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Ashish Kamat: Hello and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center, and it's a great pleasure to welcome to the forum once again, a dear friend and a true expert on all things bladder cancer, Professor Jeffrey Holzbeierlein, who is Physician in Chief at the University of Kansas Cancer Center.

Jeff, thank you so much for taking time from your busy day and sharing with us your viewpoints and some snippets from the latest updates on the management of non-muscle invasive bladder cancer that you guys have put out through the offices of the AUA. Thanks again.

Jeffrey Holzbeierlein: Thanks, Ashish. Glad to be here today and looking forward to updating everyone on the new guidelines for non-muscle invasive bladder cancer.

So just as a little bit of background and to remind everybody a little about the guidelines, the guidelines are published by the AUA. The AUA typically partners with another organization, and in this case, it was the Society for Urologic Oncology, to provide guidelines that are evidence-based. It's important to remember that these guidelines differ from NCCN guidelines in the fact that these are, again, evidence-based guidelines, not consensus-based guidelines.

In our original non-muscle invasive bladder cancer, which was constructed in 2016 and 2017, we knew that there was a need to provide an update. So in 2023, we re-engaged the Oregon Health Sciences Center that does the literature review, compiles the evidence, reviews that evidence, and grades that evidence. Those findings are then summarized and sent to the guideline committee, which is the guidelines committee for non-muscle invasive bladder cancer. The committee then reviews the evidence and makes decisions as a group on which guidelines should be updated. The guidelines are then revised by that committee, so the language or the supporting documentation would be updated, and then it is sent out for public comment. In this instance, it was sent to SUO members for comments, and then those are sent back to the committee and revised again. It is important to remember that the committee can only consider published evidence. So if a trial, a treatment trial, or some other finding has been presented at a conference but has not been published, we're unable to consider that in the guideline.

So the first update has to do with variant histology. Our previous evidence in variant histologies back in 2016 and 2017 was really at the beginning of our understanding of variant histologies. As our understanding of variant histologies has matured and more data has presented itself regarding optimal management, we revised statement number seven. And that is first that, "If a bladder sparing approach is going to be considered in a patient with variant histology, then a restaging TURBT should be performed within four to six weeks of the initial TURBT."

That's really based on a study that looked at patients with unresponsive non-muscle invasive bladder cancer and found that those with variant histology had significantly poorer outcomes. We also then continued to update the supporting evidence on statement number eight, which is, "Because of the high rate of upstaging with variant histologies as well as the lack of evidence of effective intravascular therapies for the variety of variant histologies, upfront cystectomy should be considered." This really I think is not something that's particularly surprising or really out of what most urological oncologists would practice, but really just again, including this data in the guidelines and updating the supporting documentation with some evidence, again showing that variant histologies can have very poor outcomes and that an aggressive approach to their management really should be considered.

The next update was regarding the use of urinary biomarkers. And so the guideline update was regarding the response to BCG using UroVysion and FISH, as well as using UroVysion, FISH, and ImmunoCyt. And of course, Ashish, you've done some of this work in the past, looking at FISH and its utility, particularly immediately following BCG. And of course, several studies have demonstrated a correlation between persistently positive FISH following induction BCG and the likelihood of recurrence. An observational study that was published showed that the presence of a positive FISH even predicted the development of muscle-invasive bladder cancer. In addition, there's been other data that suggested that these tests can be useful for adjudicating either atypical or equivocal cytologies, and that's where we recommend their use.

And that was our primary update regarding urinary biomarkers. I'll demonstrate something in future directions as we look at some of the other ones. But again, I think we'll continue to see updated information about urinary biomarkers as well as additional urinary biomarkers and where they might be useful.

The next update was in statement 15, which was, "In patients with suspected or known low risk or intermediate-risk bladder cancer, a single dose of perioperative intravesical chemotherapy should be administered." Prior to that, chemotherapy in our previous guideline was mitomycin. Since that time, we've had the publication of SWOG 0337, which showed that gemcitabine was equally effective, although it was not a head-to-head comparison of gemcitabine to mitomycin, but it demonstrated a relative risk reduction of approximately 35%, which is in accordance with what had been previously discussed about mitomycin.

Importantly, in that trial, there were no grade three or four adverse events. So the guideline committee felt strongly that we wanted to make sure that gemcitabine was included as an immediate intravesical option, particularly based on its low toxicity. There's also some data that's been published regarding mitomycin and epirubicin, which demonstrated a similar risk reduction of approximately 31%. But again, significant grade three, four AEs were more common in that. So the guidelines committee did not select a preferred option, but listed all of these as potential options for reducing the risk of recurrence. Of course, the caveat being that these should not be given if a bladder perforation is suspected.

Probably the greatest area of change within the new guidelines was regarding the use of adjuvant intravesical therapies for BCG failures. And certainly, this is an incredibly busy space, and as we know there are a number of other therapies that are coming down the pipeline. But we again can only talk about those that have published evidence. And so again, we reviewed that evidence. And just to sort of summarize the highlights, nadofaragene has been approved by the FDA and has become available for clinical use. And that trial was a trial that the SUO helped complete reporting phase three data of a 53.4% complete response rate at three months, and at 12 months, 45% of those continue to have a response. So an overall complete response rate of approximately 24%. Importantly, toxicity was low in this treatment, and so again, it is included as an additional therapy that can be offered to patients after failure of BCG.

In addition, there has been published data regarding sequential gemcitabine and docetaxel. So the so-called doublet therapy. This was based on a multi-institutional review of 276 patients demonstrating a one-year recurrence-free survival of approximately 65% and a two-year recurrence-free survival reported at 52%. So again, a promising option for patients with BCG failure.

And then finally, for patients with BCG failure who have carcinoma in situ, pembrolizumab has been approved, and this is based on the KEYNOTE-057 study that demonstrated a 41% response rate at three months. It is important to note that at one year, that response rate dropped to 19%, and it does have a serious AE rate of grade three to five AE events of 13%. So when we're considering treatment options, those things need to be taken into account. But those things were all included in the update in the guideline as potential options.

Finally, in terms of enhanced cystoscopy, our recommendation did not change for the use of blue light, and we do recommend the use of blue light to increase detection and decrease recurrence when it's available. However, we did update the supporting documentation to review the PHOTO trial that was published, and that trial was a randomized trial with newly diagnosed bladder cancer between white light and blue light. The conclusion of that trial was that it did not appear to be an improvement either in detection or recurrence between white light and blue light. However, the committee reviewed that data and felt that there were significant flaws in the conclusion, particularly due to high-grade tumors because it was underpowered to detect a difference in that. And so therefore, we did not change our recommendation for the use of blue light to detect or decrease recurrences, but we did update the supporting documentation to reflect the PHOTO trial. In addition, there's a statement regarding narrow band imaging, and although there's not strong evidence that it increases detection or recurrence, we felt that the risk of using this technology was low, and therefore because it's widely available, it could be used when blue light is not available.

I mentioned previously that we did give some thought to some future directions. When we talk about future directions, we are typically talking about things that we know are either in trial but there's insufficient evidence or insufficient publications to support a new guideline. The first of those is the use of novel urinary biomarkers. Those two that were highlighted in our future directions included the CX bladder test, which is a urine-based genomic biomarker test that can be used for detection or for surveillance. A fascinating study that was published looked at the use of this test during the Covid pandemic, reporting a 91% negative predictive value based on a follow-up cystoscopy. So we'll continue to monitor the data on CX bladder as it becomes available, and with our next update, we may see an amendment to the guideline.

The other one that's very exciting as well is the use of cell-free DNA, and early studies are showing the utility of cell-free DNA, either to predict recurrence or possibly predicting the progression to muscle-invasive disease or upper tract non-organ-confined tumor. Again, there's insufficient data to recommend its use, but it is something that we will continue to monitor.

Also, in terms of imaging, the use of multiparametric MRI using a VI-RADS system has some interesting early data that may help us prevent the need for follow-up TURBT, perhaps in T1 tumors, or being able to predict the progression to muscle-invasive bladder cancer. But again, insufficient data to be included in the guidelines at this point in time.

Ashish Kamat: Thanks so much, Jeff, for taking the time and condensing a lot of information into a very concise presentation. It really was very precise, and thank you for doing that.

Let me start with a question that comes up very often, right, this question of urinary markers. And I'm so glad that you brought this up, not just when you actually talked about the urinary markers, but also when you talked about the future directions as to what the guidelines committee can look at and can talk about and can recommend. In all the review that you all did and the future directions that you looked at, is there a plan to look at the literature on an ongoing basis? Because there's so much activity going on in the urinary marker space, so do you plan to look at it in six months, a year, or how does that process go about? Just for the education of our audience.

Jeffrey Holzbeierlein: Yeah, it's a great question, Ashish. The problem with the guidelines is that they're really expensive. And so we only undertake amendments at a certain interval frequency, so there really won't be an opportunity to update the guideline itself and publish that within six months. Usually, it's going to be a two to three-year process before we would update it again. Certainly, we recognize, and maybe not in any space more than non-muscle invasive bladder cancer, how fast the field is moving. Again, I sort of mentioned all the treatments that are in the pipeline. I really think that we'll have a very different guideline, particularly in terms of adjuvant therapies or even maybe upfront therapies as we move forward. But again, we probably won't see that in a published form for two to three more years.

Ashish Kamat: And as you just mentioned, the field is just moving so quickly when it comes to BCG unresponsive disease, when it comes to intermediate-risk bladder cancer, perioperative therapy, all of that. And you highlighted in the guidelines, the use of nadofaragene, the use of pembrolizumab, the use of gemcitabine and docetaxel, which I think is a good piece of information for the practicing urologist because at least now they can go and say, "Well, the AUA guidelines mentioned these drugs, but they also mentioned the off-label gemcitabine and docetaxel." Can you tell us a little bit about your perspective as to not just the hierarchy of those recommendations, but what factored in when you considered the off-label use of gemcitabine and docetaxel and including that in the same sort of guidelines as the drugs that are approved?

Jeffrey Holzbeierlein: Yeah. Of course, mitomycin is a bit off-label as well, right? I mean, although we've used it for a long time, it never really had that indication. And so it's not a foreign thing for us to maybe recommend things that we use off-label. Where we came with gemcitabine and docetaxel was that there is very strong published evidence supporting the use of the doublet therapy and its effectiveness, and so we felt comfortable recommending the use of that doublet therapy and felt it's necessary to talk about that, particularly in the fact that I think it's an intravesical chemotherapy option as opposed to say, an immunotherapy option. So the guideline committee felt strongly because there was sufficient evidence to include that in our guideline statement as an alternative.

Ashish Kamat: Yeah, because again, in the US at least, it's in many ways become standard of care. And it's important that it's mentioned in our guidelines because it's used so commonly, and then people go to the guidelines and it's not in there. So I think that was a great thing you guys did.

Again, you and I could talk about bladder cancer and other things for a long, long time, but in the interest of time, let me just ask you to leave the audience with any closing thoughts on what you just talked about or the guidelines or anything bladder cancer in general.

Jeffrey Holzbeierlein: Yeah, well, first of all, there will be an update on the muscle invasive bladder cancer guidelines, that should be coming out within the next couple of weeks. So not only did we address non-muscle invasive, but we addressed muscle invasive. And I think you'll want to compare those two. Because obviously non-muscle invasive and muscle invasive, there's a lot of overlap. So I think understanding both of those sets of guidelines will be important in helping manage patients with bladder cancer.

Again, I think non-muscle invasive bladder cancer is a rapidly moving space. I think we will continue to see a lot of advances in our treatment of that disease and our understanding of that disease. And hopefully, again, moving towards who really needs upfront cystectomy, who really needs early cystectomy, and who are those patients who can get additional intravesical or even ID therapies? What are the appropriate patients for that? So I think we'll continue to see our knowledge and our understanding of that evolve, and I think that's going to lead to better outcomes for our patients.

Ashish Kamat: Thanks so much. We'll definitely have you back when the muscle invasive guidelines update comes out. Always great to see you, Jeff. Take care. Thanks again.

Jeffrey Holzbeierlein: Thank you. Take care.