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Ashish Kamat: Hello, everyone, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, and I'm here at AUA 2024. I'm joined by two bladder cancer experts, Professor Mariappan and Dr. Psutka, who are joining us today to share with us, the audience, their views on a very important topic, which is how do we take patients that are on whatever treatment, surveillance, etc., for what we consider to be low-grade intermediate bladder cancer? And how and what do we do with them as far as treatment, observation, de-escalation of therapy, or ramping of therapy is concerned? So it's a very important topic nowadays. Everyone's discussing this. Let me start off with you, Sarah. So you have a patient that has low-grade, intermediate-risk bladder cancer that comes to your clinic. What's the thought process in your mind when you're considering what to tell that patient?

Sarah Psutka: First and foremost, this is actually a really challenging patient population. I would just say I'm grateful that at this point I think it's become a high-priority topic that a lot of us are talking about because we've realized, one, it's a big patient population, a lot of our patients fit in this box, and the decision-making is actually pretty complex. Largely, because we have a couple of different options, but I'd say the key points of the conversation are, one, this disease process is really problematic. It's incredibly bothersome, it is likely to recur, and it causes a tremendous impact on patients' lives, their quality of life, and how they live their lives. I also tell patients, "We're going to be friends for a really long time because this is something where we're going to be seeing each other repeatedly to have conversations. There's going to be escalations and de-escalations in the intensity of our conversation." So I think setting that stage early just allows patients to understand what they're about to grapple with and contend with.

But then a big part of the next steps in the conversation is actually getting to know the patient. So we talk about the fact that there's a high risk of recurrence. Most of the recurrences are going to be low-grade, almost all of them, but it has a higher likelihood of continuing to come back. And so then, we get into a conversation with patients about what is their appetite for... What is the most important thing for them and the highest priority outcome? So I say, "What does a good outcome look like to you? Is it minimizing time in my office, in the operating room, in undergoing therapy and minimizing side effects? Or is it doing everything we possibly can and minimize the likelihood that this thing comes back so that we just go onto a surveillance plan?" And once we have that conversation, I sort of know how to start to present data and to think about risk stratifying and then talking about the intensity of approach of therapy.

Ashish Kamat: That's a great point you bring up, right? Because when you think about patients, we have to not only think about what we know about the disease but what does the patient know about the disease. And you brought up the issue of risk stratifying. So, Param, your thoughts on how you counsel a patient, but also if you could share with us how you risk stratify this broad category of patients that's intermediate-risk bladder cancer?

Param Mariappan: Absolutely. And, Ashish, the points that Sarah made just now are completely valid. It is important that we tailor the management of these patients and all of the bladder cancer patients according to the patient who's sitting in front of us. Gone are the days when we go to the patient with data and describe, "This is what is probably best for you," not really taking into account what the patient actually desires. For me, the focus should be slightly a bit more upstream in ensuring that the first resection and the resections afterward are done well. Documenting tumor features so that we can determine what's the best intravascular treatment that this patient should have and ensuring that the cancer is cleared properly. And only after that do we sit with the patient and discuss where we go from here.

So the risk stratification that we would approach this with is to try and ensure has the first resection been done properly? Have we cleared it? Is the quality good? Have we got to choose the muscle? Not necessarily in all of the low-grade cancers. Have we used a single installation of chemotherapy afterward, and have we adopted adjuvant chemotherapy? Once we've established that, then we discuss, is there any role for any further adjuvant treatment, and how do we want to tailor surveillance? Surveillance is also important. The quality of that surveillance is also vital because we are starting to think about using methods such as enhanced PDD, for instance, to try and identify little subtle tumors that you may otherwise miss. Now there are patients who actually desire to have the tumors cleared rather than having cancers followed up. Active surveillance, for instance. But again, as I say, it needs to be tailored according to the patient who's sitting in front of you.

Ashish Kamat: So, you again raised the issue of TURBT initially when you see a patient that has intermediate-risk bladder cancer, right? So let me push back a little bit on that and ask you, do you really think that every patient that has a prior history of low-grade disease and comes and sees you with new tumors in the bladder needs a TURBT? And I'll ask you and then I'll ask you, Sarah, too. So first, you.

Param Mariappan: Not necessarily. Again, a lot of it depends on, "Have I got enough information to determine or tell me what the biological potential of this cancer is going to be?" If the answer is no, then I'd like to establish more information from either looking back into the bladder myself using all of the adjuncts that I have to try and establish that diagnosis. If we have established that, then following this patient up, either with active surveillance or office fulguration. We have lots of tools in our armamentarium now to try and adopt minimally invasive procedures, and including maybe even discussing something like chemoablation, although that's a bit dubious.

Ashish Kamat: And Sarah?

Sarah Psutka: Yeah, I think... So, the point, what we know about these tumors is that up to five years out, the likelihood that we're going to get a high-grade recurrence if we've had multiple low-grade papillary tumors previously, so this patient truly fits into that intermediate-risk bucket, then we're pretty certain it is likely to be a low-grade recurrence. So we are also, I think, as a community, as folks who see a lot of these, pretty good at determining the likelihood that a tumor is going to be low-grade. If that tumor that recurs, if the area of recurrence looks atypical, that's somebody who I want to rebiopsy. If I'm worried that this could be a conversion to CIS or if it has higher-grade features, it's more sessile, it doesn't have the typical papillary, sort of more indolent appearance that we associate with these. That's somebody who needs to be re-resected, for sure. And I let patients know if I'm uncertain, and I would counsel them in that direction.

But for someone, for example, who crops up with a one to two millimeter papillary lesion that looks like the tumors that I've been seeing in their bladders for years, I have a low threshold to offer other options. And I present the smorgasbord, which is everything from going to the operating room to, a lot of times, if I am going to offer an in-office procedure, I do a biopsy before I fulgurate, just to have that as a second sort of gut check. And, of course, your cytology, because I don't do the biopsies in the same session that I diagnose them. So if I'm doing a surveillance cystoscopy and I see something, I get a cytology. Normally, you obviously wouldn't do a cytology in someone that you're surveilling for intermediate-risk disease usually, or certainly if they have a history of low-grade tumors.

But if I do see a recurrence, I do check a cytology because if that's high-grade, then that changes my pathway obviously considerably. But if they have surveillance cystoscopy with a low-grade appearing tumor and negative cytology. Those are patients who I would certainly offer the opportunity to, one, come back in the short term for surveillance. But I would say I generally do that less in practice, but I do very much utilize in-office biopsy and fulguration for small, recurrent papillary tumors. And patients oftentimes will sort of lead you with, again, their priorities in terms of the intervals between those interventions and also their willingness or preference to avoid another general anesthetic.

Ashish Kamat: Both of you are obviously core members of the International Bladder Cancer Group, and the International Bladder Cancer Group has put out the risk stratification to try to help us understand what buckets these patients fall into. Do you use that in your practice? Do you find that useful at all?

Sarah Psutka: Yeah.

Ashish Kamat: Sarah?

Sarah Psutka: I certainly do. I think that looking at things like size and obviously the grading is important in this stage, but I think that the other things that I do think about are obviously interval to recurrence, sort of the temporal nature of this patient's disease process. And that oftentimes, I think, also helps to inform the decision-making, but specifically with respect to risk-adapted surveillance and the intensity with which you treat that tumor. I think it's a really helpful, data-driven paradigm. And obviously, it's been validated, as you've recently published.

Ashish Kamat: Param?

Param Mariappan: I would agree. I don't necessarily use it all the time. And again, the emphasis being a bit more upstream in ensuring that the cancers are cleared well. Because I believe that if... Because intermediate-risk is made up of both new and also recurrent tumors, we can actually reduce the proportion of patients who have recurrent cancers, and thereby reduce future recurrences as well. So it is part of the toolkit that we have, but unfortunately, it's not necessarily all of it.

Ashish Kamat: Absolutely. So we have to take all of these factors. And just to summarize for our audience, you would look in the bladder, number of tumors, size of tumors, prior history. Are you comfortable with the pathology, cytology? Especially if you're considering active surveillance, as shown in the Italian studies, very, very safe to do it so long as you follow certain criteria. But now I'm going to ask you something controversial, and there's a big push in many places... And, of course, we have to do these studies to see if it can start treating patients that have intermediate-risk disease after resection with drug X, whatever that drug is. And on the other hand, we're talking about de-intensifying treatment, right? We're talking about doing less to patients, taking them less to the operating room, less anesthesia. So where's that balance? Why are we going in both directions? And here, just share with me your personal thoughts, and let me start with you, Param.

Param Mariappan: I think we need to be very honest with patients, sitting with the patients and making sure we have established what is important for this patient. Regular visits to the hospital, regular visits into the theater, and having resections or even surveillance for that matter may not fit well. And in the NHS, it's really quite challenging these days to try and bring patients into the OR. So what I'd rather prefer is to sit down with the patient and decide, "Do you really want drug X, which might come with additional side effects and a burden of surveillance and keeping an eye on potential side effects, etc.? Or would you rather me just keep an eye on things remotely and come back to me?"

There are a population of patients who actually prefer to not come into the hospital but actually come back to us when they actually have a problem. So the low-grade, intermediate-risk patients, if that's the group that we are still talking about, are not necessarily life-threatening illnesses, and the patients need to recognize this. Yes, we do count recurrences as endpoints suggested by the IBCG, obviously, but they may not necessarily be patient-centric endpoints.

Ashish Kamat: And Sarah?

Sarah Psutka: Yeah, so I think the trade-off with chemoablation is you're avoiding the trip to the operating room, which is a general anesthetic, and it's a day lost for a patient. The risks associated with that procedure, which are arguably compared to a lot of what we do, low risk, but there's substantial risk, especially in this highly vulnerable patient population associated with any general anesthetic. I have patients who talk a lot about the impact on things like their short-term memory or the fact that even if you take... I have a number of nonagenarians in my practice. And a day of general anesthesia is generally followed by several weeks of getting back to their baseline. So that's substantial. There's also, I think, cost associated with that. And discomfort, catheters, potential risk of retention after the procedure, things like that. On the other side, chemoablation, you're talking about potential financial toxicity. You're talking about multiple trips to the clinic, not necessarily in the operating room. You are avoiding the general anesthetic, but then there's the potential side effects of the therapy. And so it comes down to patient priorities.

But I do think that a lot of the chemoablative studies that have demonstrated three-month CR rates that are actually fairly encouraging if we look at the UGN-102 data. If we look at even the intensified mitomycin-C data, 70% of patients could have avoided a TURBT. That's substantial. If you want to think about healthcare systems, cost savings, and days in the hospital, and OR time when we're all under increasingly strapped situations where it's hard to get our patients into the operating room because of the volumes of people we're seeing, that's something to be considered from as a societal perspective, not just a patient perspective. But it ultimately, of course, comes down to the person that we're talking to in front of us. And again, what does a successful outcome look like to them? I think that it'll be very interesting as we start to think about novel drug delivery techniques and options if we can develop treatment options that allow a lighter touch, less time intensity, less treatment burden. The question, of course, is going to be, "What do the side effect profiles of those drugs look like?"

Ashish Kamat: Right. Exactly. And we have to use everything in our armamentarium. For some patients, active surveillance might be the best thing. For another patient, you might want to actually intensify treatments so they don't have to come back for these repeated procedures. You might want to do targeted therapy with FGFR-based therapy or what have you. This has been a great conversation, but I still want to leave you both with the opportunity for closing educational thoughts for our audience on the best way to approach a patient with intermediate-risk bladder cancer. So I will start with you and then give the lady the last word. Param?

Param Mariappan: Sitting with the patient. This is hugely important. We need to start measuring quality of life as part of our day-to-day practice. So we are now embarking on projects where we are using PROMs and PREMs as part of day-to-day practice as opposed to just within clinical trials. So I would encourage all clinicians to sit down with your intermediate-risk bladder cancer patient and discuss the data once you've established what the patient actually wants.

Ashish Kamat: And Sarah?

Sarah Psutka: Yeah, I couldn't agree more. I think that ultimately it comes down to trying to understand what trade-offs a patient is willing to make and what's important to them. I do have a lot of patients with intermediate-risk disease who go through these periods of disease quiescence, which are really wonderful. They can almost, for at least short bits, kind of forget that they're a patient with bladder cancer. Then the disease comes back, and we really whack it hard to try to get that thing back into submission, and that's what they're looking for. Other patients don't want to go through those treatment intensification intervals because the risks associated with that are relatively too great for them.

So it's a very individualized decision-making conversation. It's a very big patient population, and it's a patient population that we have to pay more attention to because it's a very nuanced discussion of how we ultimately choose the right treatment for that patient. But I also think it's really encouraging that, like I said before, there's a lot of attention being paid to this space, which is exciting. A lot of new trials on the horizon, and hopefully we'll have more options that we can then select from in an appropriately intensive, patient-specific manner as we go forward.

Ashish Kamat: Yeah. And well said, both of you. As expected, May is Bladder Cancer Awareness Month. So it's a perfect opportunity across all stages of bladder cancer, but especially this group of patients, that it truly needs to be not just about what we think is right, but what's right for the particular patient. And I'm glad that both of you brought that point up. Thank you again for taking the time.

Param Mariappan: Thank you.

Ashish Kamat: And enjoy the rest of the AUA.

Sarah Psutka: Thank you so much.

Param Mariappan: Thank you.