Ashish Kamat: Hello everyone, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, urologic oncologist, and it's a pleasure to be joined today and to welcome to the forum Dr. Kristen Scarpato, who is joining us, and in this episode, going to talk to us about something that she was active in and working on during the recently concluded Think Tank, which was held and hosted by BCAN (Bladder Cancer Advocacy Network), as they do. So, Kristen, thank you so much for taking the time and take it away.

Kristen Scarpato: Thank you so much for having me, Dr. Kamat, and UroToday. The Think Tank this year, as always, was fantastic. I was part of a really exciting session looking at non-invasive monitoring in bladder cancer; we called it "Beyond the Scope," and it was myself, Dr. Salari, Dr. Lotan, and then we had Dr. Choudhury, who is a radiation oncologist. So, the session was attended by many patients, patient advocates, urologists, and a whole mix of providers and advanced practice providers, and it was great. We talked a little bit about why this is such an important topic, and where we are with urine markers, which currently is really the biggest area beyond the scope, and what the guidelines say about markers. We talked about several trials; I'll highlight two here, and then finished up with what's new and exciting in this space.

So, as urologists, we know that there are many indications for cystoscopy. Patients with hematuria make up over 20% of referrals to urology, and many of those patients go on to have cystoscopy, and then of course there's risk-based follow-up for surveillance in patients who have a diagnosis. So, why is it that we're interested in looking beyond the scope? Well, first and foremost, it's an invasive, uncomfortable procedure for patients, and we certainly can't discount that. There's a lot of talk about financial toxicity in bladder cancer, and we know the cumulative impact of needing to scope patients certainly adds to that. There are certain constraints just even logistically that came up as important for consideration. We want to make sure we're scoping the right patients, with the right risk, at the right time. And we had a really interesting discussion about de-escalating care: are we doing too much? And then looking at other fields like colorectal, where the gold standard of direct visualization of the colon has in some instances been replaced with non-invasive tests.

And then, finally, what do patients think? And there's this one study, I'm sure Dr. Kamat is very familiar with it, and we've talked a lot about it in bladder cancer: how good does a test have to be for patients to say, "Okay, I'm willing to forgo my cystoscopy"? And it turns out the bar is really high, and understandably so. So, any of these non-invasive tests really have to pass a high bar. What is a potential role for urine markers? Well, to triage hematuria, and importantly, a new guideline, or an updated guideline, I should say, from the AUA was recently released, and this is one of the first instances where we see a biomarker being recommended in this case for patients with intermediate-risk disease who want to avoid cystoscopy.

We can also use urine markers to improve the quality of our cystoscopy, and there's good evidence behind that. De-escalation, so getting at that "scoping the right patient at the right time," and improving upon the currently available and recommended markers, like cytology, which has been really part of the management of patients for a long time, but has shortcomings, as does white light cystoscopy. We reviewed the various types of markers that are currently available. For a long time it's been protein-based and cell-based markers, but more recently and excitingly we're looking at DNA that has been shed in the urine, and analyzing with next-generation sequencing and PCR this cancer DNA in the urine, which makes complete sense because the urothelium comes in contact with the urine and we know that this is a disease where there are many mutations present. And so we'll get into that in just a minute.

But two exciting trials that Dr. Lotan highlighted were the UroFollow, which is a randomized controlled trial looking at how accurate markers are in the follow-up of patients with low- or intermediate-risk non-muscle-invasive bladder cancer. So, patients here were randomized to either the standard-of-care arm or to the marker arm, where after randomization they were followed with markers every six months or so, and we see that there were really similar recurrence rates in both arms, and no tumor progression to higher stage or grade in the entire group. So, it's interesting that this may be a strategy utilized to decrease the number of cystoscopies performed without compromising outcomes—non-inferior, in the short term anyway, in patients with low- and intermediate-risk cancer.

And then, somewhat similarly, but in a different patient population, we talked about this Dreyer study. So, this is now high-grade patients, high-grade non-muscle-invasive bladder cancer, so either CIS, Ta, or T1 high-grade, alternating cystoscopy with marker. In this case, it was the Xpert marker, which is an RNA test, mRNA test, and again, non-inferiority. So, in the short term, we're avoiding the high frequency of cystoscopies without compromising cancer outcomes in terms of progression in stage and grade. And then, finally we finished up talking a lot about the promise of genomics and looking at cell-free DNA in the urine, particularly with the UroAmp test. This particular test has really shown some significant promise in the initial diagnosis and the follow-up of patients with non-muscle-invasive bladder cancer, assessing response to therapy, as well as predicting recurrence-free survival in different patient populations, but does pose some unanswered questions.

The biggest one that we talked about was how do you manage a positive test in the setting of a negative cystoscopy? And so, patients were very interested in that as well because this test has been shown to detect cancer before we're seeing it with white light cystoscopy. So, it was overall a really robust and interesting discussion. We concluded that urine markers really do have significant potential benefit in this patient population across the board, but really we need high-quality evidence, and right now, randomized controlled trials are lacking. But I highlighted some that we talked about, and these are certainly advancing the field. DNA markers and genomics are really exciting for personalizing care and improving our sensitivity. And right now, the guidelines don't endorse any marker's ability to replace cystoscopy other than what I highlighted for the asymptomatic microscopic hematuria guidelines. And really, patients and their input and perspective are so important as we're looking beyond the scope.

Ashish Kamat: Thank you so much, Dr. Scarpato, that was really a very succinct summary, I'm sure, of a lot of effort and time that went into this working group. A couple of questions: we've always talked about patients having this high bar when asked an open-ended question, right? You were alluding to that 99% number, or 99.9% in some patients, but I think it's up to us to educate the patients about the different risk categories. For example, patients with low-grade disease, we are offering active surveillance, which is, "Hey, we know you have cancer in there, come back in three to six months, it's totally okay." So, that group of patients, once they're told that, will likely say, "Well, in that case I can use a marker, right? And I don't need it to be 99% accurate because I know there's something in there." Was that kind of patient education discussed at the working group, and what were some of the insights you got from the patients and the advocates that were there?

Kristen Scarpato: Sure. We did in fact discuss that, and I do think that exactly what you're getting at, the provider has to believe in it and feel comfortable too. I think that we have concerns about missing bladder cancer, and our bar for accepting tests is certainly very high as well, but patients were, in this session anyway, very willing with a high-quality test to forgo cystoscopy. And we heard in many of the panels how some patients already just said, "I can't do it anymore, it's too uncomfortable," whereas others were saying, "Hey, how many years of surveillance cystoscopies must I go through? Is there something else that we can do in place?" So, I do think patients are savvy and willing to change up what we've always done, provided that we can give them the reassurance that this is a new test, but it's a really good test, and here's the evidence.

Ashish Kamat: Yeah, I think that's critical, because again, I'm sure you have, just like I do, some patients who just refuse to let go, and sometimes I'm telling them, "You're 15 to 20 years out and you had a low-grade tumor," and they're like, "No, we want to come back, at least once every other year." So, sometimes I'm seeing patients every 18 to 24 months just because of that anxiety that they have. On the other hand, there are some patients who say, "Okay, I can't do it, I know I have T1 high-grade disease, but I can't do it." Right? So, it's a spectrum of people we're treating.

A quick question about, well, I shouldn't say quick question because this is something that we as a field have wrestled with for years: markers and cytology. And we've had an IBCG retreat, we're having one in just a week, talking about the same thing. What was the general gist, or where do urinary markers fit in with the overall paradigm when it comes to something like a working group at the Think Tank, right? Is it something where we need more patients to get buy-in so we could roll it out to them, or is it something where we need the markers to actually become better?

Kristen Scarpato: I think we need the markers to become better. And universally, the four of us who were leading this session were aligned on that, and I think Dr. Lotan was kind of leading the charge there. But we need high-quality evidence, which means we need good studies, we need to enroll patients, we need to look across different risk strata and different patient populations to figure out where the highest need is, and where the best evidence is. But a lot of it focused on response to therapy and surveillance of patients, because those patients are often heavily treated: a lot of cystoscopies, a lot of TURBTs, different therapies in the bladder. And any way that we can limit some of the treatment burden by doing a non-invasive test is needed and much appreciated.

Ashish Kamat: I'm glad you said that, because we hear sometimes from press releases and ads that patients bring in, where markers are touting themselves as, "This is the best thing, ask your doctor for this test," and then we have to sort of talk to the patient and say, "That's fine, it's not good for you," or "It's not something where we can hang our hat on." So, I'm glad your group concluded that. One last question: globally, ultrasound of the bladder has a very high sensitivity because the folks that are doing it are able to pick up small tumors. Here in North America, unfortunately, we don't have that skill set that we've been teaching our residents, or certainly not the radiologists. Is there any thought about maybe going away from markers necessarily, but improving the education and training of folks so they can just do a quick ultrasound on the abdomen and pick up a tumor? In Europe they can pick up a 3-millimeter tumor on a bladder ultrasound; we can't do it here, so any thoughts about that?

Kristen Scarpato: I think that is an exciting possibility. We did not actually talk much about ultrasound, although that was part of the UroFollow study; they included ultrasound in that surveillance arm. We talked a little bit about MRI, and of course that's a much more invasive, labor-intensive test, and a point-of-care ultrasound would be preferable to that if we could have the skill set to reliably look at patients' bladders and detect tumors in that way.

Ashish Kamat: Yeah, that's something I hear all the time because Bernd J. Schmitz-Dräger, who led the UroFollow, and then Joan Palou, who led the CUETO studies, and they're like, "Why don't you in America just shine an ultrasound on the bladder? It takes all of 10 minutes max, and you can see it just as well as looking in the bladder sometimes." And on the other hand, we're talking about MRI, which is, like you said, so expensive and labor-intensive. I think sometimes it's good to learn from our international colleagues and translate more here too. Kristen, thank you so much for taking the time, always a pleasure, and looking forward to seeing what your working group has in store for us next year.

Kristen Scarpato: Thank you so much, Dr. Kamat, pleasure to be here and talk with you.