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Intermittent versus Continuous Androgen-Deprivation Therapy in Prostate Cancer

Panelists: Raoul S. Concepcion, MD, FACS, The Comprehensive Prostate Center; Jorge A. Garcia, MD, FACP, Taussig Cancer Institute; Alicia K. Morgans, MD, MPH, Vanderbilt University Medical Center; Ashley E. Ross, MD, PhD, Johns Hopkins Medical Institution; Daniel R. Saltzstein, MD, Urology San Antonio
Published: Thursday, Dec 15, 2016


Transcript:

Raoul S. Concepcion, MD:
Dan, shifting gears a little bit, when you do start androgen-deprivation therapy for whatever the trigger is, do you tend to move towards continuous or do you tend to move towards intermittent therapy based upon some of the data that’s been published? And also, specifically, how low do you think it becomes meaningful? How low should we drive testosterone?

Daniel R. Saltzstein, MD: Well, I’ll answer both questions. I think, in Europe, they’ve already made the change. The EAU (European Association of Urology) has already decided that 20 is the appropriate testosterone level. I think that’s based on some data from both retrospective and prospective trials showing that there is a delay in development of CRPC. There’s an improvement in survival and a decreased risk of death when you can suppress testosterone to less than 20. The old data were when we didn’t have sensitive enough assays to test testosterone at that point in time. And, again, all of our clinical trials, at this current time, are based on a level of 50 of testosterone. But, going forward, now that we know, in an orchidectomized male, that the normal level of testosterone is about 15, I would see in the future, even in the United States, going to a much lower level of testosterone because I think these gentlemen have an improved overall survival. When we do it in a clinical and community setting, I think, at this point in time, if the gentlemen presents with metastatic disease, we can actually document that we’re not using some of the newer imaging modalities. We are putting that patient on continuous hormonal therapy trying to suppress his testosterone to as low as possible. In the biochemical recurrence state, even though we know that’s probably micrometastatic disease, we’re probably opting, at least in the lower-risk guy, to managing with more of an intermittent. And, again, cost, side-effect profile, and toxicity have contributed to those decisions.

Raoul S. Concepcion, MD: So, in the patient who gets started on androgen-deprivation therapy in the biochemically recurrent space with negative radiographic imaging, I’m assuming you’re checking PSAs on an intermittent basis. Are you also concomitantly checking testosterone levels?

Daniel R. Saltzstein, MD: Again, we are checking testosterone levels, now, and some of the studies use a PSA decline to less than 4 to use their trigger. That’s a great response, and then they’ll put them on intermittent therapy. I, unfortunately, now, tend to use that when that testosterone rises above 50, to determine when to maybe restart that individual on hormone therapy. But, yes, we are measuring testosterone concurrently.

Raoul S. Concepcion, MD: So, Alicia, what about your thoughts on intermittent versus continuous ADT? What are the advantages, disadvantages? There have, obviously, been lots of publications over the past few years looking at this.

Alicia K. Morgans, MD, MPH: In the biochemical recurrent state, I completely agree, we use intermittent ADT. At our center, at least in my practice, I’m not using testosterone levels, I’m using PSA levels to trigger when I will restart ADT. And, it’s interesting—and we talked about this as a group, briefly, I think, even before we started—that so many institutions have different methods of doing that. In my practice, I base it on multiple things, even as I think about what I do from patient to patient. Sometimes, I use doubling time, sometimes, I use PSA back to the level at which we started therapy. I also will have an absolute threshold sometimes. I don’t want to go above 20, so it really depends on the patient in the situation. And, if it’s that variable, even within my own practice, I’m sure that it’s even more variable at various institutions. Regardless, in the biochemical recurrence space, I do use intermittent ADT.

In the metastatic space, based on the Hussain data from SWOG, I always use continuous ADT, and I say, always, with a caveat. If patients are experiencing profound side effects from that, we always have a negotiation. I make an agreement with them that if they understand the data and they understand what they’re dealing with, I won’t tie their hands and tell them that they cannot use intermittent therapy, making sure that they know the data that we have. From my perspective, and I mentioned this earlier, it’s all about side effects and survivorship because these patients are living with this disease for years. It’s my responsibility to not only keep them alive, but to make sure they experience that, in the best way possible. I think that we’ve seen data, recently, on depression, on cognitive dysfunction, and even on cardiac events, the variability that we may see between continuous and intermittent androgen-deprivation therapy, and the effects on those outcomes that really come into play when I think about patients. I know I was very surprised to see the side-effect data related to the Hussein paper, the SWOG paper. When Don Hirschman linked that data with Medicare charges and found that, in that clinical trial, when you followed patients longer, they actually had, for the intermittent therapy, a higher rate of cardiovascular and thrombotic events. I was definitely surprised by that, and, if you think about the biology, there may be some plausibility there, in terms of hormonal levels and fluctuations altering the coagulation cascade and platelet sensitivity, perhaps. But, that was surprising. So, as we continue to do the work and find out what these complications are, I think these decisions become more challenging. But, I think about all of that as I’m making those decisions. I use intermittent in biochemical recurrence and continuous in metastatic.

Transcript Edited for Clarity
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Transcript:

Raoul S. Concepcion, MD:
Dan, shifting gears a little bit, when you do start androgen-deprivation therapy for whatever the trigger is, do you tend to move towards continuous or do you tend to move towards intermittent therapy based upon some of the data that’s been published? And also, specifically, how low do you think it becomes meaningful? How low should we drive testosterone?

Daniel R. Saltzstein, MD: Well, I’ll answer both questions. I think, in Europe, they’ve already made the change. The EAU (European Association of Urology) has already decided that 20 is the appropriate testosterone level. I think that’s based on some data from both retrospective and prospective trials showing that there is a delay in development of CRPC. There’s an improvement in survival and a decreased risk of death when you can suppress testosterone to less than 20. The old data were when we didn’t have sensitive enough assays to test testosterone at that point in time. And, again, all of our clinical trials, at this current time, are based on a level of 50 of testosterone. But, going forward, now that we know, in an orchidectomized male, that the normal level of testosterone is about 15, I would see in the future, even in the United States, going to a much lower level of testosterone because I think these gentlemen have an improved overall survival. When we do it in a clinical and community setting, I think, at this point in time, if the gentlemen presents with metastatic disease, we can actually document that we’re not using some of the newer imaging modalities. We are putting that patient on continuous hormonal therapy trying to suppress his testosterone to as low as possible. In the biochemical recurrence state, even though we know that’s probably micrometastatic disease, we’re probably opting, at least in the lower-risk guy, to managing with more of an intermittent. And, again, cost, side-effect profile, and toxicity have contributed to those decisions.

Raoul S. Concepcion, MD: So, in the patient who gets started on androgen-deprivation therapy in the biochemically recurrent space with negative radiographic imaging, I’m assuming you’re checking PSAs on an intermittent basis. Are you also concomitantly checking testosterone levels?

Daniel R. Saltzstein, MD: Again, we are checking testosterone levels, now, and some of the studies use a PSA decline to less than 4 to use their trigger. That’s a great response, and then they’ll put them on intermittent therapy. I, unfortunately, now, tend to use that when that testosterone rises above 50, to determine when to maybe restart that individual on hormone therapy. But, yes, we are measuring testosterone concurrently.

Raoul S. Concepcion, MD: So, Alicia, what about your thoughts on intermittent versus continuous ADT? What are the advantages, disadvantages? There have, obviously, been lots of publications over the past few years looking at this.

Alicia K. Morgans, MD, MPH: In the biochemical recurrent state, I completely agree, we use intermittent ADT. At our center, at least in my practice, I’m not using testosterone levels, I’m using PSA levels to trigger when I will restart ADT. And, it’s interesting—and we talked about this as a group, briefly, I think, even before we started—that so many institutions have different methods of doing that. In my practice, I base it on multiple things, even as I think about what I do from patient to patient. Sometimes, I use doubling time, sometimes, I use PSA back to the level at which we started therapy. I also will have an absolute threshold sometimes. I don’t want to go above 20, so it really depends on the patient in the situation. And, if it’s that variable, even within my own practice, I’m sure that it’s even more variable at various institutions. Regardless, in the biochemical recurrence space, I do use intermittent ADT.

In the metastatic space, based on the Hussain data from SWOG, I always use continuous ADT, and I say, always, with a caveat. If patients are experiencing profound side effects from that, we always have a negotiation. I make an agreement with them that if they understand the data and they understand what they’re dealing with, I won’t tie their hands and tell them that they cannot use intermittent therapy, making sure that they know the data that we have. From my perspective, and I mentioned this earlier, it’s all about side effects and survivorship because these patients are living with this disease for years. It’s my responsibility to not only keep them alive, but to make sure they experience that, in the best way possible. I think that we’ve seen data, recently, on depression, on cognitive dysfunction, and even on cardiac events, the variability that we may see between continuous and intermittent androgen-deprivation therapy, and the effects on those outcomes that really come into play when I think about patients. I know I was very surprised to see the side-effect data related to the Hussein paper, the SWOG paper. When Don Hirschman linked that data with Medicare charges and found that, in that clinical trial, when you followed patients longer, they actually had, for the intermittent therapy, a higher rate of cardiovascular and thrombotic events. I was definitely surprised by that, and, if you think about the biology, there may be some plausibility there, in terms of hormonal levels and fluctuations altering the coagulation cascade and platelet sensitivity, perhaps. But, that was surprising. So, as we continue to do the work and find out what these complications are, I think these decisions become more challenging. But, I think about all of that as I’m making those decisions. I use intermittent in biochemical recurrence and continuous in metastatic.

Transcript Edited for Clarity
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