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Systemic Treatment Options and Sequencing in pNETs

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: Thursday, Apr 14, 2016


Transcript:

Matthew H. Kulke, MD:
We have even more systemic treatment options for pancreatic neuroendocrine tumors, as well. Diane, I’ll start with you again. We talked about the options for carcinoid. If we now think about the options and sequencing for pancreatic neuroendocrine tumors, how do you think about that situation?

Diane Reidy-Lagunes, MD: I may be challenged on this, but it’s not dissimilar. For an asymptomatic pancreatic neuroendocrine tumor, I’d like to look at the CLARINET data. I think it’s such a fantastic important trial for our disease because we’ve learned so much from it. And so, unquestionably, the role of somatostatin analogs has been proven, that they slow down the rate of disease progression. But when you look at the placebo arm—the pancreatic arm—they didn’t grow for about a year. Now, it was a select group, but we, as clinicians, are good at selecting that group. So, when a patient that’s otherwise asymptomatic has very low volume disease, I will watch them. And, again, many times they do well for several months and then several years without that treatment.

We don’t let them go away for very long because the pancreatic neuroendocrine tumors I worry a little bit more about than the carcinoid. I think we know that the overall survival, in general, is a lot less than the midgut carcinoids, at least. In a patient with functional tumors, you want to consider: is this something that should be operated on? Is this just somatostatin analogs right away? The VIPomas, for example—albeit it very rare—that is a debilitating hormone, and those patients can get very, very sick. With gastrinomas, as well, those patients can be quite sick. So, you have to be careful with the ones that are functional. In patients with heavy tumor burden, generally I will try a cytotoxic therapy, and I’ll often do that up front if they have a very large pancreatic mass. I don’t have great data to say that that’s exactly what we should be doing, but we worry about those tumors because they can pick up their pace and get into trouble.

And, as Eric alluded to, the distal pancreatectomies are a little bit lower in terms of morbidity, and those can actually bleed. They can invade into the spleen, and they can get quite large. So, treating them up front with cytotoxic treatments, in efforts to shrink, is helpful. And if the primary does grow in that way, I think we absolutely have considered and have done distal pancreatectomies in patients, because the tumor itself, for unknown reasons—even when the disease in the liver is not growing—sometimes that pancreas mass can grow. We have to be careful about those. I think it’s exceedingly rare for me to ever do a Whipple procedure on these patients in the setting of metastatic disease. You worry about the risk of abscesses after embolizations and surgeries, and things like that. So, doing a Whipple on these patients, in the setting of metastatic disease, should be really questioned.

Matthew H. Kulke, MD: James, for pancreatic neuroendocrine tumors, reframing the question: you’ve got somatostatin analogs, you’ve got mTOR inhibitors, you’ve got angiogenesis inhibitors, you’ve got chemotherapy, and we haven’t even gotten to PRRT. How do you think about sequencing these when you have a patient in front of you?

James C. Yao, MD: I think much of the same factors do come into play, although you have a little bit more options here. The way I usually think about it is if someone has so little disease and if they progress 20% in the next 3 months, that’s not going to put them in any sort of danger; that’s a patient you very well may decide still to observe if they’re asymptomatic. But in patients with a little bit more disease, we want to be more aggressive. I think the CLARINET data show somatostatin analogs could be good in the stable disease population. In progressive patients with a heavier tumor burden, then to me, it’s more the targeted therapy, everolimus or sunitinib. In the patients who have really 60% liver replacement, where stable disease is not good enough, that’s the group that I usually take and do chemotherapy, streptozotocin. We talked a lot about temozolomide, but streptozotocin is another option, as well. And finally, the group of patients who has very indolent progression—so, big tumor volume but you know it took them years to get there—that’s the group I’d take to sometime, whether it’s liver-directed therapy or debulking.

Matthew H. Kulke, MD: If we now think about PRRT—which may be coming down the line, we all expect—how do you think that’s going to fit into our thinking about sequencing these various treatments? What are some of the considerations in terms of patient selection and where that might fit in?

James C. Yao, MD: Yes, that’s a really good question. So, some of these treatments require some special selections, others don’t. PRRT, you need very heavy uptake in the Krenning scale. The data for whether you need a positive Octreoscan or gallium PET down the road for a somatostatin analog is a little bit less clear. CLARINET did require a positive Octreoscan, but PROMID did not. I think the other factor, especially with PRRT coming, is that you have to think in terms of what are the options down the road and are you closing any bridges by using some of these treatments too early. There are some treatments that you can use and repeat. Others, you get one shot and possibly two and then you’re done, and I think PRRT falls into that category. So, when do you want to employ it and what’s the risk to the bone marrow? Are you giving the patient a lot of isotype, treating very little disease and taking a risk on the bone marrow, or are you treating it in a patient that doesn’t have options and this may buy them quite a bit of time? I think these are unanswered questions. I don’t know if they ever will be answered. Prospective study, I can’t even imagine how to design that trial. But I think much of the principle we talked about will apply here, too.

Matthew H. Kulke, MD: Diane, in terms of PRRT, the same tough question, but where do you see this fitting in and how might you think about it for your patients?

Diane Reidy-Lagunes, MD: Yes, I totally agree. I think what’s so unsettling is if you had a patient whose counts were low and then you couldn’t get the FDA-approved drugs in appropriately. It’s one of our own fears. Thankfully, it’s the rare, but serious, side effect. So, it’s unlikely that you have bad side effects. But it is one of those because our patients live for so long, are we willing to take that risk type of thing? There’s 3% risk of leukemia—maybe 2% to 3%. That’s low, but it’s leukemia. We have to be very mindful of that. But I think it is low, thankfully. Again, unfortunately, despite efforts to better define who’s at risk for those rare but serious effects, we don’t really know. It’s the first time coming to this side of the pond, so we’re hoping to get some of these answers and further understand the biology of the treatments. And I think it’s a very exciting treatment to add. Personally, right now, because we haven’t had it, logistically it just made sense to sort of save it to the end when you didn’t really have other therapies. But we don’t know if that’s the right thing to do. I would probably put it along the lines of, certainly, somatostatin analogs first, targeted therapies first, and then where you may consider cytotoxic therapy, maybe at that point. So, somewhere around there without any data yet to say that that’s the right place to put it.

Transcript Edited for Clarity
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Transcript:

Matthew H. Kulke, MD:
We have even more systemic treatment options for pancreatic neuroendocrine tumors, as well. Diane, I’ll start with you again. We talked about the options for carcinoid. If we now think about the options and sequencing for pancreatic neuroendocrine tumors, how do you think about that situation?

Diane Reidy-Lagunes, MD: I may be challenged on this, but it’s not dissimilar. For an asymptomatic pancreatic neuroendocrine tumor, I’d like to look at the CLARINET data. I think it’s such a fantastic important trial for our disease because we’ve learned so much from it. And so, unquestionably, the role of somatostatin analogs has been proven, that they slow down the rate of disease progression. But when you look at the placebo arm—the pancreatic arm—they didn’t grow for about a year. Now, it was a select group, but we, as clinicians, are good at selecting that group. So, when a patient that’s otherwise asymptomatic has very low volume disease, I will watch them. And, again, many times they do well for several months and then several years without that treatment.

We don’t let them go away for very long because the pancreatic neuroendocrine tumors I worry a little bit more about than the carcinoid. I think we know that the overall survival, in general, is a lot less than the midgut carcinoids, at least. In a patient with functional tumors, you want to consider: is this something that should be operated on? Is this just somatostatin analogs right away? The VIPomas, for example—albeit it very rare—that is a debilitating hormone, and those patients can get very, very sick. With gastrinomas, as well, those patients can be quite sick. So, you have to be careful with the ones that are functional. In patients with heavy tumor burden, generally I will try a cytotoxic therapy, and I’ll often do that up front if they have a very large pancreatic mass. I don’t have great data to say that that’s exactly what we should be doing, but we worry about those tumors because they can pick up their pace and get into trouble.

And, as Eric alluded to, the distal pancreatectomies are a little bit lower in terms of morbidity, and those can actually bleed. They can invade into the spleen, and they can get quite large. So, treating them up front with cytotoxic treatments, in efforts to shrink, is helpful. And if the primary does grow in that way, I think we absolutely have considered and have done distal pancreatectomies in patients, because the tumor itself, for unknown reasons—even when the disease in the liver is not growing—sometimes that pancreas mass can grow. We have to be careful about those. I think it’s exceedingly rare for me to ever do a Whipple procedure on these patients in the setting of metastatic disease. You worry about the risk of abscesses after embolizations and surgeries, and things like that. So, doing a Whipple on these patients, in the setting of metastatic disease, should be really questioned.

Matthew H. Kulke, MD: James, for pancreatic neuroendocrine tumors, reframing the question: you’ve got somatostatin analogs, you’ve got mTOR inhibitors, you’ve got angiogenesis inhibitors, you’ve got chemotherapy, and we haven’t even gotten to PRRT. How do you think about sequencing these when you have a patient in front of you?

James C. Yao, MD: I think much of the same factors do come into play, although you have a little bit more options here. The way I usually think about it is if someone has so little disease and if they progress 20% in the next 3 months, that’s not going to put them in any sort of danger; that’s a patient you very well may decide still to observe if they’re asymptomatic. But in patients with a little bit more disease, we want to be more aggressive. I think the CLARINET data show somatostatin analogs could be good in the stable disease population. In progressive patients with a heavier tumor burden, then to me, it’s more the targeted therapy, everolimus or sunitinib. In the patients who have really 60% liver replacement, where stable disease is not good enough, that’s the group that I usually take and do chemotherapy, streptozotocin. We talked a lot about temozolomide, but streptozotocin is another option, as well. And finally, the group of patients who has very indolent progression—so, big tumor volume but you know it took them years to get there—that’s the group I’d take to sometime, whether it’s liver-directed therapy or debulking.

Matthew H. Kulke, MD: If we now think about PRRT—which may be coming down the line, we all expect—how do you think that’s going to fit into our thinking about sequencing these various treatments? What are some of the considerations in terms of patient selection and where that might fit in?

James C. Yao, MD: Yes, that’s a really good question. So, some of these treatments require some special selections, others don’t. PRRT, you need very heavy uptake in the Krenning scale. The data for whether you need a positive Octreoscan or gallium PET down the road for a somatostatin analog is a little bit less clear. CLARINET did require a positive Octreoscan, but PROMID did not. I think the other factor, especially with PRRT coming, is that you have to think in terms of what are the options down the road and are you closing any bridges by using some of these treatments too early. There are some treatments that you can use and repeat. Others, you get one shot and possibly two and then you’re done, and I think PRRT falls into that category. So, when do you want to employ it and what’s the risk to the bone marrow? Are you giving the patient a lot of isotype, treating very little disease and taking a risk on the bone marrow, or are you treating it in a patient that doesn’t have options and this may buy them quite a bit of time? I think these are unanswered questions. I don’t know if they ever will be answered. Prospective study, I can’t even imagine how to design that trial. But I think much of the principle we talked about will apply here, too.

Matthew H. Kulke, MD: Diane, in terms of PRRT, the same tough question, but where do you see this fitting in and how might you think about it for your patients?

Diane Reidy-Lagunes, MD: Yes, I totally agree. I think what’s so unsettling is if you had a patient whose counts were low and then you couldn’t get the FDA-approved drugs in appropriately. It’s one of our own fears. Thankfully, it’s the rare, but serious, side effect. So, it’s unlikely that you have bad side effects. But it is one of those because our patients live for so long, are we willing to take that risk type of thing? There’s 3% risk of leukemia—maybe 2% to 3%. That’s low, but it’s leukemia. We have to be very mindful of that. But I think it is low, thankfully. Again, unfortunately, despite efforts to better define who’s at risk for those rare but serious effects, we don’t really know. It’s the first time coming to this side of the pond, so we’re hoping to get some of these answers and further understand the biology of the treatments. And I think it’s a very exciting treatment to add. Personally, right now, because we haven’t had it, logistically it just made sense to sort of save it to the end when you didn’t really have other therapies. But we don’t know if that’s the right thing to do. I would probably put it along the lines of, certainly, somatostatin analogs first, targeted therapies first, and then where you may consider cytotoxic therapy, maybe at that point. So, somewhere around there without any data yet to say that that’s the right place to put it.

Transcript Edited for Clarity
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