Sam Chang: Hi, my name is Sam Chang. I'm a urologist at Vanderbilt University Medical Center, and one of my brightest, smartest, most skilled and favorite partners is actually Dr. Dan Joyce. Dan is an assistant professor at Vanderbilt University Medical Center as well. After finishing his fellowship at Mayo Clinic in Rochester, he actually now leads a center of excellence focusing on health policy at UroToday. And I asked Dan to actually give us a summary of an important work that came out of his research, looking at actually the cost-effectiveness, the impact, cost of care of actually trimodal therapy for patients with invasive bladder cancer. Really a topic that's gaining much more attention as we perhaps move away from just considering cystectomy as the local therapy of choice. So Dan, thanks so much for spending some time with us and look forward to the insights that you and your co-authors presented in this manuscript.

Daniel Joyce: Well, Sam, thanks so much for having me. It's always a pleasure to talk to you, honor to be here. Really appreciate the interest in the work. I can talk a little bit about where the idea for the study came from. In 2019, there was a systematic review, meta-analysis that compared the outcomes of trimodal therapy and radical cystectomy and found that cystectomy was actually better for cancer-specific and overall survival. In 2023, there was a multicenter retrospective study that really shook a lot of our understanding of the comparative effectiveness of these two treatments. And as a result, I think a lot of people have wanted to use trimodal therapy in an expanded use. And rightfully so, patients we know, want to keep their bladders. And so that new retrospective data, which found that there was no difference in metastasis-free survival, recurrence-free survival, cancer-specific survival, overall survival, no difference between trimodal therapy and radical cystectomy in a very, very well done retrospective study.

And of course prospective studies, randomized control trials, have been really difficult in this space. We tried the SPARE trial and had really poor accrual, and so we're really dependent on retrospective data. And what those authors did is they used really good statistical methods to adjust for confounding and bias. And I think that to date is really the best evidence we have for using trimodal therapy in comparison to radical cystectomy for a very specific group of patients. And I want to stress that. The patients in that study were patients who were fit for radical cystectomy. So these are the patients we would operate on normally, and they had very specific disease requirements. So they had to have a solitary tumor of less than seven centimeters, no or unilateral hydronephrosis, not have extensive CIS within the bladder, and then they had to have good functional bladders that could tolerate trimodal therapy.

So number one, it's important to know who we're talking about in this study. The goal of our work was based on these new data. Comparing these two treatments, we wanted to see, well, what's the highest value option for our healthcare system? And we know that that's an important question to ask because bladder cancer is the costliest cancer per patient lifetime, and we can probably anticipate that that's only going to get worse with some of the newer treatments we have in the systemic space, as well as the non-muscle-invasive bladder cancer space, specifically in the BCG unresponsive group of patients. So understanding how trimodal therapy affects our healthcare system, how it compares from a value perspective to radical cystectomy, was something that really interested us.

And so what we did is we built a microsimulation model that runs hypothetical patients through the various scenarios that can happen downstream after receiving either of these treatments, either trimodal therapy or radical cystectomy. And we used the probabilities, so the cancer-specific outcomes, from that retrospective data in our model. So we equated the cancer outcomes from trimodal therapy and radical cystectomy in the patients we simulated. We then relied on a literature review to look at quality of life among those patients long-term. And a lot of the long-term quality of life data that we have actually comes from that same group of patients that were analyzed in that retrospective study.

And what we found is that at five years, trimodal therapy was not cost-effective compared to radical cystectomy. A big reason why it was not cost-effective was the exorbitant cost of trimodal therapy. We actually did find that it improved the quality of life for patients compared to cystectomy, although those quality of life gains were rather modest. However, when we extended our model out to 10 years, that quality of life advantage became even more pronounced. Again, it's about a tenth of a year that people are gaining in quality-adjusted life years between the two treatments. But that's significant.

It's worth knowing what that quality-adjusted life year is. We basically rate a patient's and society's preference on a given health state. So you could say, if I have irritated voiding symptoms for the entire year, how do I view that on a scale from zero to one, zero being that's the same as death, one being doesn't bother me at all, that's equal to perfect life. And we can use those ratings or those utility values and multiply them by the amount of life that a treatment gives. So if you have a utility value of 0.8 and you live for a year, your quality-adjusted life year is 0.8.

I go through all of that methodology because a lot of the limitations of our study are the lack of really good prospectively gathered quality of life data. And that matters because if we're going to evaluate the comparative value of these options, we need to know how that quality of life is when people preserve their bladders compared to radical cystectomy. I think we saw really interesting findings from the CISTO trial in the non-muscle-invasive bladder cancer space that did just that. We looked at good prospectively gathered quality of life data between bladder preservation options and radical cystectomy and found some interesting results there. I think we would find interesting results if we looked at it in the muscle-invasive bladder cancer space as well.

Now, that's the general overview of what we found, but I always caution people in interpreting the overall results of a cost-effectiveness analysis and leaving it there. So you get your ICER, incremental cost-effectiveness ratio. That is the term we use to decide whether something's cost-effective. But the point of this study isn't really to say trimodal therapy is not cost-effective, move on. Where the real value in these analyses comes is in the sensitivity analyses. And what we can do with those is we can change one particular variable within the model, and we can vary that until our model actually changes outcomes and so trimodal therapy is no longer the least cost-effective option, but the most cost-effective option.

And we found a couple things, a couple of variables in the model that we could identify points in which our model would switch the outcome. The first was cost of trimodal therapy. So the initial cost of trimodal therapy in our model is about 40 grand. If you could reduce that down to about 17 grand, then trimodal therapy would become the most cost-effective option. The other is probability of progression and progression, I mean cancer recurrence, having to deal with what happens when the initial treatment doesn't work from a cancer control perspective. The difference between trimodal therapy and radical cystectomy would have to be reduced to about 11% in order for trimodal therapy to become cost-effective. And of course in our model it was 0%, we treated them as equal. I think that probability is unlikely, although if you can target the right patients, perhaps we can see even more gains in favor of trimodal compared to cystectomy when you think of perioperative morbidity and mortality. However, I think that kind of gain is unlikely.

And so the real crux of the value here is in cost. That cost is interesting because one, we modeled those costs as much lower than what has been previously reported in SEER Medicare data, claims data. In fact, it was significantly lower the cost we used because we were just basing them on CPT codes as opposed to real-world practice.

The second thing is that there was in 2022, a cost-effectiveness study done from a Canadian healthcare perspective comparing trimodal therapy and radical cystectomy. That study found that trimodal therapy was indeed cost-effective compared to radical cystectomy, which raises a lot of questions. Well, why in a Canadian healthcare system is trimodal therapy cost-effective and it's not in a US healthcare perspective? And I think those kind of questions need to be asked as we need to understand why trimodal therapy is so costly, especially in light of the fact that this is a treatment that my goal here is not to say we shouldn't do trimodal therapy. I absolutely believe we should be offering trimodal therapy to our patients. But if we're going to do that and if we're going to expand its use even beyond muscle-invasive bladder cancer, then I think we need to be thoughtful about how much it's costing our healthcare system and our patients.

Sam Chang: Dan, that was an incredible summary of the rationale behind your study, the specific mechanisms you all used to attempt to do this comparison. And then the findings. A couple of things came to mind as you were discussing this, and you actually touched on a few as you were describing the retrospective evaluation that was done. The first thought, obviously just as you mentioned was, gosh, can we do this as we did with CISTO? I don't think currently now or in the future will we ever be able to do a randomized trial assigning patients randomly in terms of what type of treatment they get. I can definitely see though, those patients that are in this cohort of patients who are healthy enough to go to cystectomy yet have disease that can be effectively treated by radiation.

So you're cutting actually both sides a bit. Lopping off the group that clearly is unhealthy, that we usually tend to move towards radiation, be it correct or incorrect. And then those patients that have actually disease that we really should lean towards radical cystectomy due to the possible decreased effectiveness of radiation therapy. But once that decision is made, you can see, or I can imagine a CISTO-type evaluation of patients upfront where we may get findings that surprise all of us, just as we did with CISTO. CISTO's primary endpoint was basically physical functioning and outcomes associated with that, and in fact was better. Nobody would've thought that. So I agree with you totally that the prospective evaluation of functional and patient outcomes, I think, will be really important with this.

But that long comment now leads to the second question, which is the cost. Were you able to break down the real, at least within the U.S. model, and we know there's difficulty with charges versus costs, et cetera, collections versus ... The cost of trimodal therapy makes sense. That's the biggest bang for the buck. What, is there a specific component of that cost that comes out? Is it the radiation treatments, is it the combination of systemic before? Is it the fact that you have to do a TURBT and all three things combined for trimodal therapy? Is there one factor that you think that we can leverage to, in fact, bring those costs down?

Daniel Joyce: Yes and no. I mean, it is complex, especially in our current healthcare system. I'll go back and just touch a little bit on your comment about the comparative effectiveness research in CISTO. It's very similar to what we did in CEASAR that gave us a ton of quality of life information that was extremely valuable for patient counseling and decision making. And so I can see a very similar advantage of doing that in the muscle-invasive bladder cancer space. So just a plug for anyone who's interested in doing that, we need it. As far as where these costs are coming from, we know chemotherapy is cheap. It's not driven by that. The chemotherapy used. We used cisplatin as a single agent, but any of the chemotherapy regimens you choose for this are going to be really kind of peanuts compared to the rest of the costs. Really it comes down to radiation billing, and that's one piece of it, but it's really a multidisciplinary approach to do this kind of work.

And that requires multiple clinic visits, coordinating that care. There are physician fees, facility fees, actual treatment fees. All of that goes into this ending up being a large cost. And you're right, in our model, we did two TURBTs per trimodal therapy treatment. I think that's reasonable. If we get better at transurethral resection of bladder tumors, maybe we cut that down to one, maybe that cuts down the cost. But then you have to ask, okay, how are we doing that? Is it with endoscopic robotic surgery? What are the costs of that? So there are a lot of things that start, as we try to become more efficient in our healthcare, that often requires more cost. And so it's tough. I think really re-looking at how we bill though is probably the most effective way we could bring down costs here. A per-fraction CPT code is probably not the best way to bill for radiation. I can see a situation where a bundled payment could help bring down costs here and motivate decreased spending with incentives. So I think some of those initiatives are going to be huge as we try to cut costs in various aspects of trimodal therapy.

Sam Chang: No, I think incredibly important, especially I think as we, as surgeons, I think hopefully have started a trend of offering patients the option, the impact of trimodal therapy for invasive bladder cancer has not been as common in the U.S. as you know historically, over the past few decades. I think it's really gaining some momentum now, but we need to balance that obviously with cost concerns, long-term follow-up concerns, all those types of things. So the more information we gather, I think incredibly important as we move forward to help decide and better counsel patients.

And the data you mentioned regarding CEASAR for prostate cancer, CISTO for non-muscle-invasive bladder cancer, I think this space will be, I think, an area of research that will be very important as we help determine the best therapies for our patients and best therapies for our society.

So Dan, thank you so much. I think those that will be fortunate enough to hear you talk about this topic will understand your promise and your leadership in this field for decades to come, and look forward to your future segments at UroToday as we talk about different types of therapies, diagnostics, screening that will really impact health policy today and in the future.

Daniel Joyce: Thanks so much, Sam. It's a real pleasure.