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Ashish Kamat: Hello and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urology and cancer research at MD Anderson Cancer Center and it is my distinct pleasure to welcome today, two stalwarts in the field of urologic oncology and bladder cancer and two good friends of mine. Joining us all the way from Sheffield is Dr. Jim Catto, or Mr. Jim Catto has you are known over there across the pond.

Mr. Catto is a Research Professor at The National Institute of Health Research and a Professor of Urologic Surgery at The University of Sheffield and he is going to talk to us today about a paper publication trial that has garnered a lot of interest in recent months and years, comparing image-guided pathway with a standard pathway for staging muscle-invasive bladder cancer, preliminary data from the BladderPath study.

And after Jim is done with his presentation, Professor Gary Steinberg, who needs no introduction. He used to be at The University of Chicago and now he is in New York at NYU. Again, a prime person and a prime in the field of bladder cancer, both from the patient perspective and the scientific community's perspective. He is going to give us his take on why TRBT is still here to stay and really should not be done away with, the results of the study notwithstanding. With that, Jim, the stage is yours.

James Catto: Great. Thank you, Ashish and Gary, I'm really looking forward to the next session. I think it will be really interesting. Those are very kind words you said. This is an interesting study. Like always, this isn't definitive, these actually reports we are discussing were published in European Urology last month. It is very much an interim report. The main study, BladderPath is powered around speeding up the time to definitive treatment. The sub-study of the preliminary feasibility study we've shown is just some of the early data about that.

I think fundamentally the reason that we are looking at image-guided treatment is not fundamentally because we believe one thing is better than the other, but we believe we have to change the paradigm. If we look at bladder cancer, it is about the only solid cancer where the outcomes are not improving. And there are many reasons why the outcomes are not improving, but one of them is going to be the slow time to diagnosis.

No matter which system you work in, whether that's the US, whether that's the European system, whether that's elsewhere in Australia or in Asia or in the UK, it seems to take a long time to get into definitive treatment. So we have good data in the UK that I know about and I've seen papers from John Gore in the US showing similar results. In the UK, we know that we have measured targets by the government to get time from treatment to diagnosis to decision. And it takes 112 days on average to go from an initial referral by your community doctor, your general practitioner, to get a decision to radical treatment. If you want it on Christmas Day, you need to be referred by early September. And that is before you recognize that a third of women have got more than one consultation before they've come to the hospital. When we look at the pathway for muscle-invasive bladder cancer, two-thirds of the time is spent on the diagnostic phase before you even get into the right person to talk about radical treatment.

So, number one, we have to improve the system. Number two, the upfront diagnostics for the invasive disease is slow. And number three, TURBT, although I'm a urologist, we all love TURBT. We all believe in it. It is not as good as we think. We all know local recurrence rates are really high. We know understanding is really common with TURBT. Here we see from Girish Kulkarni, a third of the people with high-grade muscle-invasive disease have actually got muscle invasion. And we know incomplete resection is common. The data from the EORTC combined analysis looking at a residual tumor at the site of the initial resection, depending on the experience of the operator, up to a third of patients have got incomplete tumor resections at the time of the TURBT.

And then if we look at quality measures, so what proportion of high-grade tumors have got muscle? Turns out a quarter don't. What number doesn't have a flat urothelium so we can't make a call about CIS? Again, a third to a half are missing it. And what about the use of intravesical? Or what about optimized guidelines, optimized delivery? Again, very inconsistent.

It's not as good as we think and it's not as safe as we think. We all know perforations are common, hematuria, long length of stays, infections, damage to the UO. And that's before we get to any risks about tumor dissemination. So, very few data on this, but some prospective data, [inaudible 00:04:37] from Scandinavia where they had cannulated peripheral veins and then the inferior vena cava (IVC) showed that six out of 10 patients had gotten tumor emboli at the time of the TURBT.

Is it as safe as we think? No. And then what about time for a change? The TURBT as we know it was described almost 100 years ago. So, Gary, I've put in some New York data for you here. This is the year that the George Washington Bridge opened, the year the Empire State Building opened, and look at what a car looks like in 1931. Surely we have to think about changing our paradigm rather than persisting with the same old, same old.

And that's where image guidance comes in. We've described VIRADS, which is just a language, just a nomenclature to try and improve the way we describe MRI-based imaging in the bladder. The reason we have gone for MRI is that with prostate, there are loads of MRI facilities now available. Most urologists are becoming very okay with MRI. We know the definition of soft tissues is very good so it's accessible, it gives you a high definition.

We've got a nice language now where you start to look at the extent and the depth of invasion. I'm not saying that we stop doing TURBT for all, but what I am saying is we can now start stratifying care.

Given that we are on Zoom, time to have a quick quiz. I don't know if Gary is present and whether he can speak, but Gary if you look at these cystoscope images here, this is a flexible cystoscopy, could you tell me as probably the most experienced urologist on this call, what grade and stage do you think this tumor will be?

Gary Steinberg: I think that is a TA high grade.

James Catto: I would agree. Ashish, you are the second most experienced urologist, this is a solid tumor with hydronephrosis. What grade and stage do you think this is?

Ashish Kamat: It depends upon what side I'm on. Am I on your side of the debate or Gary's? But no, if I'm trying to be honest, yeah, I would say this would be invasive and high grade, maybe even a little dedifferentiated.

James Catto: I think that with the trained eye, we can now say, do we think this is an invasive tumor? I'm not saying that all tumors do not need a TURBT, but I think in the case that you see an obvious bad tumor on flexible cystoscopy, I do think we are now in a position that we should do accelerated definitive treatment of which imaging is part of that. Thank you.

Ashish Kamat: Gary. You have the baton.

Gary Steinberg: Okay. So, is TURBT needed for the management of muscle-invasive bladder cancer? In the BladderPath study, we are going to talk about Pro-TURBT. Here are my disclosures. Jim, I know that we've got a mixed audience here, just so everyone knows, I am a Chicagoan, even though I am in New York now. And in Chicago, we have very active and enthusiastic baseball fans and we've got two baseball teams, the Chicago Cubs and the Chicago White Sox. And you are either a Cubs fan or a White Sox fan. There is a fair amount of animosity between the two. Let's just say, I am a White Sox fan and so here we go, Jim.

Gross hematuria, my initial approach is preferably a CT urogram or MRI. And so, as Jim said, it's critically important that we make a diagnosis and critically important that we image prior to TURBT. One of the worst things in the world, I think is to see a patient with a bladder tumor that just had a TURBT, no MR or no CT, which makes our clinical staging of the local tumor much, much more difficult, if not impossible.

And as we know, as Jim talked about, we've got our current imaging modalities of CT, MR, and ultrasound. I like CT, it's easier to obtain, we can get images quickly and I am most familiar with CT. And I do try to look at my CT scans to see if I can assess the stage of the tumor. However, I know that I'm usually not very accurate.

Well, you've got the patient, they've had gross hematuria. They've got a mass in their bladder on their CT or MR. Do you need to do an office cystoscopy? I don't believe so. As a matter of fact, I think that it is best to skip that and go straight to the TURBT, but clearly, the TURBT is necessary and important and I go directly to the TURBT.

Now, just as Jim was wondering, is urine sterile? Do we not need a TURBT? Let's just take a look at that a little more carefully.

In the evaluation of gross hematuria, the objectives and goals of the TURBT, again, I prefer to start with a CT urogram. I avoid the office cystoscopy if I see a mass on the CT. Certainly, an MR urogram is acceptable. If patients come in with an ultrasound, which shows a bladder mass, I get either a CT or an MR urogram prior to TURBT. If we see a large bladder mass, we have to make a histologic diagnosis. Taking a little piece of tissue is not a histologic diagnosis in my experience. We have to ascertain the presence of histologic variants, which I think is critically important now and will be in the future. There is a significant tumor heterogeneity that we want to assess with our TURBT. We want to assess for carcinoma in situ in addition to the muscle-invasive disease. Many times, we want to take a look at the prosthetic urethra and TUR of the prostate. And also we'd like to assess for lymphatic and vascular invasion.

How do we get from point A to point B in our diagnosis and therapy? As we know and as many people know me, they think that I am a surgeon and so let's just start cutting and see what happens. And so I think that is a critically important point.

First off, we need to assess our pathology. An experienced genitourinary pathology should review the pathology of a patient with any doubt in regards to a variant or suspected variant histology, extensive squamous or glandular differentiation, small cell micropapillary, plasmacytoid, or the presence or absence of lymphatic and vascular invasion. And in an era of precision therapy, histology matters.

And as Jim pointed out, the TURBT, which is critical for bladder cancer management therapy, there are limitations. We know in historical series, the clinical-stage does not equal the pathological stage. However, we also know that we can do repeat TURBTs and that when we do a repeat TURBT, we will find and remove residual cancer in many patients. We will also upstage patients from lamina propria T1 disease to muscle-invasive disease, especially if there was no muscle present in the initial evaluation.

In the MD Anderson series, in which patients were given neoadjuvant and adjuvant chemotherapy, it was a trial that goes back about 15, 20 years now, we see that there was under staging as well as a fair amount of upstaging at the time of surgery. More importantly, in the neoadjuvant therapy era, TURBT directs treatment decisions that can improve outcomes for muscle-invasive and non-muscle invasive, and also during a TURBT, we can do an examination under anesthesia.

What about the large clinical T2 mass on CT/MR? What about that? Do we need to persist and try to remove the entire tumor? The conundrum is, when is it necessary to attempt complete resection to debulk the tumor before radical therapy? For neoadjuvant therapy? For chemoradiation therapy? For curative intent? For palliation or the management of significant lower urinary tract symptoms and hematuria?

We also know that TURBT can be therapeutic. We know that in this century even, with carefully selected patients, that TURBT alone can be therapeutic and even curative. We know that in an elderly patient population that may not be able to tolerate radical cystectomy, a good quality TURBT may be all that they need.

What about in an era of precision medicine-directed guided therapy based on genomics? Well, we know that if you have mutation abnormalities in the DNA repair mutations, such as ATM, RB1, FANCC, and ERCC2, that we can potentially treat patients with neoadjuvant chemotherapy after a complete TURBT, neoadjuvant chemotherapy, a second TURBT, again, the importance of TURBT in management. And if they have no residual cancer, that they could potentially be followed on active surveillance. If they have some non-muscle invasive disease, they can either have intravesical therapy or chemotherapy and radiation or a cystectomy or again, if they've gotten the more advanced disease, go on to chemotherapy and radiation or a cystectomy.

On that same theme of trimodality therapy, this is an older study that was in the Journal of Urology, but again, the importance of TURBT for muscle-invasive bladder cancer, followed by neoadjuvant chemotherapy and actually chemotherapy for curative intent. And again, following up with a repeat TURBT, to make decisions about curative therapy and bladder preservation.

And then Jason Efstathiou published a very nice paper, looking at the benefits of a visibly complete TURBT and trimodality therapy in patients that had a complete TURBT. Their five-year outcomes of overall survival and disease-specific survival were significantly better than patients with an incomplete TURBT.  As well as looking at patients that underwent cystectomy, the patients that had a complete TURBT, there were fewer of those patients that needed to undergo radical cystectomy.

Well, why not just make a diagnosis of muscle-invasive disease by imaging and give everybody chemotherapy? Well, as we know, neoadjuvant chemotherapy is not a freebie. There is significant toxicity in neoadjuvant chemotherapy, including nephrotoxicity, GI toxicity, immunosuppression, hair, skin changes, neurotoxicity, visual, hearing impairment, paresthesias, muscle weakness, and neuropathy. Their significant potential toxicity requires justification and management, especially in the elderly bladder cancer patient population with comorbidity.

The BladderPath, the preliminary data, well again, this is a well-done study. They need to be followed further, they need more data. However, as we know, in the preliminary results, especially in the Likert 3-5 category, that is the category of muscle-invasive disease, we know in arm 1, which was standard of care for TURBT, eight of the 22 had muscle-invasive disease. In arm 2, which was treated based on findings of MR, five of the 15 that were thought to be muscle-invasive that had a TURBT were non-muscle invasive. 10 of 15 patients were treated for presumed muscle-invasive bladder cancer and muscle-invasive bladder cancer was confirmed only in five patients.

To kind of summarize, and some of "you were so preoccupied with whether or not you could, you didn't stop to think if you should".

And in conclusion, TURBT is critical in the management of muscle-invasive bladder cancer optimization of patient outcomes. TURBT requires complete resection of all visible tumors, if possible, with an adequate sampling of the bladder to assess the depth of invasion, tumor heterogeneity, multifocality, and carcinoma in situ. Newer resection techniques, such as bipolar electrocautery, enhanced cystoscopy, may serve to enhance complete resection and reduce complications from TURBT, although we certainly need to improve our technology in TURBT. And then finally, TURBT is critically important in the treatment strategies prior to neoadjuvant chemotherapy, trimodality therapy, or curative intent palliation. And lastly, the specificity with MR is currently lacking, especially with the Likert 3-5. Overall, about 40% that were believed to be muscle-invasive, were actually muscle-invasive. Thank you.

Ashish Kamat: Thank you, Gary, for that very comprehensive review of TURBTs and their importance when it comes to patients with bladder cancer. Jim, again, a lot of what Gary said, I know you agree with and for the purpose of the debate per se or the discussion, maybe I'll give you the stage so you could potentially rebut some of Gary's assertions as to why TURBT should absolutely be performed in every patient. And let's leave aside for a moment the differences in healthcare practices in the UK and the US, where clearly in the UK, there is a major delay in patients getting access. So, for the purpose of our audience, just let's leave that aside for a moment.

James Catto: Yeah. Thanks, Ashish. Firstly, with respect to Gary, he knows the field very well and he made very good points. I think I have come up with a couple of issues. Firstly, I don't think you can fully exclude the time to treatment and delay. We talked about resection, reresection, further resection. The majority of patients are not based in large New York centers of excellence. The majority of patients are elsewhere in the world. And so I think the delay is a big issue.

The next issue and I agree that MRI does not have the sensitivity and specificity yet, but I do feel it is the way to go. My next issue is likewise for TURBT. So Gary put up some compelling data to show that certainly, in Mass General, with Jason Efstathiou's data on re-resection prior to TURBT, prior to a trimodal therapy, showing how you could re-resect and you could restage the bladder, but I'd come back to that we have known for equally as long a time that reresection is not reliable. So, MD Anderson, Ashish, I say the data for you. You reported in 2018, 157 patients who were clinically T0 after two TURBTs of chemo, 25% have got T3 or no positive disease.

If we go to contemporary, Fox Chase is doing their prospective trial. Betsy Plimack, Alex Kutikov, we go forward, 61 patients, neoadjuvant chemotherapy, systematic in a trial, endoscopic reevaluation. Of those 61, 31, so half was predicted to be a PT0, turns out quarter of them have got the muscle-invasive disease. At the end of the study, the whole study was shelved because the negative predictive value of TURBT was too poor to go forward into a clinical trial. So I don't know if we are as good as we think we are at restaging the bladder.

And I come back to, if you've got aggressive bladder cancer, I want rapid treatment. It would be nice to know if it was micropapillary. It would be nice to know if there is lymphatic invasion, but it's not going to change my definitive plan, which is to get you to radical treatment as quickly as possible. And whilst I'm a urologist, I am thinking of cystectomy.  The chief investigator of BladderPath is Nick James, a radiotherapist and he doesn't think you need a radical TUR at all. He doesn't think you need debulking. He thinks you need neoadjuvant chemo and then chemoradiotherapy as quickly as possible.

Ashish Kamat: Gary, your thoughts?

Gary Steinberg: I agree pretty much on everything. I think that there is no question that our staging for bladder cancer, whether it's with CT urogram, MR urogram, and with TURBT, is far from adequate and that we clearly need to do a lot better. One of my concerns is, we see these patients that have had trimodality therapy and they are followed with MR programs and they have these masses and well, we don't see any blood flow into the mess. And yeah we think it is all treatment effect, but yet they have these masses. Then there is a cohort of those patients that you do a cysto on and a TURBT, and it comes back negative. Then ultimately they present with metastatic disease. And you clearly know that they most likely had the residual muscle-invasive disease. There is no question that our TURBTs are inadequate. And I think that there is no question that imaging needs to help with our TURBTs for us to do a better job.

Having said that, I think that again, especially today, as we are trying to move into a bladder preservation era, I think that the TURBT is a very important part of our overall management of these patients and that if we lose the ability to do good quality TURBTs, I think that in the United States, if you look at our residents, they finish a residency program not knowing how to do a transurethral resection of the prostate. And I think that if we lose that ability, we are going to interfere with our ability to provide bladder preservation strategies, whether it's with trimodality therapy or neoadjuvant chemotherapy based on genomic profiles.

And then one last thing, I believe that the greatest delay in the management of bladder cancer is not once the diagnosis has been made. I think the greatest delay is the fact that the patient has blood in their urine, then they call their internist and the internist says, "Well, here's an antibiotic." And then two to three months later again, an episode of gross hematuria, well here's an antibiotic. And then again. And so that by the time they come to the urologist, their initial sentinel gross hematuria was 12, 14 months prior.

That I think is the greatest delay that patients have, not so much once they have seen a urologist, they get on the pathway. I think that we do have time once they have had their TURBT and we've made a diagnosis to make the treatment decisions, although we want to be within three months.  I think, although that data is not hard and fast, I think that that is our goal. But I agree that we need to do a better job of their TURBTs and that is something that Ashish has talked about quite a bit and our imaging needs to be better as well.

Ashish Kamat: These are great points. Both of you raised very good points. And again, Jim, I wanted to put you a little bit at a disadvantage because there was a difference between the UK system and the US system, but let's assume that there isn't. Absolutely, access for patients to definitive care is limited in many parts of the world. And what you are proposing and the BladderPath trial, kudos to you and the members of the team for actually being able to do something like that.

I think just the way you mentioned, imaging has [inaudible 00:24;45] improved over the years, we and others have published results on CT scans being worse than flipping a coin because that is wrong more than half the time. MRI clearly is the new modality and gives us a better sensitivity.  Specificity is getting better as well. But in the same way, we shouldn't forget that TURBT has changed. You showed data from when it was first developed, but we have optical enhanced technology. We have better tools. We have HD monitors. Even the TURBTs are getting better. And again, I know both of you believe in this because you both are on the white paper that we published recently on getting a better quality TURBT training to our urologic community.

Anyway with that, I could chat with you guys forever. We haven't met in a long time, but in the interest of time, I do need to wrap it up. What I'll do is I will give each of you maybe 30 seconds for your closing thoughts. Gary, since Jim's the guest, let's give him, the final say, so I'll let you go first. 30 seconds and then Jim, you, and then we will end.

Gary Steinberg: Well, I think that I cannot agree more, that we need to continue to evolve with better technology and certainly imaging is critically important. And I think that that is something that I would like to advance as well. But having said that, there is no question that TURBT is the cornerstone of our management for bladder cancer and that I think we need to continue to enhance and improve our TURBT and enhance and improve our training and utilize it as best we can.

Ashish Kamat: Jim.

James Catto: Thank you for the opportunity. I would agree with a lot of what Gary says. I hope that BladderPath shows that we don't always have to do a TURBT. I do agree it will be the cornerstone for many patients, but I think as a urologist, if you see a band or invasive tumor, you should be thinking about a rapid radical treatment in that patient. Obviously, you're going to focus it on the patient, their age and their desires, and their goals. But I think we have to get away from the knee jerk, always TURBT. Although I agree, it will probably always be a cornerstone and I agree attention should be spared to it.

Ashish Kamat: Great. Once again, thank you both for taking time out of your busy schedules and spending it with us. It's very important for our trainees especially, and the younger faculty who haven't been able to go to meetings and hear folks like yourselves, share their opinions and ideas on what is going on in the field of bladder cancer. And I do want to thank UroToday for giving us the platform where we can bring this to them virtually. Hopefully, we'll all be able to meet sometime soon, but till then everyone, stay safe and stay well.