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Nonmetastatic CRPC: Does It Exist?

Panelists: Joe OSullivan, MD, Queen's University; Nicholas James, MBBS, PhD University of Birmingham; Noel Clarke, MBBS, Christie Hospital
Published: Wednesday, Dec 05, 2018



Transcript: 

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: A slightly controversial topic is nonmetastatic castration-resistant prostate cancer. Nick, could you describe the characteristics of this setting?

Noel Clarke, MBBS, FRCS, ChM: This is based on the paradigm that, for men presenting with localized disease, you stop the treatment typically with hormone and surgery. You may not get hormone therapy with your radiotherapy. Most of the patients who are relapsed are going to the ones who had hormone therapy. Most of them will stop, and then some of them will relapse, and they’ll relapse with their [prostate-specific antigen] PSA going up. You’ve then got this question regarding whether the PSA is going up after primary therapy. If you’ve had surgery, you perhaps have the option for salvage radiotherapy. If it’s rising post radiotherapy with or without prior surgery, you’re heading toward systemic therapy. In most parts of the world, it’s PSA going up that drives the decision to start androgen deprivation therapy [ADT] with or without some sort of kinetic considerations: PSA doubling time or a threshold PSA.

For a long time, the United Kingdom guidelines have said, “Don’t start hormone therapy until patients have metastatic disease.” I suspect those guidelines are widely ignored. I have to say, in my practice, we’ve had better access to PET scanning, in particular, we’ve taken the view that we shouldn’t start people on hormone therapy just because their PSA is rising. We wait until we see PET—the least-detectable disease—before we do anything. Often, they’re still salvageable.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: It’s a pretty big deal to castrate somebody.

Nicholas James, MD: Yes. You’re subjecting men to years of extra ADT for no plausible demonstrated benefit. At the St. Gallen conference, which you mentioned already, there was no consensus as to what the right point was. The majority were composite PSA/PSA kinetics, rather than just the threshold. Substantial minorities, of which I was one, said, “No, wait until the next study.” That’s the right thing. In my practice, M0CRPC therefore doesn’t exist, because nobody receives hormone therapy until they’re metastatic. It’s very much alive and kicking.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: It’s very much a doctor iatrogenic kind of disease. It is always viewed as an iatrogenic disease; whether or not it should exist, it does exist. Then you’ve got the problem of your PFS. When you put people on hormone therapy, obviously nothing much happens in terms of detectable disease, if you didn’t have it already. They’ll get a PSA response, which may last for years—the PSA rise. At this point, you have no licensed therapies until you’ve gone all the way to metastatic disease. People often added in further harmful things like estrogen or things that have no proven survival benefits. You’re adding more toxicities on top of the toxicities you’ve already generated with years of ADT that they probably didn’t need. Now we’ve heard that M0CRPC doesn’t exist in Birmingham—does it exist in Manchester?


Noel Clarke, MBBS, FRCS, ChM: I share Nick’s view.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: I’ll just ask you the same question. We’ve heard from Nick that M0CRPC doesn’t existing in Birmingham—does it exist in Manchester?

Noel Clarke, MBBS, FRCS, ChM: We tend to run our practice in very much the same way. There has been a tendency to practice medicine in some countries by instinct rather than thinking about biology. And I can understand elements of that. One of those pressures to do something is from the patient. When the patient sees the PSA rising, there’s a philosophy: Don’t just stand there; do something. I would reverse that and I would say, “Don’t just do something; stand there.”

Noel Clarke, MBBS, FRCS, ChM: Exactly. Because there are a number of cases who have relatively indolent disease that will not progress rapidly, the trials that have been done—particularly in the M0 space—are very different from the presentation of M1 disease.

When we were planning STAMPEDE back in 2004 and 2005, we had a feeling that it was more aggressive. Actually, when we started to see the results, we found out that we’d overestimated the rapidity of progression. There is a group, I dare say, in North America more commonly but also in continental Europe and other parts of the world, that see the PSA rise and instantly begin ADT. Time spent with a patient explaining what a rising PSA means in the face of treatment is time well spent.

Transcript Edited for Clarity 

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Transcript: 

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: A slightly controversial topic is nonmetastatic castration-resistant prostate cancer. Nick, could you describe the characteristics of this setting?

Noel Clarke, MBBS, FRCS, ChM: This is based on the paradigm that, for men presenting with localized disease, you stop the treatment typically with hormone and surgery. You may not get hormone therapy with your radiotherapy. Most of the patients who are relapsed are going to the ones who had hormone therapy. Most of them will stop, and then some of them will relapse, and they’ll relapse with their [prostate-specific antigen] PSA going up. You’ve then got this question regarding whether the PSA is going up after primary therapy. If you’ve had surgery, you perhaps have the option for salvage radiotherapy. If it’s rising post radiotherapy with or without prior surgery, you’re heading toward systemic therapy. In most parts of the world, it’s PSA going up that drives the decision to start androgen deprivation therapy [ADT] with or without some sort of kinetic considerations: PSA doubling time or a threshold PSA.

For a long time, the United Kingdom guidelines have said, “Don’t start hormone therapy until patients have metastatic disease.” I suspect those guidelines are widely ignored. I have to say, in my practice, we’ve had better access to PET scanning, in particular, we’ve taken the view that we shouldn’t start people on hormone therapy just because their PSA is rising. We wait until we see PET—the least-detectable disease—before we do anything. Often, they’re still salvageable.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: It’s a pretty big deal to castrate somebody.

Nicholas James, MD: Yes. You’re subjecting men to years of extra ADT for no plausible demonstrated benefit. At the St. Gallen conference, which you mentioned already, there was no consensus as to what the right point was. The majority were composite PSA/PSA kinetics, rather than just the threshold. Substantial minorities, of which I was one, said, “No, wait until the next study.” That’s the right thing. In my practice, M0CRPC therefore doesn’t exist, because nobody receives hormone therapy until they’re metastatic. It’s very much alive and kicking.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: It’s very much a doctor iatrogenic kind of disease. It is always viewed as an iatrogenic disease; whether or not it should exist, it does exist. Then you’ve got the problem of your PFS. When you put people on hormone therapy, obviously nothing much happens in terms of detectable disease, if you didn’t have it already. They’ll get a PSA response, which may last for years—the PSA rise. At this point, you have no licensed therapies until you’ve gone all the way to metastatic disease. People often added in further harmful things like estrogen or things that have no proven survival benefits. You’re adding more toxicities on top of the toxicities you’ve already generated with years of ADT that they probably didn’t need. Now we’ve heard that M0CRPC doesn’t exist in Birmingham—does it exist in Manchester?


Noel Clarke, MBBS, FRCS, ChM: I share Nick’s view.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: I’ll just ask you the same question. We’ve heard from Nick that M0CRPC doesn’t existing in Birmingham—does it exist in Manchester?

Noel Clarke, MBBS, FRCS, ChM: We tend to run our practice in very much the same way. There has been a tendency to practice medicine in some countries by instinct rather than thinking about biology. And I can understand elements of that. One of those pressures to do something is from the patient. When the patient sees the PSA rising, there’s a philosophy: Don’t just stand there; do something. I would reverse that and I would say, “Don’t just do something; stand there.”

Noel Clarke, MBBS, FRCS, ChM: Exactly. Because there are a number of cases who have relatively indolent disease that will not progress rapidly, the trials that have been done—particularly in the M0 space—are very different from the presentation of M1 disease.

When we were planning STAMPEDE back in 2004 and 2005, we had a feeling that it was more aggressive. Actually, when we started to see the results, we found out that we’d overestimated the rapidity of progression. There is a group, I dare say, in North America more commonly but also in continental Europe and other parts of the world, that see the PSA rise and instantly begin ADT. Time spent with a patient explaining what a rising PSA means in the face of treatment is time well spent.

Transcript Edited for Clarity 
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