Increasing Rates of Active Surveillance as the Standard of Care in Men with Low Risk Prostate Cancer- Matthew Cooperberg

November 6, 2019

Matthew Cooperberg discusses active surveillance as the standard of care for men with low-risk prostate cancer as well as data from multiple registries including CaPSURE, MUSIC, AQUA, and SEER, which report increasing rates of active surveillance in men with low-risk disease.  He further discusses the factors that may be driving lower uptake of active surveillance in some practices. 


Matthew Cooperberg, MD, MPH, FACS, Professor of Urology; Epidemiology & Biostatistics, Helen Diller Family Chair in Urology, The University of California, San Francisco, UCSF

Charles J. Ryan, MD, the President and Chief Executive Officer of The Prostate Cancer Foundation (PCF), the world’s leading philanthropic organization dedicated to funding life-saving prostate cancer research. Charles J. Ryan is an internationally recognized genitourinary (GU) oncologist with expertise in the biology and treatment of advanced prostate cancer. Dr. Ryan joined the PCF from the University of Minnesota, Minneapolis, where he served as Director of the Hematology, Oncology, and Transplantation Division in the Department of Medicine. He also served as Associate Director for Clinical Research in the Masonic Cancer Center and held the B.J. Kennedy Chair in Clinical Medical Oncology.

Read the Full Video Transcript

Charles Ryan: Hello. We're coming from the European Association of Urology meeting in Barcelona. I'm delighted to be joined by Matt Cooperberg, who is a Professor of Urology and Epidemiology and Biostatistics and the Helen Diller Family Chair in Urology at the University of California, San Francisco. Matt, great to see you. 

Matt Cooperberg: Pleasure.

Charles Ryan: And always a lot going on and a lot to talk about. You've really become one of the world's leading voices in active surveillance. Tell us what is new in the world of active surveillance.

Matt Cooperberg: Sure. There's always a lot going on. I think we are, one of the really gratifying things about the active surveillance story over the last few years is that the conversation has changed, and it's changed very, very quickly actually. I think as recently as the beginning of this decade, the question was still, should we really consider active surveillance standard of care? Is this a safe approach for men with low-risk disease? I think we've answered most of those questions pretty definitively that not only is this safe but this should be standard of care for almost all men with Gleason 3+3 prostate cancer at the outset. Of course, there's exceptions but this really is the way the field needs to be going and it is the way the field is going. 

We had a study now three or four years old, from the CaPSURE Registry which is the National Practice Database, showing rates of surveillance which have always been under 10%, suddenly jumped up to 40% in the current decade. We were a little bit worried that this was just gonna be a statistical fluke but it's now been verified in the MUSIC Registry across the state of Michigan where it's about 50%.

Charles Ryan: 50%?

Matt Cooperberg: 50, 50. In the AQUA registry, which is the AUAs national database, it's again around 50%. Most recently there was a study out of SEER again confirming about a 50% rate of active surveillance for low-risk disease. Now, this is still too low. Sweden's about 80% which is probably where we should be.

Charles Ryan: My next question is why are 50% of these people being treated if the other 50% have to conclude they don't need to be treated?

Matt Cooperberg: Yeah, so 50% is still too low. It should never be 100%. There's always gonna be some men who either it's a really young guy with a lot of Gleason 6, strong family history, a lot of voiding symptoms, there's always gonna be some reasons to treat some men with low-grade disease, but it should be a pretty small minority most of the time. 

The question relates to why things were so bad for so many years in general. Why was the rate 10% until recently?

Charles Ryan: Yeah.

Matt Cooperberg: It's a multifactorial answer. There are still financial incentives for treatment, there are still some people that have this legal concern about not treating the cancer although I think most of those are unfounded in this day and age. There is still patient anxiety. I think part of the reason that things have changed so quickly is I think word is finally on the street in the patient community that Gleason 3+3 prostate cancer is not cancer the way you know, of course, most of the population thinks about that word. That message is finally getting out into the broader community, which helps. The lesson then is kind of going into the conversation with the urologist thinking that he's dying, the easier it is to have the conversation about not treating. 

The other side of the story though with the 50% or the 40% or whatever it is, is there's still fairly extreme variations. So if you drill down either in the Michigan cohort or the AQUA cohort, depending on which urology practice you go to in Michigan, your likelihood of getting surveillance ranges from 20% to 80%. Depending on which urologist you see, the rate ranges from 0% to 100%.

Charles Ryan: Mm-hmm.

Matt Cooperberg: This is, of course, a huge problem. It's hardly unique to surveillance, it's not unique to prostate cancer or urology, this is this small area of variations problem in medicine that the folks at Dartmouth have been studying since the early 1980s.

Charles Ryan: Sorry, what was that called again?

Matt Cooperberg: Small area of variations problems. This is John Wennburg at Dartmouth. In the early '80s put together this Dartmouth Atlas of healthcare. The story, I'm not sure if this is true story, but the story was there was two counties in New Hampshire where the rate of tonsillectomy varied by five fold. With the same population, the same six generations in northern New England genetic stock, same weather, all the rest of it. The only factor that explained this difference was there was one ENT over here that like to do tonsillectomies, there was an ENT over here who was more conservative about it.

Charles Ryan: Mm-hmm.

Matt Cooperberg: That was the origin that has driven this effort. They've been at it for 30 years now. Everywhere you look in medicine you find this sort of variation. Prostate cancer management for localized disease has been one of the worst in the sense that we find fairly extreme variation, whether we're talking about surveillance rates, surgery versus radiation, external beam versus brachytherapy. Anywhere you look you see these practice styles that really define treatment, and of course, there is an extent to which that is okay, but you get to a point where 0 to 100% is not an acceptable level of variation.

Charles Ryan: Right.

Matt Cooperberg: Your treatment course cannot be defined that strongly by whose door you happen to knock on as a patient.

Charles Ryan: So sort of three perspectives. One is, who is the ideal candidate for active surveillance? Okay?

Matt Cooperberg: Yeah.

Charles Ryan: Who is the ideal candidate for therapy in a context who might otherwise be getting active surveillance, you touched on this a little bit? Then how far are you gonna push the envelope? I mean at some point, active surveillance isn't appropriate, right? I know that you and others have been thinking about how much Gleason 4 there is and that kind of thing.

Matt Cooperberg: Yep, yep. 

Charles Ryan: So address those.

Matt Cooperberg: Yeah, so we're going forward. The ways that the field is going to evolve over the next few years, I think there's a few. One is making sure that we're doing surveillance properly. The ProtecT Trial from UK showed pretty clearly that active monitoring, meaning just following PSAs without doing biopsies and imaging and things like that, is not sufficient. That will not get you the same disease control rate we would see with immediate treatment. So I think that's the first is making sure the quality is good. Some data from Michigan, from MUSIC again, has suggested quality is extremely variable in terms of who's getting surveillance done well.

But the next path forward really has to be tailoring surveillance. You think about 100 men that are going down the active surveillance pathway, some of those men are gonna be prototypical active surveillance patients. Some of them will progress, we need to keep an eye on them, we do need to do the biopsies or MR, repeat PSA testing, etc. There's a small percentage of these men who probably should go straight to treatment because they've got some incipient or hidden bad biology that we have not identified.

Charles Ryan: You mentioned family history earlier.

Matt Cooperberg: Yeah. I don't think that has turned out to be an independent risk factor once we've got the grade and stage and all that information in hand. Now the reality is, if you've got a 51-year-old with low-grade disease and his dad died of prostate cancer at 58, his anxiety level is gonna be such that he's probably not gonna stay on surveillance very long. That again is this sort of acceptable rate of treatment for low-risk disease, but it's not actually an independent risk factor in and of itself.

There's controversy as to why there are actually a known mutation CPRCA and one of the gene pair of path mutations, should drive different decision making active surveillance. That has not been studied well.

Charles Ryan: Yeah.

Matt Cooperberg: Yet. But on the other extreme, you have a lot of men with Gleason 3+3 and 5% of the single core, these are the ones that we shouldn't have called cancer in the first place. These are men that frankly don't need all the rigmarole of active surveillance and the biopsies and all the rest of it, they really can be on more of a watchful waiting path. We have a study, we actually presented it at this meeting last year which is almost about to be submitted from the Canary Consortium which is nine large centers across North America. It turns out that there's a pretty substantial cohort or subset of the active surveillance patients who you can tell with about 90% negative predictive value go home for four years, don't worry about this, we barely even need to check a PSA let alone do repeat biopsies and MR's. I think that's the way the field needs to evolve.

Charles Ryan: Give people a four year-

Matt Cooperberg: So far. We can probably go longer than that honestly. 

Charles Ryan: A little like getting a colonoscopy.

Matt Cooperberg: I was about to say, that's exactly the way I think this needs to evolve is you get a colonoscopy, it's the same as the PSA screening. You get a single PSA at 45. Three-quarters of the population has a level under one and can be done for 10 years.

Charles Ryan: Yeah.

Matt Cooperberg: You're gray zone? Okay, you need to follow the PSA. If you've actually got something more concerning, we chase that down. It's the same thing after diagnosis. There's gonna be a subset of men who probably could go home for 10 years, we need that kind of follow up to say 10 years. Then you've got your repeat sigmoidoscopy sort of cohort who need to be followed a little more carefully. Then there's the equivalent of actually finding a real tumor in the colon-

Charles Ryan: Right.

Matt Cooperberg: Which is the ... That's either the high volume 6's with some adverse findings on genomic testing for example or the 3+4's, that's where we're really sort of the waiting at now, trying to figure out which 3+4 is a good surveillance.

Charles Ryan: Right. That question's not answerable at this point. The 3+4's and the 4+3's who might be candidates for active surveillance?

Matt Cooperberg: Yeah.

Charles Ryan: You haven't mentioned Decipher at all-

Matt Cooperberg: Right, right.

Charles Ryan: Or these types of things yet. What do we do there?

Matt Cooperberg: So none of those tests ... So we've got Decipher, we've got Prolaris, Oncotype, none of them has been prospectively validated to improve decision making in active surveillance, and actually, there was just a big trial, RCT that came out of Toronto on MRI which showed that MRI does not change the rate of upgrading on active surveillance. None of these tests, if you look at the ... The only guideline out there that really focuses on active surveillance is the ASCO endorsement of Clinical Care Ontario that Ron Chen led a couple years ago, and they've seen pretty clearly, the surveillance regimen is still PSAs and biopsies. Everything else, genomics and MR, is still considered experimental or things that you can add on by option, when clinically appropriate but not that need to get baked into the protocol.

Charles Ryan: Mm-hmm.

Matt Cooperberg: The problem is these tests do not have thresholds that tell us what to do. None of them has been really well validated to say okay if you're over this line, you really need to get treated.

Charles Ryan: Mm-hmm.

Matt Cooperberg: Prolaris has got a little bit closer, there was a paper Dan Lin just published this year, that combined the Prolaris score with the CAPRA score and this combined CCR they call it, if you are below a certain threshold, likelihood of disease progression after 10 years is virtually zero. That 10 years is not enough but at least it's getting us a little closer to a threshold.

Charles Ryan: Mm-hmm.

Matt Cooperberg: Oncotype, the way they format their test result is actually often misleading to the point of causing men to make the wrong decision I think because they have this very awkward shifting NCCN risk boxes that I think actually is quite misleading in some cases. Decipher is interesting because we're getting the Decipher score there and we are seeing that is more and more for biopsy this is making. The thing about that is we're getting the entire expression array data in the back end. That platform will allow us to figure out the next generation active surveillance score for example as time goes on and we get more follow up on these men.

But the reality is we don't know how to use any of those tests in clinical practice in 2019, yet. It's coming but we're not quite at the point of saying that these should be part of a standard implementation.

Charles Ryan: Right.

Matt Cooperberg: Where we use them clinically at UCSF and other places is borderline cases. So men with a high volume Gleason 6, low volume Gleason 3+4, men who are really anxious or have a strong family history or anything else just doesn't seem right. A PSAs really high, out of proportion to what we've found, things where we think we need a little more information. Again, they're not black and white tests but they can tell us a little bit of a sharper delineation of which shade of gray the tumor might be.

Charles Ryan: Yeah, yeah. Great. Well, lots of exciting developments and it's really interesting to see this field evolve, especially from the perspective of a medical oncologist. I love the fact that there's conversation about maybe not calling some of this cancer and then pushing the envelope really in both directions in terms of trying to spare people potentially morbid treatment, but also trying to increase the baseline that we use for active surveillance versus treatment. Always a pleasure to talk to you-

Matt Cooperberg: Pleasure.

Charles Ryan: And great following your work. Thank you for joining us.

Matt Copperberg: Thanks.

Charles Ryan: Good to see you.