Laura Mertens: Thank you.
Jeremy Teoh: Hi, Ashish.
Ashish Kamat: So as part of the EAU, we do our rapid-fire debate session, which is always extremely well-attended, and the two of you participated this year in a really interesting exchange of ideas and controversies when it comes to cystoscopy versus urinary markers, because there's a camp that thinks that cystoscopy is something that's old. We should do away with it. We should actually be taking patients, for example, with low-grade disease, and just monitoring them with urinary markers rather than subjecting them to cystoscopy. And there's another group that says, "Well, whoa, whoa, wait, we're not quite ready yet. We need to actually build in cystoscopy or de-escalate cystoscopy in a sensible way." And of course, then there's the patients that have high-risk, high-grade disease, which is a whole different discussion. So the two of you had a really good back-and-forth at the EAU, and let's try to replicate some of that today, so the stage is yours.
Jeremy Teoh: Okay. So first of all, thank you Ashish for the invitation. It was a really fun debate and really fun to talk, discuss with Laura as well. I am for urinary marker, I think it is time to replace the cystoscopy, and I think for every single case, it's very important to stratify the risk of both recurrence and progression. In that particular case, although it's an intermediate-risk disease, but as we all know, intermediate-risk disease can be very heterogeneous, and therefore, it's so important to break down the different risk factors. In fact, in that particular case, it's in primary tumor solitary Ta low-grade disease without any CIS, is a peripheral cancer. The only factor that puts the patient into intermediate risk is the tumor size, which is 3.5 centimeter. Arguably, very subjective. So technically intermediate risk, but probably erring to the low-risk side. And this is important because obviously there's a risk of recurrence, but then the progression risk is relatively low, and we're talking about just about 1% at a year. So this represents a group of disease entities that we can potentially use urinary markers safely, even if there's a proportion that we may potentially miss. And we always need to look into the patient's factor as well because there's always a tendency to intensify our treatment, intensify our cystoscopy protocol. But again, back to the patient, elderly gentlemen with multiple medical comorbidities, although it's intermediate risk, but a good surgery has been done, there's a good chance of a cure.
So in these cases, should we really try to intensify the surveillance protocol or should we consider the intensification, meaning at least spreading out the surveillance cystoscopy or even potentially replacing cystoscopy with a renal marker is something that we should really think about. And of course, there are a number of urinary marker panels being available. I think most of the markers are really quite sensitive for high-grade tumors. But again, if you use it for high-grade or high-risk diseases, there's always a chance of missing the disease, potential higher risk of progression, et cetera. And in patients with low-risk/intermediate-risk disease, although this sensitivity is lower, but then it's relatively safe because the rate of progression is also lower. So in the case of overall sensitivity, we are looking into a rate ranging from around 50% to up to 90%. I think it's a reasonable sensitivity level if we want to incorporate in our real-life practice. I think there are two trials that we should know about in terms of urinary markers in the surveillance setting. First one is the DaBlaCa-15 trial, which is a non-inferior trial looking into patients with high-grade tumors, and they're randomized into the experimental arm, which uses Xpert Bladder Cancer Monitor, and then together with a 12-month and 24-month check cystoscopy, versus the standard of care, which is surveillance by cystoscopy alone, and then they look into primary outcome of recurrence-free survival defined as high-grade non-muscle-invasive disease, muscle-invasive, or metastatic urothelial carcinoma.
I think what is striking is that, basically, there is non-inferiority being demonstrated. I think looking into the curves in terms of the recurrence, it's really, really very similar between the two groups, and they're able to demonstrate that we can reduce the number of cystoscopy basically by at least half. And even when we talk about cancer that we might miss, it's really a very, very small number. So I think this is probably the highest quality of level 1 evidence that we have regarding use of urinary markers in a surveillance setting. And then the other trial is UroFollow trial. Again, a non-inferiority trial looking into 200 patients with Ta low-grade diseases, and the experimental arm would need to have a 3-month negative cystoscopy, and then followed by a 6-monthly marker plus ultrasound-based surveillance, versus standard cystoscopy surveillance, and they look into the primary outcome of detection of 80% of tumor recurrences. And I think what they demonstrated is that there is a similar sensitivity level, but I think we need to be careful because it's 96.5% in standard of care arm, it's 81.5% in the marker arm, although there's no statistical significance. But then, obviously, I think there's something that we need to be cautious in terms of the interpretation. But I think one thing for sure is that, because we are focusing on those relatively low-risk diseases, then the chance of missing disease progression is very, very low, again, representing an area that we can potentially de-intensify the whole surveillance protocol. And then the other thing is, in this gentleman, elderly men, and then even when the patient has a recurrence 3 years later, do we really need TURBT in all cases? Is surveillance a possibility?
And in that regard, if we're going to adopt a relatively conservative approach, then do we really need to start to be used for this patient? And I think this comes back to the point, we need to look into both the disease factor, the patient factor, but also in the heterogeneous group of intermediate-risk disease, this is an extremely nice risk stratification looking into five risk factors for patients with intermediate-risk disease. And in this gentleman, basically he has none of the risk factors. So the chance of having recurrence, the need of TURBT, again, is fairly low. So I think the key point is really, when we manage patients, it's not just treated as the usual intermediate-risk disease. We need to really dissect into details, really try to have a personalized management. And in the best patients, then it's really represents an area that we could potentially use markers to replace cystoscopy. So in conclusion, increasing level 1 evidence that urinary marker works. Helpful in patients with low to intermediate-risk diseases because the risk of disease progression is very low. Also, particularly helpful for elderly patients because this is the situation that we can try to de-intensify the whole treatment and also surveillance protocol, but certainly multiple factors should be considered when we try to contemplate the best surveillance protocol for our patients. So thank you very much.
Ashish Kamat: Thank you, Jeremy. You made a good case for telling us where we can replace cystoscopy with markers. And now I'm going to hand the podium over to Laura who's going to tell us why we should still stick with cystoscopy. Laura?
Laura Mertens: Thank you, Ashish. Jeremy, I think there is one thing that we agree upon, and that is that the number of cystoscopies in patients with low-risk disease or low-grade disease can and should be reduced, but I do not agree with you that a marker should fill that gap, and I will explain why. First of all, I don't want to make it too case-specific, but it is important to realize that our debate was on a patient with low-grade urothelial carcinoma. No recurrence for 2 years. Then Jeremy added a marker which turned out to be positive and a whole cascade of intervention started. No tumor was found. And then almost another 2 years later, a small low-grade recurrence was detected, which was easily treated. So in my opinion, this marker here was not useful, it was not safe, and it did not provide any benefits. First of all, the marker was not useful. I mean, we are discussing low-grade urothelial carcinomas, and we know that low-grade tumors tend to recur as low-grade disease, very predictable, very low risk of progression, as Jeremy already stated. And we also know that the sensitivity of urinary markers for detecting low-grade disease is low, with markers missing up to half of the tumors. So a marker here is not useful. And also, since the probability of detecting clinically-relevant disease is already low in this population, the positive predictive value collapses and the value will actually be even lower.
So it's not useful and also it's not safe. The real danger in low-grade urothelial cancers is not missing a tumor recurrence, the real danger is the false positives. The unnecessary interventions. So specificity is the true safety parameter here, and we know that the specificity of these markers is not perfect either. Let's assume we have a marker with a specificity of 70%, which actually is quite high already. We repeat the marker a couple of times during follow-up, let's say five times, then the chance of a false-positive finding exceeds 80%. So it's not incidental, it's actually inevitable. And those false-positive results are not without consequence, as they lead to a cascade of unwanted downstream procedures, additional cystoscopies, imaging, selective cytology, mapping biopsies, URS, more downstream procedures, more procedural harm or patient burden, resources, costs, thousands of euros because of one positive urinary marker, which was actually not intended to be used in this setting. And then third, the marker does not provide any benefit here. Let's assume the marker was right and that it detected a recurrence earlier than cystoscopy would've done. Then would early detection of a low-grade recurrence actually lead to better disease-specific survival to the patient or overall survival? No. Would it lead to better quality of life, less treatment burden? No. Is it cost-effective? No. And is it what patients want? No. So I do agree that we should strive to reduce the number of cystoscopies in patients with low-grade disease, but filling that gap with a marker that is not useful, not safe, and does not provide any benefits is a false promise. The true solution, in my opinion, would be to test smarter, not harder, risk-adapted surveillance, fewer cystoscopies, and especially not more markers when they are not beneficial.
Ashish Kamat: Thank you, Laura. So Jeremy, I have to say, both of you gave excellent talks and viewpoints, but if you have to look at pure slight animation and design, Laura wins, right?
Jeremy Teoh: Of course.
Laura Mertens: Is that all?
Ashish Kamat: That was really well done. No, no. We'll focus back on serious topics. So I agree with both of you. It's very important to weigh the risk-benefit, and clearly these topics were assigned to you, and I assigned these to you, not to say that you necessarily believe all or none. But when you're counseling a patient, and let me ask you, Laura, first, when you're counseling a patient that is sitting in front of you, and now just talk about low, intermediate, and high-risk patient, how do you tell the patient what the role of markers is going to be in their surveillance journey?
Laura Mertens: Well, I think for patients with high-grade disease, we have the data, as Jeremy showed, from DaBlaCa trial, and we know that markers can be used for you to reduce the number of cystoscopies, indeed. I think it also depends on the country or the location where you live, whether you can use a marker or not. Here in the Netherlands, we are allowed to use them. But it is, indeed, extremely important to explain them that at least cystoscopies remain necessary. For low-grade disease, the evidence is much lower to use markers. So there, I would honestly not offer to implement a marker initially.
Ashish Kamat: So again, one of the things that we always think about when we're talking to patients with higher-grade disease, high-risk disease is the fear of missing something and giving them a lead time where you could actually have issues that occur, because T1 disease that recurs and then it's quiet for about 2 or 3 months can be really dangerous.
Laura Mertens: Yeah.
Ashish Kamat: So even though some of the studies will show that you could do replacement with markers, patients, if you ask them, they want that 99% accuracy. When you factor that in, Jeremy, how are you now counseling patients based on their preference, based on your knowledge of cystoscopy and marker performances?
Jeremy Teoh: Yeah, no, I agree completely. In high-risk diseases, there's always a fear of missing a tumor, potentially disease progression. So even with high-risk disease, I think T1 disease, we need to be very, very careful. Obviously, these are the cases that there's a higher chance of residual disease and then progression as well. So even in the high-risk diseases, I'll probably select. Maybe those with Ta, but high-grade recurrent diseases, we can potentially do that. But always, I think we still need to tell them the standard of care, but then if they want to reduce the number of cystoscopies, I think it's a reasonable request, and I think it's okay to offer it, but we just need to be very careful in the case selection. And although in lower-risk diseases, then the performance of the marker is, again, not as good, but I think these other diseases, actually there's huge room for us to try to reduce the cystoscopies even if we detect it a little later. I think most of the time it's very safe. So not to an extent that we'll use markers completely, but certainly we can use markers predominantly, but have a check cystoscopy as an alternative manner. I think that's a very good approach for lower-risk disease in general, and I think I will be comfortable to do it, especially if the patient doesn't want so frequent cystoscopy.
Ashish Kamat: Yeah. And over the years, if you look at it, the most accurate marker for predicting or showing who's going to have a recurrence is a negative cystoscopy at 3 months, because I think that is really important. The quality of the resection is extremely important. And then, of course, the low-grade versus high-grade, patients' desires, performances, all that are very important. So this is a really complicated question that the two of you addressed really well. In closing, let me ask you, which is the marker that you prefer to use in the different settings? So for low-risk patients, intermediate, and high-risk patients, do you use the same marker? And if not, which marker do you prefer in different settings?
Jeremy Teoh: Well, to be very honest, in my locality, which is in Hong Kong, urinary marker is not reimbursed. The only marker that we consider using is actually CxBladder. But again, I must say, due to reimbursement issues, it's not very frequently used. It's usually when patient really doesn't want cystoscopy, then we'll discuss this possibility. And arguably, CxBladder, I think at least in the case of microhematuria, there's more evidence on it. Surveillance, we're waiting for more data on that, certainly. But this is the usual marker that we'll consider. Yeah.
Ashish Kamat: Interestingly, you didn't mention cytology. Do you not use cytology at all?
Jeremy Teoh: We do, but again, this is, again, a controversial area. We do, but then for high-grade cancer, the sensitivity is higher. Low grade, it's not very useful. But we don't regard this as a very useful marker in general. So cystoscopy is still a very important surveillance tool in our setting. Yeah.
Ashish Kamat: Yeah. I hear that from different folks across the globe, and oftentimes that is accompanied by a little footnote verbally or in written saying that the performance of the cytopathologist has gone down over the years. And I don't know why that is, because I really think just as the way that we are talking about training people to do better TURBTs, I think good cytopathologists are feeling the void and want to train cytopathologists to actually raise the level of cytology to where it can be used. So I'm glad you actually were honest in making that comment. Laura, final word to you.
Laura Mertens: If we use a marker, we can use EpiCheck because that's reimbursed in the Netherlands. Cytology, of course. But I must say that at my own hospital, it's not cost-effective to use the markers yet. And what I would like to add is that we are discussing diagnostic accuracy of markers, sensitivity, specificity, but I think more research should also focus on the patient perspective. We assume that patients want this or that, but we don't actually measure it. We do not know the trade-off, for example. So I think that should also be taken into account in future research.
Ashish Kamat: Yeah, no, excellent point there. And that is, of course, something that both of you are involved with, the patient-reported outcome tool through the International Bladder Cancer Group. So again, thank you to both of you for, of course, doing an excellent job in London during the EAU, and then again for taking the time today and spending it with us. Thank you.
Jeremy Teoh: Thank you. Thank you very much.
Laura Mertens: Thank you.