Ashish Kamat: Hello, everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of urologic oncology at MD Anderson Cancer Center in Houston, Texas, and it's a pleasure to welcome, once again, to the forum Roberto Contieri, who's joining us from Naples, Italy. Roberto, as many of you might recognize, was a resident in Italy, spent some time here at MD Anderson, was very productive, learned a few nuances on bladder cancer, especially when it comes to the management dilemma of very high-risk non-muscle-invasive bladder cancer. And I think, Roberto, you've taken this back to where you are and you've done some really good work to update the literature, update the field. Both you and José Subiela worked on this. Unfortunately, he's not able to join us, but you are going to represent both of you today. And with that, please take it away.

Roberto Contieri: Okay. Thank you very much for the introduction. It's always a pleasure to join this conversation and thank you to UroToday for the invitation as well. I will be discussing this dilemma that, as a urologist, we face every day, which is the right treatment for very high-risk patients, and the treatments include bladder-sparing treatment with BCG or radical cystectomy.

When we talk about very high-risk patients, we refer to a specific group of patients which are defined by the EAU guidelines as patients with high-grade tumor, with or without CIS, and with additional clinical risk factors including large tumor, multifocality, or age over 70. And also the EAU guidelines include in this group of patients, patients with CIS in the prostatic urethra, subtypes of urothelial carcinoma, and lymphovascular invasion. For these patients, EAU guidelines suggest to discuss the immediate radical cystectomy. However, this statement has been softened during the year, and in the last update of the guidelines, it is suggested also that we can use BCG for selected patients, in particular to those unfit for radical cystectomy who decline the surgery.

But where does this definition come from? Most of the audience will be familiar with this paper from Richard Sylvester and the EAU non-muscle-invasive bladder cancer guideline panel. In this study, they analyzed the oncological outcomes of more than 5,000 patients and identified these risk factors among the characteristics of the tumor and the patient's characteristics. And basically, on these risk factors, they defined four risk groups. Also, they set a threshold for deciding when to offer radical cystectomy to the patients, and this threshold was set as 20% of risk of progression at 5 years. And based on this, they defined the risk at very high risk of progression to muscle-invasive disease or metastatic disease. If we look at the outcome at 5 years, the risk of progression in this group is 40%.

But why don't we want patients with non-muscle-invasive bladder cancer to progress to muscle-invasive bladder cancer? Of course, because the survival is worse, but also, if a patient progresses from non-muscle-invasive to muscle-invasive, they have worse survival outcomes compared to the non-muscle-invasive bladder cancer. This is from this study by Patrick Hensley, also from MD Anderson. And also, we have to consider that there is a huge risk of understaging in T1 G3 tumors. This is an old study in which the author reports 49% of upstage at radical cystectomy to muscle-invasive bladder cancer and also 16% of lymph node metastasis. However, I'm working on a project with the Young Academic Urologists of the EAU urothelial group, and we found that if we look at only real non-muscle-invasive bladder cancer, with real I mean non-muscle-invasive bladder cancer at radical cystectomy, the risk of lymph node metastasis is very low. So the problem here, the issue is the understaging. And I think that right now we have to improve the way we stage non-muscle-invasive bladder cancer.

One of the main issues of the study by Sylvester and the EAU guideline panel was that those patients were not treated with BCG, which is actually the treatment we have to offer to our patients. And if we validate the risk group in cohort undergoing BCG, the risk of progression, even in very high-risk patients, is lower. We can see here in this study by Niyati Lobo, also working on this while she was at MD Anderson, the risk of progression to muscle-invasive bladder cancer at 5 years in very high-risk patients is 16%, which is, of course, lower than those reported by Sylvester.

What we have done was to collect all the studies reporting the progression rate of patients undergoing BCG of very high-risk patients, and we reported studies from US, from Europe, and also from Japan. And what you can see is the rate of progression at 5 years of these patients, very high-risk patients, is lower. It's consistently lower. Of course, these are retrospective studies, and of course there is selection bias because we propose BCG to patients with very high-risk but lower additional clinical risk factors. But still, these patients have, we can say, acceptable risk of progression at 5 years.

What we have done while I was at MD Anderson, we compared the oncological outcome of patients at very high risk undergoing BCG or immediate radical cystectomy. We reported 17% of progression to muscle-invasive bladder cancer at 5 years. And also, only 24% of these patients underwent delayed radical cystectomy, and delayed means after BCG. But most importantly, when we look at cancer-specific mortality, the rate of cancer-specific mortality was comparable among the two groups.

Of course, when we talk about radical cystectomy, we always think about it as the worst outcome possible for our patients. However, I want to show you the results of the CISTO trial presented this year at AUA, which are very interesting. CISTO trial is an observational study including patients with BCG-unresponsive bladder cancer undergoing bladder-sparing therapy and radical cystectomy patients. The primary outcome was the physical functioning, and they also included the secondary outcome, quality of life, emotional well-being. And what is really interesting is that, for general quality of life, emotional well-being, and also financial well-being, there was a tendency in favor of radical cystectomy. Of course, this is not a randomized clinical trial, but still, we have to improve our understanding of our patients, and this means that radical cystectomy might be also well accepted by informed patients.

So in conclusion, I think that this is a very important issue and discussing with our patients is the key to propose the best treatment. Of course, BCG still holds a pivotal role in the management of non-muscle-invasive bladder cancer, but also in the management of very high-risk patients. We have to think, also, that guidelines are formulated to be applicable universally all over the world, and this means also where BCG is not available. And I think that providing the risk of progression at 5 years in patients not undergoing BCG might be also informative for the patients who know which will be the risk of progression if they don't follow the treatment. And of course, based on the results we presented with the data from MD Anderson, but also from the results from the study from Europe that is a multicenter study, but also from Japan, I think that selected patients with very high-risk bladder cancer can be effectively treated with BCG.

I think that the most important thing is that we don't forget that we have to offer radical cystectomy in time to not lose the possibility to cure the patients. So it can be after BCG and also after several lines of bladder-sparing treatment, but still, it has to be decided with the patients in a shared-decision process. Thank you.

Ashish Kamat: Thanks so much, Roberto. Again, you provided a very nice summary of all the data to date that exists in this field. I think it's very important for folks to recognize that we are not necessarily saying that patients with very high-risk disease should not be counseled on radical cystectomy. And you made that point clear. They should be given the option of a radical cystectomy. But again, when we're counseling patients, and if you only rely on the data that came forward in the EAU guidelines or Richard Sylvester's study, essentially those are untreated patients, and if patients get the right treatment, then their progression rates are in the teens. And when patients hear that, many patients will say, "Well, let me try BCG," And it's up to us as urologists that are taking care of patients to make sure that the patient doesn't do anything that jeopardizes their life.

I think you summarized everything really, really well. Normally, I'm able to have a discussion and ask you questions, but you preempted most of the questions. That was a great presentation and I want to thank you, Roberto, for all the fine work that you're doing. So thank you very much.

Roberto Contieri: Thank you very much, Dr. Kamat.