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Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday by Dr. Katie Murray, who is a urologic oncologist at NYU in New York. Katie, thanks so much for joining us on UroToday, as always.

Katie Murray: Great, thanks to be here. It's so awesome to be here with you, Zach, and more so just chatting about the fun and the challenges of non-muscle invasive bladder cancer.

Zachary Klaassen: Absolutely, so we're going to have a really good discussion today. We'll have a little back and forth. We're going to talk today about risk stratification of intermediate-risk non-muscle invasive bladder cancer. And then the second part will be a little bit about the potential mechanisms of recurrence strictly related to TURBT quality, et cetera, and some of the limitations we may run into with TURBT. So why don't you just walk us through some of the guidelines and how they risk stratify patients, particularly focusing on this intermediate risk, which can be a little tricky?

Katie Murray: Yeah, so I think, obviously, we have guidelines now in today's world, which can be extremely helpful for us in clinical practice. And there's some alternating guidelines. But we'll start here with the AUA guidelines, the American Urological Association.

And when I guide patients or when I guide trainees to really think about these guidelines, it's really-- for these guidelines, it's easy to look at the low risk and understand that that's really the first time smaller, low-grade individuals and then those high-risk tumors, high-grade T1, any patient with CIS, variant histologies, LVI, and larger size of high-grade Ta.

So that brings us to the inner-- to everything else that falls in this middle, middle frame. And in the AUA guidelines, we can appreciate what the effort is here. But it is a mixed bag, meaning we think about low grade and we think about high grade as very different disease processes. But with that, our intermediate risk, it is inclusive of both low-grade and high-grade patients.

So it's inclusive of those smaller high-grade Ta tumors, so a patient with a high-grade Ta less than 3 centimeters. But at the same time, those recurrent low grades, or the larger low grades, or the real multifocal, those patients that you look in, and they've just got scattered little tumors throughout the bladder.

And I think in our minds, we think about this intermediate-risk categorization. But many of us, as urologic oncologists, and really, general urologists almost subdivide the intermediate risk a little bit to these low-grade patients is different than the high-grade patients within these guidelines. All of that being said, they do fall in this categorization of intermediate risk. And it is important for us to recognize that and really use this risk stratification to drive our treatments.

Now, let's flip over and look at the Europeans and the EAU guidelines. And there's some similarities, of course, across the board. But things that are important to recognize is they put this extra category of very high risk. So that really is those patients with high-grade T1, grade 3 individuals with CIS and other risk factors. Age, multi-tumor location, those kind of things. And then, of course, the low risk falls in the same categorization.

And then that traditional, that more traditional high risk that's really inclusive of those high-grade Ta individuals. And the EAU guidelines, really, is everything else. And they clearly state that. If they don't fall somewhere else, here's where to-- here's where to throw them. And it really is mostly inclusive of this recurrent low-grade Ta population that many of us, in our minds, think about as that true intermediate-risk categorization.

So here it is, kind of put right in front of our eyes to see these differences and really think about what our risk stratification is of intermediate risk. And, of course, there's some nuances and differences. But when we're considering that low-grade Ta population, the guidelines, and they both fall within that intermediate-risk categorization.

Zachary Klaassen: That's great. I think when we think about intermediate risk, this is all-- as you said, it's a catch-all. It's whatever doesn't fit in the low and whatever doesn't fit in the high. And certainly, traditionally in the guidelines, we've seen that a lot of intermediate risk kind of gets treated, in the patient treatment, as a high-risk patient.

So I think we're starting to see across several different opportunities, some clinical trials coming out in this low-grade and intermediate-risk stratification. So just this-- we look at AUA, it's kind of laid out very specifically. You mentioned high grade, low grade, a lot of different items. The EAU's a little bit of a catch-all.

How may this affect clinical trial eligibility? Because we're starting to see several trials and several that have read out already in this intermediate and specifically low-grade, intermediate non-muscle invasive bladder cancer.

Katie Murray: Yeah, so I think it's a little bit tough when we think about this for clinical trial eligibility because of that combination of having both low-grade and high-grade Ta individuals. So it does make clinical trials and then potential FDA indications that may come from those trials to be a subset of intermediate risk.

So it's intermediate risk of a low-grade individual. And so it makes eligibility a little bit tougher where it just can't be a catch-all. You can't say every patient across the board for intermediate risk falls in the eligibility criteria for this clinical trial. Or maybe in the future, like you said, trials read out for an FDA-potentially indicated drug.

Zachary Klaassen: Yeah, absolutely. I think the EAU does a great job with their clinical guidelines. But I really do focus on the AUA when I'm looking at intermediate risks. I think it's a little more specific in terms of-- and it's easier to understand when we're looking at those specific bullet points versus kind of a catch-all.

Katie Murray: I agree.

Zachary Klaassen: I think we've talked about clinical trial eligibility. I think this next bullet point kind of fits into that too. But ultimately, it's really staging this patient, giving them a proper risk stratification. So how can some of this heterogeneity in intermediate risk potentially under/overestimate the patients?

Katie Murray: Yeah, it comes down to that low grade versus high grade of an under- or overestimation. And part of that comes down to TURBTs, how we identify specimens. Do we take a separate specimen for every single multifocal low-grade tumor to ensure that there's no underlying high-grade disease, to really estimate that risk?

But I do think I'm very similar to you, Zach. I like the way that the EAU guidelines are. But I'm pretty strict in following the AUA, at least here. And I train residents and things like that. And so I do think when somebody just throws out intermediate risk, I'm really thinking of that recurrent, low-grade patient that really becomes a very annoying of a disease for that individual, when they're tired of having so many cystoscopies and so many procedures.

Zachary Klaassen: Yeah, absolutely. And we've kind of hit on this already a little bit in terms of maybe a high-grade Ta behaves a little different than a larger low-grade Ta. Depending on-- and there's a lot of discussion about this depending who you talk to across the country.

Some people don't give any BCG to low-grade tumors. They don't think it works. But they're intermediate risk, so it's indicated. The high-grade Tas, whether it's 1 centimeter or 2 centimeters, those are ones that may benefit from BCG or other therapies. So I think we've kind of talked about this. But maybe just to expand on it from recurrence risk, because once we have a recurrence, it predicts future recurrences and so forth.

Katie Murray: Yeah, I think that's absolutely it. And I think when we're initially talking to a patient who has a large low-grade Ta tumor, it really is talking about why are-- why do you fall in this intermediate risk? You fall in this intermediate risk because the risk of recurrence of this disease is so important.

But I do think that heterogeneity is really what splits us. Because I believe these are two very different actors. And those first couple follow-up cystoscopies in the office are extremely important of where that pathway plays out for these individuals. So the answer is no, they probably don't behave the same way. But then when you think about it from a guideline, you realize that's why they fall in this intermediate-risk categorization for both of them.

Zachary Klaassen: And I think just to call it a little bit, obviously, we just included EAU and AUA guidelines here. But the IBCG has done some really nice work led by Ashish Kamat, kind of teasing out a little more of this intermediate-risk heterogeneity that we're talking about. So they've got a great paper in European Urology if some of our listeners want to look at that. So great discussion. I'd love for you just to walk through a couple slides here on TURBT.

Katie Murray: Yeah, I think that the last point of the last slide kind of fit right into this TURBT. And really, when we're thinking about even the large, low-grade Ta tumors, the importance of a complete resection. An incomplete resection, all day long, will set your patient up for a recurrence.

And so here's a great picture of not necessarily an incomplete resection, but an incomplete visualization, meaning a missed small tumor of a multifocal-- maybe it's a small satellite lesion in close proximity to a bigger tumor. And whether that's low grade or high grade, you have-- it's destiny that patient has an early recurrence. And really, it was just a missed TURBT.

So I think the idea and the concept of large tumor size and full complete resections is so utterly important. And really, the mainstay of all intravesical therapy, which is where we're thinking about all of this, is solely based upon a completion TURBT.

Zachary Klaassen: Yeah, absolutely.

Katie Murray: But TURBT is not perfect, right? You and I both are in situations where we train residents, and we have students, and we've been in our own training. And TURBT is a tough and a skilled operation that sometimes is overlooked. Understaging is problematic. Ensuring that you get a good, complete resection, but have viable tissue, so that the pathologist can confidently tell you is this low grade or a potential underlying high-grade disease.

That multifocality, ensuring that you get all of those. Of course, tumor size, we see this across the board. Estimating tumor size within a bladder is probably close to impossible. I like to think we all know how big an inch is and how big a centimeter is, but I think that's probably not true.

And then, of course, tumor location, meaning there's no doubt that there's locations within the bladder that are more dangerous, more challenging. And so there is definitely a hesitancy to have a more potential incomplete resection for those individuals. Occasionally, we're talking about limitations, but they also don't come free of side effects, right? It impacts patients' lives. They miss work. They have to cancel things to come for surgery. And they might have to have lots of TURBTs and lots of surgeries. And so side effects happen at the same time.

Zachary Klaassen: No, great review. And I think, certainly, those last two slides are not fully comprehensive. We could have a full discussion on that. But that was just some of the highlights that I figured we'd throw together.

I think when we-- you mentioned it, that this is really the crux of risk stratification, right? Being able to assess how many tumors, how big they are, we saw that in the guidelines. This is crucial. Obviously, getting a good specimen, pathologists are maybe a little more apt to call high grade versus low grade because they don't want to miss something.

So all of this plays into the ability to properly risk stratify somebody specifically in that low-grade intermediate risk that we've been talking about. So maybe just expand on that a little bit because I think this is an important take-home point.

Katie Murray: Yeah, so a first-time patient with low grade less than three centimeters is a low-risk categorization. But if and when that tumor, that small tumor that we saw in that earlier picture is left behind, three months down the road, when you see that and that automatically becomes the recurrence, that patient gets upgraded to an intermediate-risk categorization.

And then that pushes them down the line into intravesical therapies. If you believe in BCG for low-grade categorization for early recurrences, it could push patients into getting BCG at an earlier standpoint. And so really, you just-- we just cannot miss things on TURBT. And we just cannot leave tumor behind because it can quickly put somebody from a low risk to an intermediate risk, or maybe even more concerning, obviously, from an intermediate risk to a high-risk population, potentially for a patient that really could have stayed at that intermediate risk had we caught it the first time.

Zachary Klaassen: Yeah, very well said. I think we talked a little bit about this already. But I think this is all about clinical trial enrollment. And I think, certainly, intermediate risk has been kind of a desert for clinical trials until recently, so whether that affected enrollment. But again, just to reiterate some of the points we've already made, this is super important for making sure that we properly risk stratify that at the time of that TURBT to get them into the appropriate trials.

Katie Murray: Absolutely, I think-- and it's kind of been, like you said, not really looked at. Nobody's been very excited. We've just kind of pushed these patients along and set them up for a lot of recurrent cystoscopies and TURBTs. And so it's a really exciting time that we may have something to offer for these individuals in clinical trials or future FDA-approval medications. But it really falls on us to make sure that we identify them correctly to make them eligible because they're there. And they are eligible. But we just have to find them and treat them appropriately.

Zachary Klaassen: Yeah, well said. Great discussion, Katie. Anything we didn't hit on you want to touch on? Maybe a couple take-home messages for our listeners?

Katie Murray: Yeah, I think the importance of guidelines, because as much as there is heterogeneity, there are very much similarities across the board. And the way we practice with non-muscle invasive bladder cancer, there's a few nuances here and there. But following guideline-based therapy is so important. The importance of an excellent TURBT really is the mainstay for these individuals.

And then that TURBT doesn't come free, meaning it does have its own limitations. Those come from the equipment. Those limitations come from our skills, from our eyes, the pathologist's eyes, and then, of course, the implications of a TURBT on a patient. So these patients exist. We must identify them so that we can put them in the appropriate trials and really advance the field and make better treatments for our patients. That's what we're here for.

Zachary Klaassen: Wonderfully said. Great summary. Katie, a fun conversation. Thanks so much for your time and expertise here on UroToday.

Katie Murray: Yeah, thank you.