Sam Chang: Hi, I'm Sam Chang. I'm a urologic oncologist in Nashville, Tennessee, and I work at Vanderbilt University Medical Center. And we have really an honor today in terms of the presence of Dr. John Gore. John has led, with Dr. Angela Smith, a very important trial looking at the impact of the decision of intravesical therapy versus radical cystectomy for patients with non-muscle invasive bladder cancer.

And we are going to be actually going over important data that he presented at the P2P-- practice-changing, paradigm-shifting-- part of the AUA session that was presented at AUA 2025 in Las Vegas. So, John, as your role at the University of Washington, helping to lead the urologic oncology division there, being the fellowship director, you've been part of important trials. Tell us a little bit about what makes this so unique and why it was actually on the practice-changing, paradigm-shifting plenary session AUA 2025.

John Gore: I think we did convince them with our acronyms. So it's the best acronym for any study that I've been a part of. This is the CISTO study. So it's Comparison of Intravesical Therapy and Surgery as Treatment Options for recurrent bladder cancer.

Sam Chang: C-I-S-T-O.

John Gore: Yeah, very cheeky.

Sam Chang: People need to Google that. They're not googling C-Y-S-T-O. It's C-I-S-T-O.

John Gore: First and foremost, this was a study that was developed in close partnership with bladder cancer patients. So that's one thing that makes it unique. It was borne out of patients telling us what research questions are important to them, and then, importantly, working with them on the study design.

So one unique thing about the CISTO study is this is not an RCT because patients told us that they would be unwilling to randomize to a comparison of a big surgery versus a bladder-sparing therapy. And so it is an observational cohort study, but it uniquely compares radical cystectomy with a catch-all of bladder-sparing therapies.

And going forward, what is also unique about the CISTO study is we're the only study that's prospectively evaluating cystectomy as one of the main comparators in non-muscle invasive bladder cancer. And this answers that patient-centered question of, gosh, what will happen to me if I have my bladder taken out for recurrent non-muscle invasive bladder cancer? What can I expect? And potentially, how can I make the best decision for me when confronted with a challenging recurrence?

Sam Chang: Incredibly important questions to consider as we, in the past, basically made up what we thought was important, what we thought would make a difference in patients' quality of life, and what we thought would be important in terms of outcomes. So to actually gather this data prospectively, to use cystectomy, which now is actually being used as a result of a treatment, avoiding cystectomy, cystectomy-free rate. Clearly a lot of morbidity and complications associated with cystectomy, but still should still be considered an important treatment option. So this study really helps give us an idea of, OK, how do we weigh the benefits, the pros and cons and the impact?

John Gore: 100%. So part of our work with patients was asking them-- we often design trials with what we think is important. So as part of the design of this, we asked patients what they think is important. And that influenced our primary outcome and our secondary outcomes. And some of what they told us is the same as what you and I would come up with.

Yes, recurrence-free survival is important. Yes, progression-free survival is important. Obviously, bladder cancer-specific and overall survival are important. But also generic quality of life-- what is the likelihood that physically I'm going to be well or back to my baseline after such a big surgery or continue bladder-sparing therapy? And then things we don't think about-- what about the impact on my financial well-being, my emotional well-being?

We do often think about urinary, sexual, and bowel quality of life. That's been part of our pelvic cancer thought process for a long time. But some of these other constructs were things that we didn't consider in a lot of our trial designs. So the main endpoint that we presented was a 12-month physical functioning endpoint. And so we hypothesized, I think, not unreasonably, that because radical cystectomy is such a big surgery, that those patients would have worse physical functioning and generic quality of life 12 months after their recurrence compared with those patients that got bladder-sparing therapy.

Sam Chang: So basically, the negative impact not at one month-- obviously, there's a difference post-operative-- but at a one-year mark of how patients do. And so what were the findings?

John Gore: So the findings were contrary to that. We found that patients who underwent a radical cystectomy had equivalent non-significantly different physical functioning compared to the bladder-sparing therapy patients. When you look at it longitudinally, just like you mentioned, you see an immediate dip on our three-month assessments. That's when patients are in the thick of their recovery process after such a big surgery.

But by about six months, their physical function outcomes were not significantly different from patients in the bladder-sparing therapy arm. And then one of the challenges for us is that bladder cancer is uniquely a cancer of older individuals. So we also looked at it in a subset of individuals over 75, where I think we all struggle with, gosh, is this too big of a thing to consider for this 82-year-old man or this 84-year-old man?

And we found that similar to our entire population in those over 75, physical functioning was not significantly different between our radical cystectomy patients and our bladder-sparing therapy patients. So what it allows you and I to do is it allows us to tell patients, gosh, if we could fast forward your life six months or nine months, you are going to be back to your baseline physical health, and it's not going to be that different than if you had retained your bladder. And I think that's something important for patient reassurance.

Sam Chang: Oh, absolutely. Obviously, with the caveat being the selection of those patients that we think can get through cystectomy, and that's a question we often have an ongoing struggle with in terms of that operation. But the ability to say, if we do this operation, and we look at how you do compared to those who haven't had the surgery, your physical well-being and function is going to be probably not too dissimilar.

John Gore: Yeah.

Sam Chang: Not the picture of, boy, this has really negatively impacted your physical functioning for long term. How about the outcomes? Did you see any differences in the outcomes? Obviously, early on--

John Gore: Totally.

Sam Chang: --hopefully not too many events in these patients that we think are noninvasive. So how about that?

John Gore: Well, so in terms of the secondary patient-reported outcomes, we saw some surprising findings that actually favored radical cystectomy. So we found that a global health metric called the EQ-5D was actually better 12 months after enrollment in the cystectomy patients. And then two really important emotional well-being outcomes-- anxiety and depression-- were worse at baseline in the radical cystectomy patients, but actually significantly better at 12 months. We hypothesize that that just relates to the fact that they underwent a more definitive cancer treatment. And that probably, for a lot of those patients, that initial anxiety was cancer-specific.

Sam Chang: Sure.

John Gore: It was fear of cancer recurrence. It was anxiety about their future cancer needs, and having a more definitive treatment probably assuages those anxieties.

Sam Chang: And over time, the realization that they've gotten through the surgery, that they're doing OK, that can only help. And then you add on the anxiety of, as you know, every patient that comes in still with an intact bladder, every cystoscopy brings a point of anxiety, just like a PSA for our prostate cancer patients, just like any kind of imaging for our kidney cancer patients. It has to.

John Gore: And they've been through it before because these are all patients who are in this study because they recurred. And so they know, even though they went on to a salvage combination chemotherapy or intravenous immunotherapy, they know that it's not a panacea. And so that's just weighing on them.

The other secondary patient-reported outcome that was surprisingly significantly better in our radical cystectomy patients was financial well-being. You would potentially think that, because it's such a large surgery with a large index initial admission, we know that about a third of these patients get readmitted within the first three months.

Sam Chang: Sure.

John Gore: But realistically, we also forget that our bladder-sparing therapy patients they're coming in for regular cystoscopies, regular intravesical treatments, taking time off work, potentially affecting a caregiver who has to bring them to these visits. So once you get through your cystectomy and recover, the health care costs are pretty minimal. But in that bladder-sparing therapy arm--

Sam Chang: --current resections, the treatments, the surveillance, et cetera. Yeah.

John Gore: And this is in an era before Anktiva and Adstiladrin were approved. So going forward, you might anticipate that those financial well-being outcomes could actually be worse in the bladder-sparing therapy arm. You did ask about the cancer outcomes.

Sam Chang: Yes.

John Gore: It is early. It's 12 months. We did find that recurrence-free survival, not unexpectedly, is better in the radical cystectomy patients because they don't have a bladder. They could theoretically recur in the urethra or in the upper tract. So that would count for a recurrence. Progression-free survival was worse in the radical cystectomy patients, but there's a big asterisk to that. And that is that we found a substantial rate of upstaging at the time of their treatment cystectomy.

So this is patients in the cystectomy arm. They have recurrent non-muscle invasive bladder cancer. They get a cystectomy. And on that cystectomy, they have upstaged cancer, which actually tells you that our providers in the CISTO collaborative are making good decisions.

Sam Chang: Yes.

John Gore: They were suspicious that this was a worse cancer than expected, and they were making good decisions. And so you might expect that over time, even though it was worse because of the upstaging at cystectomy, that it--

Sam Chang: --will flatten out. Well, then say about the same, because in those patients, you would think, OK, that initial upsurge with progression, they should be OK. And then perhaps then over time, exactly.

John Gore: Yeah. And then to reassure our patients with that kind of discrepancy, cancer-specific survival because as you mentioned, the event rate was low, was very high in both arms and not significantly different at 12 months.

Sam Chang: John, I mean, obviously a very, very important, unique, I think, groundbreaking findings for patients because now we have some evidentiary backing of what we recommend for individualized patient care. What next? I mean, this initial data is important. It's one year. What next?

John Gore: Yeah. So we were lucky enough to get funded by the NCI to continue doing work to follow up our CISTO study patients.

Sam Chang: So beyond this one year. OK. Got it.

John Gore: So within the CISTO study period, it's important to remember this is not a cooperative group trial where we can say, gosh, we need 11 years to get five-year follow-up on everybody. This was a grant and a contract. And so we could only get 12-month follow-up on everybody. We have 24-month follow-up on about half of our patients. But with this NCI funding, we're going to get clinical outcomes and those key patient-reported outcomes to at least five years on everybody.

Sam Chang: Oh, fantastic!

John Gore: So that's going to allow us to say, gosh, this is an early snapshot. That snapshot is, in my opinion, different than what we would expect for these two comparators. But we're now going to be able to generate evidence that allows you to say, two years after, five years after, this is what life looks like with these two. The other thing we hope to do is-- one thing that I think is really important to understand is when we compare two treatment arms and say an RCT, and we say that, this is better than that because it has 5% absolute survival benefit, that is an average.

Sam Chang: Sure.

John Gore: And what we really want to know is, for the patient who's in front of you in your clinic, how does that comparison shake out? And so we call that heterogeneity of treatment effects. And so what we really want to do is help our patients, help our doctors by also looking at these subgroups of patient profiles, clinically, based on their preferences, based on their priorities. How does this comparison of cystectomy versus bladder-sparing therapy shake out so that we can actually use this the system data to help everyone make better decisions.

Sam Chang: Exactly. So what do you-- obviously, there have been papers, written manuscripts that you all have put out, that the CISTO group has put out, looking at setting up the trial design, et cetera. Where next? As we get long-term data that's down the road--

John Gore: Yeah.

Sam Chang: --what else can we help answer with the data that we have now?

John Gore: Yeah, I think, number one, within CISTO, just within CISTO, we have a wealth of outcomes that eventually are actually going to be publicly available. So yes, we have our own team working on it. We have our CISTO collaborative. But as part of our contract with the Patient-Centered Outcomes Research Institute, the CISTO data is going to be available to researchers who complete a data use agreement. So it's going to be something where we hope it'll generate a lot of new findings, unique ways to look at the data. We have 200 cystectomy patients. That's a huge resource for clinicians, researchers, patients.

Sam Chang: From all over.

John Gore: From all over.

Sam Chang: Focused on what was thought to be non-muscle invasive disease.

John Gore: Theoretically.

Sam Chang: Exactly. So the amount of information and what we can gain, not only to help our individual patients now in the future, though, are incredibly important work.

John Gore: Yeah. We're also, as part of the NCI study, we're looking at some molecular characterization of the CISTO cohort. That's part of this idea of, gosh, we have this incredible 570-patient population study. How can we maximize our learnings from those patients? How can we learn as much as we can to help patients, clinicians make better decisions?

We also-- because full disclosure, Sam, you're part of the CISTO study-- we also essentially created an ad hoc cooperative group with CISTO. CISTO was built on the back of essentially friendships between myself and Dr. Smith and our cohort of bladder cancer experts across the country. Can we take that collaborative and do more with it? Do studies in muscle invasive bladder cancer, or how we investigate bladder cancer diagnostically or for surveillance. And so we're working on cool ideas to keep the collaborative together, keep the band together.

Sam Chang: Now. And it's not often I give you kudos, John-- actually, every day, every day. But the time and the effort and persistence and patience that both Angie and you really have provided to the whole bladder cancer community-- incredibly important. And so really incredible kudos to you both and to the whole CISTO team. The information that we'll glean will be incredibly important to patients as they make those important decisions. So we want to start off with thanks. And we really look forward to future presentations. And the CISTO presentation at the AUA was incredibly well received. And so again, thanks for all your efforts.

John Gore: Thanks so much, Sam.