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Sam Chang: Hi, I'm Sam Chang. I'm a urologist in Nashville, Tennessee, and I have the distinct honor, distinct pleasure to be joined by actually two of the real kind of pace-setting leaders when it comes to bladder cancer. And I think importantly, the evaluation and careful study of patient decision-making, the impact of different therapies as we and patients along with physicians try to come together with a plan of what do we do with non-muscle invasive bladder cancer in the BCG unresponsive space and all the options. And they're really the leaders of a very, very large trial called CISTO. And I'm going to turn it over to both of them because we've had actually initial publications come out looking at what this trial entails, who they enrolled, what they were looking at. And importantly and coincidentally, this trial has actually closed to accrual, and now we're gathering data and we look forward to the results. So I'm going to turn it over to Dr. John Gore from the University of Washington and Dr. Angie Smith from the University of North Carolina.

John Gore: Well, I mean, the honor is definitely, I think, ours. I mean, any chance I have to sit in a room, even a virtual one with the esteemed Sam Chang, my rule is to always say yes. And you should also add the disclosure that Dr. Chang is on the executive committee for CISTO, given his many roles that are influential in the bladder cancer world. So one of the things that we try to do with a study like CISTO is to ensure that when we have results, we can get those results into guidelines. We can get those results into practice-changing formats. And Dr. Chang's role as the chair of guidelines for bladder cancer non-muscle invasive and muscle invasive is really important. So his guidance has been really helpful to CISTO. This has come on the heels of our protocol paper that Angie and I were leads on that describes what CISTO is.

And so I'm going to just start by describing CISTO and then see what the smarter one of the two of us wants to add. But CISTO is an incredible acronym that neither Angie nor I can take credit for. It's from our colleague Erika Wolff. And it stands for a comparison of intravesical therapy and surgery as treatment options for recurrent bladder cancer. And it's looking at patients whose high-grade, non-muscle invasive bladder cancer has come back in the setting, either of a recent exposure to BCG or a more remote exposure to BCG. And those patients are trying to navigate a decision between having their bladder taken out versus sort of the hodgepodge, the warts and all, of alternative bladder-sparing therapies.

And it seems kind of crude to kind of lump those all together, but we kind of do that very practically in our practices. And so it really is sort of a comparison of taking out the bladder versus what else can we do. And our main endpoint, and this is where I think Dr. Smith's expertise is really critical, our main endpoint is a physical functioning outcome. It's not recurrence-free survival or cancer-specific survival; it's a physical functioning outcome. And I didn't know, Dr. Smith, if you wanted to talk about how that came about.

Angela Smith: Yeah, definitely not the smarter of the two of us. I will say that, but I will take a stab at this. I think that what's unique about this trial is exactly what you said. It's pragmatic. This is actually what's happening out in practice, and that's what we need as clinicians. That's what patients need when they're facing these difficult decisions. And in order to make it as pragmatic as possible, we needed to include patients' perspectives on this. And so we constructed and designed the study a little bit differently. We actually have a group and advocate advisory board of patient advocates. And we also took advantage of the Bladder Cancer Advocacy Network Patient Survey Network, which is a huge network of patients across the country, actually in Canada and some other locations as well, to better understand what the outcomes patients are looking for when they're trying to make this really difficult decision.

And so we found that there were a variety of outcomes, but the number one outcome that came up was physical functioning, because you have to remember, these patients are older, they have different comorbidities, but they also have different goals of care. And while survival is also important, and that certainly was listed in that, physical functioning was a really important one. We have a variety of other secondary outcomes, including survival, of course, but things like financial toxicity, bladder cancer-specific quality of life, things like anxiety, depression, decisional regret, all of the different items, pieces of information that patients need to make their decision. So I'm going to toss it back up to you, John, because you always have something even better to say.

Sam Chang: I'm going to just ask, make a point here. First of all, the hours and hours and days and days and weeks and weeks of effort that both Dr. Gore and Dr. Smith have put in cannot be underappreciated. But I love the two points that both of you have raised. One is the pragmatism of this study, and the second is the focus on basically what the physicians have tried to garner. We make attempts. We don't really know. What really matters is actually what the patients have said is really important for this disease process, especially in the non-muscle invasive disease. So I think pragmatism and then patient-driven really sets this evaluation apart. And as this study went, the constant updating and evaluation of enrollment during the pandemic, just afterwards, I mean, to be able to get this study off the ground, John and Angie, I want you guys to talk a little bit about the strategies you took and what... the changes you made, how you pivoted to make it even more real world and actually have it finish accrual.

John Gore: Yeah, I'm going to start, and then I'm going to hand it off to Angie because she's working on a really cool analysis with a mentee that actually critically evaluates and quantifies some of the changes we made that really helped our accrual. But we had the misfortune of opening CISTO widely. We technically started recruitment in 2019, but that was just at UW and shortly after at UNC. But in terms of wide accrual at our more than 30 sites, we opened in spring of 2020, which was not a peak time for research activities. Most research staff were sent home. And so it was a really challenging time to get a study off the ground. And I think we've all been a part of industry-sponsored clinical trials or cooperative group clinical trials. But this is one where our critical focus was being cheerleaders for enrollment. And the way we built CISTO was honestly on the back of interpersonal relationships.

CISTO was a snowball of sites that participate in a working group that was part of the Bladder Cancer Advocacy Network. And then from that, we built it out through our prior relationships. And that actually made it really easy for Angie and me to text message our friends and say, "Hey, what can we do to support increased accruals at your site?" And that pragmatism extends to the sites of practice as well. It's not just the Vanderbilts, UWs, and UNCs of the world. We had six sites that are community-oriented sites because that's where a lot of non-muscle invasive bladder cancer care takes place. But I would love Dr. Smith to talk about some of the strategies we use to up our accrual.

Angela Smith: And I think it was definitely a misfortune, but it was also an opportunity to learn more about how we can better deliver clinical trials. And there's some, I think, good things that came out of it. And I think in a pragmatic trial in particular, pandemic or not, it's complicated. BCG unresponsive disease is complicated and it is sort of a messy kind of situation, how do we define things and nothing neatly fits into a box. And we realized very quickly that defining eligibility criteria was not as straightforward as we wished it to be. First of all, there's education to be had, and add and layer on this pandemic where staffing is a challenge. We realized we needed a few things in place. One thing that we instituted was community, and we needed that even as humans in the pandemic as some way to get together. And so we created something called all-sites meetings.

And that may not be new to folks, say, "Okay, well, we do have study meetings," but these were different. They were very much geared toward research coordinators, but we layered onto these all-sites meetings, things that were most relevant to research coordinators. And so in tandem with that, we wanted to have each site, because we have so many sites in this trial, have the ability to contact us with questions because we realized very quickly some, and John, you could speak to this in a moment, that some patients would get enrolled at least at the beginning of the trial and not meet eligibility criteria. And so we noticed that very quickly, and this created this pivot, something called , which was just an email address so that individuals could say, "Hey, this is the anonymous just general information. Is this patient eligible?"

And if they are, what category did they fit? It was brilliant. I don't even remember whose idea it was. It wasn't mine, but I love the idea. It worked really well. We've used it to this day, and we used that to seed the all-sites meetings so that they were relevant to research coordinators. We were actually taking the actual cases, we were pulling them, we would say, "Hey, here's the case. What do you think? Are they eligible or not?" And the interesting thing we found, and what we're going to be sharing in the paper, is that in the beginning, the proportion of people who would get it correct was very low.

And over time, people learned, the research coordinators learned, and then new coordinators would come on and there would be all of this information sharing. We'd have breakout discussions. People really understood that, and it helped so much with the trial. So I'm just touching upon a few things of these lessons learned. But one other thing that came out of it, and John maybe you'd like to speak to it, is it gave us an opportunity to evaluate practices that were happening during COVID and a paper came out of that as well.

John Gore: Yeah. I mean, I think one thing that we wanted to be aware of was how drastic the interruptions in care were during COVID. How were each of our sites affected? Part of it was selfishly motivated. We have a funder; this is different from a cooperative group trial where you can kind of keep accruing until you're accrued, so if that takes four years or nine years. Here, we had a very limited timeframe to recruit our patients and get their primary follow-up. And so we wanted to demonstrate how drastic those were. And so we captured the state of bladder cancer care and research operations at all of the sites participating in CISTO. And it showed a couple of things. It showed that bladder cancer care was largely preserved even in peak times. And so most bladder cancer patients were still able to access their care, but there were very discrete disruptions associated with things like the Omicron wave. And then also, this coincided with another one of our BCG shortage waves, which wasn't COVID related, but happened coincidentally and really affected bladder cancer care delivery.

Sam Chang: So along those lines, John and Angie, what's coming out on the pipeline? I mean, the list of papers in consideration, ideas that are being kind of tossed around, actually publications in the works. I mean, it's a long list. If you could highlight a few of those, and then I think you guys have some good news about future projects as well.

John Gore: So the main thing that's going to come out of this cycle of CISTO is going to be a comparison of bladder removal surgery with radical cystectomy with what we now call our bladder-sparing therapy arm. And that's just because during CISTO, PEMBRO was approved as a therapy for BCG unresponsive, non-muscle invasive bladder cancer Pembrolizumab. And so it's not really intravesical therapy anymore; it's sort of bladder-sparing therapy.

And so this is going to be an overarching comparison that I think most critically is going to help us understand the role of cystectomy in this patient population. And so we're going to have 12-month outcomes for the entire CISTO study sample. I think we're going to have some really interesting insights into potentially which people do really well with cystectomy and which people do really well with bladder-sparing therapy. I think all too often in a clinical trial, we think, "Gosh, we just want to know if treatment A is better than treatment B?" But there's some heterogeneity in that and maybe, just maybe, some people do better with treatment A and some people do better with treatment B. And so trying to figure out that what we call heterogeneity of treatment effect is really important. And I think it's going to help us guide patients and physicians to make better decisions in this clinical space.

Sam Chang: I think it's hugely important, especially we have been so hyper-focused, and I think probably rightfully so, on the disease characteristics and the heterogeneity of the disease. Unquestionably that's important, and we're going to get better and better with precision oncology and choices based upon molecular classification and what we do and how we do it. But ultimately, it's still dependent upon the impact of those treatments on those individuals for the disease processes. And so that's why I think this trial is hugely important. Angie, you were going to say something where of course I really interrupted, but what were you going to say?

Angela Smith: No, it was perfect, Sam, because really what you're speaking about is nuance, right? And the additional papers that will come out of CISTO, and we're continuing to analyze here, are qualitative interviews. So, we have a variety of outcomes we've already mentioned, and they are quantitative, but we know that doesn't tell the full story in such a complex disease space where there's so much preference. So, we will also have a large number of patient interviews that take a deeper dive into each of these outcomes along with caregiver interviews as well. And so it'll give us a better flavor of what's really going on. We may have these outcomes, but we also understand why in some of the details surrounding that.

Sam Chang: Yeah. Well, that's fantastic. And then John, you mentioned as we wrap this up, you mentioned actually to me some exciting news that both of you all have to share.

John Gore: Yeah. We just received a notice of award for an R01 that's going to allow us to get on all the CISTO patients. So we talked about how next year we'll have one-year outcomes, and we'll be able to put out the main product of this initial phase of CISTO. But we all know that in this patient population, two-year outcomes, five-year outcomes are really, really important. I think we all want to be able to tell our patients what they can expect over the next five years, not just over the next 12 months. And so this funding is going to allow us to do that. It also is going to support us to continue to accrue new patients at a subset of CISTO sites, including Vanderbilt and UNC, as well as UW, which is going to allow us to continue to understand the role of radical cystectomy as we get to experience this new era of emerging non-muscle invasive bladder cancer therapies, which I think is really exciting.

When we looked at clinicaltrials.gov as we were preparing that grant, we couldn't find any active ongoing trials that were looking at the role of cystectomy in non-muscle invasive bladder cancer. A lot of the work is in explanatory trials for new therapeutics. But I think we're going to be well positioned to be one of the few studies that's looking at the role of cystectomy in this patient population. And we're going to get to continue to do that in this sort of new non-muscle invasive bladder cancer era. And then lastly, we're going to do another look back at the CISTO data to try to understand if we can do a better job molecularly characterizing these cancers. So, you guys have mentioned nuance, we've mentioned heterogeneity. There's just a massive splay in non-muscle invasive bladder cancer of cancer severity, and it's really hard to put numbers on that. And so maybe better histopathological interrogation of their cancers versus some subtyping that allows us to do a better job of understanding cancer severity. Maybe we can help guide decision-making going forward.

Sam Chang: And I think the work that you two have led is really, I hate to use the word revolutionary, but it really is, and to choose this decision dichotomy where it is drastically different. I think we do understand that a little bit, cystectomy versus not. The differences are real. And I think we all struggle with, "Gosh, who needs what and why and what?" So to help answer that question in this environment where we really are scratching the surface on our knowledge of the tumor as we struggle with the impact of our treatments, just to have that data. And then now with this R01 that was awarded, I mean, fantastic news for long-term follow-up, and then to continue to roll as treatments change.

I mean, true kudos really need to go to both of you. And I just wanted to take this chance to thank you both for the leadership that you've displayed, and thanks for spending some time today. But for sure, we look forward to the many of the publications that will be coming out that'll help guide not only our care but more importantly help patients make their decisions. So thanks to both of you all. Very good. And congratulations. Absolutely congratulations and exciting times and more patients that we need to accrue here at Vanderbilt and other sites. We look forward to working with both of you.

John Gore: Thanks so much.

Angela Smith: Thanks, Sam.