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Symptom Management in Functional NETs

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: Friday, Mar 11, 2016


Transcript:

Matthew H. Kulke, MD:
We’re talking a lot about hormones. These patients can present with a variety of different syndromes. Carcinoid patients present with flushing and diarrhea. Patients with pancreatic neuroendocrine tumors have a whole constellation of symptoms. Diane, do you test different hormone levels for these patients when they come into the clinic?

Diane Reidy-Lagunes, MD: That’s a great question. As I alluded to before, in pancreatic neuroendocrine tumors, often if they are hormone-secreting, they will have obvious clinical symptoms that will warrant for their workup. And you can allow your hormones to drive the management in that circumstance. So, for example, if they have low sugars, you don’t need to do a glucagon. So, I think you can be a little bit thoughtful on the hormone workups in a pancreatic neuroendocrine tumor, which most commonly is non-functional. In patients with carcinoid of the midgut, I generally do a baseline urinary 5-HIAA when I first meet them, for two reasons.

One, I just want to make sure that their baseline is normal if they don’t have any hormone-secreting symptoms. Certainly, if they do, then we would most certainly do that. But, we’re actually noticing that over time, these hormones from the carcinoid syndrome can be quite high in terms of the morbidity that they may have. What I mean by that is, for example, carcinoid heart. Many of our patients, thank heavens, are living for many, many years now and that’s because of supportive measures that we have, and better imaging, and the multidisciplinary team approach that we’re taking.

But, over time, these hormones can really cause damage to the valves of the heart and having a valve replacement is obviously quite risky with high morbidity. So you want to be aware. It can also cause other troubles with mesenteric problems and fibrosis. So it’s a hormone that you don’t want to miss, and I generally just do 24-hour 5-HIAA. I don’t do any additional hormones.

Matthew H. Kulke, MD: You make an interesting point. We were talking about surgery, but these patients can get valve disease, which may require valve replacement. And, Eric, I imagine you’d probably want to get echocardiograms on some of these patients before you operate.

Eric H. Liu, MD, FACS: Absolutely. Exactly correct. And I, too, order 5-HIAA, because it seems to be a predictor of those who are going to have carcinoid heart disease. And so that gives me a sense. Even if I get a baseline echo at this point, they may not have any issues with their heart now, it may progress, so I may want to watch it more carefully. The one thing I do want to add though is since carcinoid heart disease isn’t so common, thankfully.

Unfortunately, when it does strike, you want to treat it earlier rather than later. So, by getting an echo and following them with time, you can see when it is the right time to repair them. Because when someone is healthy and strong, it’s actually a very safe and extremely effective therapy. But, when they’re very, very ill and emaciated and it’s late in the course, doing a heart operation is much more complicated. It has many more complications associated with it. So we always want to make sure we stay ahead of the game rather than falling behind.

Matthew H. Kulke, MD: I guess in the best of all possible worlds we’d be able to shut down the hormone secretion and not have these complications. Let me turn to Jennifer. There have been a variety of drugs that are used to control symptoms of hormone hypersecretion. The first I think was octreotide. How do you use octreotide in your practice?

Jennifer Eads, MD: Typically, for patients who do have hormone-producing tumors and are symptomatic from those hormones, octreotide has been our go-to therapy for several years now, as the frontline standard of care to try to keep those hormone levels low and decrease the symptoms associated with both carcinoid syndrome and symptoms from pancreatic neuroendocrine tumors that produce hormones. If patients develop refractory symptoms with octreotide use, we do oftentimes raise the dose of octreotide in an effort to try to further control their symptoms.

Matthew H. Kulke, MD: Another approach that’s been discussed is that sometimes people use so-called rescue medication or injections of short-acting octreotide, as well. Do you send patients home with short-acting injections, too, sometimes?

Jennifer Eads, MD: I do, especially for patients who are capable of administering those medications to themselves. I think that’s something that you definitely have to take into consideration when you tell patients that that’s a way that we can potentially manage their symptoms. An alternative would be a higher dose of a depot injection to prevent them from having to give those self-administered injections. But, definitely because it’s not always clear. Patients have episodes that occur in their lives, stress, or dietary issues that can result in a surge of hormone production. So, having those rescue injections at home can be very helpful.

Diane Reidy-Lagunes, MD: I would just add some supportive medications, too. So, if a patient has diarrhea, Imodium works beautifully. So we can’t forget like the common medicine that is very helpful.

Matthew H. Kulke, MD: There’s another somatostatin analogue, lanreotide, and we’ve all heard about lanreotide. And we’ll talk about lanreotide for tumor control, but it’s also been used for a while for symptom control. Eric, do you want to enlighten us on lanreotide and how it might fit into symptom control in these patients?

Eric H. Liu, MD, FACS: Yeah, absolutely. Lanreotide is another somatostatin analogue to our good friend, octreotide. And, as you had said, it’s most exciting recently because of its use for tumor control. But, because it’s a somatostatin analogue, it still has effects on controlling symptoms. There was a trial that came out, the ELECT trial, which was looking at the control of carcinoid syndrome symptoms. It was found in the study—it was a different type of trial than what compared octreotide, which got its original approval—to certainly help improve some of the symptoms, too. So, it’s good to know that there are two somatostatin analogues effective with tumor control and for symptom control.

Matthew H. Kulke, MD: We were talking a little bit about the way that some patients might be on these somatostatin analogues for months or even years, but they do get breakthrough symptoms sometimes. Imodium or Lomotil are great in some cases, but don’t always completely do the trick. Let me turn to James. There’s a new drug, telotristat, which is a tryptophan hydroxylase inhibitor. What do we know about telotristat in this setting?

James C. Yao, MD: Well, Matt, as you know, tryptophan hydroxylase involves serotonin synthesis, and there’s still an unmet need for patients with refractory carcinoid syndrome. And, given that it’s really in serotonin synthesis, there’s rationale that this drug may be very helpful in patients with poorly controlled diarrhea. And recently, a large phase III study was completed, the TELESTAR study. And we’re very fortunate to have the primary investigator here, Dr. Kulke.

Matthew H. Kulke, MD: The TELESTAR study was an interesting study. It was a randomized study. It took patients who had carcinoid syndrome and had diarrhea that was refractory to standard-dose somatostatin analogues and randomized them to receive either treatment with telotristat or treatment with placebo. And the results were really quite interesting. There was a significant decrease in diarrhea in the patients who received telotristat. There was also quite a dramatic decrease in 5-HIAA, which suggests that it really is inhibiting serotonin synthesis. And we were talking earlier I know with Eric about carcinoid heart and some of these other complications of serotonin, so I think it will be really interesting to see what role this might play down the road.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Matthew H. Kulke, MD:
We’re talking a lot about hormones. These patients can present with a variety of different syndromes. Carcinoid patients present with flushing and diarrhea. Patients with pancreatic neuroendocrine tumors have a whole constellation of symptoms. Diane, do you test different hormone levels for these patients when they come into the clinic?

Diane Reidy-Lagunes, MD: That’s a great question. As I alluded to before, in pancreatic neuroendocrine tumors, often if they are hormone-secreting, they will have obvious clinical symptoms that will warrant for their workup. And you can allow your hormones to drive the management in that circumstance. So, for example, if they have low sugars, you don’t need to do a glucagon. So, I think you can be a little bit thoughtful on the hormone workups in a pancreatic neuroendocrine tumor, which most commonly is non-functional. In patients with carcinoid of the midgut, I generally do a baseline urinary 5-HIAA when I first meet them, for two reasons.

One, I just want to make sure that their baseline is normal if they don’t have any hormone-secreting symptoms. Certainly, if they do, then we would most certainly do that. But, we’re actually noticing that over time, these hormones from the carcinoid syndrome can be quite high in terms of the morbidity that they may have. What I mean by that is, for example, carcinoid heart. Many of our patients, thank heavens, are living for many, many years now and that’s because of supportive measures that we have, and better imaging, and the multidisciplinary team approach that we’re taking.

But, over time, these hormones can really cause damage to the valves of the heart and having a valve replacement is obviously quite risky with high morbidity. So you want to be aware. It can also cause other troubles with mesenteric problems and fibrosis. So it’s a hormone that you don’t want to miss, and I generally just do 24-hour 5-HIAA. I don’t do any additional hormones.

Matthew H. Kulke, MD: You make an interesting point. We were talking about surgery, but these patients can get valve disease, which may require valve replacement. And, Eric, I imagine you’d probably want to get echocardiograms on some of these patients before you operate.

Eric H. Liu, MD, FACS: Absolutely. Exactly correct. And I, too, order 5-HIAA, because it seems to be a predictor of those who are going to have carcinoid heart disease. And so that gives me a sense. Even if I get a baseline echo at this point, they may not have any issues with their heart now, it may progress, so I may want to watch it more carefully. The one thing I do want to add though is since carcinoid heart disease isn’t so common, thankfully.

Unfortunately, when it does strike, you want to treat it earlier rather than later. So, by getting an echo and following them with time, you can see when it is the right time to repair them. Because when someone is healthy and strong, it’s actually a very safe and extremely effective therapy. But, when they’re very, very ill and emaciated and it’s late in the course, doing a heart operation is much more complicated. It has many more complications associated with it. So we always want to make sure we stay ahead of the game rather than falling behind.

Matthew H. Kulke, MD: I guess in the best of all possible worlds we’d be able to shut down the hormone secretion and not have these complications. Let me turn to Jennifer. There have been a variety of drugs that are used to control symptoms of hormone hypersecretion. The first I think was octreotide. How do you use octreotide in your practice?

Jennifer Eads, MD: Typically, for patients who do have hormone-producing tumors and are symptomatic from those hormones, octreotide has been our go-to therapy for several years now, as the frontline standard of care to try to keep those hormone levels low and decrease the symptoms associated with both carcinoid syndrome and symptoms from pancreatic neuroendocrine tumors that produce hormones. If patients develop refractory symptoms with octreotide use, we do oftentimes raise the dose of octreotide in an effort to try to further control their symptoms.

Matthew H. Kulke, MD: Another approach that’s been discussed is that sometimes people use so-called rescue medication or injections of short-acting octreotide, as well. Do you send patients home with short-acting injections, too, sometimes?

Jennifer Eads, MD: I do, especially for patients who are capable of administering those medications to themselves. I think that’s something that you definitely have to take into consideration when you tell patients that that’s a way that we can potentially manage their symptoms. An alternative would be a higher dose of a depot injection to prevent them from having to give those self-administered injections. But, definitely because it’s not always clear. Patients have episodes that occur in their lives, stress, or dietary issues that can result in a surge of hormone production. So, having those rescue injections at home can be very helpful.

Diane Reidy-Lagunes, MD: I would just add some supportive medications, too. So, if a patient has diarrhea, Imodium works beautifully. So we can’t forget like the common medicine that is very helpful.

Matthew H. Kulke, MD: There’s another somatostatin analogue, lanreotide, and we’ve all heard about lanreotide. And we’ll talk about lanreotide for tumor control, but it’s also been used for a while for symptom control. Eric, do you want to enlighten us on lanreotide and how it might fit into symptom control in these patients?

Eric H. Liu, MD, FACS: Yeah, absolutely. Lanreotide is another somatostatin analogue to our good friend, octreotide. And, as you had said, it’s most exciting recently because of its use for tumor control. But, because it’s a somatostatin analogue, it still has effects on controlling symptoms. There was a trial that came out, the ELECT trial, which was looking at the control of carcinoid syndrome symptoms. It was found in the study—it was a different type of trial than what compared octreotide, which got its original approval—to certainly help improve some of the symptoms, too. So, it’s good to know that there are two somatostatin analogues effective with tumor control and for symptom control.

Matthew H. Kulke, MD: We were talking a little bit about the way that some patients might be on these somatostatin analogues for months or even years, but they do get breakthrough symptoms sometimes. Imodium or Lomotil are great in some cases, but don’t always completely do the trick. Let me turn to James. There’s a new drug, telotristat, which is a tryptophan hydroxylase inhibitor. What do we know about telotristat in this setting?

James C. Yao, MD: Well, Matt, as you know, tryptophan hydroxylase involves serotonin synthesis, and there’s still an unmet need for patients with refractory carcinoid syndrome. And, given that it’s really in serotonin synthesis, there’s rationale that this drug may be very helpful in patients with poorly controlled diarrhea. And recently, a large phase III study was completed, the TELESTAR study. And we’re very fortunate to have the primary investigator here, Dr. Kulke.

Matthew H. Kulke, MD: The TELESTAR study was an interesting study. It was a randomized study. It took patients who had carcinoid syndrome and had diarrhea that was refractory to standard-dose somatostatin analogues and randomized them to receive either treatment with telotristat or treatment with placebo. And the results were really quite interesting. There was a significant decrease in diarrhea in the patients who received telotristat. There was also quite a dramatic decrease in 5-HIAA, which suggests that it really is inhibiting serotonin synthesis. And we were talking earlier I know with Eric about carcinoid heart and some of these other complications of serotonin, so I think it will be really interesting to see what role this might play down the road.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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