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Combination Therapies in Localized Prostate Cancer

Panelists: Raoul S. Concepcion, MD, Comprehensive Prostate Center in Nashville; Evan Y. Yu, MD, Fred Hutchinson Cancer Research Center; Michael A. Carducci, MD, FACP, Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins Hospital; Neal D. Shore, MD, FACS, Carolina Urologic Research Center; Glen Gejerman, MD, DABR, John Theurer Cancer Center
Published Online: Wednesday, Jul 12, 2017



Transcript:

Raoul S. Concepcion, MD, FACS:
Neal, you brought up something very interesting. When we talk about localized disease, there’s mostly radiation or prostatectomy—the majority of which are robotically assisted. But you made mention that some of these newer therapies could be focal therapy or localized therapy. Expand a little bit on that.

Neal D. Shore, MD, FACS: I’m not promoting any of these focal therapies as having enough evidence-based literature and data—prospectively accomplished and/or published and adequately reviewed—that they’re ready for prime-time. That said, it’s intriguing, right? If I can get a quality focal therapy that limits collateral damage to my bladder, my rectum, my nerves of erection, and my voiding pattern, and put the disease in remission—or better yet, cure it—on an outpatient basis, with a minimal amount of risk of blood loss or catheterization, etc, and it’s reasonably cost-effective, I’m all in on that. Now, that could be an ablative technology with heat or cold. That could be with radiation energy. It could be with an injection, potentially. I think this is all very interesting, especially if you find that subset population that is really right for focal treatment.

The big challenge is making sure we consider the old hackneyed expression: right patient, right treatment, right time. We’re really at this era now where it’s got to be cost-effective. There has to be real economic utility. You and I have done a lot of work on this. We’re moving from this volume-based model to the value-based model. In some ways, the right focal therapy, the ideal one, would be something that was clinic-based and didn’t require any super expensive amount of technology, because the prostate is so accessible given its location.

In a blue sky, treetop view of it all—that’s how I’m thinking about it—what’s always concerning is that a lot of companies get into the field for obvious reasons of promoting their technique or technology, prematurely. We’ve seen a lot of that. I would caution everyone listening to just make sure that they understand the data rather than start embarking on things too early.

Raoul S. Concepcion, MD, FACS: Mike, Evan, and Glen, in your institutions, what about combinations of therapies, especially the uses of some of these newer agents that now are approved, obviously, in the CRPC space? Are there many trials using them in combination, especially with radiation, again, trying to offer better therapy for these localized tumors? Glen, what sort of experience are you having?

Glen Gejerman, MD, DABR: Looking at 2 different ways for the patients, who again are early in their journey but are very high-risk, we do look at combining therapies long term—whether it’s 2 to 3 years of androgen suppression along with external beam and some form of brachytherapy or whether it’s a seed implant or high-dose-rate implant. Again maximizing the dose of radiation to the cancer cells while sparing the normal tissues. So, that has been around for quite a while, and there are protocols that have been published. The data look pretty good for patients at highest risk—a Gleason score of 8, 9, or 10—that if you add high-dose-rate brachytherapy to the androgen suppression and the external beam, the patients do better in terms of progression-free survival.

Those are the kinds of things we’ve been looking at when it’s early in the journey, but for high-risk, we’re looking at adding combinations of therapy once we’re dealing with castration-resistance, where it’s metastatic. That, I think, is very exciting, and again, every week, something new comes out in terms of combining different drugs. The key there is making sure that you can do that in a safe and efficacious way.

Michael A. Carducci, MD, FACP: I think there’s a lot of extrapolations for the high-risk patient. If they’re really that high-risk, then you give hormones and radiation. Should you add a docetaxel? Should you add in one of these newer AR-targeted agents? That’s research, in my opinion, but it can be helpful to see, what is the outcome for that.

The newer group that people are talking about that still present, particularly with novel imaging for these high-risk patients, are those in which you find oligometastatic disease. And the current belief is, “Is this all that it is?” and “If you manage it…” We’ve got clinical trial protocols where we’re taking care of the local disease, either with radiation or surgery, and then hormonal therapy or chemotherapy. One of our studies is actually looking at an AR-targeted agent along with it, and then spot welding the metastatic site. That’s the kitchen sink. That’s everything we have trying to say, “This is all it is. Let’s go at it full force.” We have no idea if that makes any sense.

Evan Y. Yu, MD: But there are good trials being designed.

Neal D. Shore, MD, FACS: I think what’s important, what Mike says, is—and I’ve seen this in our leading academic institutions, and I’ve seen this both in the United States and abroad—there is this movement where the pendulum has swung back to being more aggressive on training oligometastatic disease. But your point is well taken. We don’t have any level 1 evidence that’s of value at all, and we want to be really careful to recommend it. We have to design good trials and get the evidence to find out what the right population is and what the right multimodality therapy is. Otherwise, people just start saying, “Well, we’ll start getting super aggressive again.” I don’t think we want to do that.

Raoul S. Concepcion, MD, FACS: I think, Neal, when you and I trained in the 1980s, where the thought was that there was only going to be 1 mode of therapy, the concept of what we used to do—and obviously what Dr. Walsh wanted and he advocated for early on—was that if you had positive lymph nodes, you stopped therapy. The concept was that the tumor had obviously spread outside the confines of the prostate, which made surgical cure, given the associated morbidities with radical prostatectomy, unacceptable from a quality-of-life standpoint. If you were a high-volume prostatectomy center, yes, there is associated incontinence and sexual dysfunction.

However, to me, there was always some value, especially in higher-volume tumors, to get that out. Because when they do recur, if you left the tumor in, the problem with locally advancing disease—bladder/neck obstruction, bilateral ureteral obstruction, hematuria, those types of things—is it was miserable. Mike, your point is well taken, and we can talk about this now—how it relates to the CRPC space, these newer imaging techniques that are going to start coming onboard.

Michael A. Carducci, MD, FACP: It’s the newer imaging and the safer prescriptions—these things that say “high-risk” or “You’ve got disease that we knew might be there, but we could never detect on our traditional scans.” It makes us think differently about how aggressive to be.

Transcript Edited for Clarity

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Transcript:

Raoul S. Concepcion, MD, FACS:
Neal, you brought up something very interesting. When we talk about localized disease, there’s mostly radiation or prostatectomy—the majority of which are robotically assisted. But you made mention that some of these newer therapies could be focal therapy or localized therapy. Expand a little bit on that.

Neal D. Shore, MD, FACS: I’m not promoting any of these focal therapies as having enough evidence-based literature and data—prospectively accomplished and/or published and adequately reviewed—that they’re ready for prime-time. That said, it’s intriguing, right? If I can get a quality focal therapy that limits collateral damage to my bladder, my rectum, my nerves of erection, and my voiding pattern, and put the disease in remission—or better yet, cure it—on an outpatient basis, with a minimal amount of risk of blood loss or catheterization, etc, and it’s reasonably cost-effective, I’m all in on that. Now, that could be an ablative technology with heat or cold. That could be with radiation energy. It could be with an injection, potentially. I think this is all very interesting, especially if you find that subset population that is really right for focal treatment.

The big challenge is making sure we consider the old hackneyed expression: right patient, right treatment, right time. We’re really at this era now where it’s got to be cost-effective. There has to be real economic utility. You and I have done a lot of work on this. We’re moving from this volume-based model to the value-based model. In some ways, the right focal therapy, the ideal one, would be something that was clinic-based and didn’t require any super expensive amount of technology, because the prostate is so accessible given its location.

In a blue sky, treetop view of it all—that’s how I’m thinking about it—what’s always concerning is that a lot of companies get into the field for obvious reasons of promoting their technique or technology, prematurely. We’ve seen a lot of that. I would caution everyone listening to just make sure that they understand the data rather than start embarking on things too early.

Raoul S. Concepcion, MD, FACS: Mike, Evan, and Glen, in your institutions, what about combinations of therapies, especially the uses of some of these newer agents that now are approved, obviously, in the CRPC space? Are there many trials using them in combination, especially with radiation, again, trying to offer better therapy for these localized tumors? Glen, what sort of experience are you having?

Glen Gejerman, MD, DABR: Looking at 2 different ways for the patients, who again are early in their journey but are very high-risk, we do look at combining therapies long term—whether it’s 2 to 3 years of androgen suppression along with external beam and some form of brachytherapy or whether it’s a seed implant or high-dose-rate implant. Again maximizing the dose of radiation to the cancer cells while sparing the normal tissues. So, that has been around for quite a while, and there are protocols that have been published. The data look pretty good for patients at highest risk—a Gleason score of 8, 9, or 10—that if you add high-dose-rate brachytherapy to the androgen suppression and the external beam, the patients do better in terms of progression-free survival.

Those are the kinds of things we’ve been looking at when it’s early in the journey, but for high-risk, we’re looking at adding combinations of therapy once we’re dealing with castration-resistance, where it’s metastatic. That, I think, is very exciting, and again, every week, something new comes out in terms of combining different drugs. The key there is making sure that you can do that in a safe and efficacious way.

Michael A. Carducci, MD, FACP: I think there’s a lot of extrapolations for the high-risk patient. If they’re really that high-risk, then you give hormones and radiation. Should you add a docetaxel? Should you add in one of these newer AR-targeted agents? That’s research, in my opinion, but it can be helpful to see, what is the outcome for that.

The newer group that people are talking about that still present, particularly with novel imaging for these high-risk patients, are those in which you find oligometastatic disease. And the current belief is, “Is this all that it is?” and “If you manage it…” We’ve got clinical trial protocols where we’re taking care of the local disease, either with radiation or surgery, and then hormonal therapy or chemotherapy. One of our studies is actually looking at an AR-targeted agent along with it, and then spot welding the metastatic site. That’s the kitchen sink. That’s everything we have trying to say, “This is all it is. Let’s go at it full force.” We have no idea if that makes any sense.

Evan Y. Yu, MD: But there are good trials being designed.

Neal D. Shore, MD, FACS: I think what’s important, what Mike says, is—and I’ve seen this in our leading academic institutions, and I’ve seen this both in the United States and abroad—there is this movement where the pendulum has swung back to being more aggressive on training oligometastatic disease. But your point is well taken. We don’t have any level 1 evidence that’s of value at all, and we want to be really careful to recommend it. We have to design good trials and get the evidence to find out what the right population is and what the right multimodality therapy is. Otherwise, people just start saying, “Well, we’ll start getting super aggressive again.” I don’t think we want to do that.

Raoul S. Concepcion, MD, FACS: I think, Neal, when you and I trained in the 1980s, where the thought was that there was only going to be 1 mode of therapy, the concept of what we used to do—and obviously what Dr. Walsh wanted and he advocated for early on—was that if you had positive lymph nodes, you stopped therapy. The concept was that the tumor had obviously spread outside the confines of the prostate, which made surgical cure, given the associated morbidities with radical prostatectomy, unacceptable from a quality-of-life standpoint. If you were a high-volume prostatectomy center, yes, there is associated incontinence and sexual dysfunction.

However, to me, there was always some value, especially in higher-volume tumors, to get that out. Because when they do recur, if you left the tumor in, the problem with locally advancing disease—bladder/neck obstruction, bilateral ureteral obstruction, hematuria, those types of things—is it was miserable. Mike, your point is well taken, and we can talk about this now—how it relates to the CRPC space, these newer imaging techniques that are going to start coming onboard.

Michael A. Carducci, MD, FACP: It’s the newer imaging and the safer prescriptions—these things that say “high-risk” or “You’ve got disease that we knew might be there, but we could never detect on our traditional scans.” It makes us think differently about how aggressive to be.

Transcript Edited for Clarity
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