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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 and Cancer Research from MD Anderson Cancer Center in Houston. And it is a distinct pleasure to welcome experts from across the globe today. We have Professor Babjuk, we have Professor Roupret, and we have Professor Kassouf, who are all joining us today to sort of redo in some ways the debate that we had at the EAU this year, which was so well received that we got a lot of requests to have this again pseudo live on the UroToday website so we can reach a wider audience.

We are today going to talk about this particular patient that Dr. Babjuk is going to present to us, and then Drs. Roupret and Kassouf have been given artificial sort of stances that they will defend, either TURBT and intravesical therapy alone, or active surveillance and fulguration. And then once they present their stance on the situation that was given to them, then we will have an open discussion as to the pros and cons and exactly what they would actually do in real life. So with that guys, let me hand the stage over to you. And Marko, it's your show.

Marko Babjuk: Hello, everybody. First, thank you for the invitation. It is an enormous pleasure and honor to be here with you. I have prepared a real case, which is a case from real life. We have a lot of similar cases, I believe in everyday practice. So this is a man who is more than 80. He has some comorbidities, Charlson comorbidity index of nine, and he had in January 2019, a TURBT for multiple papillary tumors, there were five lesions inside the bladder. He had a complete TURBT followed with a single instillation of mitomycin and pathology showed urothelial carcinoma, which was TA low-grade, grade one. The man was followed in a standard way, and after seven months, his cystoscopy appeared the recurrence, which was two papillary lesions. You can see in this slide, the image of these lesions, one was five millimeters, another one six millimeters, and they were of papillary appearance.

And the question is how to proceed. And was said, we have two great debaters, which is Morgan Roupret, who will support a more standard approach, which follows more or less the guidelines, and professor Wassim Kassouf will talk about active surveillance and fulguration, which is a less aggressive and more conservative approach.

And to be able to open the discussion, I would like to ask both of them whether they would change their opinion or approach if the patient were younger and had fewer co-morbidities. And also, if the tumor were of a different appearance. For instance, like these two tumors. So, the first is Professor Morgan Roupret. Morgan, you're on.

Morgan Roupret: Yeah, it's great to have this opportunity to debate again and again, around these cases, because actually, it appears to be simple, but it's not that easy. Anyway, there are not that many options on the table. I have noticed that the patient was, I would say quite old. 86 years old is something that you have to take into account. But you mentioned that I would stick with the guidelines. And usually, when we have a debate, we play a role, but I'm not playing any role, yet. I will be very straightforward. I was trained and I am used to doing a [inaudible 00:04:02] transurethral resection of the bladder and it is perfectly in line with the guidelines actually, because my goal is the complete removal of all lesions. I want to get rid of this. I want to have a good pathological assessment.

I have noticed also that there could be some discrepancies from one transurethral resection to another. And with the experience, you are not going to go too deep because the muscle in the specimen is not absolutely [inaudible 00:00:04:33] when it comes to a patient with Ta low-grade tumor and with a recurrence.

So if we go to the text, and I would be happy to see what is the opinion of Professor Kassouf for sure, but we are clearly dealing with a patient that we could put in a box of the risk stratification, it fits with the intermediate risk. And so I would go for the transurethral resection of the bladder because this is the way I do it in my daily practice. And I am open-minded. And I would like to be convinced if there are any other serious options.

When it comes to the choice of, am I doing anything after the transurethral resection of the bladder, you can see from this case that both BCG and chemotherapy are options, that are serious options in a broad spectrum of patients. So if we discuss this particular case, in this individual decision, I would advocate to do and to go for chemotherapy, fewer side effects, well-tolerated, usually no maintenance treatment, just instillation. So I would go for eight instillations of mitomycin.

So I'm not sticking only with the guidelines, as Ashish has asked us to introduce the debate and to have this discussion altogether, I was fair enough to read an old publication coming from Ashish, and I would say, worldwide colleagues. And there is this flow chart, which is very interesting coming from this paper. The patient is old, and this paper is a bit old or so, but still very interesting, and it is not outdated titled,  Defining and Treating the Spectrum of Intermediate-Risk Nonmuscle Invasive Bladder Cancer patient. You can see with the red arrow that the patient fits with the one-two situation, and he would go into the treatment, which is proposed in the flow chart.

So you mentioned, Marko, that this patient could have presented otherwise, he could have been younger and the tumor could have been, I would say a bit larger, a bulky tumor. So would I change my opinion if the patient was younger and the tumor was larger? I would say, I would go for the transurethral resection of the bladder. I would go deeper, certainly not the same TURBT, but this is very subjective. And the technical steps are not depicted in the scientific literature. And when it comes to the choice of intravesical instillation, I would definitely choose the BCG in the second situation you mentioned in that patient.

So TURBT for sure, because I've never done anything else. And the choice comes with the [inaudible 00:07:28] product for the intravesical instillation and the choice of the drug, mitomycin versus BCG. So this would be the only discrepancy between the two, I would say the two phases of the cases that you have proposed. Thank you.

Marko Babjuk: Thank you, Morgan. Excellent. And we can proceed with the next debater, which is Professor Wassim Kassouf. Wassim, it's your floor now.

Wassim Kassouf: Okay. Thank you, Ashish. Thank you, Marko, for the opportunity here. And it is a revisit of that debate which I'm looking forward to. It's an important topic and involves a lot of patients that it would be important to kind of weigh in on how we maximally benefit the patient while at the same time not harm.

So just to put it in perspective, and there are several papers that have kind of addressed this disease spectrum, the most recent one, again, Ashish with the [inaudible 00:08:24] IBCG group brought some important highlights to consider, and I share a lot of those. So the first thing is we know that the majority of bladder tumors are actually Ta low grade, 60%. At the same time, we know that the prognosis is excellent. So although the recurrence rate can be significant 30%, 60%, the risk of progression is very low. The 10-year risk of progression is 3%. The cancer-specific mortality is extremely low as well.

So what does this do? It creates what I'll say, a large treatment burden and cost burden on the society in this disease spectrum and provides for us as a urologic community, an opportunity for treatment de-intensification without compromising survival. And that is similar to what we've done in low-risk prostate cancer and small renal masses.

So the first question is, are we able to predict a Ta low-grade tumor in someone who has a history of previous Ta low-grade disease? And that has been looked at in several papers, and essentially the answer is actually we are, and we do it in a very reliable fashion. This is an earlier paper, that evaluated 144 patients. In patients with a previous history of papillary tumor, negative cytology, the ability to predict a Ta low-grade tumor reaches 99%.

And similarly in a prospective study from the UK of 250 patients, again, if you restrict them to the smaller tumors, less than two centimeters, your ability to predict a Ta low-grade disease is 88%. And this study actually does not incorporate the utility of [inaudible 00:10:14] cytology, but just the pure gross appearance of the tumor.

So, number one is, [inaudible 00;10:21] are we are able to reliably predict TLO disease. Number two is, although we do consider TURBT a very minor procedure, and we advocate this when we are teaching residents, we have to keep in mind, it's not without risks. This is a retrospective study of almost 3,000 patients published a while ago now, showing a complication rate of 5.1%.  It does implicate cost and quality of life impact on patients. And more recently, on an NSQIP database, more than 24,000 patients undergoing TURBT, again, have a similar complication rate from the NSQIP database, a 3.7% hospital readmission, and a 0.8% mortality rate. So I would say particularly in the frail, elderly, these kinds of complications and effects are not negligible. And we should weigh into that when we are counseling patients.

And lastly, one way to mitigate between being too radical for a TURBT but also not being too lenient is the approach of either an office fulguration under local anesthesia or laser ablation. Several studies have evaluated this approach, showing recurrence rates are acceptable. Progression rates are extremely low, and it is one option that I've adopted in my practice, particularly in the frail and elderly.

Now I'm going to mention as well, they had several studies evaluating just active surveillance for low-risk bladder cancer. They are both retrospective and prospective. Mind you, they are all small sample-size studies. But one thing that is evident, is the progression to muscular disease is almost zero. And even when you look at a prospective evaluation that's based on the Italian Active Surveillance Experience, a prospective database of 251 patients, and if you specifically evaluate the long-term outcome of these patients, so all these patients had more than a year and a half follow-up, you can quickly realize that the treatment-free probability in two to three years, you pretty much can avoid treatment altogether in 50% of the patients.

So in essence, the approach of fulguration, whether without active surveillance, as an approach can reduce the morbidity of TURBT and anesthesia. It can decrease patient anxiety with each operation visit and leads to cost saving in the future.

Now, regarding the question as well, would we adopt this kind of strategy in someone who is healthy with a large tumor? I have not. For someone with a tumor of three centimeters, such as the case you presented as a counter scenario, and who is healthy, in this patient, the incidence probably of upgrading is higher than the type seen in the literature. And I would advocate for a formal TURBT and dictate management depending on pathology after. Thanks, Marko.

Marko Babjuk: Thank you very much.

Ashish Kamat: This was great. Thank you everybody for sort of recapitulating the exciting debate that we had at the EAU. Marko, if I could ask you, I know you presented the case and we didn't actually get a chance to pick your brain during the official session. But if I could ask you, in a patient such as an index patient that you presented that has a small subcentimeter, low grade appearing tumor in the bladder, what is your practice pattern right now? How do you counsel these patients?

Marko Babjuk: I must say that the regular approach that I'm using is usually the more or less standard approach. So I would probably in this case, and I think we proceeded in this case with the TURBT and considered further treatment, the men had several comorbidities. So I think we used a few instillations of intravesical chemo because the pathology again was Ta low grade. So this was what we did. I must say that  I am using the fulguration today in some patients, I even use the follow-up, only the observation in some patients, but this is usually very comorbidity people with tiny lesions, with a history of lesions that are even smaller than these two tumors.

Ashish Kamat: And Morgan, if I could ask you, sometimes we have these patients, they may be young, right? They may be in their thirties or forties or quite young, that have these small one to two to three-millimeter lesions in the bladder that keep recurring, despite your intravesical therapy, despite all the workup. For those patients, at least in my experience, if you do the appropriate PDD and blue light technology, and you make sure that you're not missing anything, and then they have a few recurrences here and there, they appear to kind of almost stay stable for years without any change in the lesions. And when you take these tumors out and send them to pathology, it almost comes back PUNLMP, or it comes back so low grade that you wish you hadn't done anything. Have you experienced that in your practice with the really small lesions [crosstalk 00:15:38] or is everybody for TURBT?

Morgan Roupret: Regardless of the pathological assessment, we know that the natural history of this disease is ... there is still a psychological impact for these patients because they do not leave with a swelled up [inaudible 00:15:52] above their head, but they are feeling that they are on the chronic condition. They are always afraid that it is coming back with a severe situation.

And anyway, in this case, it is a perfect case, they would be suitable for the fulguration. The problem that we have in Europe in certain areas, and it's particularly in France, for instance, is that it is not recognized here as a procedure. So each time you do a technical procedure, there is a code and it is recognized and well admitted by the authorities. So if you do that and at some point you miss something, you could be in a troubling situation.

So we are working a lot on the protocol for bigger surgery, where we could use the fulguration and our protocol to validate the possibility, to have it not only as an option in the literature but also in our daily practice to make all private urologists in a situation where they would be comfortable to use this option in that particular case that you have just depicted.

Ashish Kamat: That is a very interesting point that obviously in North America, we haven't had to consider. The coding and what you just said, being recognized by the appropriate authorities. So that's a good point. Thanks for bringing that up because obviously, our audience is global, so I want to emphasize that. Wassim, you said that you have adopted office active surveillance and/or fulguration for these patients. Do you have a threshold? In other words, do you have a size cutoff? So if these tumors are staying stable for a while and suddenly they become excised, is that what takes you to go to the OR and do a formal TURBT?

Wassim Kassouf: To me, the active surveillance that is out there is less. So usually those patients who you alluded to, the one to two millimeters, I typically excise it under a biopsy and fulgurate it. Most patients, less than five-millimeter tumors, can be easily managed with a biopsy and fulguration. Particularly the patient that you mentioned, the one who's got a few here and there, one to two-millimeter lesions, you can argue that an excision with fulguration versus a TURBT, if you take this patient to a TURBT, often what you do is you [inaudible 00:18:08] the lesion and biopsy the base, if it was that small, to begin with.

It is more the ones that I would say, they are a bit more kind of open for debate, is those half a centimeter lesions where you know you're going to excise ... or even up to one centimeter, you know you can excise it, but there will be some small stuff left that you're going to burn, where when you do the TURBT, you can resect it a bit more formally and deeply.

So the cutoff for me in someone is roughly around a centimeter. And again, it's not a size cutoff, it's also about how wide is the base, how narrow is the stalk. My issue is particularly when we are talking about the younger patients, at least, and I think it heavily depends on where you practice. So the logistics of giving a one dose post-op chemo in someone who undergoes, let's say a biopsy in the office, it's very difficult in where I practice. So that doesn't happen. So they do not get that benefit of that one-shot chemo. So for someone who is younger, I want to offer that benefit. And I usually take them to TURBT.

But someone who's in their mid-eighties, very frail, that we are talking about, like this patient, then, although I will not be able to offer that one-shot chemo, and I understand the guidelines advocate all this, but sometimes the guideline gives you just a general recommendation for all patient populations. But individual patients are managed differently. So that patient who is mid-eighties, comorbid, I'm very, very satisfied in terms of advocating a fulguration, particularly if the tumor is small.

And in the end, what are you missing? We know that the progression is extremely low and the recurrence, yes, the recurrence is significant, but you are not missing that window of losing that opportunity to cure in that disease spectrum.

Ashish Kamat: Yeah. No, great points again. And all three of you are experts at resecting tumors and recognizing when to go deep and not go deep. But if you look at the general community, we have colleagues of ours that do not do only bladder cancer or do not do only oncology. They do everything. And the point that you raised about TURBT potentially having downsides is true. You can take a patient with a small tumor to the OR and they have a perforation, et cetera. So that's a good point you made as well.

Marko, if I could start with you and ask you, do you use any urinary markers in patients like this to sort of help you decide between who you might be comfortable with being a little bit more aggressive versus not,? Or have you, personally, I don't find cytology or anything to be useful, but have you used markers at all?

Marko Babjuk: Routinely not, because it is not reimbursed. And I think that Morgan's point about reimbursement is really very, very important. And what I'm using is urinary cytology, but usually, more not to lose the high-grade lesion, for instance, or miss the high-grade lesion in patients during follow-up. So more as an adjunct investigation to cystoscopy. But I must say that this is the question of the scheduled follow-up. And I think these are, I must say, the results of new markers, of these complex markers, are really persuading. So I think this is, again, something where we may reduce the ... make our approach less aggressive.

But if I come back to what Morgan said, it is really critical because we, particularly in bladder cancer, the urologists like to do a cystoscopy. It is quite economical... and has a bit of potential for them. We are doing TURBTs because we need to train residents. We need to have a workload for the hospitals, and it is well reimbursed. If I do fulguration, I'm losing money in our system.

And on the other hand, it has a lot to do with the guidelines because usually the countries in Europe follow finally the guidelines, that they remember what we are saying. And as Wassim said, we are quite conservative in the guidelines and we make general recommendations, but we probably need to be more open to these new and less aggressive approaches, even in the guidelines. This is the way of how to change the reimbursement system. And this is the crucial point in Europe.

Ashish Kamat: Yeah. Thanks for that. Morgan, you have done a lot of work and we worked together on markers' studies and things like that. Are you excited about any potential markers that will help us in these situations?

Morgan Roupret: Yeah, we all know there are different societies coming up and so outside protocols is difficult, but there are, I would say enough effective processes supported by the authorities in France when you can, I would say initiate something. So what we are trying to do with the French association is to open up to the possibility to have a prescription.

And the question that we have now, and I think when it comes to following up, and there are certain markers that ... the markers are doing quite good in high-risk, but we are always afraid to miss someone who is evolving to something more severe. And now we see a bright future in this category of patients we have discussed today, where if we miss something, as you mentioned, for a few months, it's no big deal, and we are not going to compromise the oncological outcome.

So there are certain markers and especially based on mutilation and panel of genes and mutilation that are really interesting and more accurate in a low-risk patient or intermediate risk, because what we want to do when we have the data from the marker is, whether or not they have stratified the population, or they have taken altogether the patient or did they focus on the low risk or intermediate risk? And I think that in the near future, it may be helpful, but there is a question of cost. It's 150, 200 Euro. And we are evolving, I would say from the perspective of medicine, in a socialist system where everything has to be reimbursed. And it's always a challenge for these markers to get reimbursed compared to a big pharma company, where I used to get reimbursed for expensive drugs. But I think in our daily practice, it would be extremely useful. So I would say, yes, the question has been mentioned outside the protocol. It's a bit difficult.

Ashish Kamat: Okay. This topic is so interesting. We could talk forever, but I recognize, and I respect your time. So as we wrap it up, maybe I'll give each one of you, take 30 seconds, 60 seconds to give our audience your top highlights on this topic. Wassim, maybe I'll let you start, and then Morgan, and then Professor Babjuk can close since he started the session. So Wassim, some closing thoughts for the audience, when they are looking at a patient with low-grade lesions.

Wassim Kassouf: I think so that the default would be to do a TURBT in general, to make sure you actually get a formal resection after the one single instillation of chemo after. But I would say is make sure you also weigh into who you are dealing with, the patient him or herself, and if someone who is elderly, frail, tumors that look low grade, they should be offered and discussed the option of biopsy fulguration.

Morgan Roupret: Yeah, I think that, honestly, as I mentioned from the beginning, I'm still following the steps that I've been taught. And I would say that I would be more than happy, and I'm pushing as far as I can to develop open the possibility of ambulatory surgery fulguration and so on, but it will be restricted for, I would say a very, very small subgroup of the population. So still I see that the TURBT is going to remain the option in the vast majority of cases, but I would like to have the possibility not only to evolve in the possibility to instill new drugs, new treatments but to have this possibility that was presented by Wassim about the opportunity to use the fulguration in certain cases.

Ashish Kamat: Great. Marko?

Marko Babjuk: I fully agree with what was already said. I think our approach should be individual. So we should proceed according to the guidelines. So regular TURBT with instillations in most of our cases. But in individual situations with tiny recurrences, when we really feel safe, then I think the less aggressive approach is really a good choice. I believe in the future we will be able to be even more, or you will be able to choose a more individual approach. We have the chance of chemoablation. This is a good field for laser, I believe, outpatient laser surgery. So I hope there will come a lot in the future because I really believe that our approach is sometimes too aggressive today.

Ashish Kamat: Once again, thank you each and every one of you for taking the time to join us today and share your insights with the audience of UroToday, which includes a lot of people and a lot of countries that can't have access to big seminars. I hope we can meet in person sometime soon. Thank you again.

Marko Babjuk: Thank you.

Morgan Roupret: Thank you. Bye-bye.

Ashish Kamat: Bye.

Wassim Kassouf: Thank you.