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Sequencing Decisions in Neuroendocrine Tumors

Insights From:Jennifer Eads, MD, Case Western Reserve University; Matthew H. Kulke, MD, Harvard Medical School; Diane Reidy Lagunes, MD, Memorial Sloan-Kettering Cancer Center; Eric H. Liu, MD, FACS, Rocky Mountain Cancer Center; James C. Yao, MD, The University of Texas MD Anderson Cancer Center
Published: Wednesday, Apr 27, 2016


Transcript:

Matthew H. Kulke, MD:
One of the things that seems to be coming up in this conversation is that we’ve got lots of different treatment options, and it’s a little bit challenging right now, given the current data, how we select patients for each one. What I’d like to do is go around and get people’s sense of, how do you think about sequencing these various different treatments. We could start with carcinoid patients, for example. It might be a little bit easier than pancreatic. Diane, when you see a carcinoid patient coming into your clinic, how do you think about the sequence with somatostatin analogues, with mTOR inhibitors, with peptide receptor radionuclide therapy (PRRT) coming down the line? How do you select a treatment?

Diane Reidy-Lagunes, MD: Generally speaking, for a carcinoid patient, I’m looking at about 4 or 5 things as soon as they walk into the door. First and foremost, I want to know what the patient looks like. Is this a patient that clearly looks more chronically ill- appearing, unfortunately, that has had disease that is starting to pick up its pace and you can see that just on the patient? Most times, thankfully, for carcinoids the answer is no, that they’re pretty asymptomatic, and we’re going with, this is an asymptomatic patient in terms of looking well. The second thing I'll ask is do they have hormone-related symptoms? Is this a functional or non-functional tumor? If it’s a functional tumor, I don’t have a lot of time to wait. I want to treat that sooner rather than later. The third thing I look at is what they look like inside. What does their cross-sectional imaging look like? We’ve talked a lot about the different scans that we do. A traditional PET is not good for this disease, for a well-differentiated neuroendocrine tumor that is, and this may be different in the poorly differentiated neuroendocrine carcinomas. I’d do a baseline Octreoscan because I tell patients I want them to light up like a Christmas tree because that is a prognostic good factor, and so they come back and they say, “Do I light up like a Christmas tree?” And then we do a woo-hoo when they do.

Matthew H. Kulke, MD: That’s the one situation where a floridly positive scan is a good thing.

Diane Reidy-Lagunes, MD: Exactly. Yes, you are lighting up! That’s always a good thing when it’s somatostatin-scintigraphy positive. And you look at the burden of disease. Is this someone that has a lot of disease in their liver that I’m not going to wait and say, I’m going to see the test of time? You see all in their liver that clearly the disease grew at some point. And then you put all those together, and you decide in a patient who’s generally asymptomatic, low-volume disease, I will watch them and I’ll tell them, in 3 months I want you to come back. If you have any symptoms, which is unlikely, I want them to call me beforehand. But in a non-functional asymptomatic patient, in 3 months if their disease is still low-volume, hasn’t grown, I’ve afforded them cost-effective therapy because all of these treatments are just so expensive now and every treatment has some side effects. And perhaps I have patients that 2-3 years later were still not doing much because the disease just isn’t growing. Typically, those are older patients. The biology of the disease trumps all here. If they start to grow, somatostatin is what I call my first string players. That’s usually what I do, and then if they grow again and it’s liver only, I usually do some sort of regional approach. I speak to my surgeons. I speak to my interventional radiologists.

Now with the RADIANT-4 data, we have other therapies to consider, and so everolimus is absolutely a very appropriate treatment, which I may use more frequently now. But, again, in the patient that’s more symptomatic, that’s hormone functioning, I use a somatostatin analogue right away to help decrease that tumor burden in terms of the hormone synthesis, present carcinoid, the rare, but serious risks of other carcinoid syndrome related problems. And/or I may even consider regional approaches at that time. I actually have clinic with the surgeon because I want to know their opinion and say, what do you think, resectable, unresectable? And often we’ll have what I call a regional approach, both surgery and then embolization later on. So the burden of disease and what the patient looks like becomes important.

Matthew H. Kulke, MD: I want to turn to James on some of the same questions here because an interesting question comes up. You’ve got somatostatin analogues that improve PFS. We now know that everolimus also improves PFS. Do you ever watch these patients?

James C. Yao, MD: I actually do sometimes. Some of these patients with very low-volume disease and very indolent course, you can potentially watch. I remember a patient that it literally took me an hour to convince the patient that he doesn’t need any treatment when I met him 12 years ago. And he still has a positive Octreoscan. He still has radiologic disease. Now, it’s 12 years down the road without any treatment whatsoever, and he still has stable disease. Unfortunately, that’s not the case for most of our patients. But, I agree with a lot of the points Diane made. In some ways we’re developing evidence base, so I’m being a little bit stickler to the evidence base. In patients with the bowel neuroendocrine tumor or gastric intrapancreatic NETs, you have data now from CLARINET and PROMID to really consider SSAs in them. In lung neuroendocrine tumor, we still lack that data. How well that works, we need an answer in prospective clinical trial. Everolimus? Now you have it for the lungs and in the GI neuroendocrine tumors. So that’s a pretty broad area that you can use. And when do we use each? It’s based on what the clinical situation is.

Matthew H. Kulke, MD: Jennifer, for a carcinoid patient, in what situation would you think about chemotherapy?

Jennifer Eads, MD: To date, there isn’t a whole lot of data to suggest that chemotherapy really is effective for patients with carcinoid. Sometimes when there’s a mixed component of maybe an adenocarcinoma in combination with the neuroendocrine component, then when we’re reaching for treatment options, that may be something to consider. But, by and large, there’s not a whole lot of data to support the use of any chemotherapy in carcinoid patients.

Matthew H. Kulke, MD: With the exception perhaps of the more aggressive phenotypes.

Jennifer Eads, MD: Sure.

Matthew H. Kulke, MD: If you’re looking at the Ki67, at what level or what cutoff would you start thinking about using chemotherapy in a carcinoid patient?

Jennifer Eads, MD: To the cutoff for a poorly differentiated or a high-grade tumor is Ki67 of above 20%. Particularly, in that population, even if they’re a well differentiated tumor, but their Ki67 is higher, then chemotherapy may be appropriate in that instance.

Matthew H. Kulke, MD: And do you have a favorite regimen?

Jennifer Eads, MD: If there’s an adenocarcinoma component, I would probably favor a fluoropyrimidine/oxaliplatin like FOLFOX. Aside from that, I guess not capecitabine so much, but temozolomide-based regimens just haven’t really shown that to be a benefit, and especially if it’s not of pancreatic origin.

Matthew H. Kulke, MD: You’re thinking along the line of a fluoropyrimidine maybe in that setting?

Jennifer Eads, MD: Of a fluoropyrimidine, yes.

Diane Reidy-Lagunes, MD: I completely agree, Jen. But the one exception is going back to the foregut, midgut, and hindgut. Small study, so I don’t want to be making conclusions from that, but in patients that have more aggressive disease, for example, in the lung, in addition to platinum-based therapies, temozolomide may be helpful. And it’s a little bit tricky when you’re dealing with the lung metastases because many times those patients have been treated like small cell lung cancers. But, we know that they are more indolent and they don’t act like small cell lung cancers. They’re inappropriately getting chemotherapy when they shouldn’t, but then often can. They also don’t have the same classification in terms of pathology, so you may not know the Ki67 there and you’re like, what do I do now for this atypical lung metastasis? But, we have used temozolomide-based therapies there with good success and some of the gastric and duodenal as well. So we kind of lump those foregut, pancreatic, stomach, duodenal, lung into…When the burden of disease is higher or they’re really progressing, some cytotoxic therapy should be considered.

Transcript Edited for Clarity
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Transcript:

Matthew H. Kulke, MD:
One of the things that seems to be coming up in this conversation is that we’ve got lots of different treatment options, and it’s a little bit challenging right now, given the current data, how we select patients for each one. What I’d like to do is go around and get people’s sense of, how do you think about sequencing these various different treatments. We could start with carcinoid patients, for example. It might be a little bit easier than pancreatic. Diane, when you see a carcinoid patient coming into your clinic, how do you think about the sequence with somatostatin analogues, with mTOR inhibitors, with peptide receptor radionuclide therapy (PRRT) coming down the line? How do you select a treatment?

Diane Reidy-Lagunes, MD: Generally speaking, for a carcinoid patient, I’m looking at about 4 or 5 things as soon as they walk into the door. First and foremost, I want to know what the patient looks like. Is this a patient that clearly looks more chronically ill- appearing, unfortunately, that has had disease that is starting to pick up its pace and you can see that just on the patient? Most times, thankfully, for carcinoids the answer is no, that they’re pretty asymptomatic, and we’re going with, this is an asymptomatic patient in terms of looking well. The second thing I'll ask is do they have hormone-related symptoms? Is this a functional or non-functional tumor? If it’s a functional tumor, I don’t have a lot of time to wait. I want to treat that sooner rather than later. The third thing I look at is what they look like inside. What does their cross-sectional imaging look like? We’ve talked a lot about the different scans that we do. A traditional PET is not good for this disease, for a well-differentiated neuroendocrine tumor that is, and this may be different in the poorly differentiated neuroendocrine carcinomas. I’d do a baseline Octreoscan because I tell patients I want them to light up like a Christmas tree because that is a prognostic good factor, and so they come back and they say, “Do I light up like a Christmas tree?” And then we do a woo-hoo when they do.

Matthew H. Kulke, MD: That’s the one situation where a floridly positive scan is a good thing.

Diane Reidy-Lagunes, MD: Exactly. Yes, you are lighting up! That’s always a good thing when it’s somatostatin-scintigraphy positive. And you look at the burden of disease. Is this someone that has a lot of disease in their liver that I’m not going to wait and say, I’m going to see the test of time? You see all in their liver that clearly the disease grew at some point. And then you put all those together, and you decide in a patient who’s generally asymptomatic, low-volume disease, I will watch them and I’ll tell them, in 3 months I want you to come back. If you have any symptoms, which is unlikely, I want them to call me beforehand. But in a non-functional asymptomatic patient, in 3 months if their disease is still low-volume, hasn’t grown, I’ve afforded them cost-effective therapy because all of these treatments are just so expensive now and every treatment has some side effects. And perhaps I have patients that 2-3 years later were still not doing much because the disease just isn’t growing. Typically, those are older patients. The biology of the disease trumps all here. If they start to grow, somatostatin is what I call my first string players. That’s usually what I do, and then if they grow again and it’s liver only, I usually do some sort of regional approach. I speak to my surgeons. I speak to my interventional radiologists.

Now with the RADIANT-4 data, we have other therapies to consider, and so everolimus is absolutely a very appropriate treatment, which I may use more frequently now. But, again, in the patient that’s more symptomatic, that’s hormone functioning, I use a somatostatin analogue right away to help decrease that tumor burden in terms of the hormone synthesis, present carcinoid, the rare, but serious risks of other carcinoid syndrome related problems. And/or I may even consider regional approaches at that time. I actually have clinic with the surgeon because I want to know their opinion and say, what do you think, resectable, unresectable? And often we’ll have what I call a regional approach, both surgery and then embolization later on. So the burden of disease and what the patient looks like becomes important.

Matthew H. Kulke, MD: I want to turn to James on some of the same questions here because an interesting question comes up. You’ve got somatostatin analogues that improve PFS. We now know that everolimus also improves PFS. Do you ever watch these patients?

James C. Yao, MD: I actually do sometimes. Some of these patients with very low-volume disease and very indolent course, you can potentially watch. I remember a patient that it literally took me an hour to convince the patient that he doesn’t need any treatment when I met him 12 years ago. And he still has a positive Octreoscan. He still has radiologic disease. Now, it’s 12 years down the road without any treatment whatsoever, and he still has stable disease. Unfortunately, that’s not the case for most of our patients. But, I agree with a lot of the points Diane made. In some ways we’re developing evidence base, so I’m being a little bit stickler to the evidence base. In patients with the bowel neuroendocrine tumor or gastric intrapancreatic NETs, you have data now from CLARINET and PROMID to really consider SSAs in them. In lung neuroendocrine tumor, we still lack that data. How well that works, we need an answer in prospective clinical trial. Everolimus? Now you have it for the lungs and in the GI neuroendocrine tumors. So that’s a pretty broad area that you can use. And when do we use each? It’s based on what the clinical situation is.

Matthew H. Kulke, MD: Jennifer, for a carcinoid patient, in what situation would you think about chemotherapy?

Jennifer Eads, MD: To date, there isn’t a whole lot of data to suggest that chemotherapy really is effective for patients with carcinoid. Sometimes when there’s a mixed component of maybe an adenocarcinoma in combination with the neuroendocrine component, then when we’re reaching for treatment options, that may be something to consider. But, by and large, there’s not a whole lot of data to support the use of any chemotherapy in carcinoid patients.

Matthew H. Kulke, MD: With the exception perhaps of the more aggressive phenotypes.

Jennifer Eads, MD: Sure.

Matthew H. Kulke, MD: If you’re looking at the Ki67, at what level or what cutoff would you start thinking about using chemotherapy in a carcinoid patient?

Jennifer Eads, MD: To the cutoff for a poorly differentiated or a high-grade tumor is Ki67 of above 20%. Particularly, in that population, even if they’re a well differentiated tumor, but their Ki67 is higher, then chemotherapy may be appropriate in that instance.

Matthew H. Kulke, MD: And do you have a favorite regimen?

Jennifer Eads, MD: If there’s an adenocarcinoma component, I would probably favor a fluoropyrimidine/oxaliplatin like FOLFOX. Aside from that, I guess not capecitabine so much, but temozolomide-based regimens just haven’t really shown that to be a benefit, and especially if it’s not of pancreatic origin.

Matthew H. Kulke, MD: You’re thinking along the line of a fluoropyrimidine maybe in that setting?

Jennifer Eads, MD: Of a fluoropyrimidine, yes.

Diane Reidy-Lagunes, MD: I completely agree, Jen. But the one exception is going back to the foregut, midgut, and hindgut. Small study, so I don’t want to be making conclusions from that, but in patients that have more aggressive disease, for example, in the lung, in addition to platinum-based therapies, temozolomide may be helpful. And it’s a little bit tricky when you’re dealing with the lung metastases because many times those patients have been treated like small cell lung cancers. But, we know that they are more indolent and they don’t act like small cell lung cancers. They’re inappropriately getting chemotherapy when they shouldn’t, but then often can. They also don’t have the same classification in terms of pathology, so you may not know the Ki67 there and you’re like, what do I do now for this atypical lung metastasis? But, we have used temozolomide-based therapies there with good success and some of the gastric and duodenal as well. So we kind of lump those foregut, pancreatic, stomach, duodenal, lung into…When the burden of disease is higher or they’re really progressing, some cytotoxic therapy should be considered.

Transcript Edited for Clarity
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