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Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. We are a one-stop destination for the latest developments in the field of bladder cancer. I'm Ashish Kamat, Professor of Urology and Cancer research at MD Anderson Cancer Center in Houston, and it's my distinct pleasure to welcome Dr. Angela Smith today who is joining us from North Carolina. Angie is well-known in the field of bladder cancer. She is an Associate Professor at the University of North Carolina and Director of Urologic Oncology and has done a lot of deep dive and thinking into things to benefit both patients and the community when it comes to bladder cancer.

And today she is going to talk to us about her thoughts on the deintensification of the management of low-risk, non-muscle-invasive bladder cancer, which is a very important hot topic currently, as we try to decrease the burden that our patients with bladder cancer have to face in their navigation through this journey. So, Angela, it is my pleasure to welcome you. And if you're ready, you have the stage.

Angela Smith: Yes. Thanks so much, Dr. Kamat, I'm really pleased to be here, and I am really excited about this particular topic. As you said, we talk a lot about high-risk, non-muscle-invasive bladder cancer, but, there's a lot to consider also in the low-risk, non-muscle-invasive bladder cancer category. And so I'm going to be talking a little bit about deintensifying, what we know to be the management of that today, and I will just kind of briefly run a few, and we can have a nice discussion about it. I'll talk a little bit about deintensifying management of low risk in the context of surveillance biomarkers, as well as treatment. But before I get into the bulk of that talk, I just want to recognize that we should really ground ourselves in the risk categories and what those are.

So these are the AUA risk stratification tables with three categories; low, intermediate, and high risk. And the reason I bring this up is that low-grade bladder cancer can go either into the low-risk category, or it can be an intermediate risk. So if I'm just talking low risk, this is the solitary, smaller, low-grade lesion, that has not recurred. But if it's recurred, especially if it's recurred within one year, if it's multi-focal, if it's large, it is then an intermediate risk. And so I just want to sort of frame this conversation, but I will be talking about both risk categories because I think there is relevance in both with regard to the low-grade disease.

And in terms of the natural history of low-grade Ta bladder cancer, I think it's important to speak about it because that is why the risk groups matter. There was a large retrospective series of around 1400 patients with low-grade disease that they looked at this low-risk and intermediate-risk categories, and what they found was that overall five-year progression-free survival was 95%, cancer-specific survival is 98%. But if you take the risk categories, those who were intermediate risk, so those who were recurring or had larger tumors, had higher recurrence rates, higher progression rates, and higher cancer-specific mortality, albeit still low if they were low grade.

And so with that backdrop in mind, I'm going to start with surveillance and describe what we know. I always like to go back to the guidelines. And so here are just sort of a table that I put together based on a variety of guidelines. And I sort of ordered them in, let's call it, more aggressive on the left, to more conservative on the right, I guess, depending on the way you'd look at it.  AUA says that we should be doing a cysto at three months, I think everyone agrees there, but there is a little bit of diverging opinion about basically how frequently to survey, and also when to stop surveillance. So if you look at the AUA risk categories and the search suggestions in the guidelines, it talks about shared decision-making after five years.

EAU guidelines on the other hand, say no cystoscopies after five years, and the NICE guidelines actually say no cystoscopy after 12 months for the low-risk categories. So, you definitely see a divergence of opinion on how often we survey. And so there is this question about whether we are surveying too much or not enough. I would very easily argue that the answer is not, it's not enough. I mean, it's definitely, either we are surveying as much as we need to, or potentially too much. And so there is a study out from Dartmouth, with Florian Schroeck's group, looking at the overuse of cystoscopic surveillance among patients with low-risk disease, and what they found in a span of about six years was, cysto overuse occurred in about 75% of these patients with low-risk disease, with in excess of 1800 more cystos performed than what we are recommending. And this is just with the AUA related guidelines. This is not even speaking about whether those guidelines could be potentially relaxed in this patient population.

And what does that translate to? Well, it's costly. In terms of cost, there was basically a Markov model that Matthew Mossanen took a look at looking at non-muscle-invasive bladder cancer and found that the accumulative excess cost was about $52,000 for low-risk disease and even higher for intermediate-risk disease, almost $150,000, due to the excess of surveillance. And this is not just costly in terms of money, but also in terms of patient burden.

So we have to think about all the excess cystoscopies these patients have to undergo. And this is a study out of the UK, and I thought it was interesting because they posed this hypothetical biomarker that could be done in lieu of cystoscopy. And interestingly, despite this idea of patient burden, I think that if we were to move in this direction, there is really a high bar that is really being set by patients because what they found was that a majority, around 90% of patients preferred flexible cystoscopy if the test sensitivity wasn't 90% or higher. And so they, in essence, had a pretty high bar before they would give up cystoscopy. Now, that being said, I'm sure there are other studies that could be done in terms of acceptance and understanding as this was a hypothetical situation.

So I think that argument for overuse of cystoscopy for surveillance leads naturally to this biomarker idea and biomarkers could either improve cystoscopy, in terms of when we are worried about missing something or in this particular case, maybe avoiding cystoscopy or deintensifying the surveillance strategies. And going back to the guidelines, really no biomarker has really been accepted either in the EAU or the AUA guidelines at this point.  We just really haven't gotten to that point where it can supplant cystoscopy.

And I'll just very briefly run through a few biomarkers. I think that largely, there are three, Cxbladder Monitor, Xpert Bladder Cancer Monitor, Bladder EpiCheck, and we can talk a little bit about these. I don't use a lot of biomarkers. I'm interested in discussing this with you Ashish. But, I have with the pandemic, started thinking about using Cxbladder Monitor, which is particularly, basically a biomarker that looks at the expression of five genes in voided urine. It also incorporates some clinical factors to determine essentially a score.  And Xpert Bladder Cancer Monitor is another one, Bladder EpiCheck is a third. And sensitivities range, they are not as sensitive in low-grade disease, 90% in terms of the range, the negative predictive value is around 90%, but certainly not hitting the bar that we would want at least with what patients seem to desire.

And then the last thing I'll say is, just any advancements in the treatment that we have for the low-grade disease. We covered surveillance, we covered biomarkers, and what about strategies to de-intensify management? Well, again, going back to those guidelines, there are statements about using fulguration or laser vaporization of the small papillary recurrences among patients who really you know, they are just frequently recurring low grade, bladder cancers, but we don't have good prospective comparative studies to assess outcomes over time.

But it's certainly an option that both guidelines highlight. And then, Ashish, you are part of, of course, the IBCG, so this is your paper, of course. And I think it's a good one because it talks about risk-adapted management of low-grade bladder tumors. And in that paper, it says, we can consider management conservatively with office cysto and fulguration, or taking an even step further, active surveillance protocols. And there have been some trials that have been tried, but it is difficult to recruit to trials like that.

And then I'll end with a new agent that is a non-surgical treatment for low-grade, non-muscle-invasive bladder cancers. Basically, it's UGN-102, and it's essentially a thermoreversible hydrogel, which what that means is, unlike a liquid that you would have in a cup at room temperature, which would be obviously liquid. But in this particular case, this agent at room temperature would be a gel. It turns into a liquid if it is frozen or if it is left in colder temperatures, but it can be, basically combined with mitomycin-C to allow longer dwell time. This was already studied in the OLYMPUS Trial for upper tract urothelial and its been approved, but it is also being evaluated in the lower tract as well for low grade, intermediate-risk, non-muscle-invasive bladder cancer, and the ATLAS Study is going to be taking a look at that.

I'll just show right here, the complete response rate here was 65%. So, especially for these patients who have frequently recurring low-grade disease, it could be a potentially very useful option to avoid surgery. And I'm doing a study right now looking at whether we as urologists tend to minimize the impact of TRBTs. We do so many of them, but there are certainly, there are a lot of challenges with them. I mean, patients have to take off work, they undergo surgery, there are costs, there are symptoms, the list goes on, so we have to consider that as well.

So I'll just leave you with these take-homes, that I think there is a really good case for deintensification of low grade, non-muscle-invasive disease for bladder cancer. There are a lot of strategies that we could potentially consider to do this effectively. One is reducing surveillance. Another is thinking about how to effectively use biomarkers. The third is surveying known small, low-grade tumors which are potentially not growing very quickly and using non-surgical management of novel therapies to manage recurrences rather than proceeding directly to the OR for TRBT. So with that, I will end and I'm interested in having some discussion about the topic.

Ashish Kamat: So thank you so much, Angie, I really enjoyed listening to you speak both today and previously when you've given this talk, per se. You raise very, very important points and points that most of us that are in the field of bladder cancer, have had to think about either because we think about it ourselves or our patients make us think about it, right? And the fact that you've been able to distill all of that into one talk is really commendable. For the interest of our audience, per se, let me just highlight a point that you made, which is that even though you will often hear people say that, "Oh yeah, patients hate cystoscopies, they can't stand it." If you actually ask the patients, they like the certainty that looking in the bladder gives them, as far as you being able to tell them that there is no cancer in the bladder, right?

So I'm glad you highlighted that particular study and others as well.  Some of them actually quote that patients want a 99% certainty before they will forgo a cystoscopy. But then on the other end of the extreme is that patients with low-grade disease who almost never will progress on the first two to five years, don't need to have cystoscopies every three months. So, you presented that table where you compared and contrasted the different guideline recommendations. Could you share with us your thoughts on what you do with your patients and what you think is the best guideline in some ways? I guess the Angie Smith guideline for low-grade bladder cancer.

Angela Smith: Yeah. I think that's like the million-dollar question and what I have to say is that I'll share my approach, and I think my approach is consistent, but I don't think my answer is consistent because it really depends on the patient. So I guess if you have to pick one of those categories, it's the shared decision-making model. I like shared decision-making. I think it's a great method because every patient is different in terms of their preferences, their anxiety. I mean, we might take into account, the cost and the issues surrounding cystoscopy, the risks. But, we also have to consider the risk of anxiety that that patient might have. Now. I do see my role as educating my patients about some of these risks. Really, what are they? I mean, are they as bad as they might think, and that answers often with low grade, "No, it's not."

And so that may take time. I usually, with each patient, actually use the prior cystoscopy to set up the next one, meaning that I plant a seed in their head. I talk about the fact that this is a disease that can recur but is unlikely to progress, just as you mentioned. And we tend to relax surveillance because of that. So, maybe next time, if you show that you, again, don't have a recurrence, let's consider relaxing that next time. And it allows them to just mull it over, versus me just saying it right then, and they have to make a split-second decision, which I'll tell you, most people will not do. I think they are accustomed to having the surveillance, knowing it, and feeling confident in that, even if they don't like the cystoscopy itself.

So I would say as my consistent message is that I try to stay a little ahead of it, to plant seeds of thought to the patient so that they can consider that it would be safe to deintensify surveillance. And many times, especially as patients get older, have competing co-morbidities, I try to convince them that having these cystoscopies are not really necessary at this point. And I'll say, I'm not always successful. They sometimes really feel more comfortable with having annual cystoscopies. Sometimes there is always a negotiation between a year or maybe 18 months or two years. So I just try to do that in a way that also honors their needs but also educates as well.

Ashish Kamat: So that was very well articulated because I think what you essentially summarize it, that it is a shared decision making, and obviously we have to not only treat the disease that the patient has but the patient as well. And I'm complete with you as far as educating the patients. Sometimes it's just telling them repeatedly that, "Hey, I've done your cystoscopy today, but you really didn't need it. And look at your bladder, it looks so great." Right? And then they get used to that. But again, I have patients who are now 20 years out of their low-grade bladder cancer, and I've told them you don't need to see me anymore. And we don't even schedule something, but they will show up in clinics and go, "Can you please do it anyway?" Right? So we have to kind of respect some of the wishes that our patients have and take care of them in that sense.

This brings me now to markers. And you brought up markers and again, our guidelines don't really recommend the use of any urinary marker other than cytology and UroVysion for high-grade bladder cancers, and it's based on some of the work that we did here many years ago. But for low-grade disease, low-risk disease, none of the markers are actually recommended, but I think that is because currently the markers have been used as an adjunct to cystoscopy. So notwithstanding the data that you alluded to, what has your sense been when you've been thinking about this and chatting with patients and considering all the various studies that you are involved with, with patient outcomes, as far as designing a study of markers versus cystoscopy and looking at outcomes?

Angela Smith: Yeah, it's a great question. I think that interestingly, so I would say that I'm a person who very uncommonly uses markers, it really has to change my management. I feel like a good biomarker study needs to well-defined whether a meaningful change in management occurred, and that would potentially, in this case, a meaningful change in the way that we survey. And so, what I've noticed is with the pandemic, I think that sort of got me thinking about how to effectively use some of these biomarkers in that way. And as just one example, and I'm kind of curious to see, Ashish, how you use them because I found that urologists certainly differ in the way that these are used because well, they are relatively new. But, I now use Cxbladder Monitor for some of my patients who really didn't want to come in for cystoscopy and they were nervous.

They wanted to do something, but they wanted to have a sort of, I always say, you need two points to draw a line, three points is even better. They just needed that one additional point that made them feel comfortable that they could come in safely during a pandemic. Now, our hospital was safe, I think. But this is all again, how the patient is viewing their situation. And so I did, I used Cxbladder Monitor for that purpose and I think it served its purpose and there were several patients that had low risk. And so they stayed home and we basically decided, and we are actually going to in perpetuity at this point, use it to alternate between, these are intermediate risk patients, but alternate between using Cxbladder Monitor and a cystoscopy. So I don't know what the right answer is, but certainly I think whatever study that looks at biomarkers needs to make sure that it is evaluating whether changes in management actually take place.

Ashish Kamat: Right? No, I agree. And since you asked me, I'll share what I do, but I do want to put in a disclosure. I've been involved with all the companies that you mentioned and some more in the trial design and some of the publications. So with that disclosure in mind, let me just state, I do not use any of them. In patients that have low grade, whether it's low risk or intermediate-risk patients, I use cytology. And the reason I use cytology is because, and again, this is after discussing with a patient, right? Because what I tell them is that if you are worried and you want to have more frequent surveillance, it's because you're worried that we will miss something that is high grade, because if you miss something that is low grade, even if you wait for four, five, six months, there is something known as active surveillance for bladder tumors that are low grade.

And sometimes, patients that have an active tumor in the bladder, we'll both look at it on the screen and I'll look to the patient and I'll tell her, "Hey, we're going to watch this. I'll see you in six months. And if it grows, we'll do something with it or not." So that's why I don't really need to know if the patient has a low-grade tumor, if we've decided we're not going to do anything about it for a while, but I want to make sure they don't have a high grade tumor. And our cytopathologists with the new PARIS Reporting System can report out high grade cells, fairly reliably. Low grade, not so much, but that's okay, because I'm not that worried about missing it.

So I use cytology, but using any of the markers in the way that you've mentioned as a replacement for cytology in the setting of low grade disease is very reasonable. The reason I don't is because they all have false positives. And then, we did studies previously that suggested that you, even though it's a small number of patients, there are enough patients that we would then chase and keep doing imaging and ureteroscopy, et cetera, because they had one marker and were anxious, even though you knew it was probably a false positive, that it wasn't worth the mental anguish for them. So that's how I use it. But your strategy is something, it's very reasonable.

Angela Smith: Yes. And I've actually, I'll just say, I would say I'd probably do the same thing, I just didn't communicate that very well. I use cytology, absolutely, I agree completely. I state that to the patients as well. I think what I, and for the pandemic, what the issue was, in order for me to get cytology, the patient has to come in and give me their urine. And I had some patients who didn't want to come in. And so these biomarkers, there are opportunities that they can send their urine in.  And so that was just a unique way that I didn't foresee using them but did in those particular cases and it was just a handful of them, but it was useful when they didn't want to leave their home. They could literally put in a package, have it sent and that was that. But yeah, I agree with you, cytology is incredibly useful for the reasons you describe.

Ashish Kamat: Oh yeah, no, again, just to clarify, I don't know if your lab doesn't do this, but there are mail-in cytology kits where essentially a [crosstalk] was sent to the patient.

Angela Smith: Oh, I see. I see. Yeah, no ours doesn't do that.

Ashish Kamat: Yours doesn't do that. Okay. Because they can essentially mix the preservative themselves and then mail it in the same way they would do a marker. I know the folks that make Cxbladder and others, they make it very easy with a self-contained kit, but you could potentially do that for cytology as well. Angie, this is a great discussion and we could chat a long, long time, but in the interest of time, I do need to wrap up. So I'll give you the stage, maybe share your closing thoughts with our audience.

Angela Smith: Yeah, absolutely. I would say that just like in prostate cancer, we've gone through this transformation of basically deintensifying the way in which we treat the way we think of this disease. I think we need to do the same for low-grade, non-muscle-invasive bladder cancer. We all see the very common sentence that bladder cancer is the most expensive cancer to treat from diagnosis to death and low grade contributes to that cost. And so I think, it's not just a monetary cost, but also a burden to both a workforce issue, as well as the burden to our patients as well.

And I think there are just a number of strategies to do it. We can think about surveillance. We can think about biomarkers and finally ways to minimize the sort of, we didn't get to it, but to minimize surgery that was required. And I would argue not really required for these small, recurrent, low-grade lesions that could potentially be surveyed or potentially use novel agents for chemo ablation to prevent future recurrence. So I do appreciate you asking me on here, and it was really an interesting discussion.

Ashish Kamat: No, the pleasure was all mine. Once again, thank you so much for taking the time. And I guess even though it's 2021, I still have to say, stay safe and stay well.

Angela Smith: Absolutely, you too.