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Ashish Kamat: Hello, everyone. Welcome to the Bladder Cancer Center of Excellence at UroToday. We are here at the AUA 2024 in San Antonio. I'm Ashish Kamat, and I'm joined today by Doctors Pohar and Bree. Thank you for taking the time and spending it with us today.

The concept of surveillance for bladder cancer, monitoring bladder cancer patients, is really one of the things that hasn't changed much over the years. If we look at guidelines and urinary markers, it's a topic that every urologist and every patient is always faced with. So what we want to talk about today is the subject matter of your debate that's going to happen at the AUA-IBCG Forum.

Let me start off with you, Kamal. When you have a patient that is on surveillance for bladder cancer, and let's assume right now it's high-grade, low-grade, just take your pick. What are the markers that you routinely use in your practice?

Kamal S. Pohar: Well, I certainly use cytology. I don't use any other markers.

Ashish Kamat: And how about you, Kelly?

Kelly Bree: I'll use cytology for my high-risk patients. If it's atypical, I'll use a UroVysion FISH sometimes. I also will use blue light in those patients as well.

Ashish Kamat: Tell me a little bit about the atypical. Is it a reflex where you'll do the UroVysion test, or is it just everybody gets a UroVysion and it's ordered by pathology to do that reflex?

Kelly Bree: I only do it on the patients that are atypical.

Ashish Kamat: Okay, great. You brought up blue light, right, which is something that we all have done studies with and it really helps with the additional detection of high-grade tumors, especially CIS. And it is approved for use in the clinic. Unfortunately, it's not being supported by the device folks anymore.

But assuming you are using blue light for surveillance of patients with bladder cancer, in the setting of blue light, what do you think the role of the markers is?

Kelly Bree: It's a great question. I mean, I think that there can still be some ambiguity with the blue light areas that look a little bit purple instead of really fluorescing nicely. And so I think a marker with a really high negative predictive value where you could feel confident that that is just some inflammation from their prior intravesical therapy and we can safely forego taking those patients to the operating room, is what I am looking for in a biomarker. Saving patients from procedures in the operating room.

And ideally, as we expand it to surveillance, also hopefully eliminating some of the cystoscopies we're doing in-clinic potentially.

Ashish Kamat: Yeah, I mean, that's obviously key. We want to de-escalate therapy, our patients are older. But in the same vein, we don't want to miss tumors in these patients.

Kelly Bree: Correct, yeah.

Ashish Kamat: Kamal, your practice?

Kamal S. Pohar: A couple of comments about that. I think the role of markers in the atypical urothelial cell population is quite important, but I think it's important to recognize that the Paris Consensus Classification of urine cytology has made a significant impact in clinical practice. It was a very nice effort to develop that consensus classification, not really knowing how that's going to truly impact practice. And one of the goals was to reduce that category of atypia. And I think follow-up studies have now demonstrated that that population is five to 15%, so let's say 10% of the NMIBC patients we're following. I think Dr. Bree's comments are very relevant, that using markers for this atypical setting, but that category I think has narrowed because of that important development.

With regards to blue light cystoscopy, we're not using it in our clinics and in the follow-up surveillance setting. I wish we could, but because of some of the nuances you brought up about the technical ability to acquire the equipment, it's problematic. But there's a lot of positives about blue light cystoscopy, I think increasing tumor detection, but obviously the false positive rate is somewhat problematic.

But my view is technological advancement of enhanced cystoscopy, multi-parametric cystoscopy, I think that will be a field of fruition moving forward as we merge platforms of enhanced cystoscopy, NBI, blue light, and other parameters, merging them together. I think moving in the future, enhanced cystoscopy is like a biomarker, and so I think there's a lot of ways to improve that as a way to use technology as a biomarker.

Ashish Kamat: Yeah, you make some great points. I mean, the Paris Classification, and I think you were part of that as well when it was developed, there was a lot of resistance from a lot of folks to make it that strict. But it's very important that we follow those specifications. And I think for the audience that's listening in, if your pathologist is not following that, you should make sure that they are. And if they are, then you should make sure that the clinicians know what the different categories of a cytology being positive for high-grade, negative for high-grade, atypical, etc., mean.

But again, focusing on the markers per se, because there are so many markers that have been developed that are not used. There are so many markers in the market right now that people don't use. I mean, both of you, Dr. Bree, Dr. Pohar, both of you said that you use mainly cytology and UroVysion only as a reflex. So if you could, Kelly, just walk me through the other markers that you've thought about using and why you don't use them in your own practice.

Kelly Bree: I think the main limitation for more broad implementation of the biomarkers is a real lack of large, multicenter randomized control trials. I think when we talk about prostate cancer, for example, there's a ton of biomarkers and they have been quickly adopted into practice and guidelines, and we haven't seen the same thing happen in bladder cancer.

There are some exciting markers. Cxbladder Monitor is one I think a lot of people began implementing during the pandemic when patients couldn't be coming to clinic. It has a really good negative predictive value and is something that I think, with more data, we could easily implement into our guidelines and practice. In particular, I think the intermediate-risk and low-risk patient population—we do a ton more cystoscopies than we need to be doing. We know that low-grade tumors have a very low risk of bladder cancer-specific mortality progression.

And so these patients, I think, are the ideal candidates for us to be implementing some sort of urinary biomarker to allow us to space out the frequency of cystoscopy. Many of the biomarkers aren't great at identifying low-grade tumors, but if we're missing a small low-grade tumor for a period of time, that's very unlikely to impact a patient's cancer-specific outcomes. And so I think it would be a really important place for us to be doing larger studies to get the support to get these into our guidelines, so that more people can be incorporating them and we can be doing fewer cystoscopies for our patients.

Ashish Kamat: Yeah, no, it's important to recognize that the AUA Guidelines don't mention any marker, only cytology. And it does mention UroVysion, but that's more in risk prediction or BCG response or with atypical. Kamal, your practice, similar, different?

Kamal S. Pohar: One point that I'd like to share is we've all realized that our guidelines and our practices are trying to reduce the intensification of medical practice, reducing cystoscopy.

So if you look at the NCCN Guideline, the 2024 edition, relative to the low-risk non-muscle invasive bladder cancer category, the intermediate risk is only two additional cystoscopies, because it's recommended to do a cystoscopy at three months, six months, 12 months, 18 months, and then annually. And so there's only two additional cystoscopies in the first five years. So we've already moved towards a de-intensification of reducing cystoscopy, realizing that our previous practice patterns were probably too intense for patients so you don't require that.

There's no doubt missing a low-grade non-invasive tumor is not a threatening event, and I don't think any of us worry about that. But I would bring up that I think the IBCG publication of looking at intermediate-risk patients and stratifying based on risk factors—is there a progression risk defined as a change in grade of tumor or, more importantly, stage of tumor—was striking to me because I really didn't have that perception until the publication came out, that it varies from three to 17%.

So there is a small population in the intermediate-risk category who is at risk of progression. If the marker doesn't pick up the tumor, the sensitivity is good but it's not perfect for high-grade tumors, and you delay cystoscopy for a year, let's say for instance, I mean, there are potential people who progress. I mean, the denominator, the numerator of that is low, but it is an important event for a patient. So I think it is a tight balance about using a biomarker to exclude cystoscopy.

Ashish Kamat: Yeah, no, that's a very important point you bring up. And maybe it's a pathology thing or maybe it's the way that different centers grade. But even here at the AUA this year, in 2024, there have been some publications where if you look, the low-grade tumors are progressing. Now, are they truly low-grade tumors, or maybe there's a 10% high-grade component? We don't know. But yes, will the marker that you use pick it up, is the big question. And I think that's why the guidelines are very clear about the fact that you can't omit a cystoscopy completely unless we do these studies.

On the other hand, we find that we talk about de-intensification, but there are so many companies and drugs coming into the low-grade space, trying to increase the amount of treatment we do for patients. So it's a very confusing field, and the more you look at it sometimes, the more you get lost.

Again, just in closing, because we do have to close for time, but high-level thoughts and take-home messages for the audience that's listening. And we'll start with you and give the lady the last word. Kamal?

Kamal S. Pohar: Well, I think certainly we've moved away from single-protein cellular assays, and now multiplex assays. They're kind of pushing the field forward. I think the future's bright, biomarkers probably have a role. There's a lot going on, there's a lot that's been untapped. MicroRNAs, circular RNAs, gene profiling.

So I think biomarkers have the space, I just don't think we're there yet in many aspects of non-muscle invasive bladder cancer care that we're delivering. But I think the future's bright. There's a lot to do in the field, and I think there's a lot that could potentially push us forward as we move markers forward.

Ashish Kamat: And bottom-line message, what would you advise people listening to do in their practices as far as markers are concerned?

Kamal S. Pohar: I think cytology still remains in the vast majority of settings that we use, that we consider using a marker. I think cytology still is the relevant one in almost every setting, except for potentially adjudicating an atypical urothelial, an atypical cytology.

Ashish Kamat: And, Dr. Bree?

Kelly Bree: Yeah, I mean, I would echo a lot of the things Kamal said. I think that it's a really exciting time to be working in bladder cancer. I think there are going to continue to be more biomarkers in the space that are going to be options for us. And doing multicenter randomized control trials to help us decide which of these many biomarkers is the best one for us to be using and really focusing on how we can de-intensify care for the low and the lower intermediate-risk patients, I think will be really important.

Ashish Kamat: So if it's fair to summarize, use markers selectively, use cytology as much as you can, trust our cytopathologists, and push for more high-quality trials to be done so we can actually answer the question. Correct?

Kelly Bree: Great summary.

Kamal S. Pohar: Correct.

Ashish Kamat: Great. So with that, I want to thank both of you for taking the time. Enjoy the rest of the AUA, as I know I will.

Kamal S. Pohar: Appreciate the invitation.

Kelly Bree: Yeah, thank you so much for having us.

Kamal S. Pohar: Thank you.