A Clinical Exploration of Radiation and Trimodality Therapy in Bladder Cancer Presentation - Scott Delacroix

August 22, 2023

At the 2023 Bladder Cancer Advocacy Network (BCAN) Think Tank meeting Scott Delacroix elucidates on the role of radiation therapy in treating non-muscle invasive bladder cancer, focusing on its potential and his personal experiences with trimodality therapy for muscle-invasive bladder cancer. He discusses a Single Arm Phase 2 study (RTOG 0926) and its outcomes, and presents data on combining immunotherapy with radiation therapy, showing some promising results in small studies. He highlights the evolution of his practice, from a surgery-oriented approach to exploring other treatment options like trimodality therapy through clinical trials. Dr. Delacroix emphasizes the importance of optimizing bladder cancer outcomes beyond bladder preservation, suggesting the potential for hypofractionation and the combination of novel systemic agents with radiation therapy. He concludes by stressing the need for smart clinical trials to focus not just on the bladder but also on systemic recurrences and distant failures.


Scott Delacroix, Jr, MD, Urologic Oncology (Bladder/Prostate), LSU School of Medicine / LCMC-East Jefferson, Gulf South NCORP, New Orleans, Louisiana

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Scott Delacroix: I'm from Louisiana. I'm from LSU. My tasks are threefold, discuss the role of radiation in non-muscle invasive bladder cancer. Really, the potential role. You'll hear more about that from Dr. Bauman later on. And really give you just a general experience of my experience with trimodality therapy for muscle invasive bladder cancer. And really where I see, as a humble clinician amongst a bunch of scientists, where I see potential future directions are to try to improve outcomes in this disease. And to try to stay on time. So, the role of radiation therapy in non-muscle invasive bladder cancer has some data, although it's limited. RTOG 0926 was a Single Arm Phase 2 study that accrued patients over an eight-year period. These were operable patients with T1 disease who were recommended to undergo cystectomy. Again, it was a Single Arm Phase 2.

Patients received seven weeks of radiation therapy with either cisplatin as a radiosensitizer or 5FU and mitomycin. The number of patients accrued over eight years was 37 patients. The primary endpoint was different than the primary endpoint if you're familiar with 1806. The primary endpoint here was freedom from cystectomy. So, it was not bladder intact event-free survival, which is a composite endpoint of recurrence survival and freedom from cystectomy. This was just freedom from cystectomy. The freedom from cystectomy on the data was 88%. But in the overall survival though, is when you drill down into it again on 37 patients, overall survival at three years was 69% and 53% at five years. Large confidence intervals, because we have small numbers of patients. The distant metastatic disease was 12% at three years and 20% at five years.

So, we look at other data that's out there on radiotherapy and non-muscle invasive bladder cancer. And this is data from Dr. Kassouf at McGill, and he was looking at combining immunotherapy with radiation therapy. There's some data that suggests that radiotherapy can increase PDL1, and he looked at timing of application of radiotherapy along with immunotherapy in a basic science model. He looked at it from a neoadjuvant, a concurrent arm and an adjuvant arm. And interestingly, when you look at tumor growth in this study, controls which received nothing, as you would expect, showed growth, PDL1 and radiation. Both showed independent size reduction or reduced growth rates. But the combination of radiation with PDL1 had the best outcomes in this small study. And when they looked at the timing of immunotherapy, either concurrent, neoadjuvant or adjuvant, it really didn't seem to matter. So, I think it's probably going to be an issue, or may be an issue depending upon the results of 1806 and subsequent trials as to whether or not concurrent is necessary or are we getting our bang for the buck if we give it neoadjuvantly or just adjuvantly.

In 2015, there was a clinical trials planning meeting, and out of this came two ideas for clinical trials. One of the trials was a platform-based trial that, as written in 2015, this is what it looked like. It had 20 arms. One of these arms had radiation in it. And the successor to this idea actually was just recently published. And this is the ADAPT-BLADDER study. This was published last month, and this was a Phase 1 trial of durvalumab in combination with BCG, durvalumab alone, or with external beam radiation therapy. Again, these are small numbers. This is in non-muscle invasive bladder cancer. And so, this is BCG unresponsive patients. They could have been CIS or papillary, with or without CIS. And there were three cohorts, monotherapy IO, monotherapy or durva with BCG, or durva with external beam radiation therapy.

And the radiation therapy was six gray, just in cycle one on days one, three and five. Mandatory biopsy at six months to assess for presence of CIS, regardless of what the cytology showed. When you look at the data, there were some differences between the cohorts, as you would expect in a small study, with CIS components and papillary components being a little bit different in each of the groups. But the CR rate was pretty impressive on cohort two, which was durva plus BCG. Now, when you look at cohort three, because we're talking about radiation therapy, cohort three did show a more impressive rate than IO alone. But the really interesting cohort was the durva plus BCG, and this was recently published. I'm now going to jump over to trimodality therapy in the muscle invasive space. And evolution of my practice as really just a simple urologic oncologist who takes care of patients.

I'm at LSU in Louisiana. Did my residency, everything for bladder cancer was surgery, surgery, surgery. Fellowship at Anderson, it was neoadjuvant chemotherapy and surgery, surgery, surgery. Really, radiation was something that worked in Boston and in Europe and it didn't really work anywhere else. My first eight years in practice, just did what I had learned, neoadjuvant chemotherapy, surgery, incorporated robotics and those kind of things. And then really got interested in, are there other options that truly are at play? And although I didn't have the knowledge to be able to step out into a trimodality therapy field on my own, the ability to do this on clinical trial has given me pseudo-expertise to be able to offer this to patients with some degree of confidence. And it's through these clinical trials that I have learned about this. And the two trials that came to mind that we opened up go by ERAS trial.

And then within six months of that opening, the SWOG trial opened. This is where I've got the majority of our experience. And here's the NCT03609216 trial, which everyone in the room probably knows about and will be discussed. And here's Dr. Singh's trial and he'll tell you about that, which has accrued amazingly well. And despite what my initial biases were, patients in this trial are very happy to sign up for it. Initially I was telling patients, "Look, depending upon what data you look at, you may be sacrificing 10 or 12% survival rate by choosing to do TMT." Again, I had my surgical bias hat on.

Patients were still willing to sign up for this trial. They are really highly motivated to try to spare their bladder. I wouldn't tell that to patients today after my experience of treating about 75 patients so far on this. So, one thing I've learned is maximal TUR is important. We utilize fiducials. This slide is really just to show a point that fiducials in the bladder do move around. So, this is fiducials around a T2 site with a bladder full and bladder empty. Our radiation oncologists, my partners who are radiation oncologists, they really like that we place fiducials. I'm not a radiation oncologist, but they love it. So, the further away the tumor is from the bladder neck, the more movement you'll get.

And this is really what I wanted to talk about, optimizing bladder cancer outcomes beyond bladder preservation. You're sitting here in a bladder preservation work group. We're talking about optimizing bladder preservation. But where I think the field and the trials need to go is optimizing bladder cancer outcomes, not just looking at the bladder. My general impression and the data suggest and doesn't suggest, it shows, that we can do a good job of sparing the patient's bladder and preventing muscle invasive occurrences in the bladder. The problem is with distant failures. That's not a problem with the trimodality therapy locally. It's potentially a problem that our systemic therapy agent that we're combining with our local therapy is not equivalent to what we're doing on the surgical side. So, on the surgical side of patients coming in, they're getting four cycles of dose-dense MVAC. We're marinating them like a pickle, and then we're taking out their bladder. And then if they still have today, if they still have unfavorable disease post-neoadjuvant chemo, we're then offering them adjuvant therapy. In the trimodality therapy space, we're behind the time.

Mainly it's because of the lack of adoption of trimodality therapy, so there's no adjuvant studies in this space. So, we're falling behind on distant failures. Where on the surgical side of things, we're treating more aggressively systemically. Should we give neoadjuvant chemotherapy prior to concurrent TMT? The data is all over the place, depending upon what you read. A recent trial just came out that says, "Yeah, there's a benefit." You look at the data from Dr. Kassouf in European Urology. But there are two or three other papers that say, "No, it doesn't make a difference." There's a lack of adjuvant data here. These patients, if we treat TMT like surgery, why aren't we doing adjuvant trials in this space? And then systemic treatment intensification, if we're going to go down this road, how do we do this smartly? Clinical staging sucks. It's not great. You can use MRI. My TUR may be better than the 75-year-old urologist.

Our staging is not great. Can we do this more smartly? Can we do this with circulating tumor cells? Can we do a Signatera to determine who needs neoadjuvant chemotherapy or who, post-trimodality therapy, needs adjuvant therapy? How do we make smart trials to go beyond just caring about the bladder, but the systemic recurrences that occur? And then obviously focusing on the bladder, if I go beyond the distant recurrences, seven weeks of radiation therapy is a lot. And patients need to travel for this. Is there a role for hypofractionation? Is there a role? I know there's data out there on 20 fractions.

Is there a role for ultra hypofractionation in this space? We don't know, but it's an opportunity for a trial. Nodal treatment, also very variable data that's out there on whether or not there's a benefit versus no benefit in treatment of the nodes at the time of trimodality therapy. And can we use novel systemic agents in combinations, along with radiation therapy, to not only help preserve the bladder, but to help preserve distant recurrences? That's an opportunity potentially for clinical trials. And I'll leave it at that. This is us last week. So, thank you all very much. I appreciate it.