Ashish Kamat: Hello, everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, urologic oncologist in Houston, Texas. And joining us today is someone who really needs no introduction, John Gore. John, welcome.

John Gore: Very nice to see you, Ashish. Thanks for having me.

Ashish Kamat: Yeah. I mean, this effort and this collaborative and this labor of love that you've really been championing for so many years is something we've all been excited to be part of with you on this journey. And then now that we have the actual publication out there, it's no longer embargoed. Of course, you presented it at AUA, but really glad that you could join us today and share with not just our US audience, but our global audience your takeaways, your key points from the study. So take it away, John.

John Gore: Absolutely. Yeah. So the CISTO Study, so CISTO stands for a comparison of intravesical therapy and surgery as treatment options for recurrent bladder cancer, basically took patients who were choosing between bladder removal surgery and various forms of bladder sparing therapy. And then this early publication is following them for a year. So this is our primary endpoint for a PCORI-funded study, which is a 12-month endpoint. I'm going to show you the schematic for the study.

So basically we took patients with recurrent high-grade disease, and it was a pretty broad definition. This wasn't just the traditional BCG-unresponsive patient population, but also included patients that were failing some other treatment such as intravesical chemotherapy or pembrolizumab. Importantly, this was an observational study, and that was based on some work that Dr. Angie Smith and I did that showed that patients had incredibly low willingness to be randomized to a comparison of cystectomy versus bladder sparing therapy.

That jibes with what we know in our community for some other trials that failed to accrue when it was a big surgery versus a more conservative approach. So it's an observational study design. Because it was a 12-month endpoint, our primary outcome is a quality of life outcome. So it's physical functioning at 12 months, but we had a number of secondary outcomes, some of which were more quality of life oriented.

But a lot of these align with things that we care about as clinicians, definitely align with things that patients care about as well. So generic quality of life, emotional well-being, which we often think of as being depressive and anxiety-related symptoms. Unique to this study, financial well-being, so measuring financial toxicity, and then some bladder cancer-specific quality of life outcomes.

Then we have the conventional cancer-specific outcomes as well, like recurrence-free survival, progression-free survival, cancer-specific survival, things you don't expect to vary too tremendously in a one-year timeframe. And this is the main take home from the study. So our hypothesis going into the CISTO Study was that at one year, patients undergoing radical cystectomy would have worse physical functioning than patients receiving bladder sparing therapy, mainly related to just a large scale of the surgery.

It's a big operation with a big recovery. It has some life altering effects on quality of life. Contrary to our hypothesis, physical functioning did not differ between patients undergoing radical cystectomy and those undergoing bladder sparing therapy. There were some other global quality of life measures that actually favored the patients undergoing radical cystectomy.

And it's important to know all of these outcomes are pretty robustly adjusted for any differences between the two treatment arms at baseline. So we use some high level econometric methods, statistical techniques to coax randomization out of non-randomized data. There were some really key secondary outcomes that I think both clinicians and patients care about.

So our patients in the radical cystectomy arm actually had worse anxiety symptoms at enrollment, but at 12 months had much lower anxiety, lower depressive symptoms, and lower total scores on the EORTC emotional functioning domain. So better mental health outcomes for patients in the radical cystectomy treatment arm. And then this was another surprise to everybody in the CISTO Collaborative, the financial well-being outcomes were also better in the radical cystectomy arm.

So patients reporting a sense of having financial difficulties or a sense that their cancer treatment and cancer burden of care was causing them financial toxicity basically. So this is the key take home slide. So in the left-hand panel, you can see some of the outcomes that favored bladder sparing therapy. In the right-hand panel, you can see some of the outcomes that favored radical cystectomy.

And in the middle are some outcomes that didn't differ. And I would highlight that sometimes things not differing is actually a really important outcome and is important to our patients. So especially when you're talking about a big operation like radical cystectomy, things not changing, like your ability to participate in social activities that you enjoy or in your role in your community as you foresee it, that's actually an important outcome.

Taking out your bladder doesn't take these things away. So I do look at that no difference box as really an important box as well. So you can see that bowel and sexual health was better among patients undergoing bladder sparing therapy at 12 months. That lowest construct progression-free survival has a small asterisk by it. And that's because in the radical cystectomy arm, a substantial portion of patients had upstaging to muscle invasive bladder cancer, which flagged as a progression event.

And it's also just indicative of some of the challenges we have as clinical providers with really accurately clinically staging our patients. And that weighs into the clinical conundrum that is how to make good decisions in this recurrent non-muscle invasive bladder cancer population. Looking at what favors radical cystectomy, as I showed you, physical functioning for the whole cohort did not differ, but there were some subgroups where it did.

So in patients with concomitant carcinoma in situ and unpartnered individuals, their physical functioning after cystectomy was actually better than it was after bladder sparing therapy. Some mental health outcomes were better. Some financial health outcomes were better. And then not surprisingly, because you've taken out the bladder, recurrence-free survival was better in the radical cystectomy arm. And then, as I mentioned, no difference, physical functioning overall.

But also if we looked at older patients, patients over 75, there similarly was no difference in 12-month physical functioning outcomes between people undergoing cystectomy and people in the bladder sparing therapy arm. And then urinary health, which was worse in the radical cystectomy arm at enrollment, and then not surprisingly was worse early after surgery because it is a big surgery, did not differ by about the nine-month mark and was no different at 12 months.

And then cancer-specific survival and overall survival, and again, this is only at 12 months, did not differ between treatment groups. And so our key take home messages are radical cystectomy is really an important management strategy in this patient population. And I don't want to undermine that. I think that if you look at what's going on in active clinical trials in the non-muscle invasive space and specifically the BCG unresponsive space, there aren't a lot of studies that are including radical cystectomy as a comparator.

But I think what our study shows is that it has an important place in guidelines and in clinical decision-making. And that's just because physical functioning was similar between treatment groups. And so the patient-centered take home of this is that when your patients ask you about the life-altering aspect of radical cystectomy, because of this data you can say, "Well, gosh, actually, if we were to project out to a year, your physical wellbeing will not be different if you undergo a radical cystectomy versus the bladder-sparing therapy options."

And then some of these key secondary outcomes were actually better in patients undergoing radical cystectomy. And then just to think about where the CISTO data is going to go going forward, we know in the cancer community that 12-month outcomes are important, but also are inadequate. Two things can be true. And so through some funding from NCI, we're going to be able to collect longer-term outcomes.

John Gore: I was and I wasn't. There's a reason we construct these hypotheses. And so I think our hypothesis was not a... We weren't gaming the system to plan a hypothesis that we didn't believe in, that we thought the data would counteract. And so I really felt like especially at the 12-month mark, which is reasonably early after cystectomy, I felt like a lot of the general quality of life outcomes were going to be worse.

What I kind of thought would happen is that if we were going to be able to get longer term follow-up, the benefit of cystectomy would reveal itself in the future. So I really didn't expect it to show these early beneficial outcomes. At the same time, I know from my own practice that a lot of these patients do spectacularly well, and it makes me reflect on some of the own...

We all have our spiels that we share with patients when we're talking about different things that we want to either explain or in our arguments for why people should strongly consider a treatment or another treatment. One of those spiels I have is that in this population, which is a heavily pre-treated population, sometimes we reach the point where your bladder is no longer your friend.

And it sounds really weird to say this, but for a subpopulation of these patients, taking out their bladder does truly give them a better quality of life. And I think we've all had that experience where we've had patients in our practice who are really grateful because their quality of life with a urinary diversion is actually uniquely better than it was with their native bladder.

Now, that's a subset. That's not the entire CISTO population. And some of the work that you'll see coming out after is going to look at some of the other unique outcomes that we assess in CISTO like patient preferences and health state utilities because we also know that there are a lot of patients that have a really strong preference for keeping the bladder.

It's sort of like keep my bladder at all costs. And then there's this middle ground gray area where patients are fairly agnostic to one or the other. And one of our hopes is to subsegment this CISTO data to try to really understand some patient profiles where we can use this data to improve counseling. So it's almost like if you were to walk into a room, who is like me and how did they do?

So we can say, "Gosh, if you are older and have some poor urinary function, your preferences don't include a strong preference for retaining sexual function, and you have some cancer characteristics like maybe some more severe cancers, I think our data would show a superiority among considering radical cystectomy. If you are younger, you strongly prefer keeping your bladder, plus you have good sexual function, you probably would do better on all of these quality of life domains with bladder sparing therapy and these middle ground patient profiles." That's one thing that we would hope to construct out of the CISTO data.

Ashish Kamat: Yeah, I couldn't agree more. I mean, we always talk about personalized treatment, Personalized cancer therapy, but it's also personalized counseling. And in fact, one of the questions I always ask my patients when they come to see me, I'm like, how happy are you with your bladder and how happy are you that you actually are potentially going to be able to keep it? And I've had patients tell me, "Well, I'm glad you asked me that question because I was sent to you for bladder sparing therapy, but I'm miserable with my bladder."

And again, if we can tease those out from the CISTO data and truly have a personalized, who knows, maybe it's machine learning, whatever it is, but be able to apply specific parameters to specific patients, that would be ideal. But I think that summary slide that you showed that shows equivalent outcomes, better outcomes, and in a few cases, suboptimal outcomes of radical cystectomy is really going to help us as a field put radical cystectomy back on the guidelines.

Because I'm sure you've felt this too, announcing this to different guidelines committees that I sit on, with the newer drugs and therapies that are coming out, radical cystectomy is almost now going, well, maybe you shouldn't be offering this to patients. Maybe you should be giving them intravesical treatments ad nauseam, which I think is not fair to the patient.

They need to have that option. What's your sense though on if the CISTO data had come out eight years ago when we and others proposed to the FDA the whole BCG unresponsive definition, just going back, devil's advocate, do you think we would've had this explosion of trials and novel therapies?

John Gore: I think we still would, in part because bladder cancer remains a burdensome cancer, that we know that bladder cancer is one of the commonest cancers. Most bladder cancers are non-muscle invasive, and most patients are searching for other options to help them keep their bladder. So even if we had produced this data eight years ago showing that cystectomy patients do really well, it wouldn't change the fact that a significant proportion of patients are really striving for options to help them keep their bladder.

And that's a great thing. What I think is this data doesn't show that for every patient cystectomy is better, right? It shows that for the average patient, you do pretty well with a cystectomy, maybe better than we all would've expected, especially when you're comparing it to a cohort of patients that still have their bladders. At the same time, I think we still would see this explosion because there's still a huge burden of need in that category of bladder sparing therapy.

In terms of informing guidelines, one of the unique structures we have with a PCORI-funded study is this multi-stakeholder executive committee and external advisory board. And so that's why, for example, Sam Chang was on our executive committee as a representative of guidelines through the AUA, but we also have a number of site PIs who sit on NCCN Guidelines panels. And I think that's a really valuable input. And I do think you're going to see radical cystectomy retain a place on our non-muscle invasive bladder cancer guidelines.

I mean, I know you were at the AUA. One part of our presentation at the AUA is we followed a series of industry-sponsored trials and non-muscle invasive bladder cancer. And the repeated refrain was how horrible cystectomy was for patients. And then I was the last to talk in the session and I got up and said, "Actually, it's not so bad." And I think that's just important to remember.

Ashish Kamat: No, it is. It is, absolutely. And of course, I help out with the European Guidelines. Of course, our IBC Guidelines. I think every guidelines committee is going to take stock of this because we've always felt the way you felt when you presented the data, but it was hard to quantify it.

And again, people will try to poke holes at this and say, "Well, it's a selected group of patients. They self-report it," but that's the kind of patients we see in clinic. Patients will self-report. I think that's the best kind of data. So again, congratulations to you, the entire team, and thank you so much for taking the time and sharing with us.

John Gore: Thank you so much.