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Sam Chang: Hello, everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee. We're very lucky to have Dr. Ashish Kamat. I've known Ashish for many, many years. He's a professor at MD Anderson Cancer Center and has really led so many different initiatives and trials within different areas, focusing on bladder cancer, not only non-muscle invasive disease but also invasive disease.

But today, I wanted to focus on a recent article that his team put out looking at the impact or perhaps the lack of impact of age on patients actually receiving therapy with... or patients who have non-muscle invasive bladder cancer. So, Ashish, first of all, welcome and thanks so much for spending some time with us. And why don't you give us a little bit about the background of the study, how you put it together, and then we can talk about some of the findings.

Ashish Kamat: Thanks so much, Sam. I will go into the study, but before that, I do want to say that I don't know if you remember or not, but you were the one that led me around when I was interviewing for a fellowship. So you've always been one year and one step ahead of me in everything. And truly, you don't need any introduction, so it's a pleasure to be here with you.

So, this article, really, one of the questions that I asked myself and our team is, "Should we look at age? Why do we need to look at age again when there have been multiple studies in the past looking at age?" But the issue with age is that the different studies have always suggested that age may be involved. Older patients may not do well with intravesical therapy. And then what happens is this has made it into the guidelines in different countries.

And I think what pushed us over the edge to look at this question was when Richard Sylvester did his meta-analysis showing that older patients did not do well after intravesical therapy. And then that made it into the EAU guidelines in 2021, and that became a risk factor. And of course, if you dig down deep into that meta-analysis, and Richard says that too, these were patients who were not being treated with the standard of care. This was the natural history of the disease.

And I'm sure you started seeing this too, patients who are older being counseled, "Oh, it's not going to work. You should do a radical cystectomy instead." So we're like, "Wait a minute, let's look at a contemporary data set with patients treated appropriately with intravesical BCG, and see if actually age is a reason to withhold or recommend against this treatment for the patient."

And of course, I have the fortune of having Kelly Bree, who was in my lab at that time, Pat Hensley, and a visiting resident from Italy, Roberto Contieri, really gung-ho guys who did a lot of really good statistical analysis along with our statistical team to come up with the results of the paper that we're discussing.

Sam Chang: I think the point you made, Ashish, about that sentiment, there's no question that has always been hanging over that patients who are older don't do as well with different types of therapy, and specifically people would say BCG, that they aren't as successfully treated, even though the majority of our patients, as you know, tend to be elderly. And we have had results for years when it comes to BCG, but there was that sentiment that definitely was growing in the community.

We would see patients, just as you said, referred for other treatments because they were considered too old to get intravesical therapy, intravesical BCG, etc. So I don't want to obviously spoil the key findings, but why don't you tell us a little bit about your initial cohort? Remind me again, 6,000 patients. You had multiple, multiple patients that then you got a comparison between those less than 70 and then greater than 70. Tell us about the results.

Ashish Kamat: Sure, Sam. So what we wanted to do was see if a patient is treated as per guideline recommendations and we picked the EAU guidelines, but these are guidelines that are applicable in Europe as well and get what we consider at least the minimum adequate BCG. So at least an induction and one maintenance course. So if patients are treated the way they should be treated, then what is the impact of age or is there an impact of age on their outcomes with intravesical BCG?

The other thing that we wanted to factor in is overall mortality because when patients are older... Kaplan-Meier estimates of cancer-specific survival or progression-free survival that don't consider overall mortality as a competing event and just purely censor patients when they die will tend to overestimate the downside of being older. So we used death from any other cause as a competing event rather than a censoring event.

And again, we found that in both groups, patients less than 70 or older than 70, there was no difference in recurrence-free survival, no difference in progression-free survival, and there was no difference in cancer-specific survival. Clearly, overall survival was different, but when we accounted for that as a competing event, you can see that if patients are treated appropriately with BCG, whether they're over 70 or under 70 should not really matter when it comes to counseling the patients on that treatment choice.

Sam Chang: So hugely important. I want to emphasize that when it comes to disease characteristic endpoints, disease-specific survival, progression-free survival, etc., there was no difference, no impact as one would expect. Those patients who were older than 70, as compared to those who were less than 70, there were more deaths in patients who were older than 70. But like you said, with your modeling of getting rid of that as a censoring event and making it a competing event, there really was no disadvantage to age when it comes to the effectiveness of therapy. Is that correct? A good summary?

Ashish Kamat: That's an excellent summary, Sam. Absolutely.

Sam Chang: So, in looking at other impacts, I'm sure you looked at other variables as well. Were there other things that you were able to tease out in this evaluation of those patients who were more or less likely to gain benefit from BCG? Or was the focus really just on the demographic differences in age?

Ashish Kamat: No, again, when we're going to put our efforts into a paper like this, we looked at all the usual suspects, and what was great was that all the usual suspects were equally important in both arms. So, the presence of T1 disease, CIS, re-TURs, all of that mattered no matter whether you were younger or not so young. And I say not so young because most of our patients are in that age group. So over 70 is young for a bladder cancer patient nowadays.

What was a little bit interesting that we found was that the older patients tended to have fewer re-TURs done, which makes sense if a patient is older, you may not want to subject them to a second anesthesia. But despite that, they did just as well as the younger patients, which was good. But what we also found was that older patients do tend to have a decreased tolerance for the full course of BCG.

So, the median number of BCG instillations in older patients was less than those in younger patients. And that's something that's been shown in prior studies where if a patient is older for whatever reason, the bladder is more irritable, they have higher PVRs. They don't tend to be able to go through that full three-year regimen. So we were actually able to validate prior findings.

What was interesting was that in a parallel study, which Niyati Lobo, who was a Fulbright scholar from the UK in my lab around the same time, she looked at the impact of age on UROMOL analysis, the next-gen sequencing that Lars Dyrskjøt has done. And then we married the two papers to do a little subset analysis. And what we found was that older patients tend to have more UROMOL 2a and 2b type of tumors which are more aggressive when it comes to the natural history of the disease, but they also have higher TMB and neoantigens, and that's why they might respond better to immune therapy such as BCG. So even though age does correlate with worsening disease characteristics in our patients, they still do well with immunotherapy, which is BCG.

Sam Chang: Oh, now you've opened up a can of worms here, Ashish. When you start looking at obviously the molecular classification of these different tumors, noninvasive, invasive. The more research that comes out, in all honesty, the more confused I get with what really impacts, etc. But your theory regarding the innate nature of the disease may, in fact, be more aggressive. But with that aggressiveness and its characteristics, it may actually be more responsive to certain intravesical therapies like BCG is not too dissimilar to some of the invasive molecular classification findings.

So along those lines, and we need to continue to improve this understanding, really risk stratification, then being at our institution, the buzzwords are precision oncology. Then being able to better adapt certain therapies for certain disease characteristics, I think, will most likely make the most difference for these patients, not only noninvasive disease but for invasive disease down the line. So as you look at age and you look at this non-muscle invasive bladder cohort, is there anything else that comes out that is either concerning to you or reassuring to you?

Ashish Kamat: Not specifically from our dataset, Sam, but as you have also been championing, it's still disheartening to us as a bladder cancer community that if you look across the United States, older patients don't get any treatment. So here we are trying to fine-tune, "Should they get BCG? Should they get cisplatin? Should they get EV-pembro across different disease states?" But you look at the population-based studies, our older patients often get no treatment. It's access, it's cost. So not specific to my study, but since I have this platform, I want to say we need to improve the care of our older patients across the board, get them access to that first step, to the urologist, to evaluation of the hematuria, to a good quality TURBT. Once that's done, everything else will fall into place, I think.

Sam Chang: Yeah, really good point. The discussions that we have regarding access to quality care it's a very difficult road. And along those lines, unfortunately, as disease progresses, that access to quality of care even becomes more difficult when you look at invasive disease or advanced disease, etc. And it is sobering when you look at the National Cancer Database, how many patients, in fact with invasive disease or with advanced disease don't receive, not only not even talking about quality match, but don't get any therapy. It's just as you said.

So I think your point, Ashish, is actually a very, very important one. And I'm glad you raised that and helped trumpet that. Ashish, thanks so much for spending some time with us. The work that you've helped lead at MD Anderson has been incredibly impressive for many years, but I think your international and your national efforts to help actually raise the educational level and allow better care for all our patients, not only in the US but internationally, is something that really needs to be applauded. And I just wanted to say for all of us, thank you so much for all your efforts.

Ashish Kamat: Yeah, pleasure being with you, Sam. Always.