The Uromigos Episode 119: EAU—Surgery in Urothelial Cancer

Dr. Ashish Kamat walks through ongoing issues at EAU 2021.

Episode Transcript

Brian:
Welcome everyone to another EAU Uromigos podcast. We’re here with Ashish Kamat, MD Anderson. We’re going to talk through some of the bigger bladder cancer topics and controversies presented at EAU. So, if you want to introduce yourself and then maybe just kick off with what you think is sort of the most timely topic that was presented at EAU this year.

Ashish Kamat:
Sure, absolutely. Brian and Tom, thank you for inviting me, always a pleasure chatting with you guys. As you said, I’m Ashish Kamat from MD Anderson, Houston, Texas. I’m professor of urologic oncology and cancer research. And I’m fortunate enough to lead two large bladder cancer coalitions, the international bladder cancer group, and the international bladder cancer network, both of which you are guests and invited speakers at various times.

The EAU was actually a very kind of a mixed meeting this year, mixed in the sense that there was a lot of exciting stuff presented, but because it was virtual, a lot of the groundbreaking and breakthrough messages got lost a little bit.

So, this is a great venue to touch upon what I think are some of the main advances in the surgical realm when it comes to urothelial cancers. First off, if you look at diagnosis and then you look at treatment and then you look at advanced treatments, I think that’s the way to break it up.

And let’s focus on the diagnostic aspect at the moment. When it comes to the actual diagnosis of bladder cancer, we all know patients present with hematuria, then they have a workup, but what happens after that workup and that’s always sort of been this black box where before patients actually get diagnosed with bladder cancer, what’s the delay, what’s happening with them.

As you guys know and your reader listeners know, cytology is the only marker that’s been recommended in various guidelines, but its performance is poor and it’s actually getting worse over the years, partly because cytopathologists are not specialized in urothelial cancers anymore and I don’t know the reason for that, but there were a lot of markers discussed at the EAU and several were discussed, Arquer has one ADXBLADDER, EpiCheck has another one, which was discussed as well.

And in a full disclosure, I have advised several of these companies in their clinical trials, but Morgan Roupret and Richard Sylvester discussed the ADXBLADDER. They talked about its very high, negative, predictive value, which essentially would allow us as in the urology field to avoid unnecessary procedures in patients undergoing surveillance for a bladder cancer.

Tom:
And Ashish these are markers in urine cytology, is that right?

Ashish Kamat:
Correct. Absolutely. These are markers, urine markers and they’re based on, for example, the ADXBLADDER is based on MCM5, which is expressed by most cancer cells and definitely by urothelial cancer. The EpiCheck is based on a proprietary marker MRNA panel that they developed.

That’s the other marker that was discussed and Fred Rich has talked about that. It was an interesting study. It was born out of COVID times. It wasn’t a study that was devised initially to be studied other than the fact that everyone was finding that patients could make it to the hospital.

And they sort of used the EpiCheck [inaudible 00:03:45] test to see if it could alternate or what would happen in patients who are forced to skip cystoscopies and alternate cystoscopies and found that used appropriately, you again did not miss any dangerous cancers if the patients skipped every alternate cystoscopy so to speak.

So, these are actually very good because it helps patients in areas of poor access, which unfortunately even in the US, we have many and there’s a lot of delays in diagnosis of bladder cancer, especially in women.

So having markers that would help us detect the tumors early would potentially help us decrease the death rates even more than what we saw in the most recent report where death rates from bladder cancer have gone down.

Tom:
Ashish, would this be something maybe even used in primary care offices? By the time they get to a urologist, it’s often many months into a hematuria workup, et cetera, so would these more markers be used early by primary care docs?

Ashish Kamat:
You know what, Brian, that would be my hope and my goal for these markers. I’d be a little afraid to recommend that right now, because it has not been studied in that setting, but absolutely something that we could have our primary care physicians or GPs in the UK as they’re called use, where they could literally say, hey, you have blood in the urine end, we’re not going to send it to the urologist, we’re going to get this marker and if that marker has a good performance for detecting aggressive tumors and also a high negative [inaudible 00:05:15] tumors that would actually be very useful in the primary care setting.

Tom:
Ashish, we’ve been talking about this for ages. I remember five years ago, having discussion about urinary markers, the FDAs approved loads of these markers in the past, they’ve never really caught on, what’s gone wrong and why are things different now?

Ashish Kamat:
So, Tom, we’ve been talking about these for, I guess 20 years now, right? Multiples of five years. And what’s always happened is these markers are developed for hematuria screening because that’s the large, the money place, where all the money is and the companies see the big dollar signs and the number of patients, et cetera.

But I think their performance gets lost because the performance of any marker is dependent on the prevalence of disease and the incidence of disease and the incidence of bladder cancer in microhematuria is low, right. Some series it’s 1 to 3%. So, if you then look at it, yes, in a clinical study, it looks great, but in the real world, they don’t get translated because it ends up being the markers don’t really perform well in the setting, they were developed for from a marketing strategy.

As you and I and all of us listening recognize the bigger use of these markers is in the patients who are actually truly at risk of their cancer.

So those with the smoking exposure or those with gross hematuria, those who actually have a prior history of bladder cancer or lung cancer or any other cancer that’s related to similar carcinogens. And now the studies are looking more at the markers in these groups of patients.

We put a white paper a couple years ago and European Urology actually calling out companies to say, hey, we understand why you’re looking at markers in this space where there’s a lot of potential for sales, but let’s look at it in spaces where there’s actually a lot of potential benefit to our patients.

Tom:
What’s the next step with this? What’s ready for prime time now? What advice do you give your colleagues in office-based urology practices around the world? Should they be using these, which ones should they be using? Are there trials that are ongoing that they should be taking part in?

Ashish Kamat:
Yes, to the latter Tom, there are absolutely trials that everybody should be taking part in and enrolling. There are patients in as many of these trials as they can because you can collect a large amount of urine and you can send that to multiple different studies.

There’s no paucity of urine collection. But when it comes to actually recommending it, I would be cautious about using any of the markers currently as standard of care. Because for the very reasons you mentioned, there have been markers developed in the past that haven’t really born out in the real world.

The only markers that have actually made it into the guidelines is the UroVysion FISH test. And that is something that we studied at MD Anderson many years ago and it actually allows you to look at chromosomes 3, 7, 17, and 9p21. And leaving aside the FDA approval, which is for hematuria in these patients, it actually is more useful for predicting response to intravascular immunotherapy in BCG.

So, it has made it into the guidelines for that reason as a recommendation to use it to monitor response to therapy, but from a pure diagnostic standpoint, the only marker that’s recommended in the guidelines which I agree with is urine cytology done well.

Tom:
And Ashish, it seems to me using these markers to spare or space out cystoscopies in those high-risk patients, so as the diagnosis seems like a targeted use and I’m sure patients would love to spare themselves, cystos every three months. Are there studies going on to validate its use in that setting?

Ashish Kamat:
Yes. So, there are studies that have been developed and have been slow to [inaudible 00:09:10], but are still moving on and to answer your question in a nutshell, absolutely that is one of the areas where there’s a huge unmet need and ongoing studies.

Tom:
Ashish, let’s move on to topic number two. I think we’ve done number one. So, you said, you had something to do with muscle-invasive disease, you were excited about it, is that right?

Ashish Kamat:
It actually is treatment of bladder cancers, and this is where we’re talking about the resection of the tumor. And I know it may sound like a very basic first step, right?

Tom:
Don’t worry.

Ashish Kamat:
Whether it’s non-muscle invasive or muscle invasive bladder cancer, the treatment paradigm is completely different, right. For non-muscle invasive bladder cancer, we don’t often rush to recommend radical cystectomy. For muscle invasive bladder cancer, there’s more of a push to have neoadjuvant therapy when appropriate and then move on to local consolidation, whether it’s with XRT or radical surgery, which is primarily the modality in the US.

But the first step is the resection of the bladder tumor. And that actually has gone by the wayside when it comes to training people on how to do it well. So, I was really encouraged to see studies and reports at the EAU addressing that. Addressing en bloc resection, addressing the use of blue light or PDD to enhance the removal of the tumor, so we could actually better staging information and along with better staging information, you obviously get information on histology, presence of LVI.

Again, it wasn’t one study, or it wasn’t one very important large study, but there were so many smaller reports, and we had a debate in our session as well. I was encouraged that people have again recognized the importance of the primary TURBT being done well.

Tom:
Ashish, what is the issue? Is that trainees are not getting adequate training or are there new techniques that aren’t incorporated, what’s the issue?

Ashish Kamat:
It’s a little bit of both. This is another report that we have, human staff had led the effort to [inaudible 00:11:28]. But, if you look at where all the advances in technology and bladder cancer surgery have come about, it’s been in the robot and I’m sure you guys have heard about the advantages of “robotic cystectomy” even though there are none and that’s all market and genius, right?

So, here’s millions of dollars being spent on robotic cystectomies where there’s no advantage even when you compare patients and head-to-head randomized studies and then technologies when it comes to the TURBT have really not progressed.

The biggest advantage has been blue light technology, but again, that’s old, that’s been available in Europe for almost 20 years now, in the US many places still don’t have it because they just don’t hear about it or want it.

And then because of that, trainees are not exposed to the marketing, they’re not exposed to these, hey, we’ll fly you here and train you on this when it comes to TURBTs. So, it’s a little bit of both. They’re not trained appropriately, but they’re not trained appropriately also because there’s not that much being developed in that space.

Blue light is absolutely important, [inaudible 00:12:40] imaging is important and newer techniques, but they’re not new, they’re just new to a lot of people.

Brian:
Can you explain blue light a little more? I know it’s a way to find tumors that you can’t visually see, but what’s the technology?

Ashish Kamat:
Sure. So, it’s based on the foreign pathway and there are many different substrates. There’s one approved in the UK, one in the US, but essentially, it’s a substrate that’s put into the bladder of patients about an hour before you actually want to do the procedure or do the diagnostic evaluation, and this is then metabolized into a fluorescent agent.

So, white light is essentially the normal white light that you and I will see when you look out the window and when you turn on the blue light, per se, any cancer cell will shine in bright pink, and it actually works well. It works really well for those that are not experienced at looking at tumors, because [inaudible 00:13:47] tumors, but even then, miss about 10-12%.

But when it comes to carcinoma in situ, which again, extremely dangerous, you can pick up as many as 40%, even if you’re an experienced urologist, because those are just small flat lesions that sometimes hide in different nooks and crannies [inaudible 00:14:03] you biopsy it.

So, it really helps in picking up tumors and once you pick up a tumor and stratify the patient as having high grades CIS as low-grade popular tumor, of course, as you know, the treatment changes quite dramatically.

Tom:
Ashish my question that builds on that, what is a proper resection? What’s the best resection that you need to do for a patient who has a non-muscle invasive bladder or CIS?

Ashish Kamat:
So, the ideal TURBT is one that, A, gives us all the information we need, B, removes the tumor as completely as possible. And C has minimal morbidity to the patient. There should be no mortality of course, but minimal morbidity to the patient. And because of that, for example, bladder’s not a very thick organ, right?

It’s no thicker than a pair of jeans, maybe folded over twice. And within that, what we’re trying to do is go underneath the epithelium, go into the lamina propria, and get the entire tumor out, sample some of the muscle without making a hole in the bladder. And that’s where the technique of TURBT is really, really important.

But if you can get the tumor out completely and also give our pathologist sufficient tissue where they can examine the deeper layers, give us appropriate staging, even sub staging preferably would be very, very useful because a T1 tumor, which is lamina propria invasive tumor is really just as aggressive as a Gleason 10 prostate cancer PSA-75, 12/12 cores positive, but they’re taught of as superficial tumors and they’re not, right. I mean, they’re invasive, if we pick those up appropriately.

Brian:
What percentage [inaudible 00:15:58] in the US do you think meet those three criteria?

Ashish Kamat:
You’re asking me the question that’s going to put me on the spot, but I will.

Brian:
I’m not asking you where it’s done, but I’m just saying, broadly speaking, given the experience issues and the training issues and the marketing and all that, is it 20%? Is it 90%?

Ashish Kamat:
I would say, TURBT that meets all those criteria without commenting on where it’s done would be less than 50%, 40% would be a mark.

Tom:
Ashish, what’s the muscle content, so what’s the chance of having a TURBT without muscle included in the sample? That seems to be a really common problem. And how often do we need to go back in a second time? And when should we go back in a [inaudible 00:16:49].

Brian:
Tom likes to ask multi-part questions.

Ashish Kamat:
No, that’s a totally fair question. It’s actually just a continuum of a question and response that I’ll give. So essentially missing the muscle happens quite often. And if it’s intentional, as in a low-grade bladder tumor, that’s totally fine because you don’t want to necessarily go too deep and create excessive scarring in a tumor that’s obviously low grade.

But in high grade tumors, absence of muscle occurs about 50% of the time. And if there’s no muscle present in the tumor, the chance of missing residual tumor in some series is as high as 55 to 60%. And the chance of missing muscle invasive T2 disease is as high as 15 to 20%, which is why we’ve put in all the guidelines, any guideline that I’ve been fortunate enough to be a part of that in a patient that has high grade T1 disease and there’s no muscle present on the initial resection, you should go back in four to six weeks when the patient’s initial resection has healed and resect more of the base where the tumor used to be, even if you don’t see anything.

Because think about it, right, if 20% of patients actually have muscle invasive disease and we’re treating them with BCG, clearly, it’s not going to work.

Tom:
Ashish, we’re going to move on to the third topic now, we’re running out of time. I think we’re doing pretty well overrule, but we’ve got to steal the deal now with a third topic. So, what are you going to pick?

Ashish Kamat:
There’s lots of things, but let me just pick a little bit of a controversial topic here.

Tom:
Oh yeah, great.

Ashish Kamat:
I left that for the end, right. I’m going to here talk a little bit about the pros and cons of radical cystectomy versus not doing a radical cystectomy and using Trimodal therapy and the [inaudible 00:18:42] imaging that goes hand in hand with that.

And again, this wasn’t really, we talked about at the EAU in any one session per se, but the gist of what I want to say is that there was a good amount of talk on how robotic radical cystectomy is really not the answer to our patients when it comes to radical cystectomy.

Most of the morbidity of a radical cystectomy is not whether you use a robot or a scalpel. It’s the actual urinary diversion, what happens afterwards and what we can do to try to save our patients from having to lose their bladder. Anything we can do that saves their bladders but doesn’t compromise their longevity is a useful thing to consider.

And that’s where bladder preservation comes in. And bladder preservation clearly can be done in many different ways. Number one is if a patient doesn’t need a radical cystectomy in the first place, so you are aware of all the studies ongoing, of course, that are using markers to see who can spare their bladder after neoadjuvant therapy [inaudible 00:19:43] plus XRT studies where you could come in after immunotherapy with radiation as a local consolidation is important.

But even aside from that, just focusing now on being able to select patients out who may not need a radical cystectomy and actually might be able to go on directly to bladder preservation with trimodal therapy, as for example in a bladder pad study, where they actually just do a biopsy, do an MRI, stage the tumor appropriately, and then go on to definitive local therapy.

And that’s of course done in the UK. So, it’s heavily weighted towards radiation and fair enough. I’m not saying it’s a bad thing. I am just saying it is heavily weighted towards radiation.

I think these are all exciting trials and progress that were mentioned at the EAU. Nothing was reported in any sort of finalized manner, but I think this was something that I was encouraged to see.

Tom:
And so, Ashish, is there sort of a revisiting of Trimodal therapy in the US as you say it’s been heavily weighted towards cystectomy, Europe does more of the chemo RT, is it sort of creeping back into the US maybe because of some of these neoadjuvant trials that are ongoing?

Ashish Kamat:
Yeah. I’ve been puzzled for many, many years as to why Trimodal therapy hasn’t cut on the US. I’ll be candid and say, I send a good number of patients in consultation to our radiation oncologist, not just in my center, in other centers where they are, and they come back and there are many reasons why they can’t get radiation therapy.

And when I mentioned this to folks across the pond where Tom is saying, well, these are the reasons we can give radiation to these patients. They’re like, well, that’s humbug. We do it for those indications all the time. There’s no reason you can’t move the [inaudible 00:21:33] out of the way.

There’s no reason you can’t this ABC, I’m not a radiation oncologist, so I don’t know much about the simulation, but that surprised me.

But I think with the recognition amongst patient advocacy groups and now with the studies, and I think that’s where the immune oncology field has allowed us to revisit it. Is just having newer studies in the modern era with molecular markers and everyone’s excited about that, it sort of is a segue to get Trimodal therapy back in discussion and get everybody involved.

Tom:
A lot of the folks who I talk to say to me that the initiation of the immune oncology drugs will result in enthusiasm in this field, which inevitably will result in more data and that data may change practice.

Why do you think there has been this reluctance to take up on this trimodality therapy? And do you genuinely think some of these neoadjuvant trials, which are ongoing with radiation can potentially change practice? There were two randomized trials, for example.

Ashish Kamat:
Right. And that’s my hope, Tom. Maybe I didn’t make that clear in my response, but that is exactly what I was saying. I don’t know why it hasn’t been brought on, and I really don’t know why.

It’s [inaudible 00:22:57] every patient, but even in the patient in whom it is appropriate, there seems to be a very low percentage of patients in the US who actually get radiation therapy, but I do think that the randomized trials and even the non-randomized, investigator-initiated trials, all of these are bringing bladder preservation in some form or the other and Trimodal therapy is just one form of bladder preservation back in discussion, back in limelight.

And the more people talk about it, the more data comes out. The more people again feel the need to follow the signs. I think it will bring about a resurrection in bladder preservation. That’s my hope.

Tom:
Ashish, this has been great. I think we’re up against time, but thanks for your time and your thoughtful contributions. I think it’s a lot of topics here, especially to a couple medical oncologists, very interesting.

Brian:
Terrific. Enjoy your holiday, Ashish.

Ashish Kamat:
Thank you so much and hope to see you guys soon.