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Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. We are live at ASCO 2024 in Chicago, and I'm delighted to be joined today by Brent Rose, a radiation oncologist from UCSD in San Diego. Brent, thanks so much for joining us today.

Brent Rose: Hey, it's my pleasure, Zach. Thank you so much for inviting me.

Zach Klaassen: We're going to talk about a presentation you gave at ASCO looking at bladder-sparing therapies for localized bladder cancer. Important need, tell us about the unmet need in this disease space.

Brent Rose: Yeah, it's interesting because organ preservation is so common in lots of other disease sites, like larynx cancer, anal cancer, and you would think that bladder cancer would be the stereotype for that. Patients are older, frail, have comorbidities. Cystectomy works well, but there are significant risks associated with the surgery and quality of life issues as well.

Zach Klaassen: Sure.

Brent Rose: So you would think that organ preservation would be a very common thing with this patient population, but really only about 10% of patients undergo chemo radiation for bladder cancer.

Zach Klaassen: Especially you mentioned, I mean, I take out bladders, comorbid population, we know about the risks of the procedure. Not just the morbidity, but there's a mortality risk as well as we get older. So tell us, just walk us through a little bit of the efficacy of chemo radiation in that disease space.

Brent Rose: Yeah, it's interesting. It's not quite as well-developed as cystectomy. There are lots and lots of randomized trials that you can point to, cystectomy with or without chemotherapies. So we really have the main one as the BC2001 study. It was randomized between radiation to the bladder alone versus radiation with mitomycin C and 5-FU, and that's really our benchmark. You can see invasive local regional recurrence rates are about 20%. Distant metastatic rates are about 40%, overall survival five years about 50%.

And while we all wish that there was a direct randomized trial between surgery and radiation, there's not, there probably won't be for the foreseeable future. So you can kind of compare to other studies and say, "Well, if you look at the clinical trials from the cystectomy literature, they're about the same endpoint." And you tend to see that 50% survival at five years is a pretty consistent benchmark across most studies. There are patient selection issues, you can't directly compare it like that.

There are lots of retrospective studies. There's one in Lancet Oncology recently that showed pretty similar outcomes actually in terms of distant metastases-free survival, overall survival, not a lot of differences, but retrospective studies have a lot of limitations. So generally, the way I think of it is we're lacking the level of evidence to directly compare, but the evidence that we do have puts them in about the ballpark, so it's enough to get on the same page and have a shared decision-making conversation about the lack of direct comparisons, but both modalities showing fairly good efficacy.

Zach Klaassen: Awesome. What about patient tolerability? For our listeners, whether they may be medical oncologists or urologists, as a radiation oncologist, what's the general message on tolerability and side effects of that treatment?

Brent Rose: Yeah, yeah. If you're looking for data, there's a great study, again from BC2001, the patient-reported outcomes, where they gave the patients questionnaires all the way throughout their treatment. And you can see it really echoes what we see. And then generally speaking, almost all patients get through the treatment just fine. There was a pretty big impact on peeing frequently, urgently, maybe a little bit of urinary control issues and getting tired and having some diarrhea, but people are getting through the treatment. That's the acute phase.

Within three to six months, people are feeling pretty close to back to normal again. And on average, that's probably what we see the most of. It is important to realize though that not everyone's going to have a great outcome, and you can see from those patient-reported outcomes about a third of patients are going to see a clinically significant decline in their bladder function. And then somewhere in the one or 2% range are going to have such a bad issue that they're going to need a cystectomy because of the side effects they've had.

But generally speaking, that means the majority of patients actually do pretty well. They get to avoid the big surgery, maintain their native bladder, and have good quality of life.

Zach Klaassen: That's a good rundown. Let's take a patient. Let's say they're 60 years old. They're a good candidate for either one, and I want you to walk through some of those criteria for us, but how do you work in shared decision-making? Because even in my clinic where I'm talking about cystectomy, patients sometimes think, "If I have the surgery, everything's going to be perfect." We know there are recurrences after both. So how do you sit down with a candidate that's good for both and what's your criteria you're looking for?

Brent Rose: I think there are really two different selection criteria that are really important. First, how fit are they for a cystectomy? It's a big surgery. Not only is it black and white, can you or can you not have a cystectomy, but what is your complication risk going to be as you get into your seventies and eighties? Maybe you could get the surgery, but the complication risks are going to go up. So that's one dimension that I look at.

The other dimension is how likely are they to have a good outcome with chemo radiation. And that's not random; you can predict that. Smaller tumors, T2 tumors, unifocal, no associated CIS, not involving the ureters, and having good bladder function. Typically, we do do predominantly urothelial histology. Some of the variant histologies haven't been as well studied, so we do prefer the variant histologies. But again, those are the two dimensions, how well they're going to do with chemo radiation and how well they would end up doing with the cystectomy in terms of tolerability.

So there's the clear-cut, can't have a cystectomy patient, and then we're just talking about chemo radiation. There is the clear-cut, maybe the rare 40-year-old, someone like that you'll see sometimes, you're probably not having a shared decision-making discussion with that patient because cystectomy is going to be better for that patient. Where they join will depend on those risk factors. Again, if they have a small tumor, easily resected, clear cystoscopy, you might be a little more inclined to reach into the younger population to treat those patients because you think that they're going to do well overall.

If, on the other hand, the tumor's big, growing through the bladder wall, involving the ureter, those are patients we try not to do chemo radiation on, if they have another good option and cystectomy is a great option. So those patients probably need more than we can offer.

And so we try to sit down and personalize it for every specific patient. Like you mentioned, sometimes people will have very strong opinions. They'll say, "I'm not going to have a cystectomy no matter what." And that's a starting place. We can have that discussion, break down what they're feeling, why they think that, and see if we can allay some of those concerns. On the other hand, some people say, "Well, I'll just have a cystectomy and I'll be totally cured." And so you have to really walk through. And realistically, in both cases, the distant metastasis risk is what's going to drive their mortality most of the time.

Zach Klaassen: Mortality rate. Yeah.

Brent Rose: So whether you're going to get chemo or radiation or a cystectomy to take care of the local disease, we really have to think about the distant disease as well.

And so we just go through the numbers, figure out what life is like with the cystectomy, what the reconstruction will look like, how that fits into their quality of life from their perception. And then we go through that again with the chemo and radiation. And again, we talk through the numbers, how likely they're to have a good outcome. How would they feel if they had poor urinary function after the treatment was over, and just try to have a shared personal decision.

Zach Klaassen: That's a great answer. I think you made a good point about there's the patients, as surgeons, that we are not operating on and they're going to go get chemo or radiation no matter how bad the tumor is. But I think from really the classical discussion, shared decision-making, is those patients that probably would do reasonable with both.

Brent Rose: Yeah.

Zach Klaassen: You had a great slide on your experience at UCSD and how you logistically go through. Maybe walk our listeners through your guys' experience on how you do chemo or radiation?

Brent Rose: Yeah, yeah. I trained at MGH, and MGH was one of the real founders of bladder preservation, at least within the US. The UK has done great things as well. And they came up through the RTOG way where they were doing split-course radiation, where you had a stop halfway through and do a cystoscopy and see it. And so some of the ways that we're doing it were a little complicated and a little bit harder to get through.

And so I think there's a lot of good reasons why they did it that way, but we like to streamline things, make it a little simpler, a little smoother. So we borrow a lot from the way the UK does it. One, because that's where the Level 1 evidence is from the BC2001 trial so we typically prefer mitomycin C, 5-FU. You could do weekly cisplatin, you could do twice-weekly gemcitabine in certain circumstances, but our default is 5-FU, mitomycin C. The patients actually do fairly well with that. You might think older frailer patients might not do great with that combination, but in our experience, they've actually done quite well.

In terms of the radiation, I'm a radiation oncologist so if you've got a couple of hours, we'll sit here and talk about it in detail, but realistically simple is probably better. In the BC2001 study, they did a randomization between treating the whole bladder or treating the tumor to the full dose and treating the whole bladder to a slightly lower dose. Turns out it didn't affect outcomes either way. So it didn't change local recurrence rates at all, but also didn't reduce toxicity to do this cone-down approach.

Zach Klaassen: I see.

Brent Rose: Typically, again, borrowing from the Level 1 evidence, we often do 55 gray, 20 fractions. So the shorter course. One, because that's how it was done in the study. There was actually another study that combined data with the BC2001, it looked like that shorter course maybe marginally better without an increased side effect. We like it, logistically it's easier too. And it's easier to get through because the course is over pretty fast, so patients get through that pretty quickly.

There are some open questions. Again, just taking a step back, our default 55 gray in 20 fractions to the whole bladder. We'll do a little cone-down with the radiation if it's easy to see the tumor, particularly if there are organs at risk nearby. But we don't feel like we have to because the data doesn't show that there are big differences by doing that. And then we do that with mitomycin C. So it's a pretty simple, straightforward way to go.

If you wanted to stretch it out a little bit longer because you want to treat the pelvic lymph nodes, then we'll usually default to the conventional fractionation, which is six and a half weeks of daily radiation. In that case, sometimes we also go to weekly cisplatin, but that's a little bit variable as well.

Zach Klaassen: That's great. You had a great section too on novel treatment options and really the future of how we're going to do things. And maybe just walk us through the two trials you talked about at your presentation.

Brent Rose: Yeah. Realistically, the goal of this is trying to get patients living their best life without side effects, without cancer, without major side effects. And so as much as I like radiation, it does leave side effects for patients and sometimes those can be long term.

There's a really exciting study by Matt Galsky and his group looking at neoadjuvant chemotherapy, gemcitabine, cisplatin, plus immunotherapy. And then if they had a clinical complete response, they got no local therapy unless there were signs of recurrence. It turns out those who had a clinical complete response did better than those who didn't as expected. But in those who did have a clinical complete response and underwent active surveillance, only two of 30 patients developed metastasis, which is fantastic.

Zach Klaassen: That's great.

Brent Rose: Really great result. When you look at each patient individually, the majority of the patients didn't end up needing any kind of local therapy and are still being actively monitored without any evidence of recurrence. So it's really fantastic and kind of game-changing results.

There were about nine of those 30 or so patients that did have to have a cystectomy. Eight had a local recurrence, one just wanted to have the cystectomy. So some amount of local persistent disease is likely to be there. How to find it is hard. Whether we can use molecular diagnostics to see who is more likely to respond. It didn't look like it in their trial, they studied that pretty hard. It didn't seem like that improved their ability to predict longer term outcomes. Could there be imaging, MRIs? Possibly. Circulating tumor DNA? Definitely something to think about. But right now there is that group of patients who will have recurrent disease in their bladder, and how to manage that without losing your chance of cure is important.

Particularly because if you look at the other study, the RETAIN study, which is a fairly similar design where they gave chemotherapy, in this case accelerated MVAC, so no immunotherapy. And then if they had a clinical complete response and had one of these DNA damage repair mutations, then they underwent observation, but they had a much higher recurrence rate, they were in the 60, 70% recurrence rates. Unfortunately, 10 patients developed metastases and then nine of them had a local recurrence before the metastases. So it does raise a question, if we had done some local therapy first, could those metastases have been prevented? We don't know.

Zach Klaassen: We don't know.

Brent Rose: It might've happened anyway, no matter what, but it does raise that concern. So I think that it's a really exciting new paradigm to think of. There are some patients that can be managed with systemic therapy alone, but identifying who those patients are is what we need to know before this can become a standard of care.

Zach Klaassen: I think you made a good point in the Galsky trial, 25% did have local recurrence. And if you look at some work that Alex Kutikov's done, even people with cysto negative evaluation before cystectomy, roughly 20 to 25%, which lines up with that study, still have persistent disease in the muscle lining that at this point we just can't tell.

So lots of good stuff going on. It's been a great discussion. Just maybe leave our listeners with a couple of take-home points that they can take to the clinic tomorrow.

Brent Rose: Yeah, it's a really exciting topic for me, and I'd say realistically, a lot of people just don't know that much about chemo or radiation.

Zach Klaassen: Sure.

Brent Rose: Sort of part of where they train, what they see, and what they've experienced. So I would say the take-home message for me is that chemo or radiation works fairly well in the appropriately selected patients. The side effects, generally speaking, getting through treatment is very manageable for the large majority of patients. With the long-term function of the bladder and the bowels are generally good, but there will be some diminishment in about a third of patients.

Really, what I think is probably the most important is starting the shared decision-making.

Zach Klaassen: Yeah, absolutely.

Brent Rose: Just knowing that that's an option, knowing what data to be aware of so you can have that good conversation. And there's a lot of patients that I push that, "I think you might have a good outcome with chemo or radiation, but I think you'll likely have a better outcome with cystectomy."

And that's okay. I'm a radiation oncologist, I'm happy to push them towards a cystectomy, and vice versa. There's sometimes where the urologist says, "You've had some other medical issues, maybe think about chemo or radiation. That might be the better option for you." So having that go-between, being partners with your urology, with your medical oncology teams, really helps to get the best option for each patient.

Zach Klaassen: Yeah, absolutely. I think you nailed it. The multidisciplinary aspect is huge, and that's what it all comes down to. Shared decision-making, talking amongst your peers, giving the patient the options.

Brent, thanks so much for your time and expertise. Great discussion today.

Brent Rose: Yeah, my pleasure.

Zach Klaassen: Thank you.

Brent Rose: Thank you.