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The Potential for Combination Therapy 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: Thursday, Apr 14, 2016


Transcript:

Matthew H. Kulke, MD:
It’s not perhaps so much about whether these treatments work or which treatment works better. It becomes, in many ways, a strategic decision about how you’re going to get access to all this treatment for any individual patient.

Diane Reidy-Lagunes, MD: That’s exactly right.

Matthew H. Kulke, MD: Which then brings up yet another question. If it’s this difficult to select a sequence, what about just giving a couple of them at the same time?

Diane Reidy-Lagunes, MD: Right, combination therapy.

Matthew H. Kulke, MD: Combination therapy. What do we know about that at this point?

Diane Reidy-Lagunes, MD: Well, we know little about sequencing. We know nada about combination therapy. We have some data. I mean, you did a beautiful study, a phase II of mTOR plus bevacizumab in pancreatic neuroendocrine tumors now. Everolimus and bevacizumab is generally an easier drug to add to drug therapies, and it did improve the response rates, as you know well. Although, it had some more side-effect appropriate problems—hypertension and things like that—with a little benefit, at least in the phase II trial to show an incremental improvement. But the question really becomes: in our patients that can live for many years, should we be using combination therapies that, undoubtedly, usually will add more side effects and toxicities? And I think we don’t have data to really know for sure if that’s the right answer, but we can take a play out of the breast cancer book, I think, to say that their disease is similar to ours. So, there’s estrogen receptor–positive or metastatic breast cancer where, unquestionably, combination therapy is not helpful. I think that’s something to learn from. So, it’s a great question. There are certainly some combinations one can think of that may be a little bit better tolerated. But, in general, I think we have to be extremely careful in our patients to avoid unnecessary side effects. I would favor more sequential therapy as opposed to combination.

Matthew H. Kulke, MD: So, in favor at least for the targeted therapies thinking about sequential. When we are talking about chemotherapy, for chemotherapy combinations, there is perhaps some data that giving cytotoxic chemotherapy in combination may be more effective than single-agent therapy. How do you think about that?

Jennifer Eads, MD: Well, at least for temozolomide-based regimens, we can use it in combination with capecitabine or as a single agent. And with streptozotocin, that has been shown to have an increased benefit when used with either a fluoropyrimidine or an anthracycline. So, I think for chemotherapy, it’s a little bit different. I do agree with Diane in the sense that we have a population of patients who live for extended periods of time. And unless we feel that the combination is going to result in an improved survival benefit over one followed by another, then we have to really question if that’s the right approach, especially given the toxicities associated with the treatments.

Matthew H. Kulke, MD: Another question that comes up and sometimes is forgotten, with somatostatin analogs: sometimes we don’t even think that much about adding another treatment to the somatostatin analog. James, in your practice, how do you think about combining somatostatin analogs with other types of treatments or even, in fact, for some of your studies? RADIANT-2 looked at everolimus with octreotide, RADIANT-4 did not.

James C. Yao, MD: Yes, I think that’s definitely an interesting question. I think it depends on what the clinical situation is. If this is a patient with carcinoid syndrome or a functional tumor, clearly you need SSAs for essentially the symptom control. When that’s not enough, adding another agent may be very well appropriate. But a nonfunctional patient, I think there isn’t data yet to support the theory that combination with SSA is better than single agent. For example, in the Cooperative 2 study that you did, we saw that there may be a little bit of benefit in terms of response rate. But adding pasireotide to everolimus, there wasn’t any PFS benefit. So, that’s an instance where you may argue that adding the SSA may have increased some of the hyperglycemia without really bringing much in return.

Matthew H. Kulke, MD: For a functional patient or a patient who is having symptoms of hormone hypersecretion, it’s pretty much a no-brainer: you have to keep the SSA going. But for those patients who are not secreting hormones, it becomes a much more challenging issue. Whether you keep it going or whether you just move on to the next one and stop.

James C. Yao, MD: I think the SSA beyond progression is still a clinical trial question many people believe we need the information for.

Matthew H. Kulke, MD: Exactly. This has been a great discussion. We’ve covered a lot of information regarding the management of various types of neuroendocrine tumors. Before we end this discussion, I’d like to get final thoughts from each of our panelists. Thank you all, by the way, for terrific discussion contributions. Dr. Eads, any parting thoughts?

Jennifer Eads, MD: I just think that we just are very fortunate, as a group of neuroendocrine physicians, to have had such a wealth of positive trials over the last couple of years. And I think that the opportunity to be able to integrate things that are not yet available to us, such as PRRT, is very exciting. It obviously leads to a lot of unanswered questions. But I feel very grateful that we now have the options available for both pancreatic neuroendocrine patients and carcinoid patients.

Matthew H. Kulke, MD: Thank you. Dr. Liu, parting thoughts?

Eric H. Liu, MD, FACS: Well, I just want to stress the idea that having a multidisciplinary team is so very important. I am very pleased and honored to be among you very famous medical oncologists. However, there are other doctors who are very important as well: gastroenterologists, endocrinologists, interventional radiologists, pathologists who are a very important part of the team. Because sometimes taking care of these neuroendocrine patients, it’s not really what to do. The art of neuroendocrine cancer sometimes is when to do it, and we all come in with our different biases from our different experiences and training. So, making sure that we have an open conversation about the patient, and really trying to find the very best timing, sequencing, ordering of our therapies I think is critically important.

Matthew H. Kulke, MD: Thank you. Dr. Reidy-Lagunes?

Diane Reidy-Lagunes, MD: I couldn’t agree with you more. I think that it is certainly a privilege to take care of patients with this terrible disease. I think that one of the biggest struggles for our patients, and for us quite frankly, is the heterogeneity of the disease. Every patient is different, and so my job is to define that plan for that patient. Fortunately, or unfortunately, there’s a lot of patients that say, “But my friend X, who also has neuroendocrine, got this. And why don’t I go to surgery? Dr. So and So said we all should go to surgery.” Sorry, Eric, but there are doctors out there that say we’ve got to go to surgery. So, I actually feel like it’s my duty, and I’ll be looking to spend a lot of time with my patient to define why I think their disease needs to have the following treatment. That’s my job, and I thank heavens for Dr. Kulke and Dr. Yao. You really did change the face of the way that we care for this disease. Our patients have a cancer that’s pretty terrible, and they deserve the evidence, and the trials, and just because we have rare diseases doesn’t mean we can’t conduct these studies. Thankfully, they’re happening and it’s sort of a new era. I think it’s been really remarkable. We have a tumor, unlike other cancers, that has had an explosion of therapies. You don’t see that in other diseases that we take care of. So, there’s good things. Obviously, there’s a lot more work to be done, but there’s good stuff going on.

Matthew H. Kulke, MD: So, Dr. Yao, a lot of progress, but I think a few more trials still need to be done, no?

James C. Yao, MD: Yes, I think there’s definitely still need to further [improvement]. I guess my one take-home message from this is we are moving to the age of, essentially, evidence-based therapy, and there’s room still for some further improvements. Like it’s not uncommon from a referral center that we would see patients with pulmonary carcinoid, atypical carcinoid of the lung with a Ki-67 in the 5% or 10% range coming to our office having had a lot of etoposide and platinum with their alopecia and neuropathy, and absolutely no evidence of benefit. I think we need to kind of move away from that, and with the newer treatment available, I think we can really improve the quality of life in these patients and offer more effective therapy.

Matthew H. Kulke, MD: On behalf of our panel, we thank you for joining us.

Transcript Edited for Clarity
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Transcript:

Matthew H. Kulke, MD:
It’s not perhaps so much about whether these treatments work or which treatment works better. It becomes, in many ways, a strategic decision about how you’re going to get access to all this treatment for any individual patient.

Diane Reidy-Lagunes, MD: That’s exactly right.

Matthew H. Kulke, MD: Which then brings up yet another question. If it’s this difficult to select a sequence, what about just giving a couple of them at the same time?

Diane Reidy-Lagunes, MD: Right, combination therapy.

Matthew H. Kulke, MD: Combination therapy. What do we know about that at this point?

Diane Reidy-Lagunes, MD: Well, we know little about sequencing. We know nada about combination therapy. We have some data. I mean, you did a beautiful study, a phase II of mTOR plus bevacizumab in pancreatic neuroendocrine tumors now. Everolimus and bevacizumab is generally an easier drug to add to drug therapies, and it did improve the response rates, as you know well. Although, it had some more side-effect appropriate problems—hypertension and things like that—with a little benefit, at least in the phase II trial to show an incremental improvement. But the question really becomes: in our patients that can live for many years, should we be using combination therapies that, undoubtedly, usually will add more side effects and toxicities? And I think we don’t have data to really know for sure if that’s the right answer, but we can take a play out of the breast cancer book, I think, to say that their disease is similar to ours. So, there’s estrogen receptor–positive or metastatic breast cancer where, unquestionably, combination therapy is not helpful. I think that’s something to learn from. So, it’s a great question. There are certainly some combinations one can think of that may be a little bit better tolerated. But, in general, I think we have to be extremely careful in our patients to avoid unnecessary side effects. I would favor more sequential therapy as opposed to combination.

Matthew H. Kulke, MD: So, in favor at least for the targeted therapies thinking about sequential. When we are talking about chemotherapy, for chemotherapy combinations, there is perhaps some data that giving cytotoxic chemotherapy in combination may be more effective than single-agent therapy. How do you think about that?

Jennifer Eads, MD: Well, at least for temozolomide-based regimens, we can use it in combination with capecitabine or as a single agent. And with streptozotocin, that has been shown to have an increased benefit when used with either a fluoropyrimidine or an anthracycline. So, I think for chemotherapy, it’s a little bit different. I do agree with Diane in the sense that we have a population of patients who live for extended periods of time. And unless we feel that the combination is going to result in an improved survival benefit over one followed by another, then we have to really question if that’s the right approach, especially given the toxicities associated with the treatments.

Matthew H. Kulke, MD: Another question that comes up and sometimes is forgotten, with somatostatin analogs: sometimes we don’t even think that much about adding another treatment to the somatostatin analog. James, in your practice, how do you think about combining somatostatin analogs with other types of treatments or even, in fact, for some of your studies? RADIANT-2 looked at everolimus with octreotide, RADIANT-4 did not.

James C. Yao, MD: Yes, I think that’s definitely an interesting question. I think it depends on what the clinical situation is. If this is a patient with carcinoid syndrome or a functional tumor, clearly you need SSAs for essentially the symptom control. When that’s not enough, adding another agent may be very well appropriate. But a nonfunctional patient, I think there isn’t data yet to support the theory that combination with SSA is better than single agent. For example, in the Cooperative 2 study that you did, we saw that there may be a little bit of benefit in terms of response rate. But adding pasireotide to everolimus, there wasn’t any PFS benefit. So, that’s an instance where you may argue that adding the SSA may have increased some of the hyperglycemia without really bringing much in return.

Matthew H. Kulke, MD: For a functional patient or a patient who is having symptoms of hormone hypersecretion, it’s pretty much a no-brainer: you have to keep the SSA going. But for those patients who are not secreting hormones, it becomes a much more challenging issue. Whether you keep it going or whether you just move on to the next one and stop.

James C. Yao, MD: I think the SSA beyond progression is still a clinical trial question many people believe we need the information for.

Matthew H. Kulke, MD: Exactly. This has been a great discussion. We’ve covered a lot of information regarding the management of various types of neuroendocrine tumors. Before we end this discussion, I’d like to get final thoughts from each of our panelists. Thank you all, by the way, for terrific discussion contributions. Dr. Eads, any parting thoughts?

Jennifer Eads, MD: I just think that we just are very fortunate, as a group of neuroendocrine physicians, to have had such a wealth of positive trials over the last couple of years. And I think that the opportunity to be able to integrate things that are not yet available to us, such as PRRT, is very exciting. It obviously leads to a lot of unanswered questions. But I feel very grateful that we now have the options available for both pancreatic neuroendocrine patients and carcinoid patients.

Matthew H. Kulke, MD: Thank you. Dr. Liu, parting thoughts?

Eric H. Liu, MD, FACS: Well, I just want to stress the idea that having a multidisciplinary team is so very important. I am very pleased and honored to be among you very famous medical oncologists. However, there are other doctors who are very important as well: gastroenterologists, endocrinologists, interventional radiologists, pathologists who are a very important part of the team. Because sometimes taking care of these neuroendocrine patients, it’s not really what to do. The art of neuroendocrine cancer sometimes is when to do it, and we all come in with our different biases from our different experiences and training. So, making sure that we have an open conversation about the patient, and really trying to find the very best timing, sequencing, ordering of our therapies I think is critically important.

Matthew H. Kulke, MD: Thank you. Dr. Reidy-Lagunes?

Diane Reidy-Lagunes, MD: I couldn’t agree with you more. I think that it is certainly a privilege to take care of patients with this terrible disease. I think that one of the biggest struggles for our patients, and for us quite frankly, is the heterogeneity of the disease. Every patient is different, and so my job is to define that plan for that patient. Fortunately, or unfortunately, there’s a lot of patients that say, “But my friend X, who also has neuroendocrine, got this. And why don’t I go to surgery? Dr. So and So said we all should go to surgery.” Sorry, Eric, but there are doctors out there that say we’ve got to go to surgery. So, I actually feel like it’s my duty, and I’ll be looking to spend a lot of time with my patient to define why I think their disease needs to have the following treatment. That’s my job, and I thank heavens for Dr. Kulke and Dr. Yao. You really did change the face of the way that we care for this disease. Our patients have a cancer that’s pretty terrible, and they deserve the evidence, and the trials, and just because we have rare diseases doesn’t mean we can’t conduct these studies. Thankfully, they’re happening and it’s sort of a new era. I think it’s been really remarkable. We have a tumor, unlike other cancers, that has had an explosion of therapies. You don’t see that in other diseases that we take care of. So, there’s good things. Obviously, there’s a lot more work to be done, but there’s good stuff going on.

Matthew H. Kulke, MD: So, Dr. Yao, a lot of progress, but I think a few more trials still need to be done, no?

James C. Yao, MD: Yes, I think there’s definitely still need to further [improvement]. I guess my one take-home message from this is we are moving to the age of, essentially, evidence-based therapy, and there’s room still for some further improvements. Like it’s not uncommon from a referral center that we would see patients with pulmonary carcinoid, atypical carcinoid of the lung with a Ki-67 in the 5% or 10% range coming to our office having had a lot of etoposide and platinum with their alopecia and neuropathy, and absolutely no evidence of benefit. I think we need to kind of move away from that, and with the newer treatment available, I think we can really improve the quality of life in these patients and offer more effective therapy.

Matthew H. Kulke, MD: On behalf of our panel, we thank you for joining us.

Transcript Edited for Clarity
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