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Ashish Kamat: Hello everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from Houston at MD Anderson Cancer Center, and it is my pleasure to welcome again, two true experts in the field of bladder cancer and close friends of mine, Professors Palou and Witjes, from Spain and the Netherlands, respectively. We had this session at the EAU recently this year, which many of you, I'm sure, were able to attend, but for those of you who were not able to attend and see this occur live, Professors Witjes and Palou have been kind enough to join us today and discuss the optimal management of high-grade T1 bladder cancer.

They have each been given a position to defend, but of course, we'll have a nice discussion at the end where we will actually find out what they truly think about the situation. For the purpose of this discussion, we are presenting a hypothetical, very healthy patient, which normally is not the case with bladder cancer. So let's assume this patient is in their late forties, early fifties, healthy, has a first-time diagnosis of hematuria, which is worked up. Everything is clear except for the bladder, and in the bladder, there is about a 2-centimeter tumor. It's resected, it's clearly T1 high-grade on pathology, no question about it. There is some CIS-associated. There is muscularis propria present, which is clear. No invasion into the muscularis propria.

And again, for the purpose of this discussion, we will throw in different parameters such as what if it's T1b? What if it's micropapillary? All of that. But for this part here, let's hear what our experts have to say about T1 high-grade bladder cancer in a healthy patient with CIS. So, with that, Joan, I'll hand the stage over to you and have you go first.

Joan Palou: Okay. Thank you. Thank you, Ashish. A pleasure to be here together on this nice summer day and talking about T1G3 high-grade and CIS, and I will defend going for intravesical therapy.

I have no conflicts of interest.

First concept: "your own bladder". Why take out the bladder? The best bladder is your own bladder. So even if we do very nice neobladders and so on, if possible, we have to try to preserve the bladder. Would cystectomy cure-all T1G3 high-grade tumors? Well, we know that up to 20% will not be cured by cystectomy, the results really are not so different. We know that when we treat patients with T1G3, real T1G3, with restaging, 15% to 20% progress.

And is early cystectomy really better? Well, everybody is talking about this paper by Denzinger, which is early versus deferred cystectomy, but I think it's completely a wrong paper because they compared all the patients that went through a cystectomy to those who failed, to BCG. So they did not compare all the groups of early versus all the deferred plus BCG treated patients, probably the curve would have been different. So I think this is not a reason to decide on early cystectomy.

Why a conservative approach? Well, quality of TUR. The quality of TUR is really important. It's not perfect, but it's important to do it correctly. If you see, for example, this picture says, "Okay, I've resected the tumor. Is that okay?" No, I think not. We have to see better, the muscle and resect much more [inaudible 00:03:46] and if it would be a bigger tumor, I would resect much more, but always some margin, always going deeper because then this is what happens, we see in the publications that 15% were T2, the average, T2 disease at re-TUR. So that means that a lot of people are doing a very bad first TUR. And you see only a few groups had 5% at re-staging.

This is a letter to the editor that we made when we first published the first paper by Harry Herr in 2005, that we already said, "You have to do a wide and aggressive resection, and there has to be the muscle in the specimen. Otherwise, we are not doing a good job."

And these are our numbers, we published them years ago, and now we are updating, but instead of 60% residual disease, we have 17% residual disease. In T1 disease, our understaging is 0%, and when there is Tx, then it's 4.2%. So I think these are important numbers. We have to really do a good TUR in order to know that we are treating, as was mentioned by Dr. Kamat, that we are really treating a T1 tumor. And also, in this paper, just a retrospective study of 2,400 patients, in those that there was muscle in this specimen, re-TUR did not really improve recurrence and progression related to the others.

So micropapillary pattern, it was mentioned that this patient had also some micropapillary pattern. It looks like, with cystectomy, they do much better. And in this paper that was published by the group [inaudible 00:05:38] at Kamat, they showed that it looks like the focal does better than extensive, of course, and apparently, those that had early cystectomy did better than those with delayed cystectomy. Of course, again, those who fail, do worse. That's clear, my dear.  But what's our experience? Our experience is that if you do a complete TUR, the percentage of micropapillary patterns, it's really quite small, you see that finally, the majority of patients that receive BCG are alive without tumors. But it's important, complete TUR, and in this case, these patients even have CIS. And for us, the important part is the diagnosis of involvement of the prostatic urethra. We have seen several papers that having [inaudible 00:06:29] none of those patients with a T1G3 plus CIS, not including those in the prostatic urethra, the results are quite similar. But when you have involvement of the prostatic urethra, it really makes a difference.

And another important thing, give the correct intravesical treatment. We had to look at this some years ago and only 60% of the patients received the recommended treatment. So 40% were incorrectly treated. So if we do not do a correct TUR, we do not do a maintenance treatment, then we are treating incorrectly these patients, and we know that maintenance BCG is mandatory in order to see improvement in recurrence and progression.

So intravesical therapy in this case, why? Well, quality of TUR. Correct first TURB and re-TURB, if necessary. Percentage of micropapillary pattern, if it's really a small percentage, probably we can use it, but again, with a complete TUR. CIS important? Yes, but it's not the same to have just one bite of CIS, but full [inaudible 00:07:49] involving prostatic urethra with CIS, it makes a big difference. And BCG maintenance improves the results. So it has to be used again. So selection is the key. If you have, of course, multi-focal, all the bladder full of T1G3, but if you have a single tumor, a bite of CIS, not involving prostatic urethra, why not offer intravesical therapy? Thank you.

Ashish Kamat: That was great, Joan. Thank you for presenting such a concise summary in defense of intravesical therapy. We will now hand the stage over to Fred and hear from Fred why early radical cystectomy is something that we should consider for these patients that present with T1 high-grade bladder cancer. Fred?

Fred Witjes: Okay. Ashish, thank you very much. So I thank Joan for a good presentation and of course, he has reasonable arguments, I can't argue that. What you already heard were a few buts in his arguments. Yes, of course, but. And I think these are very important, so I guess cystectomy also certainly deserves a place to consider in these patients.

I don't have any conflicts of interest for the subject, except for the fact that, of course, I'm a surgeon and I like to take out bladders if necessary.

So let's look at the two guidelines we use much: the EAU guideline and the AUA guideline. If you see and read the AUA guideline, "In fit patients with high-grade T1 after BCG or T1 with CIS, or other nasty things like a lymphovascular invasion, variant histologies like this patient, you should offer radical cystectomy." And also, the EAU, in their new guideline from 2021, states that you have to discuss immediate cystectomy with patients at the highest risk of tumor progression. So strong recommendations and this patient obviously is in the highest risk group of tumor progression.

Why such an aggressive approach? And I totally understand that BCG is something you could try, but why maybe consider such an aggressive approach? Well, the first issue you have, and Joan already mentioned that he said 15%, and I think maybe it's even a little bit less currently, but still you will have upstaging in 10% to 20% of these tumors. So they are not T1, but they really are invasive, even in spite of maybe a good TUR, and those patients are undertreated with intravesical therapy.

One of the things that may be helpful in the near future is the use of MRI. You will see that in this update of around 1,800 patients, it is especially good at differentiating between T1 and T2 bladder tumors. Sensitivity and specificity are good, 92% and 88%, respectively. Of course, you have to have experience, you have to have three-tesla, you have to mind all the technical aspects of MRI, but this is maybe something we can use in the near future.

Then, even if it is a real T1, and even if you have treated it with BCG, still you see there is progression. Not all those patients do very well. This is a large EORTC trial, maintenance BCG, T1 patients, high-risk patients, and you see that T1G3 patients do not do very well. 1 and 5-year progression rates are more than 10% and almost 20%, respectively. And we all know that these progressive patients do very badly. Here, you see two large series, one of around 2,000 patients, individual data, and you will see that if there is a progression from non-muscle invasive to muscle-invasive, you'll see 60% cancer-specific mortality after progression. And an update I did around 10 years ago with 3,000 patients, you see the same. If you have a progression from non-muscle invasive to muscle-invasive disease, you will have this cancer-specific mortality in four years of around 65%. So then you have missed a window of opportunity.

And like we probably will discuss in the discussion after this, there are several factors that might make it even worse for a pT1 tumor. Of course, you see in red: CIS, and then lymphovascular invasion, variant histology, if you do not treat with BCG, if you have a large tumor, I think this all makes sense. And of course, very important, there is a T1 subclassification.

So I will show you a slide of Professor Kamat's that he produced some years ago. What is the disease-specific survival with T1 high-grade bladder cancer, that is comparable to clinical T3b, Gleason 5+5 prostate cancer, 12 out of 12 cores positive, with a PSA 75? And I think in those patients, you wouldn't really think this is an innocent disease.

So my conclusion for why cystectomy in pT1 is high-grade with CIS, which is a very high-risk non-muscle-invasive bladder tumor, cystectomy gives the best cancer-specific survival and is in the range of 90%. Obviously, still, some patients will die of cancer. Quality of life after cystectomy is comparable to that of the general population. There are still no standard alternatives, hyperthermia, immunotherapy. Like a recent review in European Urology said, "Bladder-sparing therapies achieved modest efficacy in patients with non-muscle invasive bladder cancer after BCG," and I think the same goes for this high-risk group. However, I realize it is overtreatment in a significant percentage, and even in experienced hands, it is major surgery, with quality of life impact, with morbidity, and with mortality.

Finally, in 25 years of practice, I've become much more conservative in prostate cancer, but much more aggressive in high-risk non-muscle-invasive bladder cancer. Thank you for your attention.

Ashish Kamat: Thank you, Fred, for that summary and highlighting why you would consider a radical cystectomy in this patient. I like your last statement about how over the years you've become more conservative in prostate cancer and more aggressive in high-risk non-muscle-invasive bladder cancer. I think that happens to all of us as we realize how insidious and dangerous the disease can be. Now, we recognize that you were each given a position, and of course, we had a robust discussion at the EAU, we have a little bit more time during this session to delve into the intricacies of why you do something a particular way. So Fred, since you just finished, let me ask you, what are some of the risk stratification criteria that you use to, in your mind, counsel patients on considering radical cystectomy versus let's consider intravesical therapy? How would you counsel our listeners and audience, and even patients, as for certain risk factors that you look for?

Fred Witjes: Well, I think a very important risk factor, Ashish, is the pT1 subclassification. It is still not in the guideline. The reason why it's not in the guideline is that it hasn't been studied in the studies that have been used to make the guideline recommendations. But in many studies, you see that the T1b tumor, obviously, which is almost a T2, has a much worse prognosis than a T1a tumor. So for T1b, I have become more aggressive. If you have some kind of variant histology, which we recognize more and more currently, it was seldom 10 years ago, but at the moment, I think we see in 15% to 20% of our patients some kind of varied histology. And if that is extensive, certainly for me, is a reason to be more aggressive. And over the years, I've seen that women do worse, so also in women, I am a little bit more aggressive with my advice for cystectomy than in men.

Ashish Kamat: And, Joan, do you have any risk criteria — for example, the re-TUR data — to help you drive patients one way or the other?

Fred Witjes: Yeah, well, to be honest, I was one of the coauthors of the manuscript that Joan showed. If you do a good TUR, and you are certain that you did a good TUR, you have the [inaudible 00:15:48] muscle present, it's negative, and you have good pathologists, I don't do a re-TUR, but obviously, I agree that a good TUR is absolutely the first step to do in these patients.

Ashish Kamat: Yeah. I've heard you say that, and I believe that too, a good TUR is something that is absolutely necessary. Unfortunately, a lot of our patients are not taken care of by bladder cancer experts, and I guess that's why the guidelines state that a re-TUR is necessary. And I think it's something to keep in mind, the practicalities. Joan-

Fred Witjes: I agree with that, Ashish, but you know, on the other hand, why not do a good TUR? Otherwise, you will postpone good treatment, BCG, for example, or your cystectomy for six weeks, four weeks, eight weeks, and that is a risk. So yeah, I understand that not everybody does a good TUR, but we should.

Ashish Kamat: Absolutely. No, we absolutely should. Joan, what about you? What are your thoughts?

Joan Palou: Yeah, I think, since, let's say it's a kind of minor surgery, this does not mean it is a surgery that we do not have to improve. Normally, I say in my lectures, "Have a look at your own re-TURs, and then you will know how good you are at your first TUR." I think this is a very important message. Have a look at your own re-TURs and if you find a lot of tumors, if you find a lot of T2 tumors, please take a course, watch some videos, have a look at some videos, or whatever, and improve your quality of first TUR. This is clear.

And another question is if we find a Ta, a T1, or CIS at the re-TUR, is this much worse or not? Well, I know that Harry Herr published, that when you find a T1 disease at re-TUR, a 75% progress, so you have to then do a cystectomy. But in our experience, [inaudible 00:17:44] published, that if you find T1 disease, the risk of progression is 25%. So the decision, I would say, is similar to the beginning. But [inaudible 00:17:55] has to be said, that if you find T1 disease, either you did a bad TUR or you are in front of the multifocal disease, which is also a prognostic factor.

Fred Witjes: Joan, I think we have to realize that ... Well, of course, you are a bladder cancer expert, however, many colleagues will just do a diagnostic TUR to make sure that they know that it is, for example, a T1 tumor. Then they refer them to a center where the rest has to be done, for example, the re-TUR. I know that it is the practice in Germany, for example, where the [inaudible 00:18:28], just do a, let's say, diagnostic TUR, but they do not attempt to do a radical TUR with the risk of perforation. That is, of course, a different way of approach than what you and I do.

Joan Palou: Yeah, clearly.

Ashish Kamat: That is very true. In our recently published series from MD Anderson, if you treat the patients the way you guys do, which is a good TUR and early BCG, et cetera, the risk of progression with T1 high-grade disease has actually gone down over the years with the recognition with PDT, with narrow-band imaging, better TUR, better high-definition monitors as well. But at the same time, let me ask you, in the patients who do progress with T1 high-grade bladder cancer, clearly, they can also progress to metastatic disease, even if the bladder is clear, how do you monitor these patients, Joan? Do you do periodic imaging along with your cystoscopies? And if so, how often would you recommend people do urograms or other sorts of imaging?

Joan Palou: Well, for us, what we do is, the BCG and BCG maintenance, those we do a conservative approach, and then the standard cystoscopy follow-up. I mean, the first two years, every three months, and then we moved to six months until five years, and then yearly. And what we see is that also, the patient that has not recurred for five years, some of them will recur after that, after five years, but not so many.

And then related to the upper tract, for the follow-up, I think to find that those who respond, we know that 5% to 10% will finally develop metastatic disease with the bladder clean, but there is also to go for it and detect these cases, I think it's really difficult. And when the diagnosis appears, they already have metastatic disease. So mainly we follow the upper tract, and then in these patients, normally we do a CT scan every two years because 60% to 70% that present with an upper tract tumor, which is in, let's say 11%, 15% that will develop upper tract tumor, mainly are in the first six years, six to 10 years. So we do every two years, but it's not really established or accepted exactly when we have to do it.

Ashish Kamat: Fred, what about you? How often do you do it and how often do you recommend other people do it?

Fred Witjes: Well, I think the cystoscopy schedule would be the same for me. So initially every three months, and then slowly go to four months, six months and go down to once yearly. In my experience, it's difficult to discharge patients, they are very happy that they are checked. That's one thing. Upper tract imaging, I also do that not very often, but what I do in high-risk patients, I do a CT of the abdomen every year certainly, initially to see if there is not any metastatic disease. Sometimes that's difficult because BCG also gives some notes sometimes, but then you have to cope with that. But certainly, the first two, three, four years I'm quite aggressive in monitoring those patients because those are the years that they will have problems. After that, I become much more conservative.

Ashish Kamat: Yeah, I'm similar to that. I'll do yearly imaging for the first three years or so, and then after that, stretch it out a little bit. And just like you mentioned, I find it very hard to convince patients even after five, some even 10 years, to not have cystoscopies or to go back to referring physicians and it is very difficult.

So with that in mind, let me ask you, what markers do you use? Joan, maybe you start, do you use additional markers other than cytology to help you with these patients that have high-risk or very high-risk non-muscle-invasive bladder cancer?

Joan Palou: Well, we are participating in a lot of trials, we're still in some trials, in two trials now, and deciding a little bit will be the strategy. Also, because it's not established, let's say, from the legal point of view, but if you just started using a marker and then suddenly there is a problem, you do not detect a tumor, you might have a problem. So I think this is an important point, but we are thinking about probably using different markers, according to following low-grade tumors or high-grade tumors. So I think in low-grade tumors if we have a very good marker with a very high negative predictive value, it's okay. Even if we are missing some tumors, it's a low-grade tumor, nothing really happens, we know by the natural history of these tumors.

And I think in high-grade tumors, we need a high negative predictive value, but also high sensitivity because we cannot miss too many high-grade tumors. And I think this is the debate right now in our center, and probably in a few months, we will decide a little bit which one in each area. And we are waiting also, for some results of two studies that we are participating in with different markers. And then also finally, when we have selected for low grade and high grade, they also have to look at the cost, which is important.

Ashish Kamat: Now, Fred, do you do anything differently?

Fred Witjes: Well, not really. Markers to predict whether this patient has a bad prognosis and whether we should do a cystectomy, we've studied a lot and we are still doing some studies, but to be honest, they are not useful currently in clinical practice. And as a follow-up, there have been some studies now recently that have shown that some of these markers have a very nice and very high negative predictive value for high-risk tumors. So we currently really only use one in clinical practice to have fewer cystoscopies, which, of course, is a burden for you as a patient, for you as the doctor, for the healthcare system. And so far, we are all very pleased with the practice we have now so I alternate [inaudible 00:24:28] a test with cystoscopy.

Ashish Kamat: Great. Of course, I could continue chatting with you guys forever, but in the interest of time, we'll wrap this up. And in closing, let me leave each of you with the ability, what are some of the two or three main points about T1 high-grade bladder cancer that you would want our audience to take home? Your take-home messages, two or three points. Fred, you go first.

Fred Witjes: Well, I'll probably have the same take-home message as Joan. I really think, I still fully support doing a good TUR. Whether you do it in one or two or three or four times, do a good TUR. Consider all additional potential bad risk factors like a lymphovascular invasion, variant histology, pT1b, and then decide on conservative or radical treatment, but also consider radical treatment.

Ashish Kamat: Joan?

Joan Palou: Yeah. Well, I agree with my lecture. I would add here, always include, whenever there is something in the bladder, and you think about CIS, always include the prostatic urethra. Still, a lot of centers do not do it.

Fred Witjes: Very important [crosstalk 00:25:42].

Joan Palou: When there is positive cytology, and you doubt about the bladder, take a bite of the prostatic urethra, because this might give some more valuable information.

Ashish Kamat: Great. Great points. Again, thank you both for taking the time and doing this for our audience. A lot of trainees in many parts of the world are able to get this information from this site. So thank you, and hopefully, we'll be able to see each other soon. I don't know when, but hopefully soon.

Fred Witjes: Okay, thank you. Bye-bye

Joan Palou: Okay, thank you. Bye-bye.