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Ashish Kamat: Welcome, everybody to UroToday's Bladder Cancer Center of Excellence. We are pleased today to be joined by Professor Marko Babjuk, who is an expert in the field of bladder cancer. He has sat on and led multiple clinical trials and is the chair of the EAU guidelines on non-muscle-invasive bladder cancer. He joins us today from the Czech Republic and has taken time off from his busy schedule to discuss with us the EAU guidelines on non-muscle-invasive bladder cancer. Professor Babjuk, take it away.

Marko Babjuk: Good afternoon. I should talk, and I promised to talk a little bit about the EAU guidelines for non-muscle-invasive bladder cancer. And I first should certainly mention all my collaborators who, because we are working as a panel and as a group, and it is a fantastic operation. I would like to talk about the updates from this year. The text was published in March this year, and the system is that we prepare the updates every year. So I will talk about the updates from this year, but I will also mention some limitations, which I feel inside the text. And maybe also mention what we are working on this year, because we are already preparing the next year's update, so updates of 2021 already.

First, if we are talking about the muscle-invasive bladder cancer management, we need to remember the basic principles, which is certainly translated into the guidelines text. And these principles are reliable diagnosis and complete TURB. This is the risk stratification according to parameters that we achieve from the diagnosis from TURB. According to the risk group certification, we should offer to the patients that we want treatment according to the risk stratification. And finally, in those patients who progress, or will potentially progress in spite of intravesical treatment, we should in time indicate radical cystectomy.

Talking about that, we also should remember the principles, how the guidelines are preferred. First, it must be based on scientifically correct text. All recommendations should be supported by the highest evidence which is available in the moment. The published evidence cannot be replaced with expert opinion, if there is any published evidence. On the other hand, this scientifically correct text should be presented in some logic way, so the readers should understand that, and the whole text should represent the logic and synoptic guidance of disease management... of individual steps of disease management.

Unfortunately, I'm not sure whether we are so successful in that because we know that the guidelines on non-muscle-invasive bladder cancer have still very low compliance by urologists. But it is not just the problem of EAU guidelines. It is the problem of AUA and all guidelines in this area. So we need to be better in the future.

But let's talk about the individual recommendations and individual parts of the text. First, a crucial recommendation is connected with TURB. We recommend clearly that in patients suspected of having bladder cancer, you should perform a TURB followed by pathological investigation. And we should remember what is the goal of TURB; it is to perform a complete resection of non-muscle-invasive tumor and to make a correct diagnosis of the tumor. To be able to achieve that, we should do the procedure correctly. And you should remember that the TURB is a complex procedure. It should be performed systematically. There are several steps that should be performed; it is listed in guidelines. And it is also given in which situations the individual steps should be performed.

Another recommendation is that you should use the modern methods of tumor visualization. I mean advanced visualization, like PVD and BA image, as if this is available in the operating theater. We are talking very frequently, in last years, is the technique of resection, the technique of how we remove the tumor. The guidelines allow, in fact, two approaches. First is a traditional one, which is the resection in fractions. It means the separate resection of individual parts of the tumor and of the underlying bladder wall. And then another approach is a modern one, the so-called En-bloc resection, which we believe can at least, in defined situations, provide some benefits concerning the quality of specimen and the final results.

Just remember, this is just an example of three papers published recently. The first one is the expert opinion about why we believe that TURB is still an under-discussed procedure in the urological community. The second one is the consensus statement on En-bloc resection, which tried to define the individual steps and make the approach or the resection more precise and more effective. And the third paper provides some recommendations on how to do the TURB to be able to achieve the best optimal results in this moment.

I believe we will improve the technique of resection. I know that many groups are now working on trials, comparing the standard resection with En-bloc resection. I hope, at the end of the day, we will be able to really provide some clear recommendations when to use each method, how to do that, and we will improve our results. 

In individual situations, we should do the right TURB with the early re-resection within two to six weeks after the initial resection. You can see that there are defined individual situations when each will be performed. The reason why we recommend that is that we know that there are still a very high risk of residual tumors, even tumor under-staging in T1 tumors, for instance, after initial resection.

I believe that this is some limitation. I hope that we should be more precise in the recommendation. So let's say, not recommend a second TURB in all T1 tumors, but only in specific T1 tumors, but we need to have better data on that. But I, again, believe that many groups are working on that so that we will be able to provide more specific recommendations in the future.

Concerning risk stratification, this again, I think that at a crucial point in the guidelines you should use all data that you collected during the diagnosis and during the TURB. According to these parameters, stratify patients into the risk groups.

We have basically three risk groups. Recently in last years, we decided to propose also the subgroup of high-risk tumors, which is called the highest risk tumors. But I will talk about it a little bit later.

Here you can see how the EAU guidelines define individual risk groups. It is interesting or important to know that in the beginning, when we came with this recommendation about eight years ago, we analyzed all these parameters using the EORTC risk papers. We exactly know what is the risk of recurrence and progression in individual risk groups.

I think that this is one of the limitations, this stratification. There are two reasons. First, the EORTC data, which helped us eight years ago to define individual risk groups, are relatively old. These patients were treated 20 years ago. Definitely, at least the endoscopic surgery improved since that time. We know that the prognosis of patients with bladder cancer generally are better today than they were 20 years ago. And another problem is, and it is a more important problem, is that the prognostic data are available for 1973 WHO classification. So from 1973 grading system, but not for 2004 classification, which is predominantly recommended by pathologists today. It is a problem because the EORTC calculator is based on prognostic tables from on 1973 classification, but the urologists have 2004. It is not the same. We cannot say that grade three is the same as high grade. You can see from this slide, some of you cannot consider the high-grade tumor as complete fully the same as grade three. Apparently the group of high-grade tumors is much bigger than those of grade three tumors and their prognosis generally is a little better and more heterogeneous than the prognosis of grade three tumors. We really need to have new prognostic information which takes into account the new WHO classification. We are now working on that — we, in this moment, prepare the final text for publication. We made the analysis of individual patient data analysis of more than 5,000 patients from many urological centers. For all of these patients, we have available both classifications, so we can provide new prognostic models and we hope it will influence also the update of the guidelines in the next year. We will, a little bit, change the definition of the individual prognostic groups.

Based on the risk stratification or, one of the reasons of risk stratification, is to be able to provide individual treatment recommendations. This slide demonstrates how we can work with this stratification. Let's say, if we say that the patient is in the intermediate-risk group, then we know that these patients, according to the calculator have up to 7 to 8% risk of tumor recurrence within five years, and about 6% risk of tumor progression. So the problem in intermediate-risk tumors is the risk of recurrence. And this is the recommendation: today we recommend to use BCG or intravesical chemotherapy, according to the decision or individual situation. If you've got a higher risk tumor, we know that the risk of progression in these patients is much higher comparing to intermediate risk group. It is above 17%. So the problem in higher-risk tumors is, in fact, the risk of progression. These patients can die of the disease. That's why we, in all of these patients, recommend to use BCG treatment, not intravesical chemo, because BCG can reduce the risk of tumor progression.

We also recommend in the guidelines how the BCG should be used. It means what is the optimal schedule of BCG? And we have some more data this year. This is just the paper that was published recently. These are the results of phase three Nimbus trial organized by the EAU research foundation. We know that if we reduce the number of installations in induction and maintenance, probably, the patients will be at the risk of higher recurrence rates. Probably this original and schedule is the optimal one and we should stick to that.

Also, I already mentioned the problem of the highest risk tumors. The problem is that we know that even after BCG treatment, some patients will progress and can die of the disease. We know that between T1 grade three tumors, the risk of disease related to death is about 11%. So about 11% of patients with T1 grade three tumors can die of the disease in spite of the correct approach. And the idea is to, or the philosophy is to detect or try to specify these tumors even before the albumin treatment and recommend them immediate cystectomy in these patients because they probably will not respond to BCG. Here you can see how it is defined. These are particularly the patients with unusual pathologies or this lymphovascular invasion. And also the worst T1 grade three tumors in combination is carcinoma in situ, multiple T1 grade three tumors and so on. In these cases, you should discuss immediate radical cystectomy with the patient.

Of course, the patients who are at the highest risk of tumor progression are patients who don't respond to BCG treatment. This is the definition of BCG unresponsive tumors. I'm happy this was updated this year. The definition now was updated and it is now fully, in full agreement with the definition recommended by [inaudible], and accepted by the FDA. The definition is based on pathology after BCG, which should be always high-grade tumor. It is based on resistance or timing of recurrence, and also on the adequate BCG or amount of BCG which was given. You can, again, look into the definition. It is very important. I think it should be uploaded that we already were able to unify the definition because it is not only important for the prognosis of our patients, but it is also important for clinical trials that are planned, and that will be performed, to have really a unified inclusion criteria for these trials.

Those patients who are BCG unresponsive... BCG unresponsive means that this is a tumor where the further BCG is unlikely to provide the benefit for the patient. In these patients, we should change the strategy and the standard recommendation today is to perform radical cystectomy. But, we have today, on the horizon, several treatments which are tested, some new approaches, like the gene therapy, like immunotherapy, even with systemic administration. There are a lot of drugs which are on the horizon, but what we today recommend is, in BCG unresponsive tumors, is this radical cystectomy. But if the patient is not a candidate for radical cystectomy, you should consider the clinical trial or some other preserving strategies outside the clinical trial as a third option. I believe the problem of BCG unresponsive tumors is very complex. We should also try to work on the monitoring of these tumors, on how to detect the failure of the disease and so on, and so on. I think there is a big space on how to improve.

So finally, don't forget the basic principles of non-muscle-invasive bladder cancer management, where I believe that particularly a TURB is of critical importance. And, finally, use guidelines on non-muscle-invasive bladder cancer. This is my final recommendation. Thank you for your attention and I hope you have a good time.

Ashish Kamat: Thank you, Marko. This is really, really excellent. You covered a lot of important points in a short time, and I really just want to ask you a few questions to highlight some points for our audience. The first is the question regarding a complete inadequate TURBT. As you mentioned, you know the TURBT is an extremely important part of the initial diagnosis and restratification of patients. Could you share with us what you would recommend for the viewers should be the absolute minimum when it comes to the quality of the initial TURBT? What do you recommend to people when you're training them, for example?

Marko Babjuk: I think first, what I always recommend is to really consider it as a very important procedure. This is not the procedure where the resident, at least in the beginning should be alone in the operating theater. This is the first point.

The second point is that it should be done systematically. From the beginning of your training, you should learn individual steps that should be performed. It means to start with the insertion of the resectoscope under the vision with careful cystoscopy and so on and so on. This is defined in the guidelines. This is definitely a systematic procedure, and you should do it step-by-step. You should find your own approach. I mean that you don't miss any step when you are doing that.

And, finally, you should evaluate your results. It is very important. You know, the problem is you mentioned the quality of TURB. The point is how to evaluate the quality, which criteria we can use for quality evaluation. Today, we use the presence of the detrusor muscle, but this is probably not enough. I believe, you know we need to be aware, let's say two weeks or one month after the procedure, whether we really did a good job. And if we did not do a good job, then we need to repeat the TURB.

This is very important to evaluate your own results. And also it's very important for our further research activities to evaluate all potential parameters that can be used to really improve the criteria of quality that we have today. Because you know, it is the principle of En-bloc resection. The one advantage is that potentially we can consider the margins of the resection, which we use in all other oncologic surgery, but not in TURB, which is a problem.

Ashish Kamat: Very good points. And I think you know getting to TURBT techniques formalized, maybe even having people send in videos so that our expert panel can comment and give appropriate feedback would be very useful in many parts of the world that don't have access to experts like yourself for training. You mentioned a little bit about detrusor muscle and re-TURBT. There's a lot of debate in the community and of course, you know, you and I have debated this at various meetings. But for the average urologist that is following patients with non-muscle-invasive bladder cancer, would you recommend that they consider a re-TURBT in all patients that have T1 disease, all high-grade patients? Or would you even recommend to people in the community to try to risk stratify these patients for a re-TURBT?

Marko Babjuk: I think the standard recommendation should be to perform the re-TURB in all T1 tumors. This is the point of debates, as I mentioned. If you have the meeting of the guideline panel, one of the longest debates every year is the problem of re-TURB. But, you know, we are discussing about that because we don't have data, in fact. So, my first recommendation is to do that. You should do it, in my opinion, in T1 tumors. But you should also register and evaluate your own individual data, in redo TURB's. And if you have no residual tumors, let's say between T1 tumors smaller than 1 cm, and you really have such a good data, then I believe it is definitely possible to make your own limitation or make your own limits when you perform the redo TURB. But the general recommendation, in the beginning, should be to do that.

Ashish Kamat: To emphasize, the reason we debate this at multiple meetings and conferences is because it's all the experts who are debating it. But it's better to err on the side of caution when it comes to patients. My personal opinion is if it's a TURBT that anybody's not 100% sure that there is absolutely no involvement of the muscle, then a re-TURB would save a lot of patients from being under-staged. So, I agree with you. And, of course, once you collect your individual data, then people can modify their practice. You know, it was interesting that the guidelines have a strong recommendation for the use of both the 1973 and 2004, 2016 grading systems. And again, it's another point that I completely agree with you on. Has there been any work in the pathology community that also parallels the recommendations of the urology guidelines?

Marko Babjuk: No, this is one of the problems, in my opinion, because they, to my knowledge, they did not do a lot about that. In fact, the pathologists recommend to use the new classification. They are strongly against 1973, but they have no data about which prognostic advantage it has. They are talking only about reproducibility and so on. But the reason why we use the grading system is to have some prognostic parameters or prognostic information.

I'm not aware of papers coming from the pathology part, evaluating the prognostic role of this 2004 grading system. Anyhow, what we did, and it is interesting and we are now preparing a couple of papers on that [inaudible] and all our panel, and many other people from Europe. It looks like that really the older system had a little bit better, prognostic power, particularly concerning the progression rates.

So even the best prognostic role would be achieved if you use the fourth year system. It means if you use both and so if you subdivide the grade two category into the grade two, low grade or grade two high grade, and then have grade one and grade three if you understand how I mean that. This probably would bring us the best prognostic information.

But the reason why we recommend to use both, in fact, is simply because we don't have the prognostic data for the new classification. So, if you would like to use the EORTC model, then you need to have grade one, grade two, grade three information. But, on the other hand, we cannot say to pathologists that we don't use their new system. That we use only their old ones. That's why this is a little bit practical recommendation, why we use that. But, in reality, we will really publish very interesting data on what is the prognostic power of both classifications.

Ashish Kamat: Again, very good points. I just want to bring up one last thing before we close, in the interest of time. That's, as you mentioned, the BCG unresponsive tumors. That definition came about with discussions that our group had with the FDA many years ago. Essentially the FDA wanted to have a clear unified definition to allow patients to enroll into clinical trials that were single arm. That way the patients would not have to be randomized to radical cystectomy because there was no... or still, really, is no true valid option, even though currently pembrolizumab is approved and, hopefully, the gene therapy, as you mentioned, which was developed at MD Anderson will be approved.

But it remains a definition that's more to help pharmaceutical companies and investigators and organizations perform these single-arm studies for registration purposes. I agree with your words of caution when it comes to incorporating those in clinical practice. We have to be a little bit more pragmatic in selecting the appropriate therapy for the patient and recognize that radical cystectomy still has the strongest recommendation. Marko, I want to thank you again for taking the time off from your busy schedule. This is wonderful. Our audience will really, really appreciate it. Stay safe and stay well.

Marko Babjuk: Thank you very much. Nice rest of summer and nice rest of the year for all of you. It was a pleasure to be able to participate. In fact, this new era is a little bit complicated, but it is amazing how we can stay in touch sitting in our offices or homes. So we need to challenge that and we need to use all the limitations we have, and to use that for the better future, I believe so. Thank you very much and have a good time.

Ashish Kamat: You too, take care.