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Zach Klaassen: Hello, my name is Dr. Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today for this UroToday discussion with Dr. Mark Tyson, who is at the Mayo Clinic, Arizona, urologic oncologist. Mark, thanks so much for joining us today.

Mark Tyson: Happy to be here. Thanks for having me, Zach.

Zach Klaassen: Awesome. So we're going to talk about a recent publication that just came out very recently in Urology Practice looking at Cxbladder. So just tell our listeners a little bit of background on what Cxbladder is before we get into your recently published study.

Mark Tyson: Sure. Yeah. The article pertained to Cxbladder Detect, which is a noninvasive urinary genomic biomarker test that's really designed to assess the risk of bladder cancer in patients who are presenting with microscopic hematuria. It works by looking at a patient's urine for the presence of five specific mRNA biomarkers, four that are over-expressed in cancer and one that's over-expressed in inflammation to help them weed out the false positives. The biomarkers are associated with bladder cancer and they are used to generate a risk score that's then given to the physician to help determine what the likelihood of cancer is.

And in some of the early studies that were done, in particular, the O'Sullivan study, the performance of this test was really quite good with a sensitivity of around 97% for patients with a high-grade disease and a specificity of around mid-80s. And so essentially it's used to help reduce the need for invasive diagnostic testing such as cystoscopy, and I think it can potentially offer an approved way to diagnose bladder cancer patients potentially presenting with microscopic hematuria.

Zach Klaassen: Yeah, we've seen even with the recent microhematuria guidelines from the AUA that we see this all the time for family practice, private practice, that come in to see us. Who do we do the full workup on in terms of cysto, CT scans, et cetera? And so this may be a nice adjunct to maybe even triage those patients, correct?

Mark Tyson: I think so. Yeah. And I think the AUA guidelines made significant strides a few years ago when they switched to a risk-stratified approach. And I think to the extent to which we can reduce unnecessary invasive testing, that's a noble endeavor. But really, there's only about five to 10% of patients in the low-risk category that are presenting with microscopic hematuria. So there's still more work to be done in risk stratification.

Zach Klaassen: For sure. For sure. So let's dig into your paper. So published in Urology Practice November 1st, and this was really a decision tree analysis. And maybe just walk our listeners through what a decision tree analysis is and then maybe the background and genesis for this project.

Mark Tyson: Yeah, I think the background and genesis for the project really comes from my belief, and I think it's just that, I can't support this with truly high-level empiric data, but it's my belief that in general, we probably perform too many cystoscopies, both for asymptomatic microscopic hematuria patients and also for bladder cancer patients, but that's a separate discussion.

And so this project really stemmed from my belief that we need to make this pathway better for patients. A lot of the traditional diagnostic methods that we do involve cystoscopy. And it's not terrible to have a cystoscopy. It's a little painful for a couple of days and it's a little costly, but for the most part, people get through it. But then there's the CT scans and everything else involved, and when you can take it all together, it's just kind of a lot for the healthcare system and it's a lot for patients. So that's really the motivation behind this.

And so the question under study here is is there a better path forward from the perspective of costs? We know how the tests performs based upon published data, and we know for the most part what patient's preferences are. But from a payer's perspective, from a healthcare systems' perspective, what does this test do to cost if it's integrated into a risk-stratified pathway?

And so we use a decision tree analysis, which is just a type of modeling technique that helps assess the clinical and economic outcomes of different diagnostic strategies. And in this case, it allowed us to compare a pathway incorporating Cxbladder directly to the risk-stratified guidelines from the AUA. And we essentially include all of the potential outcomes in each of the nodes that are published there in the paper. All the false positives and the true positives of Cxbladder would undergo a traditional evaluation that the high-risk patients would undergo and all the false negatives and the true negative patients would get reassessed in six months with a UA, and then if that was positive, undergo the high-risk evaluation. And then we essentially run through several iterations of that to generate the total costs, the overall costs associated with each of those outcomes with each of those pathways, and then also the effect of that biomarker on things like how many procedures are being done, how many TURBTs are being done, how many correct bladder cancer diagnoses are being made, and so forth.

Zach Klaassen: That's great. So take us through some of the key findings, money saved, missing tumors, and all the things that are great about these kind of studies, really seeing both the cost benefit and also maybe sparing procedures and whatnot.

Mark Tyson: Yeah, underlying the findings are two important facts. The performance characteristics that we use are from the published literature and also the costs that we use are from Medicare allowable fees. And so there's a little bit of regional variation on that and variation by payer.

But all things considered, using those two standards, essentially what we found from the view of the payer is that the use of the Cxbladder in the diagnostic pathway for microscopic hematuria results in a pretty significant reduction. If you're looking at a total cost of 1,000 simulated patients, that's a large, six-figure sum of money for those 1,000 patients. If you're looking at it from the cost of an individual patient, it's around $550, and that's despite being slightly more expensive than the Medicare allowable fees. The Cxbladder test is slightly more expensive than the cystoscopy.

If you look at it from the patient's perspective though, about one procedure is saved every three patients. There's 0.38 procedures per patient saved. And if you look at that at an aggregate level, 1,000 patients, that's about a median of 86 TURBT. So not just endoscopies done in the clinic, but also surgeries done in the operating room. And so substantial reduction in number of diagnostic procedures, and all of that without compromising diagnostic accuracy in that bladder cancer cases' detections remain the same.

Zach Klaassen: So in your mind, this is microhematuria, so gross hematuria, we're not looking at that population. This is strictly people that come in with non-visible hematuria, correct?

Mark Tyson: Right.

Zach Klaassen: Yeah. In your practice or how you would integrate this, is everybody that has microhematuria that you're seeing, would they get a Cxbladder test or is there certain ones where you would say, "I still think we need to do a cysto"? How are you triaging those patients?

Mark Tyson: I think it's really important to just pause here and remind the viewers that the AUA guidelines have a strong recommendation against using urinary biomarker tests, not just Cxbladder, but any urinary biomarker test as a replacement for cystoscopy. So the very first thing I would say is that this has not yet risen to the level of being included in the guidelines, and I think that's an important distinction.

However, I do think it's still very useful for patients who are essentially saying, "I'm not sure that I really want to do any of that," and that's a large number of patients. I mean, how many people sign up for cystoscopy when it's recommended? It's not 100%. So it's very useful in that population of patients.

And I think as more data emerge, as we see more real world validation of this test and more prospective data come to bear, I think we're going to see this test start to get a more favorable view, not just by the field, but hopefully by the guidelines panel.

And I meant to mention this at the very beginning, Zach, and I think it's very important. I have no conflicts of interest with this company. I'm not a paid consultant. In fact, you could argue that my conflict of interest lies with cystoscopy. I just did 30 of them this morning before this interview. So I am not paid by them, and it just really does come from my belief that we do too many of these cystoscopies.

Zach Klaassen: No, that's great. I think your point is well taken. You get the patient that's going to get a cysto for bladder cancer every three months, they kind of get used to it. But that patient that's coming to see you for the first time and you say, "Oh, by the way, we're going to do this, this, and this," they go, "Hang on a second." That's where we have that sort of give and take with patients to try to even convince them to do a cystoscopy for that workup, right?

Mark Tyson: Right. And if I may just add one more thing. One of the feedback that we got from the reviewers, and there's an editorial that'll accompany an article on this as well, is that there's actually a lot of benign pathologies that are diagnosed on cystoscopies that would otherwise be missed with an algorithm that incorporates Cxbladder in lieu of a cystoscopy. And I think a good example of that is BPH. You do a cystoscopy, you find BPH and can treat that.

My response to that criticism was twofold. One, most of those asymptomatic patients that have incidental benign pathologies do not need cystoscopy to make those diagnoses. BPH, for example, can be adequately diagnosed based upon history and physical exam alone. And the first-line treatment does not depend, generally speaking, on the findings from cystoscopy. And second, if they are asymptomatic and they do have a subclinical problem that'll eventually become symptomatic, when that patient becomes symptomatic, it's probably a more appropriate time to do the cystoscopy anyway. If somebody has a subclinical stricture that's not impairing their voiding, that eventually will progress to the point of needing treatment. The time to do the cystoscopy is the point when they need treatment.

So the downsides of missing benign pathology, aside from the occasional perhaps rare bladder stone, don't really justify the argument, in my mind, to continue doing cystoscopy for asymptomatic microscopic hematuria patients. We're really looking at cancer here, and cancer is rare. I mean, cancer is rare, and we're talking about 5 to 10% of patients with asymptomatic microscopic hematuria that have cancer. And most of those cancers, by the way, aren't life-threatening. Most of the bad cancers are presenting with gross hematuria. So let's just say we do miss the occasional non-muscle invasive bladder cancer. It's still probably not worth subjecting the other 1,000 people to routine cystoscopies when there's a less invasive alternative available.

Zach Klaassen: No, that's great. Very well said. I think just to conclude, anything we haven't hit on, and maybe a couple of take home points for our listeners to take to the clinic tomorrow?

Mark Tyson: Yeah, I think that the big take home points, I would look at it from four vantage points.

From the vantage point of the patient, this is a lot better process. Instead of having an invasive test, you could potentially have a noninvasive test. That's very, very good.

From the standpoint of the urologist, I think that this creates capacity. The APP can do the Cxbladder, and you don't need to book your cysto time with this. You can save your cysto time for people that need it. So there are some healthcare resource allocation arguments to be made, as well.

From the payer's perspective, at the very least, this is a budget-neutral proposition. We didn't talk about it, but in the probabilistic model, which is presented in the paper, the 95% credible interval, which is a Bayesian equivalent of a 95% confidence interval, does not cross zero, but it gets close to zero. So even if the estimate is closer to zero, it's at least budget-neutral. And if that leads to some improved satisfaction from patients, that might be a worthwhile cost.

But then lastly, there's an environmental point to be made. Cystoscopies, all the disposable equipment that gets thrown into the trash and thrown into the waste, and all the TURBTs that are done and all the driving back and forth to the appointment, all that carbon footprint can be saved, I think, without having to subject all these people to cystoscopy.

That's something that we saw during the pandemic. This test was very useful in helping people stay away from healthcare and get some type of evaluation during the COVID-19 pandemic.

So those are the four vantage points from which I would look at the efficiencies and cost savings standpoint, and I think that's what I would encourage the viewers to walk away with.

Zach Klaassen: That's fantastic. Very well said. Enjoyed the discussion, Mark, and we appreciate your time and expertise today.

Mark Tyson: Thanks for having me, Zach. It's good to see you.

Zach Klaassen: You, too.