene if the tumor is less than 2 cm.
But guidelines suggest that these tumors can be safely observed until they reach right around 2 cm, and we're right at around 1.5. It would be very reasonable to pursue observation at this point, so talking to them about the rationale for that and at what point we might start getting a little more enthusiastic about getting toward the OR is usually how I start those first visits.
Dr. Virginia Corbett:
Yeah, I think it's also important to note that with MEN1, they're genetically distinct tumors. Oftentimes we think of it being a metastatic tumor in various places, but because it's all genetically distinct, we consider them as separate primaries.
I don't know if that's been your experience as well.
Dr. Daniel Halperin:
Yeah, I think we'd also exactly be thinking about these as the individual separate tumors in the pancreas in this context.
Any commentary either of you would like to make on what we might expect in terms of natural history for this localized tumor, particularly in the context of MEN1?
Dr. Virginia Corbett:
Over time we tend to be a little bit more aggressive than patients who do not have MEN1. I feel like these patients need close monitoring and, again, frequent screening both through their hormonal markers and through imaging.
Dr. Daniel Halperin:
Sure, so we will move along with the case. We do in fact after an extensive discussion follow the patient for several years. But unfortunately the lesion does eventually grow to 2.2 cm.
And so Dr. Maxwell, how's the enthusiasm level for surgery now that we've crossed that 2-cm threshold?
Dr. Jess Maxwell:
Very enthusiastic.
Dr. Daniel Halperin:
Which is good because in this case the patient goes for the distal pancreatectomy and we have this mildly grade 2 pancreatic neuroendocrine tumor. Ki-67 is 4%. As we think about following this patient, any thoughts on observation vs any sort of therapy in this context?
Dr. Virginia Corbett:
I think that if it's an isolated tumor that's resected, observation is very reasonable.
Dr. Jess Maxwell:
That's what I would recommend to the patient as well.
Dr. Daniel Halperin:
Yeah, me too for what it's worth. Just curious what folks thought.
Now we follow the patient for several years, and unfortunately we discover a solitary liver metastasis. This being solitary tumor with a fairly long disease-free interval after the index resection, we go right to the operating room and clear the disease, I am sure much to the enthusiasm of our surgical colleagues. Things go well for a couple of years until unfortunately we see disseminated but low volume disease. And so here I've estimated for the sake of argument it's only about 10% of the parenchyma, but it's distributed throughout both sides of the liver.
We'll move things along and just say that we do start a somatostatin analog with lanreotide and get about 2 years of stable disease. When the disease progresses to about 20% of the parenchyma, we move on to everolimus. There we get a little more than a year, and now we start to see some more progression to about 30% of the parenchyma.
And so I'm curious if we could pause for a moment and talk a bit about that selection of everolimus with the progression on somatostatin analog. I may toss it to Dr. Corbett first as our medical oncology commentator. What are your thoughts on the selection of everolimus, and what sorts of data are there to guide us here?
Dr. Virginia Corbett:
Yeah, so I believe everolimus was first established in pancreas neuroendocrine tumors based on the RADIANT-3 trial. Everolimus is a drug that's very well tolerated in neuroendocrine tumor patients and it has a great disease stability. I think the median progression free survival is usually around 11 months, so this patient's course seems very typical for that drug.
It's not a drug that causes a lot of response, and so it's not going to shrink the tumor dramatically. In the initial study overall response was around 5%, but it's a good choice because it's well-tolerated and can cause disease stability.
An alternative would be to consider PRRT. I think that really depends on the patient and a patient-specific discussion of their overall status and their preferences, but I think it's worth a discussion as context as well.
Dr. Daniel Halperin:
I wonder, Dr. Maxwell, if I could lateral to you, any thoughts on the PRRT discussion here in light of perhaps the COMPETE data that are recently out?
Dr. Jess Maxwell:
I don't have a lot to add in terms of all of that. I mean, when I think about holding people steady and just thinking about what role that surgery might play in the future, either one of those therapies would be very reasonable. Not necessarily if we think about neoadjuvant intent, but in terms of my ability to be able to intervene should we get, for instance, oligoprogression in a liver metastasis that we think surgery might be the best option for.
As a surgeon, that's how I conceptualize most of these therapies.
Dr. Daniel Halperin:
Sure.
Dr. Corbett, I saw your face light up when I said COMPETE. Do you want to comment on the data there at all?
Dr. Virginia Corbett:
Yeah, sure.
It's pretty new data, but the COMPETE trial evaluated a different type of PRRT. I believe it's 177 Lu-DOTA-TATE vs everolimus. It showed an improved median progression free survival of the PRRT therapy over everolimus in that setting, and I believe it improved overall survival as well.
But again, I think even with that data, it really depends on a patient-specific discussion in every context because everyone is different. And then MEN1 patients also have specific needs. You know that there's going to be further neuroendocrine tumors coming in these patients. They could get any sort of foregut neuroendocrine tumor including bronchial, thymic, and so I think I try to reserve PRRT for these particular patients until I really need to do it.
And so in this situation, I think the COMPETE data is interesting and important to note, and it's important to include in patient discussion, but I do think everolimus is a very reasonable choice.
Dr. Daniel Halperin:
Yeah, that's really exactly the discussion I was hoping to get to, right? We do see a PFS benefit. I think has a ratio about 0.67 or so in that study, but that doesn't necessarily mean it's always the right choice every single time. We have this nuance of the individual patient situation that I think you both have illustrated so nicely.
This being before the data were out, we went on to CAPTEM chemotherapy. While getting this all lined up, the patient independently obtained some DPD testing, which has of course been in the news lately. Finds out she's heterozygous and declines to take the capecitabine.
And so we're going to go on single agent temozolomide here, an old school approach. We do see response at 3-month imaging, and then it sustains for about... It continues actually to deepen over the course of 9 months and sustains for a couple of years despite the fact that we complete the chemotherapy at month 12 or 13 if we're going precisely by 2211.
I was wondering, given both of you I think know the temozolomide and CAPTEM literature quite well, if you guys would like to comment a bit on the relative merits of temozolomide and CAPTEM for patients with pancreatic cancer?
Dr. Virginia Corbett:
Yeah, I think this is also really interesting. We started doing DPD testing more commonly in our patients and our neuroendocrine patients just recently. I think that's really important. I think it also illustrates how our patients are such wonderful advocates for themselves in seeking out these opportunities and seeking new treatments, and I think that's really a special part of treating neuroendocrine tumor patients.
The data for CAPTEM and advanced pancreas neuroendocrine tumor patients, I think it's really interesting. The median progression free survival, as you said, improved in the patients who had combination treatment with temozolomide and capecitabine. But the overall response rate is actually pretty similar, not significantly different between the two arms and the overall survival was pretty similar.
And so I really think it, again, it's a patient-specific discussion. Not only DPD testing, but other things can cause you not to use capecitabine. For example, patients who have some sort of reaction to 5-fluorouracil-based therapy, cardiac toxicity, something like that. Temozolomide is still useful as a single agent in this setting.
Dr. Jess Maxwell:
I think philosophically what this supports too is just the evolving role for more personalized medicine. Probably across oncology in general, but particularly in patients where we're introducing new therapies all the time and different variations, the different flavors of PRRT or different ways that we can offer systemic therapies. It's really critical that patients with these more rare tumors have folks that are really experienced in taking care of patients with their rare tumor as a part of their team so that we make sure that we're offering them really the most optimal therapy for their tumors across their lifespan.
It's important for everybody, but it's certainly critical for patients who we would expect even in advanced setting to live many years with their disease, right? It's a marathon. It's not a sprint.
Dr. Daniel Halperin:
Yeah, very well said, Dr. Maxwell.
And so with that, we'll illustrate just a couple of key clinical takeaways for folks from the case, all of which of course our panelists, I think, hit on really nicely, the first being that multifocal pancreatic neuroendocrine tumors does generally prompt a genetics evaluation. We are usually specifically thinking about multiple endocrine neoplasia type 1.
Next, I think is that 2-cm threshold, where we tend to get more enthusiastic about intervention as pancreatic nets get above 2 cm or so with some gentle caveats.
And then lastly, the notion that we do have nice randomized evidence that capecitabine and temozolomide improve PFS, but not necessarily objective response rate over single agent temozolomide. We can often leverage that to individualize the therapy for each patient.
That brings us to the end of this first case. Please see the other segments for further discussion about the latest research and studies in neuroendocrine tumors or the ascopost.com. Thank you.
