Charles Ryan: Hello from ASCO GU 2022 in San Francisco. I have a local talent here, Dr. Matthew Cooperberg, professor of urology and epidemiology and biostatistics at the University of California, San Francisco, right down the road from where we're filming. Great to see you, Matt.

Matthew Cooperberg: Great to see you.

Charles Ryan: Been a long time.

Matthew Cooperberg: It has.

Charles Ryan: Former colleague, and I always look to you for advice on the issue of localized prostate cancer, in particular the issue of risk stratified therapy, who should get active surveillance, who shouldn't, et cetera. So, we're going to talk about that.

Matthew Cooperberg: Great.

Charles Ryan: But before we do that, I want you to just give me a current snapshot of the U.S. Based on the epidemiology of prostate cancer, how many patients, based on the best published literature, could be undergoing active surveillance as their mode of approach versus how many actually are having that as their approach?

Matthew Cooperberg: Yeah, so it depends on what data source you look at. I am very enthusiastic about our latest data, which are coming from the AQUA Registry. And just to give you a preview, we're going to be presenting this at AUA in a couple months.

The rates have been going up quite rapidly, actually. So, the paper that we had out of UCSF from the CaPSURE Registry in 2015 showed that in the prior decade, the 2010s, we finally broke out of the 10% range where we had been stuck for many years. That's 10% of low risk patients getting active surveillance. We had made it up to about 40% by 2013 or '14.

So, the AQUA registry is a national registry the AUA has been running since 2014. Now it includes data from about 250 practices around the country. It's about 280,000 prostate cancer patients now, and the rate of surveillance has continued to go up pretty much linearly up to about 60% for 2020, which is a lot of progress in the right direction, and this is probably the best source of data we've got for what is happening in general community urology practice currently.

60% is getting much closer to where we should be. There's a lot of discussion about what that optimal target should be. I think if you look at the papers that Stacy Loeb has written from Sweden and from the VA; both those settings show a rate of about 80%, and that has always seemed about right for low risk disease.

There are always going to be some exceptions for men who have what looks like low risk disease who may want immediate treatment either because they also have severe obstructive symptoms. They've got really high volume, low grade disease and are young. Maybe they've got a biomarker that is concerning or an MRI finding that's concerning. There are plenty of exception reasons, but we're really trying to force this consensus that the default assumption for low risk disease, whether very low risk or not, should be active surveillance.

Charles Ryan: Okay.

Matthew Cooperberg: And of course, that raised in controversy with the NCCN last year.

Charles Ryan: And has the definition of low risk disease evolved over time, and what is it currently?

Matthew Cooperberg: Yeah. That has been, if you follow this whole business with the NCCN late last year; the NCCN has always sub-categorized low risk into so-called very low risk, and not very low but otherwise low risk. And the very low risk definition is still the 1994 Epstein criteria for biopsy prediction of what would be found at prostatectomy to be a organ-confined, low grade, and less than 0.5 cc tumor. So, it is an exceptionally conservative definition, and it came from the era of sextant systematic biopsies.

In this day and age where we're doing extended template biopsies plus targeted biopsies, usually multiple cores hitting a target, it is impossible to hit the very low risk threshold. Because to hit that definition, you can have no more than two cores involved, no more than 50% of any one core involved. It's a totally anachronistic definition for contemporary practice in 2022.

And this controversy ensued because they temporarily took the word "preferred" out of the active surveillance listing for the treatment options for men with low but not very low risk disease. Whereas the reality is you can have a prostate basically replaced by Gleason 3+3, and it has zero metastatic capacity.

Obviously the patient with high volume 3+3 is more likely to eventually develop 3+4 or higher, but as long as it's all 3 3, that patient in, I think clearly not everybody's view based on the NCCN. But those of us have been doing surveillance for a while, we put almost all those men on surveillance.

Charles Ryan: Any progress on redefining Gleason 3 3 as a non-cancer?

Matthew Cooperberg: That's a whole different conversation. I am definitely more...

Charles Ryan: It's a pathology conversation.

Matthew Cooperberg: Well, it's funny, actually. So, I've been involved in that conversation for a while. Scott Eggener is the other one who's really been trying to drive that conversation. It's a multidisciplinary conversation. Ultimately, pathology seems to hold the keys to the conversation, and they did successfully undiagnosed a subset of thyroid cancers a couple years ago. And there are some pathologists that are in this camp, although at think it's a smaller minority than urologists so far. Because ultimately they're still looking at what the histopathology looks like on H&E.

But I think the more we look at the biology comprehensively, you look at a lot of these small volume 3 3s, and it's hard to find any distinctions versus the normal adjacent prostate. And clinically, we know from some big series now; 3 3 does not have metastatic capacity. So, nobody's saying we should call it normal and it should be surveilled. If you have a polyp in the colon, you get more frequent sigmoidoscopies, colonoscopies, but nobody would ever take out your colon or radiate it for a polyp. And we need some terminology that is along those lines, whether it's idle or P lumps, or who knows what.

Charles Ryan: More to follow on that, but I just thought I couldn't resist that idea.

Matthew Cooperberg: No, it's a great conversation.

Charles Ryan:It comes across my desk, so to speak, quite a bit, honestly.

Matthew Cooperberg: I did one of these videos with Scott Eggener on that topic.

Charles Ryan: Oh, really?

Matthew Cooperberg: Actually, yeah. Anybody listening to this can go find that.

Charles Ryan: Well, we can refer them to prior Uro Today videos on this topic.

Matthew Cooperberg:  Exactly.

Charles Ryan: So, with regards to what men facing a decision about active surveillance go through; there's the uncertainty of it progressing to a more malignant type of cancer, there's uncertainty about whether they should undergo some form of focal therapy just so that they can stop worrying about having a focal localized prostate cancer. So, you've addressed the issue of the low malignant potential of the Gleason 3 3. And just to keep it relatively simple on that point, you're not recommending genomics or other things be done on 3 3s?

Matthew Cooperberg: I think it's individualized, okay? We do not use genomics routinely on all 3 3s. I think that genomics have a role for anything that becomes an edge case. So, the 56 year old with nine cores of 3 3 actually probably is a reasonable candidate for genomics. Likewise, patients with low volume 3 4, patient with a strong family history and what looks like 3 3 BRCA mutation. These are all scenarios where I am perfectly comfortable putting that guy on AS, but this is where the genomics can be helpful. Either to make the decision cleaner and/or easier at the moment, but also to give us a bit of a sharper crystal ball picture as to what's going to pan out over the next five years.

Charles Ryan: And the genomics aren't going to be binary.

Matthew Cooperberg: No.

Charles Ryan: They're going to give you an another point on a spectrum that you have to think about.

Matthew Cooperberg: Exactly.

Charles Ryan: So, it really all boils down to, as you said, for the patients out there listening; how old is the patient, how much volume is there, what do the genomics say, family risk, et cetera?

Matthew Cooperberg: One other point on that, which is it's also how the use of these biomarkers and the genomic tests from that perspective of what it does to the patients to making is also really driven by how the report is presented to the patient. And there was a great paper in JCO this last year from Adam Murphy looking at the Oncotype test in a low health literacy population.

And the use of the test for low health literacy men actually tended to drive men away from AS. And they didn't really do the qualitative why questions, but I think it's in large... I'm assuming that it's at least in part because the way those reports are formatted can cause false anxiety because of the terminology that winds up on the test report. So, it's another thing just to remember. When we order a genomic test, how exactly you interpret that number in context becomes very, very important.

Charles Ryan: That's another video we should do, honestly.

Matthew Cooperberg: Yeah, sure. Sure, definitely. Definitely.

Charles Ryan: So, I want to talk just about the Gleason 3 4s. Where is your cutoff? Is there a point of no return where you say, "You need therapy"?

Matthew Cooperberg: Yeah. So, subdividing the 3 4s has been a big area of interest for us for the last 10 years probably at UCSF, and I think we're getting better at it. It's increasingly clear that... So, it's a few things we look at. We look at volume of pattern 4, what percentage of the cancer is pattern 4? We look at the subtype, and again, we will use genomics in these cases. It is increasingly clear that the patients that have 5% of the cancer is pattern 4 and it's the fused or poorly formed gland subtype, or the glomerular subtype; these genomically look exactly like the 3 3s.

In fairness of the pathologist, it can be very hard to tell, in a small tumor, whether this is a sectioning artifact versus actual fusion, and very experienced pathologists will legitimately disagree on these calls.

So, those is less and less of even a question. We will offer AS to those patients. The flip side, you have somebody with... It's 3 4, but they've got six cores of 3 4, it is cribriform, or even worse expansile cribriform subtype. Those absolutely have potential for badness. I have seen patients like that who had lymph node positive disease at time of surgery.

We will offer those men surveillance, but much more cautiously. I will get genomics there. I don't recommend surveillance to those patients, but if they're really motivated for it, and they understand that treatment is a question of when rather than if; we will still offer surveillance, but their horizon is not forever. They're going to get treated in the next couple years.

But that is an important point that we always stress about surveillance is it does not mean we're never going to treat your prostate. It means it's not an emergency today. And that patient, the latter type of patient; I'm not even thrilled about for a year, honestly, because we have seen them progress quickly, but we're not going to throw the patient out other clinic if he has a strong preference for it. I've had patients who are pretty young and still trying to have another child, for example, and the delay of the year, if the genomic score is not that bad, is probably safe.

Charles Ryan: Okay. Very good. So, final point is focal therapy. A lot of people asking about it. I know there's a lot of evolution in the technology. What are you telling people now?

Matthew Cooperberg: So, there's been a ton of evolution of the technology and it's all almost beside the point, to tell you the truth. Whether we use cryo, HIFU, interstitial laser, photodynamics, irreversible electroporation, eye of newt, something...

Charles Ryan: So, just for the patients watching, there's the decision about whether you should have focal therapy, and then there is what type of therapy. And let's just say that we don't know that there is a... If you're going to have focal therapy, there's no consensus nor is there any data to show that one of them is better than the other.

Matthew Cooperberg: Zero data. No, my point in rattling all those things off is that we have lots of good ways of destroying prostate tissue. The question with focal therapy has always been, "Do we know which part of the prostate to destroy reliably?"

So, we've been doing this at UCSF selectively for many years. Katsuto Shinohara has led this program, now Hao Nguyen is doing a lot of it. We're doing focal cryotherapy. We've done about 100 cases in 10 years, and actually one of our residents just read this out. So, we're pretty selective about it, and it's a small number relative to our overall volume.

We now have the new generation HIFU system, so it's using heat rather than cold. The advantage with the new system is the ablation is actually done under realtime imaging guidance. You can really see the zone of ablation a lot more clearly than we could with cryo.

Does that translate to better outcomes? Definitely TBD, but we've really tried to be quite careful about who was a good candidate for focal. There's a lot of folks around here and actually plenty of other parts of the country who will treat pretty much any prostate cancer from one stack of 3 3 up to a whole gland taken over by 4 3 with ablation, and both of those extremes are inappropriate.

Overtreatment with focal therapy is still overtreatment. So, we are really trying to reserve focal in our practice to 3+4 or 4+3 tumors where there is an imaging visible lesion on either MRI or ultrasound, and there's no more than a small spec of 3 3 on the other side. We're trying to get genomics on everybody to make sure we're not missing bad biology, because we have seen that from time to time, and we do get a biopsy on everybody one year after to make sure that the cancer has been effectively ablated.

Focal works. We can definitely destroy tumor when we know what we're going after, and we don't see a lot of infield recurrences. You can grow a new tumor, but it doesn't usually come back in ablation.

Charles Ryan: Sure. So, that's the question is, what is victory from focal therapy? Are we ever going to do a randomized trial to look at overall survival? Probably not. Are we ever going to have a consensus, maybe we will, a short-term intermediate endpoint that we can say, "This is associated with clinical benefit." Put on a regulator hat here and say, "What is clinical benefit from focal therapy?"

I'm not against it either. I talk to a lot of people about it, but I'm also just.... I feel like I'm in the middle of a ongoing conversation about what it is and when we should do it. I agree, people go and they tolerate it pretty well and it does ablate the cancer. The question is, should I be overtly recommending it to my patients, or should I be dissuading my patients from getting it, or should I be neutral?

Matthew Cooperberg: It's neither of those extremes of course. It is an option, like everything else is an option. Like I said, it's a very legitimate option for carefully selected patients. The regulatory question, this has been going on for a couple years now, Peter Scardino and Peter Carroll and others have been meeting with FDA to try to come up with endpoints that we can really live with. And still, the jury's still out on all that. The UK is running a randomized trial.

Charles Ryan: Good.

Matthew Cooperberg: The PART trial. It is. They're putting anybody with any Gleason 7 on the trial. So you can have a high volume 4 3. They're randomizing versus prostatectomy, and the endpoint is quality of life. So, the outcome is preordained.

Charles Ryan: Well, so I think that in talking to a lot of patients, they will say, "Focal therapy might improve my quality of life because it'll give me reassurance if my PSA is down and my cancer's been ablated." That may be a clinical intervention that we who are oncology focused wouldn't say is gold standard, but it may mean a lot to the patients. And so, I think that's an area of discussion.

Matthew Cooperberg: It can be. The anxiety thing though, I think we have to be careful about that, because the anxiety is very much in our hands, for most patients. Obviously some people are really anxious about this...

Charles Ryan: It's an educational challenge as opposed to a clinical one, right?

Matthew Cooperberg: It is. The guy who rushes off and gets radiation for the one stack of 3 3 because he was too nervous...

Charles Ryan: Nervous, yeah.

Matthew Cooperberg: ... For AS, that is usually failure of counseling. There's exceptions, but that's our job.

Charles Ryan: That's a great point. I'm going to leave on that point, because...

Matthew Cooperberg: Good point standing.

Charles Ryan: It all comes back to why we sit here and do this.

Matthew Cooperberg: Exactly.

Charles Ryan: Which is so that we can educate patients, we can educate doctors, and we can communicate results of research, and that's what we want to do in the Prostate Cancer Foundation.

I want to congratulate you for your work through PCF and other entities over the many, many years we've worked together and look forward to more from you. And I always love talking because it just clarifies my own thinking so much. Matt Cooperberg from UCSF, thank you for joining us.

Matthew Cooperberg: Great to see you.