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Ashish Kamat: Hello, everybody. Welcome once again to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from MD Anderson Cancer Center, and it's a pleasure to welcome to our forum today Professor Francesco Soria, who's joining us from Italy all the way from Torino. Francesco, you published and led this effort on a very important topic, sort of validating the IBCG scoring system for intermediate-risk bladder cancer. It's gained a lot of press and a lot of interest in both clinical circles and also regulatory circles where people are trying to use this risk stratification to help design clinical trials. So we are really looking forward to hearing what you have to say, and with that, the stage is yours.

Francesco Soria: Thank you. Thank you, Ashish. It's a great pleasure to be with you today, and thank you for the kind introduction. I will discuss some points of our study. The idea of our study originated from the recognition that the intermediate-risk non-muscle-invasive bladder cancer group is really a heterogeneous group of diseases, and that it is usually defined, especially by the EAU guidelines, as something that is not low-risk and not high-risk disease. So this group of diseases encompasses all the cases that do not fall into the low-risk or high-risk, very high-risk disease. And if we look further into the guidelines, we can see that in the intermediate-risk group there are probably patients with really small single Ta low-grade at the first recurrence from one end, and from the other end there are multiple larger Ta low-grade diseases and even T1 disease. Of course, with the introduction of the EAU 2021 scoring model, some selected Ta high-grade cases are also included in the intermediate-risk disease, but we know that there is no consensus about the inclusion of the high-grade disease into the intermediate-risk group.

But anyway, we can all probably agree that this is a heterogeneous group of diseases, and this heterogeneity also translates into a heterogeneity of recommendations by the guidelines. For example, these are the recommendations from the EAU guidelines regarding the treatment of intermediate-risk patients. The EAU guidelines suggest treating these patients with intravesical chemotherapy, with or without maintenance, or with intravesical BCG up to one year based on the EORTC data. But at the end of the day, the final choice is left in the hands of the treatment physician. Also, if we look at recommendations regarding follow-up, we see that there is just a recommendation to use a follow-up scheme that is in between the low-risk and high-risk disease, but, of course, there is a need for better stratification of these patients because this category is really huge and a lot of patients fall into this category.

With this aim, the IBCG, as you previously said, proposed in 2022 a new substratification model based on the presence or absence of five different risk factors: the presence of single or multiple tumors, the timing of recurrence (early or late recurrence), frequent recurrence or not, the tumor size, and the failure of previous intravesical treatment. Based on these risk factors, the intermediate-risk group was divided into three different subgroups. This model is really logical from my point of view and also easy to use in everyday clinical practice. But, of course, it was lacking clinical validation.

So the aim of our study was to provide the first clinical validation of this IBCG substratification model. To do this, we relied on a large multi-center retrospective European cohort of patients with intermediate-risk non-muscle-invasive bladder cancer who were treated with adjuvant intravesical chemotherapy. All the patients received at least intravesical chemotherapy, an induction cycle, in order to have homogeneity in our cohort. Also, to keep this homogeneity, we decided to exclude the high-grade Ta patients in order to avoid the disagreement that there is about the high-grade disease in this category of patients.

Overall, we included almost 700 patients. The vast majority were Ta low-grade. But if you look at table one, we can see that half of the patients presented with a recurrent tumor, and also, more or less, half of the patients had multiple tumors. All these patients were divided based on the five previously discussed risk factors into three groups, and we called these three groups intermediate-risk low, intermediate-risk intermediate, and intermediate-risk high groups. We, of course, analyzed the risk of recurrence and progression in these three groups. If we look at the Kaplan-Meier curves, we can, of course, see that regarding recurrence-free survival, there is a significant difference between the three groups in the risk of recurrence. What is also interesting to me is that the progression-free survival was significantly different, especially between the intermediate-risk high group and the other two groups.

These survival curves translated into these probabilities of disease recurrence and progression at one and three years. We have to acknowledge that the median follow-up time of the study was 36 months, so we were able to provide one-year and three-year recurrence and progression probability rates. And if we look into the details, we can highlight some aspects that are really interesting. These are the facts that the intermediate-risk low group has more or less a similar risk of disease progression to the 2021 low-risk group of diseases. And this risk of progression is really insignificant, it's 0 at one year and almost 0 at three years. But on the other hand, the intermediate-risk high group has a similar risk of disease progression to that of the EAU '21 high-risk group, with 8% of progression at three years. We have to underline that these patients are only treated with intravesical chemo and not with BCG.

In summary, this was the first clinical validation of the intermediate-risk non-muscle-invasive bladder cancer substratification model that was proposed by the IBCG, and of course, this validation paves the way towards the implementation of this model into everyday clinical practice, leading to probably better personalized treatment of our intermediate-risk patients. There are, of course, some open questions, but in my opinion, probably intermediate-risk low patients should be better treated as low-risk non-muscle-invasive cancer, and in my opinion, these are probably the optimal candidates for this treatment deintensification, such as active surveillance, for example, of disease progression. And on the other hand, the intermediate-risk high group should be treated as high-risk non-muscle-invasive bladder cancer. So I would say with BCG up to one year, and maybe even up to three years, and probably these are the optimal candidates for clinical trials in the BCG-naive population. So these were just some key points, but, of course, we can also discuss other points that are present in the papers. Thank you very much.

Ashish Kamat: Thank you so much, Francesco. That was a very nice summary of the paper. Just for a little bit of context to the audience, the IBCG risk classification was first proposed in 2014, and then, of course, we updated it in 2022. And, of course, your paper then came out and has validated that in a very nice way so that we can now actually say this can be used in the clinic and not just as a researcher or for clinical trials. I like the way you highlighted the point that the intermediate-risk high group has significant progression because a lot of people forget that with the advent of active surveillance and de-escalation of therapy that some of these patients can progress, right? It's not a completely benign disease just because you have low-grade tumors. Now, based on what you proposed, have you changed your clinical practice? What are you teaching your residents and fellows now?

Francesco Soria: Yeah. Actually, yes. I was really interested from the beginning after the publication of Tan in 2022 about this substratification, and ideally, I was really already using it before this clinical validation because I had the feeling that this was really logical to me. But this was probably more logical regarding the frequency of recurrence and also the risk of recurrence in my mind. But with this clinical validation and what you were saying, what is impressive is the risk of progression. It is really different. So usually also when we discuss our patients in our board, we pay really close attention to the high-risk intermediate population because they have a really high risk of progression, and we underline the need to treat these patients with BCG, maybe sometimes even up to three years.

Ashish Kamat: Yeah, and that's another good point that you raised because the European studies, the EORTC studies, have actually shown that BCG is superior to chemotherapy in patients with low-grade disease. But, of course, in the time of BCG shortage, we want to allocate BCG appropriately. So the patient who's intermediate-risk with that first recurrence, we all know that using BCG there is a waste of resources. But when you have clinical parameters such as these and you know that these patients are not 0% progression, I think the point you raised is you can allocate BCG appropriately to those patients even in today's day of shortage. Is that pretty much what you're doing?

Francesco Soria: Yeah, of course. It is also because we know that it is important to administer BCG with maintenance and not just give maybe induction BCG. So it's probably better to select the correct patients and to give the BCG with maintenance, a full cycle of maintenance, and maybe to treat other patients with chemo, just intravesical chemo, mitomycin, gemcitabine or whatever, in order to preserve, of course, the number of BCG. We have no problem now in Europe with the BCG shortage, but, of course, who knows. Maybe this can happen again.

Ashish Kamat: Hopefully not, right? Hopefully.

Francesco Soria: No, hopefully not.

Ashish Kamat: Yeah, it's a crazy problem. And lastly, I want to, again, emphasize that when we do clinical trials in this intermediate-risk population, the number of patients has to be huge because you have to essentially look at all-comers with recurrences from 16% all the way to 40%, progression 0 all the way to 8%. So data such as this can now help people design clinical trials that are powered more appropriately if you select the right subset of patients. And with that in mind, I wanted to ask you in trials that you are designing or looking at, are you factoring in these risk criteria for stratification?

Francesco Soria: Well, I would say yes because we were just discussing probably the possibility to translate some clinical trials that are now used in the BCG-unresponsive disease, maybe into other categories of patients, something like it happens, for example, in the SunRISe trials from Janssen and whatever. And, of course, the BCG-naive population is an interesting population, and if we want to go back maybe from BCG-unresponsive to high-risk BCG-naive and then back to intermediate risk, of course, the intermediate-risk high group is a category of patients that could probably benefit from treatment intensification of new clinical trials.

Ashish Kamat: Francesco, you sit on several panels at the EAU and of course lead the Young Urology Association. Do you have any insight into whether your work is going to result in maybe a change in the EAU classification system?

Francesco Soria: Well, I have some insights. I mean, probably, of course, the results of this work will be cited and used for the new EAU of 2020, non-muscle-invasive bladder cancer guidelines. Maybe not to change the stratification model, but, of course, to say that there is the possibility to restratify intermediate-risk patients, and we will probably encourage our colleagues to do this in order to treat our patients properly and not just consider them as a single big category of patients. But these are different patients with different profiles of risk regarding not only recurrence, but even progression.

Ashish Kamat: One thing I can say is that based on all the work you've done, I would be very happy to welcome you to join the effort, maybe create an online calculator that we could then put out for people to use who want to use this in the clinic because it's really important to get people to use this for the benefit of our patients. So I welcome you to join that effort.

Francesco Soria: That would be very nice. Very nice and very useful. Thank you.

Ashish Kamat: So once again, thank you for taking the time, sharing with us, and congratulations on the publication.

Francesco Soria: Thank you again, Ashish, and thank you to the UroToday community.