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Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of Urologic Oncology at MD Anderson Cancer Center. And it's my distinct pleasure to welcome two experts in the field of bladder cancer, Professor Morgan Roupret, and Professor Laura Mertens, who are joining us today to recapitulate the exciting discussion that we had during the EAU23.

Professor Morgan Roupret needs no introduction. He's been with us on this forum many, many times. Welcome again, Morgan.

Morgan Roupret: Thank you.

Ashish Kamat: And Laura, this is the first time with us on UroToday, but I suspect it's going to be the first of many visitations we have from you on the stage.

So let me start the stage a little bit. This is again, a recapitulation of our common problems of bladder cancer, the rapid fire debates that we had. And this subtopic is on very high-risk non-muscle-invasive bladder cancer.

Essentially, the EAU has been at the forefront of defining the different risk stratifications of bladder cancer. Until the year 2020, it was relatively easy to follow, didn't need a nomogram. Anything that was T1 or high grade was high-risk bladder cancer. And of course, in 2021, in order to refine the findings, the EAU came up with substratification, the high-risk, very high-risk. It became a little bit complicated, and that's why there's a nomogram that's available on the EAU website, where you can plug in these different parameters.

Now, just for our audience that may not be familiar with this, this nomogram was designed without considering patients that had had BCG. So of course, when we debate this a little bit later, our debaters will have the option to use BCG. But if you use BCG, then of course, that nomogram is not relevant. And it's especially relevant to today's case, because if you look at the patients that have very high-risk disease, in the Sylvester predictive model, the progression rate at 50 years was 40%, but that's 40% without BCG. So with BCG, the playing field's a little bit more level. And again, I'm just saying this so our debaters don't have to stay away from BCG if they don't want to.

So with that, here's the case that was presented in Milan by Professor Li, Roger Li, who was moderating at that point. This is a 72-year-old male with gross hematuria. A CT scan shows a classic three centimeter tumor. Lymph nodes, nothing else in the upper tract. The TUR here showed T1 high grade disease. And for the purpose of this discussion, let's throw in the fact that the patient had focal micropapillary features, which makes him very high-risk. But Morgan, Laura, you can pick any very high-risk feature.

A Re-TUR was done, and muscle was present in the specimen. And the question now to our debaters is that, this patient has very high-risk non-muscle-invasive bladder cancer. We sort of agree, based on this, and the question is, what is the best treatment? So take it away.

Morgan Roupret: Well thank you, Ashish. I think it's a very nice opportunity to discuss cases that are not imminence based but real cases coming from the real world. And Laura has the slides that we will discuss together. This is my conflict of interest, of course.

So when you look at the recurrence and progression, what we know from our experience, but also from the field in the literature, is the data from Sylvester. And it is true, so that the paper released in 2006 let us think that we are facing two kind of diseases. There is the low grade category NMIBC. And we all know that we are facing a population where we do try to deescalate the way we manage for the surveillance for the treatment. And there is the high grade category, 30% of the population we are facing in the western world. And this is a tricky situation, because we do know that we're in a gray zone, where we face borderline cases that are likely to move to the muscle-invasive bladder cancer stages. And that could be, this is where we do not want to miss an opportunity to cure the patient and to keep the bladder. Thank you.

So the flow chart is quite easy. And you mentioned particularly the CIS also and the high-risk, because the former classification of the EAU, as soon as you add a CIS, you were into the high-risk. And then you know that you need to undertake the BCG as an adjuvant treatment, which is the only one that works on CIS. The high risk, which can be a T1 high grade of course, is also again today to BCG. But you can see, that in the intermediate category, they are patients that are likely to receive a chemotherapy.

So the new stratification is a little bit sophisticated, I would say. Maybe potentially misleading the clinicians. Because if you go to the high-risk category, you can see that the high-risk is any T1 high grade, except those included in the very high-risk group.

And we go back to the case that you just presented, you need to go down the slides, and to see that any T1 high grade without CIS, and with the three risk factors, is going to belong to the very high risk. So if we very stringent and we follow by the rules, the new classification, then we have a 72 years old male, and he's three centimeters. But he doesn't have, or he is not really in the category. So we can discuss, but in my mind, he should stay in the high-risk. This is maybe the point of debate that we will have with the low harm.

Then, we go to the probability of progression by risk group. And if you look at five year, the high-risk is only 9.6. So there is obviously, an opportunity to preserve the bladder, and to try as much as possible, to deliver, I would say, a BCG adjuvant instillation.

And then, I'm going back to the paper you just mentioned, coming from your institution, about the fact that this new EAU classification overestimate the risk of progression. So on top of that, I've just displayed some data in a population that did not receive BCG. And on top of that, there is obvious data, saying that probably we overestimate the risk of recurrence and progression in this patient. So honestly, I would be on a tumor board discussion. I will be a frank and honest discussion with the patient, but it is a patient, we are in a situation where I would be keen to propose adjuvant instillation of BCG.

So of course, we are at risk of treatment failures. And on top of that, you in the US, and us in Europe, with trials where there are opportunity, even if the patient is unresponsive to BCG, to enroll him in a trial where there is a new opportunity. There are several in the pipeline. You have the pembrolizumab in the US which is approved. You have the nadofaragene firadenovec, and we are enrolling patient with some enfortumab vedotin situations in a Phase I. So there are opportunities today, so I will not close the door and move straight forward to the cystectomy in that setting, considering that the patient is naive from BCG. So it's not refractory at all from the beginning.

So this is my position in that situation. I am sure that Laura will think otherwise, and we'll see if we can have an agreement at the end.

Laura Mertens: Thank you, Morgan, for sharing your side of the story. I would like to discuss, however, why it may be better to offer a patient, a healthy patient with very high-risk NMIBC, an up upfront radical cystectomy. And as you mentioned before, it's very important to set the definition first.

So to clarify the definition, there is high-risk NMIBC, but there's also very high-risk NMIBC, and that is a group of patients with a combination of poor risk features, so many poor risk features together. And this fourth category has been added to the EU Guidelines, based on the Sylvester paper, showing that there's actually just a very, very small group of patients with an extremely high-risk of progression. So high-risk NMIBC, for which Guidelines recommend to use BCG, versus very high-risk NMIBC for which Guidelines recommend, it's a strong recommendation, to offer a direct cystectomy. And the reason for this is, because intravesical therapy in patients with the highest risk features may lead to poor oncological outcomes.

First, there is understaging, we know from the high-risk NMIBC group, that already, up to 20% of patients turn out to have muscle-invasive disease, or even turn out to have unexpected lymph node metastasis. And this is just a high-risk group. So these are not figures from the very high-risk group.

Then a second reason for aggressive treatment, is a high-risk of progression. In Sylvester's paper, ultimately, more than half of the patients progressed, but this was without BCG. BCG will reduce the risk of progression, but it still needs to be validated in this very high-risk group. And already in the high-risk group, we know that 10 to 20% of patients progress despite adequate BCG.

And then a third reason to consider direct cystectomy is the poor prognosis. So if a patient with non-muscle-invasive bladder cancer progresses to muscle-invasive disease, there is a three-year disease specific survival of only 37%, and this is significantly worse than of patients with de novo muscle-invasive bladder cancer.

And then, some other factors to take into consideration. For example, tumor biology, and the highest risk non muscle-invasive bladder tumors show high rates of gene alterations and mutational burden, and may more look like muscle-invasive tumors instead.

Then there is subtype histology. There's actually not a lot known about the impact of subtype histology in the specific very high-risk group, but there are some series indicating benefits of direct cystectomy. And according to the Guidelines, patients with subtype histology NMIBC should be considered very high-risk.

Then the final point is, that there are no reasonable alternatives yet. I completely agree with Morgan, that there is a lot in the pipeline, but most of those studies focus on BCG unresponsive disease, in patients who are unfit or refuse a cystectomy, and then ultimately, still a large percentage will recur.

So I agree, that the risks and benefits of a cystectomy should be weighed in every patient, and that we should try to avoid overtreatment as much as possible. At the same time, very high-risk NMIBC represents a small subset with a high risk of progression, and a very poor prognosis in case of progression. BCG needs to be validated. There's no reasonable alternative yet. So I think that offering an radical cystectomy may provide a window of opportunity to cure these patients.

Ashish Kamat: That was great. Thank you so much. So let's have a little discussion. Both of you presented your sides really well. And I have to let our audience know that these sides were given to you, right? So as much of an expert as both of you are, I'm sure Morgan could have talked on your side, Laura. And Laura, I'm sure you could have spoken on Morgan's side. But given the fact that you were given these situations, let me ask you, Laura, would you absolutely not recommend or discuss BCG with a patient that has very high-risk disease?

Laura Mertens: Yes, I would discuss it. And then I would discuss the chance of understaging, the chance of progression, the poor prognosis, la, la, la, everything that I just mentioned. I would discuss both options, and I would honestly say that the Guideline currently recommends this, but that it may be likely that a subset would also benefit from BCG.

Ashish Kamat: And, Morgan, knowing you, I know that you would do the same, you would discuss all the options with the patients, how would you help a patient? For example, sometimes we have patients in the US that come and tell us, "I'll do whatever you recommend." How would you guide that?

Morgan Roupret: It's very rare, no, that I have this situation in Paris with the patient saying, begging on his knee, "I do whatever you want. You let me know what you want." And the problem is that the patient are seeking a lot of information on internet and so on. And that's good also for the quality of the discussion. There may be some discrepancies according to catchment area in the way we propose the option and so on. But I'm convinced that Laura and myself, or yourself, would discuss all the options. Would I influence myself the patient to undergo cystectomy right now? To be extremely honest, not really, because I don't feel that we are in a situation where he will lose some chance. Maybe I will be very honest, and I will let him know. Look, we may postpone the cystectomy by doing the BCG, I'm not sure. I cannot guarantee that I will cure, but there is this window of opportunity and we should go into it.

But it is true also, and Laura is right, she has a point when she says that at the end of the road, ultimately, high proportion of these patients will undergo the cystectomy. The question is, are we losing a chance or an opportunity by delaying the cystectomy in case he receives it ultimately? I don't think so.

Ashish Kamat: Yeah. And that's a very important point you make. Because when I counsel patients, I say the same thing too. I said we can try to delay the cystectomy. We may get lucky and avoid it completely, but more than likely, we'll delay the cystectomy. Let's try something intravesical.

And both of you talked about the risk of understaging. And Laura, you mentioned our paper that suggests, that if a patient becomes muscle-invasive on BCG, because they've had more time for potential metastatic disease than then need chemotherapy, right? But how do you address this issue of understaging? Do you use MRI? Do you do other things when you're trying to select out the patients that you would say, well let's try BCG in you, rather than cystectomy? What are some of the tools that you're using nowadays?

Laura Mertens: Yeah. I think MRI may be a valuable tool indeed. We don't regularly use it yet in every patient with NMIBC, because we actually still do cystoscopy CT transitory section, and then only in case of muscle-invasive disease we would do an MRI and FDG PET/CT. But of course, we would do Re-TURBT in those very high-risk cases, to lower the chance of understaging CT. Actually, we also perform FDG PET/CT in those very high-risk patients, because we just, last month actually, we just published a series of high-risk and very high-risk NMIBC patients, in which we found lymph node metastasis in 25% of cases. So pretty high chance. So we try to stage them as good as possible.

Ashish Kamat: Yeah, stating is critical, because if you have metastatic disease, clearly, even cystectomy won't help them. Morgan, what about you?

Morgan Roupret: Yeah. Now, the fact that this patient in particular had a second look, and the second look there was no remnant tumor, makes me confident that even more that there is this opportunity to propose the conservative management. I would not be as confident if on the second look we would've discovered some random tumor or some CIS and so on. At the moment, aside from the experimental practice that we can have in some trials, there is no use of the MRI in daily practice at this stage. And for the type CT or nuclear imaging, as Laura stated already, we do use it but only for muscle-invasive bladder cancer.

Ashish Kamat: And Morgan, you mentioned Re-TUR, right? And that's in the Guidelines to do a Re-TUR for T1 high grade disease. If you do a Re-TUR, and the patient has residual cancer, does it matter if it's TA, CIS, to you? Or does it have to be T1 for you to recommend cystectomy? Does any of this matter?

Morgan Roupret: No. No, it does matter. Because at the end of the day, I even discuss with some colleagues and they told me you should go for a third look and say, look, if we do have a T1 high grade, and I deliver the TURBT, and then again, I have the same stage, same disease. For me, it's a straight indication for cystectomy. If it's some low grade, or some random tumor on the scan, and not a big volume, I would say that I could consider this opportunity, or also to move forward with the conservative management. So of course, it makes a big difference, because it's not a TURBT, a two steps TURBT, it's a real Re-TUR. So you need to reevaluate the situation, and the patient has been warned from the beginning, that we will balance the decision also on the outcome of the second TURBT.

Ashish Kamat: Does age factor in to either of you? If it's a younger patient, you tend to go one way or the other?

Laura Mertens: According to the Guidelines, age older than 70 is one of the risk factors.

Ashish Kamat: Laura, let's ignore Guidelines for now. Right?

Laura Mertens: Okay. Okay.

Ashish Kamat: In your clinic, if someone is young, healthy, and has many years ahead of him or her, does that tend to factor one way or the other in your discussion?

Laura Mertens: It depends, because I would very much highlight that it's not very likely that we are going to avoid cystectomy, but that it may be possible to delay cystectomy. And if someone is 50, I will be pretty sure that he will still be fit to undergo a cystectomy at age 55 or 60, for example.

On the other hand, in older patients, maybe 79 years old, on the one hand, I would say maybe let's go for the least invasive option and treat with intravesical BCG. On the other hand, I think maybe at 79, someone is still pretty fit for cystectomy. And at age 84, he isn't anymore. So that's always part of the discussion, I think.

Morgan Roupret: Yeah. We all know the difference between the real age, physiological age, and the age. So I need to see the patient, and probably, the one who has the relationship with the patient, who was seen at these clinics, we have probably the good behavior. Because on a virtual tumor board, when you discuss a case, you have not seen the patient and it makes, I know it's irrational, I know it's a bit subjective, but it makes a great deal of difference. And at the end of the day, of course, if there is an opportunity to do a neo bladder, and you feel that if you postpone for many years the cystectomy, you will have an nearly a conduit and so on, because it's too old, it will influence.

The question is there the quality of life? And then to discuss around the bladder what's going on in the life of this man that you are facing, his quality of life, sexual life, and so on. And it is on request. Some patient, they want to be safe and secure. Some patient, they want to take the opportunity to also preserve as much as possible the quality of life, including their sexual life. And of course, having your bladder from that perspective is far better.

Ashish Kamat: Yeah. Very, very important points. And again, Morgan and Laura, you and I, the three of us could chat on this forever, but in the interest of time, let me close. And in closing, let me give both of you a final word. So I'll let Professor Roupret go first, and then Professor Mertens, just final words for the audience to take home.

Morgan Roupret: What I do like in this case is the session you organize ensure the EAU is that we are facing the reality of our practice, and this cannot be really a black and white situation. So there are many points that have been highlighted by Laura and I agree on. I was happy to be chosen to defend the BCG, because this is really what I would have done for this patient. And at the end of the day, I'm sure that Laura is right, that we are in a good situation to propose the cystectomy. But I would not feel comfortable myself to propose this from the beginning.

Ashish Kamat: And Laura?

Laura Mertens: I agree with a lot of points that Morgan said. On the other hand, if I would see a fit patient with a very high-risk T1 micropapillary tumor, I wouldn't feel bad to propose a direct cystectomy. I think one of the important final points would be, that it's all about the discussion with the patient. And sometimes it's a short discussion, sometimes it's a long discussion, or it's more discussions. And that we should discuss the advantages and disadvantages of both options, and then we'll find a solution.

Ashish Kamat: Great. No great points. And I want to thank both of you for taking the time to spend with us today. And also, to UroToday, for allowing us to highlight this very important debate that we had at the EAU. This way, folks that may not have been able to attend the EAU, can also learn from your wisdom and your experience. Thank you very much.

Morgan Roupret: Thank you, Ashish.

Ashish Kamat: Thank you.