Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence, your one-stop destination for the latest developments in the field of bladder cancer. And along these lines, it's my pleasure to welcome today, Professor Anne Schuckman, who is Assistant Professor and Director of Urologic Oncology at USC/Keck Department of Urology in Los Angeles, California. And I'm Ashish Kamat, Professor of Urology and Cancer Research at MD Anderson Cancer Center in Houston.

Anne, thank you so much for taking the time and sharing your presentation that you gave at the GU Cancers Symposium last month. Our audience obviously would like to hear the presentation, and then also the discussion that you and I will have at the end of it. So, with that, if you're ready, you have the stage.

Anne Schuckman: Great. Thank you so much, Ashish, and I really appreciate the invitation to share today.

So today, I'm going to talk a little bit about cystectomy for non-muscle invasive bladder cancer, who and why. And we'll go through the slides fairly quickly, so we have a little bit more time for discussion at the end of the presentation.

Non-muscle invasive bladder cancer obviously accounts for the vast majority of all newly diagnosed bladder cancers, with approximately 70% being in the Ta stage, 20% in the T1, and 10% with carcinoma in situ.

Unfortunately, we know that there are multiple patients who can progress from non-muscle invasive disease to muscle invasive disease, are about 22% of patients. If those patients do progress to muscle invasive disease, there's only about a 30% cancer specific survival in this group.

So when it's said in another way, we know that, as opposed to patients who present with Denovo T2 disease, patients who progress to muscle invasive disease fare much worse, in terms of recurrence-free survival, cancer specific mortality, and overall mortality, as demonstrated here.

When we're talking to patients about treatment for high risk non-muscle invasive disease, we seem to be on two sides of a really giant chasm, sometimes talking about TURBT and intravesical therapy, and other times talking about radical cystectomy. We worry about how to counsel patients, given that these two treatments seem so radically different. On one side, I worry a lot about progression to muscle invasive disease. On the other side, I worry about overtreatment, and the morbidity of surgery, although it would probably be highly successful in achieving a cure in these patients.

So how do we find the needle in the haystack and define the highest risk non-muscle invasive bladder cancer, or try to figure out who's likely to progress with conservative therapy?

There are several tools available, including the EORTC risk calculator, which uses clinical pathologic variables, including number of tumors, grade of disease, and stage, to predict recurrence and progression.

Or the Cueto model, similarly using clinical pathologic variables listed on the right here, such as number of tumors, recurrence, presence of carcinoma in situ, to predict recurrence and progression. Unfortunately, both of these models have been shown to really overpredict the rate of progression, due to inconsistent, or no use, of BCG when they design these models.

In 2016, when the AUA redid their guidelines for non-muscle invasive bladder cancer, they came up with risk stratification, trying to pull out who the highest risk patients are, including T1, high-grade Ta, carcinoma in situ, BCG failure, variant histology, lymphovascular invasion, and prostatic urethral involvement.

And based on this risk stratification, gave us some guidelines as to who to consider for non-muscle invasive disease, undergoing cystectomy. And we'll dive into these a little bit further today and look at each of these recommendations.

All of these predictive models are really based on appropriate clinical staging. Unfortunately, we know that appropriate and correct staging of T1 disease can really be half the battle.

We know that in patients who have no muscle in a TUR, up to 45% of those can be upstaged to T2 on re-TUR. And even those who have muscle in the specimen, about 15% of those may be upstaged on a repeat immediate TUR.

At USC, we looked at patients who underwent cystectomy for non-muscle invasive bladder cancer, who had T1 at the time of their last TUR. And depending on the presence or absence of muscle, 23 to 28% of those patients did have muscle-invasive disease, and about 10% of the patients actually had lymph node positive disease; really highlighting the extent of under staging in this population.

Denzinger completed a meta analysis, trying to look at high grade T1 patients and teasing out which clinical pathologic variables could best predict for patients who might do well with an early cystectomy, versus a deferred cystectomy. And they found that the presence or absence of carcinoma in situ was highly significant for patients who would benefit from an early cystectomy, as opposed to a deferred cystectomy, in the T1 high-grade space.

So again, looking at T1 [inaudible], we can see the carcinoma in situ is certainly a good predictor. Lymphovascular invasion may be important. Extensive involvement of the lamina propria, or T1 B disease, may be appropriate, or multifocality and large tumors.

How about variant histology? The World Health Organization recognizes about 13 to 15 different subtypes of urothelial carcinoma that are recognized as variants.

And how do these variants do with intravesical therapy? Well, this is a study from Israel, where they looked Ta and T1 high-grade variant histology in patients who either have underwent BCG therapy or cystectomy.

They looked at multiple variant histologies.

And across the board, all of these patients had worse recurrent-free survival, progression-free survival, disease-specific survival, and overall survival, when they underwent BCG therapy, compared to conventional urothelial carcinoma.

At MD Anderson, you guys actually looked at your T1 high-grade micropapillary patients, and found again, that those patients who underwent upfront cystectomy had significantly improved disease-specific survival, over patients who underwent primary BCG therapy.

And Case Western also looked at their micropapillary cohort, and found that there was about a 30% upstaging amongst non-invasive micropapillary patients who underwent cystectomy, and about 30% of those patients actually had node positive disease, as opposed to about 10% in their non micropapillary cohort.

So again, we can see that all of the factors listed here that we've discussed, clinical pathologic variables, are good indications to consider an upfront cystectomy. Other clinical variables, such as unresectable volume of disease, intractable hematuria, and certainly patients with multiple predictors of progression on the various nomograms that we discussed, should be considered for upfront cystectomy.

Many patients will opt for BCG. I think it becomes a really tricky question to tease out who can receive salvage intravesical therapy, versus when to pull the trigger for radical cystectomy. I think that the management of BCG refractory disease, it's a little bit beyond the scope of this article today.

However, we know that many of the predictors of response to BCG are the same as some of those variables we've discussed; such as older age, presence of carcinoma in situ with T1 disease. And specifically, what the response is to BCG at the three or six month post induction biopsy.

We also know that patients who have failed multiple cycles of BCG are certainly more likely to continue to fail going forward.

Beyond just clinical pathologic variables, I think really interestingly, going forward, hopefully we'll have some molecular and genomic predictors that can help us tease out which T1 and non-invasive cases are really the very highest risk.

This is just one study highlighting a group that chose to look at T1 patients, to try to define low risk versus high risk non-muscle invasive tumors using specific mutations, such as ERC C2, and BRACA, which may portend to patients who would have a better response to more conservative therapy, versus those with a p53 mutation, or others, which may suggest early cystectomy may serve them better.

Finally, just to review the guidelines, the AUA suggests that high grade T1 disease on repeat TUR, patients with carcinoma in situ, and lymphovascular invasion, those who fail BCG, and those with variant histology, as well as unresectable clinical disease, would benefit from an early cystectomy.

Finally, I think it's important to highlight the role of individual decision-making in this patient population. Patients will have very different thresholds of risk acceptance. They come in very different overall states of health, which may impact the morbidity of a cystectomy, with different expected longevity. And many patients have current poor bladder function and already poor quality of life, which potentially would not lead to any benefit from trying to preserve the bladder.

Thank you. I look forward to our discussion.

Ashish Kamat: So Anne, that was a very, very good presentation. You covered so many different points in such a short time. I have to commend you for that.

I just want to say right off the bat, that I agree with pretty much every point that you made, and I want to emphasize to our readers, that non-muscle invasive bladder cancer is considered non-invasive because it doesn't invade the muscle layer of the bladder, but it is invasive once it gets into the lamina propria, and patients really need to be given the best chance of long-term cure, rather than sacrifice life years for the misconception that it's not invasive, and the old term, superficial. So again, I just want to commend you for bringing that to the forefront.

If I could just ask you a few questions to highlight some of the points that you made. Because, like I said, you've covered everything so well that, it's right there for our viewers and listeners to listen to. But if you would look at the outcomes of patients that are treated with BCG, some of the older series suggest that BCG doesn't work really too well. Some of the newer series from your center, and even ours, suggest that if BCG is done appropriately, then it has actually a good longterm protection against progression of disease, and freedom from cystectomy. So with that in mind, how would you counsel a patient that's sitting in front of you and presents with say, T1 high-grade disease, and is essentially asking you, "What should I do now?"

Anne Schuckman: Yeah. So I think, in reality, patients who have high grade T1 disease, I 100% agree, I really try to counsel them that they already have invasive disease. So first of all, just to highlight, I would certainly recommend a re-TUR. And I think that we always do that, whether or not they have their initial TUR with us, or not with us. And I think it's important, I use Blue Light all of the time when I do this, and so it's really important to try to identify whether they have something like concomitant carcinoma in situ, or lymphovascular invasion, or some of those other factors that might help substratify that T1 patient.

So depending on where you end up after that, I do usually recommend that we try induction BCG therapy. Some patients at the highest risk, maybe we would omit that completely, but usually I do recommend that. But I give patients a number such as about a 50 to 60% chance of long-term success with BCG therapy. And if somebody comes to me, having already had induction BCG therapy and they've failed, I really try to discuss upfront that, while there are salvage options available, I always discuss cystectomy, and I never recommend that we try more than one salvage option.

Ashish Kamat: Okay. Which, obviously, brings me to the topic that we now have an approved drug. I mean, we have many, but valrubicin is not really used that much.

Anne Schuckman: Right. Right.

Ashish Kamat: But now, we've got pembrolizumab that's approved, and potentially nadofaragen, and maybe even vicinium. So in that situation, when you have a patient that, and again, this may not be the direct topic of your talk, but how would you counsel someone that comes in just like you said, that has T1 disease, has had an induction course of BCG, and has recurrent T1 disease, and is asking you, "Hey doc, should I be considering a radical cystectomy, or one of these other agents that are out there?"

Anne Schuckman: Well, right. So in the patient you mentioned, where they had T1 disease and then they have recurrent T1 disease after induction, I 100% would counsel that patient for a cystectomy. I think that that patient is at an extremely high risk of failure.

Now, I think the trickier situation is somebody who maybe has high grade TA disease, or carcinoma in situ residual after their induction. In that case, I will have a very honest conversation and say, we have all of these other options, but the data is still doesn't really show that any of these have really have more than maybe a 30% chance of long-term survival, or longterm disease-free survival. And so I think that many patients will say, "Great.", that's 30%. Others will say, "Well, that seems like I'm going to go through all of this, and end up with a cystectomy anyways." So I think that that is really where individual risk tolerance comes into play, and overall patient health, and trying to assess how their life is likely to be affected by undergoing a cystectomy.

Ashish Kamat: Right. Right. And when it comes to risk stratification, you touched upon the importance of re-TUR, which I completely agree with. And there are some people that say that, well, if it's a TA disease, and you've done a good resection, and you've got muscle present, and it's an experienced bladder cancer surgeon, then you may not need a repeat TUR, but in T1 disease, you absolutely do need it. And I think your slide where you showed that, if I remember the marks correctly, T1, last TUR, whether there's muscle present or not, the incidence of upstaging, in your series, was more than like, 20 to 23% of the [crosstalk 00:15:15] . Right?

Anne Schuckman: Yeah. It's very high. Yeah.

Ashish Kamat: Right. So, what's your take home to people that are listening, as to the presence or absence of muscle in the TUR specimen with T1 disease?

Anne Schuckman: My take home is whether or not you have muscle on your TUR with T1 disease, I would recommend a re-TUR. I think that even if you feel like it's a great resection, that iceberg slide is what always is in my mind, when I think about T1 disease. You just don't really know where that muscle invasive component may be. You don't know where you got your deep bites, versus where the tumor might be invasive. I think we just don't have the visual tools at this point to be able to assess that, and that the data would show that re-TUR people will still be upstaged, even if you add muscle.

Ashish Kamat: Right. Very important point. Then the other point that you made early on in your talk was, progression to T2 disease is clearly worse than DeNovo T2 disease, because I think it's just because the patient has had tumor recur, or present sufficient amount of time, that there is micro metastatic disease. Right?

Anne Schuckman: Right.

Ashish Kamat: What's your-

Anne Schuckman: Yeah. I've thought about that a lot. I think in many of those patients, it's probably just, those are the patients where we've just been managing T2 disease all along, sort of conservatively, which we know isn't likely to be effective. And so, exactly, they're likely to already have micro metastatic disease, or systemic disease, by the time we get around to treating them for muscle invasive disease.

Ashish Kamat: Right. And your group and ours have collaborated on the low risk/high risk criteria for selecting new adjuvant chemotherapy. One of our fellows here has recently put together a very nice work that suggests that patients who progress on intravesical therapy, whether BCG or other, and then become T2, clearly fall into that high risk category, and need chemotherapy, even if they have just a small focus of T2 disease. I think you're right. It might be that there is unknown T2 disease to begin with, or there is micro metastatic disease, or what have you.

Now, switching gears to, in the last few minutes, the molecular genomic predictors, we're all eagerly waiting some marker that will be able to tell us if, or not, this particular patient would benefit from a cystectomy, or intravesical therapy, chemotherapy, or radiation therapy, what have you. But in my read of the literature to date, everything appears to thus far sort of be a research tool. Right?

Anne Schuckman: Yeah.

Ashish Kamat: They've been looked at in centers, validated within their own centers, or with collaborations with other centers, including our own work here. What's your take on it? Do you think any of them are ready for prime time?

Anne Schuckman: I absolutely don't. This is actually a discussion point that really came up at the ASCO meeting, and we were lucky enough to have Peter Black on our panel, and some people who I really think have been leaders in this field. I just don't think there's anything at this point that's clinically ready for use.

Ashish Kamat: Right. Right. And Peter's one of the first people to admit that these markers are not necessarily ready for clinical use. But then, you'll see several people stand up and say, "Oh, I use it in the clinic, and I get insurance to cover the markers." I just wanted your take on it.

As always, I've thoroughly enjoyed our discussion, and there's so much more you and I could chat about, but in the interest of time, I guess we'll close this, but I'll leave you with the opportunity to share your closing thoughts with our audience.

Anne Schuckman: Sure. Thank you. I think that the takeaway here is that patients and clinicians often, I think, fear proceeding with cystectomy, due to perceiving morbidity, and worrying that it might be too aggressive. Whereas I think that for patients who have high risk T1 disease upfront, radical surgery can really offer their best chance for cure, with really excellent long-term outcomes.

Ashish Kamat: Great. Once again, Anne, thank you so much for taking the time to be part of this very important educational activity. I really always appreciate you taking the time, and enjoy our sessions together. Stay safe and stay well.

Anne Schuckman: Thank you so much.