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 of Hematology and Oncology at Emory University. And joining me today are two wonderful colleagues.
Dr. Jess Maxwell:
I'm Jess Maxwell. I'm an Assistant Professor at the MD Anderson Cancer Center in Houston, Texas. I'm a surgical oncologist, and I subspecialize in the treatment of patients with GI neuroendocrine tumors.
Dr. Virginia Corbett:
Hi, I am Virginia Corbett. I'm a medical oncologist at the Mount Sinai Icahn School of Medicine in New York City, and I specialize in neuroendocrine tumors.
Dr. Daniel Halperin:
And today we'll be discussing the treatment and management of neuroendocrine tumors with three patient cases. Our third installment will focus on the role of radioligands in advanced neuroendocrine tumors.
So T.N. is a 72-year-old man, and he's incidentally discovered to have these small hypervascular liver masses on a screening coronary artery CT. He has abdominal imaging next that reveals a 1.8-cm pancreatic tail lesion, as well as disseminated subcentimeter liver metastases that have approximated at 20% of the liver parenchyma, and they're distributed through all of the segments. He undergoes an endoscopic biopsy, and it reveals a grade 1 neuroendocrine tumor with a Ki-67 of 1%.
So I'll ask maybe Dr. Maxwell first what your thoughts are on the next treatment step for this patient.
Dr. Jess Maxwell:
As much as I would love to say that we would take him away to the operating room, I don't know that that's the correct answer for this patient in particular.
I will say that probably at 1.8 cms, it's already proven itself to be something of a bad actor despite its Ki-67 to 1%, right? We usually recommend for patients to undergo resection when that tumor hits 2 cm. And not that that's like the tumor knows that that's the time to metastasize, but clearly even at a smaller size, this tumor has begun to behave badly for this guy.
So I think that probably some type of other medical therapy is best for them, and we would typically start with an SSA.
Dr. Daniel Halperin:
Thoughts, Dr. Corbett?
Dr. Virginia Corbett:
Yeah, I think I agree with SSA initiation at this time. I think these small pancreas neuroendocrine tumors can sometimes cause trouble, and I think we have the guidelines in place.
But in some situations in patients even without metastasis and tumors between 1 and 2 cm, if it looks like it's rapidly growing and things are changing quickly, sometimes surgery is needed earlier. But in this case, I agree with lanreotide or any sort of somatostatin analog.
Dr. Daniel Halperin:
Sure. So fortunately, we have consensus, and so we went on to lanreotide. And despite the concerns I think nicely articulated by Dr. Maxwell, less of a bad actor. We have about 3 months of therapy, and we do see that slow creep over time that I think all of us are familiar with.
And now we see about a quarter of the liver, 25% of the parenchyma replaced with the disease. The tail mass is now at 2.2 cm, and we're just starting to see those gastric varices, and a little bit of splenomegaly telling us that it's really just not quite in the best spot.
So we do engage in a discussion with the patient, and he does articulate some concerns about targeted therapies and being on a pill every day now that he's been on shots for several years, and he's not really sure that's what he wants to do.
So in that context, what would we pick next? And I wonder Dr. Corbett, if I could turn to you to think about some of the options in this setting for this patient.
Dr. Virginia Corbett:
Yeah. So I think the options include other types of systemic therapies. We mentioned he's not very interested in pills, but certainly in this situation you can try everolimus.
As we discussed earlier, everolimus is considered a medicine that has improved median progression-free survival in advanced pancreas neuroendocrine tumor, however, doesn't really have a strong response rate. So it's something that could cause stability and is overall pretty well-tolerated.
Cabozantinib could also be an option. However, in this particular patient it may also be difficult because it does have sometimes side effects. And if he's interested in avoiding side effects of targeted therapies, it might not be the best choice for him.
And then pancreas neuroendocrine tumors also respond well to capecitabine and temozolomide. And so this is a combination that, as we mentioned before, has an improved median progression-free survival and improved significant overall response rate so that also would be a great option for him. CAPTEM also is associated with toxicity over the long term, and so it's something you have to monitor closely.
And then in this situation, if you're trying to really individualize the care to the specific patient who wants to avoid taking pills, wants to avoid these frequent evaluations, I really do think PRRT is the best option. PRRT would allow him to get a safe and targeted therapy, but minimize disruption to his life. It's very well-tolerated, and I think it would be a good option for him.
Dr. Daniel Halperin:
Anything you'd like to add, Dr. Maxwell, on that topic?
Dr. Jess Maxwell:
No, I agree. I think this is a guy who doesn't sound like he's too interested in having to do anything on a daily basis. And I think four treatments, four swings with PRRT might really get it where he needs to go.
The only other thing that I noticed about this patient that it's evolving even though we don't have imaging, is that if we're starting to see gastric varices, it probably means that there's some evolution in the primary tumor, and we need to be thoughtful about bleeding risk and potential splenectomy or other considerations like that. And so that's something that always needs to be in the back of the multidisciplinary team's mind.
Because although surgery might not provide this patient with oncologic benefit per se, some type of operation, either splenectomy on its own, or sometimes even like a distal pancreatectomy is the fastest way to get you where you need to go, it might really provide these folks with some benefit so that when they're progressing later on and on to their next line of therapy, they've already got that problem out of the way. Because as the tumor progresses, it only gets more and more difficult to offer an operation for any number of reasons, but, in part, even just because of the tumor bulk itself.
Dr. Daniel Halperin:
Yeah, and I wonder if on that note, I could toss it back to Dr. Corbett to touch on the significance of splenomegaly, not just in terms of bleeding risk, but cytopenias in the course of therapy for our patients.
Dr. Virginia Corbett:
So increased splenomegaly increases risk of cytopenia, especially thrombocytopenia with treatment. And I believe there's some data with PRRT treatment even there's that increased risk of splenomegaly.
I think also important, another reason why cabozantinib may be a difficult choice for him with the varices certainly increased risk of bleeding.
And so I think again, surgical option should be considered in any turning point when a patient's coming to a multidisciplinary tumor board, we're discussing all the treatment options, I think surgery should always be on the table as part of the discussion.
But given everything going on in this patient and his preferences, I still think that PRRT is probably the best choice for him.
Dr. Daniel Halperin:
Oh, definitely. And I wasn't trying to push back on that notion, but just thinking through sort of just what an important decision it is around the spleen and splenomegaly and resection, I feel like, often ended up stuck with folks over the years where we end up taking aim at the spleen.
And so as you both alluded to all of us, the patient does decide to proceed with PRRT, and he feels really well throughout the therapy. But as it happens, by the time we get to that final dose, we do have some delays due to thrombocytopenia as we were all alluding to.
We do, however, see a bit of a response. We see the tail mass starting to shrink, the liver burden reduces as well. But unfortunately, about a year and a half later, we do start to see progression in the liver. And I've just estimated that as now up to about 20%, for the sake of description.
And so in this context we ask ourselves again, what would we think about doing next for this patient? Maybe Dr. Corbett, if you don't mind, walk us through your thinking in this setting.
Dr. Virginia Corbett:
Yeah. So we always hope to see prolonged benefit with PPRT therapy, but 18 months is pretty good. Things are now growing again.
I think, again, it's very patient-centered. Before he very much didn't want to be on a targeted therapy having a daily pill. But I think in the situation, probably that's the best option for him choosing from one of our systemic therapies that would be pill-based; everolimus, again, is a pill which has prolonged stability and be a reasonable option.
Cabozantinib also has excellent data in this setting and pancreas neuroendocrine tumor is we'd have to be very cautious about the gastric varices and make sure on the most recent imaging that he is not at high risk of bleeding.
With the advent of cabozantinib, I tend to prefer that over sunitinib because there's pretty excellent data for cabozantinib. I have to choose between the two of those.
CAPTEM is also a great option for him. He hasn't seen that therapy before, and it has the potential to have significant response and improve progression-free survival.
So I think again, it has to be a really specific discussion with the patient. If he feels he doesn't want any sort of systemic therapy in pill form, re-treatment with PPRT with traditional doses is also a good option that would also improve the median progression-free survival, I believe, it's around 14 months with the re-treatment PRRT. And so really it depends on the patient's preferences at this time point, considering everything he's been through and his individual choice.
Dr. Daniel Halperin:
And I wonder, Dr. Maxwell, any additional thoughts on that, if you will, the post-PRRT landscape of systemic or radioligand therapy?
Dr. Jess Maxwell:
I don’t think I have a whole lot to add. I think Dr. Corbett really summarized everything really nicely. I think some of these things will continue to evolve as we just study more patients and have the opportunity to do so in this prospective fashion. Nothing that we've mentioned takes a lot of other things off the table, either from a surgical perspective or selecting some other therapy.
The key is what do you do next? And unfortunately, as we say in so many book chapters and papers, the proper ordering of therapies is not standard or necessarily known. And so you just have to go off a lot of individualized factors to determine what is going to work best for this patient, both from quality of life and efficacy.
Dr. Daniel Halperin:
No, I think that's very well said. I think the discussion here really is intended to kind of circle around just how complicated and individual this is.
I think here we do have randomized evidence for patients post-PRRT with cabozantinib. We have retrospective evidence about PRRT re-treatment for folks in this exact group who had progression-free survival of 18 months from initiation or 12 months from completion, I think, but still waiting on randomized data. And that's that tension between prospective and retrospective evidence, I think, has plagued all of us for quite some time and is part of why this gets so complex.
So let's look at some clinical takeaways. As very nicely said by Dr. Maxwell, the timing and sequencing of therapies, including radioligand, really is unknown. As we saw in the case, responses with PRRT are seen to be more common in patients with pancreatic NETs as well as, although not in this case, higher grade disease as we saw in NETTER-2.
The things we tend to look out for, myelotoxicity, looking at the platelet counts here and nephrotoxicity, which fortunately, we avoided in this patient. And as I think we heard some robust discussion around the notion that re-treatment is described and is a topic of studies that are ongoing, but we don't quite have prospective evidence yet today.
And so that brings us to the end of the case. Please see the other segments for further discussion about the latest research in neuroendocrine tumors or visit ascopost.com.
