Busting Common Myths Regarding Bladder Preservation for Muscle Invasive Bladder Cancer - Nick James & Ananya Choudhury

April 30, 2022

Ashish Kamat, Ananya Choudhury, and Nick James discuss trimodal therapy, or radiotherapy, for bladder preservation in patients with bladder cancer. Dr. Choudhury touches on how to differentiate treatment between moving towards cystectomy and deciding on radiotherapy. They also discuss differing radiotherapy schedules and how those differences can affect patients.

Biographies:

Ananya Choudhury, MA, Ph.D., MRCP, FRCR, Chair and Honorary Consultant in Clinical Oncology, Joint Group Leader, Translational Radiobiology, The Christie NHS Foundation Trust

Professor Nicholas James, MBBS, FRCP, FRCR, Ph.D., Professor of Clinical Oncology at the Institute of Cancer Research at Royal Marsden Hospital, London

Ashish Kamat, MD, MBBS, President, International Bladder Cancer Group (IBCG), Professor of Urology & Cancer Research, MD Anderson Cancer Center, Houston, Texas


Read the Full Video Transcript

Ashish Kamat: Hello, everybody and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology and Cancer Research at MD Anderson Cancer Center in Houston, Texas. And it is a great pleasure today to welcome two experts, colleagues, and friends from across the pond over in the UK. First off we have Professor Ananya Choudhury who is Chair and Honorary Consultant in Clinical Oncology and the Joint Group Leader of Translational Radiobiology at The University of Manchester in the UK. And then we have Professor Nicholas James, who is the Team Leader of Prostate and Bladder Cancer Research at The Institute of Cancer Research in London.

They are both taking the time today to join us for what is going to be a really truly enlightening and exciting discussion on common myths that we hear being thrown about when it comes to trimodal therapy or radiotherapy for bladder preservation in patients with bladder cancer. And clearly, this is a topic that over the years has had a lot of myths, so to speak, being propagated. Many of them are false and many of them are just old and have not evolved in our mind, so to speak. I'm really looking forward to this and with that Ananya, I'll hand the stage over to you.

Ananya Choudhury: Thank you so much. And thank you for inviting me to talk about this really interesting subject today. As I recall, it started from a Twitter conversation that we were having. So there you go, the power of social media, right there.

These are my conflicts of interest.

And when I started thinking about this, about the myths that we actually need to bust for muscle-invasive bladder cancer and trimodality treatment, there was a number. I've tried to focus on the four that I felt were most relevant to the work that I've been involved in. The four that I've picked, the fact that I often get told, usually by my surgical colleagues, but not exclusively by my surgical colleagues, that surgery is the gold standard of treatment for muscle-invasive bladder cancer. I've also been told that some patients are too elderly for radiotherapy with a radiosensitizer and therefore should be given in my opinion, less than optimal treatment. Some patients apparently are unfit for chemotherapy and can't have any radiosensitization, and that conventional fractionation of radiotherapy is the standard of care.

Taking each one of those, in turn, we'll start off with surgery being the gold standard for treatment. Now I have to admit over many decades, there have been multiple studies that have tried to address this question. There have been institutional studies where propensity matching has been used to match cohorts. As you can see here from these Kaplan-Meier curves, cumulative instance curves on the left from this study from colleagues in Toronto, there is no difference between outcomes with radical cystectomy and trimodal therapy when you match for known prognostic factors. It's also been shown at the epidemiological level where this study from again, colleagues in Canada have shown that in the state of Ontario, once you take into account known prognostic factors, there was no difference in outcome between the patients who have surgery or patients who have radiotherapy.

And finally, there is a meta-analysis that was published in 2015, which took data from all published studies looking at the outcomes of radiotherapy and surgery with and without chemotherapy. And again, showed that there was certainly no evidence that trimodal therapy was inferior to surgery. And if I was going to be cheeky, I'd tell you that actually both these meta-analyes suggest that trimodal therapy is superior to surgery.

The obvious question is let's test this in a clinical trial and the difficulty there is that colleagues here in the UK tried to do that a number of years ago and unfortunately, despite a great deal of enthusiasm for the question, the study failed to recruit and had to be closed early. And the reason for that was because once you took away the opinions of the clinical colleagues who have their own biases, patients who appreciated the fact that there could be equipoise between the treatments, actually had very set ideas and opinions about the treatment that they wanted for themselves. It was actually very difficult to randomize patients between two very different treatments, even if it was felt that the outcome would be very similar. So we haven't managed to do that and I have to admit if somebody did wish to conduct that study successfully then I think that might answer the question once and for all. But at the moment, as far as the data goes, I think it's fair to say that there is overwhelming data to suggest that both treatments are equivalent for a lot of patients.

And this has now been reflected actually in international guidelines. Here are the NCCN guidelines for bladder cancer and I am very pleased to see that at all points in the pathway, concurrent chemoradiotherapy or radiotherapy with a radiosensitizer is given equal billing to cystectomy. We did this early on in the UK when we published the NICE guidelines in 2015 and it is now being accepted in other international guidelines as well. Hopefully, that is one myth that we won't have to bust if we ever do this session again.

My second myth is that some patients are too old for radiotherapy with a radiosensitizer. There's a lot of data out there and this is very nicely shown by the paper from Boston colleagues in 2013, showing that muscle-invasive bladder cancer patients often have less aggressive treatment, if any treatment at all, as their age increases and also if they come from poorer socioeconomic groups. There is clearly an underserved population here. And sometimes when we discuss why this might be, we are sometimes told that patients are unsuitable for optimal treatment and this can be age-related.

But there is actually quite a lot of data out there showing that there is very little basis for this myth. It is really important to select appropriate treatments for patients but actually if you do that based on known prognostic factors, whereby performance status, frailty, other comorbidities are taken into account rather than age per se, then there is actually no difference in the outcome.

This is some data from work that we carried out a few years ago, where we actually looked at patients who were treated with chemoradiotherapy and patients who were treated with hypoxia modification with carbogen nicotinamide. And we did an age-specific analysis where we divided the patients into above the age of 75 and below the age of 75. And again, what we found was when you took into account known prognostic factors, then disease-specific survival was absolutely the same. Overall survival as you would expect was higher in the younger patients but that's related to age and life expectancy, not related to disease and outcome of treatment. We also showed that there was no difference between whether these patients were treated with chemoradiotherapy or with hypoxia modification, which suggests that regardless of which radiosensitization method is used, it is about selecting the patients of appropriate fitness for treatment rather than using other factors.

And this leads me to the myth that some patients who are unfit for chemotherapy are unable to have radiosensitization. Let me introduce you to BCON, a form of hypoxia modification. This has actually been around for decades. BCON stands for bladder radiotherapy, which when it was initially delivered was given using a very basic three or four-field CT, planned empty bladder technique and can be given either in moderate hypofractionation or in conventional fractionation at a two-grade fraction. Nicotinamide, which is a B vitamin, is given orally, one and a half hours before radiotherapy at 60 mg/m squared, and the dose can be reduced if patients have reduced renal function or if there are concerns over toxicity. The main toxicity here is often nausea and that's the main reason why we reduce the dose sometimes to 40 mg/m squared. And then carbogen, which is enriched oxygen whereby the percentage of carbon dioxide in the mixture is anywhere between 5% and 2%. It is given via a closed breathing system and it is commenced five minutes prior to radiotherapy and continued during the delivery of treatment.

This is a treatment that has been not only around for decades but has been compared to radiotherapy alone in a phase three clinical trial, which was recruited in the UK. And it is used within the UK, but is less widely used outside. Although in the last few years we have had colleagues in Australia, the US and Sri Lanka ask us for our protocol so that they can initiate it in their departments.

The BCON study, which was published back in 2010, so it's over a decade old and has recently been updated, in fact, published this year in the [inaudible] journal took patients who were actually relatively elderly. You can see here that the median age was 74 but we had patients in their eighties and nineties, as well. As you would expect, they were predominantly male but although the majority of patients had T2 disease, there was a significant minority who had T3 and even some who had T4 disease. The patients had aggressive muscle-invasive bladder cancer and they also had, the majority had partial or debulking or a biopsy only. In fact, it's a minority that had a complete TURBT, which I think is again of interest and may well be a myth that we try and bust later this evening.

And what is important here is that the phase three trial showed a survival advantage when it was first published back in 2010, with the patients receiving carbogen and nicotinamide in addition to the radiotherapy, having a better outcome than those receiving radiotherapy alone. And as you can see here, the Kaplan-Meier curves split relatively early on and then stay parallel to each other, which obviously suggests that this is a real effect. Surprisingly, and actually, to the delight of those of us who use BCON, when the BCON trial was updated with 10 years of survival, the Kaplan-Meier curve continued to show that separation, even though the number of patients still alive at these later times is actually relatively small. You saw there that the average age of the patients recruited into BCON was 74. The fact that some of these patients have lived another decade is actually a real bonus.

This is a treatment that can be given to elderly patients, and it is cheap.  Carbogen and nicotinamide, in our department, costs less than 200 pounds per patient to deliver. And also it requires very little in the way of additional infrastructure. So not only is it useful in departments like mine in the UK but it actually can be really quite advantageous in places where resources are limited.

And on top of that, there was no significant toxicity either with bowel or with bladder. Giving carbogen nicotinamide alongside radiotherapy, especially if chemotherapy is unsuitable or unavailable actually is a really good idea and therefore it's something that we use in a large portion of our patients. There were hardly any patients in our practice who get radiotherapy alone for their bladder cancer. If they are suitable for radical radiotherapy, then we give them a radiosensitizer to improve the outcomes.

That takes me onto my final myth, that conventional fractionation of radiotherapy is the standard of care. Throughout the world, bladder cancer radiotherapy is given in two schedules. There's the conventional schedule where we give 64 gray in 32 doses of radiotherapy over six and a half weeks. And then there's the moderately hypofractionated schedule where we give 55 gray in 20 doses over four weeks. And certainly, in the UK, both these schedules are fairly interchangeable so there are departments and colleagues where one is preferred over the other, either for historic reasons or for logistic reasons but there really is little to choose between them. In fact, a lot of the older studies that we've done in the UK in recent history have been permissive and have allowed the use of both protocols.

This meant that we were in the perfect position to try and compare the outcomes of conventional fractionation and moderate hypofractionation because we had access to the two UK randomized control trials, which used both of these fractionations. One was BC2001 and Professor James is on the discussion tonight and this was his study. And the other was the BCON study, which was led by Professor Peter Hoskin, which I've mentioned in my previous myth where he compared hypoxia modification in addition to radiotherapy to radiotherapy alone. But most importantly, what this study did was allow centers to decide upfront whether they were going to use a conventional schedule or a hypofractionated schedule when they were entering patients into the study. It was a fractionation schedule chosen per local practice. It was not a randomized comparison, but given the numbers recruited in both these studies, we felt we could try and compare the outcomes.

And what we found was that in a non-inferiority analysis, there was no difference in outcome between the two schedules. There was no indication that 55 gray in 20 fractions was inferior to 64 gray in 32 fractions. And as you can see here, the 95% confidence intervals excluded the non-inferiority margin. Even more interestingly, what we found was that the patients who received 55 gray actually had a benefit for invasive local-regional recurrence, which means that there was actually better local control with the moderately hypofractionated schedule than there was with the conventional schedule.

And this was with no expensive toxicity. Sometimes I am asked whether giving a four-week course of radiotherapy rather than a six and a half week course of radiotherapy leads to more long-term toxicity, whether it's less well tolerated than a gentler conventional schedule, and what our meta-analysis allowed us to do was look at the outcomes and there was no difference to the toxicity profiles, either for bladder or bowel.

And this is a very nice infogram that was produced by colleagues at the Marsden Institute of Cancer Research in London, which actually puts this into context. As you can see here, we looked at two different radiotherapy schedules, and what we found was that there was a 29% reduction in cancer coming back on the shorter schedule. And that meant that patients could have 12 fewer hospital visits. During COVID time, reducing the risk of exposure but generally reducing the number of visits for patients had positive health economic benefits but also improved patients' quality and the commitment that they have to give to coming for treatment. As far as I'm concerned, it is a win all around. And I have to admit on the back of this, most of my colleagues in the UK who hadn't adopted a 55 gray in 20 fraction schedule have now adopted this. So this really should be the current standard of care.

At this point, I'm going to hand it over to my colleague, Professor Nick James.

Nicholas James: Thank you, Ananya. These are the things I thought I would comment about. I'm not going to say too much about surgery because Ananya has covered that. I will just make a couple of points in addition to what she just said. But I will say something about when it does come up, which is, what happens if you have to do salvage surgery after chemoradiation? Because there is important data on that. And a related thing that comes up is that if you irradiate people's bladders you get a small, poorly functioning bladder, which is actually just not true. And then finally, I'll get onto a particularly favorite hobby horse of mine, which is TURBT, and do we really need it?

The first thing in relation to surgery is, this is the age distribution in the UK, but it's the same in the US and most major economies, the predominance of men at peak age in the mid-seventies or so. What you do with older patients, as Ananya has already said is very important. This is the median age in two big surgical trials. This is the neoadjuvant MVAC trial, and this is the neoadjuvant CMV trial, and this is the median age in the big University of Southern California series with 1,000 odd cystectomies, well below the median age of the population. As Ananya showed, what happens to this group is very much underrepresented by surgery. And to me, the question about whether surgery is better or worse than radiotherapy is actually irrelevant. The question is, what do you do with these patients who are not getting surgery, as they demonstrably do not in increasing numbers as you get older.

And so bladder preservation techniques, they are sort of low toxicity or low enough toxicity to deliver to these people, they are relevant and Ananya has already gone over the BCON trial. The trial, I led, which is the BC2001 was using 5FU/mitomycin which is a very elderly-friendly regimen, doesn't need platinum. It was independent of renal function, you can give it to patients on dialysis. It's very well tolerated, like the BCON thing. And the two trials have a median age much nearer to the median age of the population. And we have plenty of patients over 75, over 80 in our trial, just as there was in BCON. These are different treatments to surgery, not really competitive treatments at all.

The second thing is, can we salvage local failures? Overall, in BC2001, just under 10 years follow-up, we had around 10% of patients getting salvage cystectomy. The first part of this is that most patients do not need to be salvaged. They don't fail locally, just as surgical patients, most of them failed with metastases and this is why surgery and radiotherapy essentially have the same long-term outcomes. It's because it is the metastatic disease that kills you, not the local failure. But if you do get a local failure, can you salvage it?

This is data. I'll show you two bits of data from Ananya's hospital, The Christie. The first is primary versus salvage cystectomy. And this is not a randomized trial clearly, but the numbers are huge and the follow-up is long. And what you can see is that roughly similar numbers of primary and salvage cystectomy and the time, your survival from surgery is the same. And this is well known for example, for anal cancer, where the standard of care has flipped from primary surgery to primary chemoradiation to salvage surgery and there's no reason on the basis of these sorts of things. You shouldn't adopt the same policy in bladder cancer in my view.

The second report from the same group, even more patients here, over a very long time period. Looked at over 800 primary and salvage cystectomies, this overlaps with the one I just showed you.

The important thing here is that for all the major components of surgical complications, there is no significant difference in the rate of complications. They conclude, and this is a group of surgeons writing this, this is not oncologists, that there was no reason on salvage surgery being difficult grounds to not do upfront chemoradiation.

The next myth is about bladder function. I'll just show you some data from the BC2001 trial. The randomization here was chemoradiation or radiotherapy alone and we [inaudible] 55 in 20 or 64 in 32. And so this is half of the meta-analysis on fractionation that Ananya just showed you. The important thing here is this is the clinician assessed RTOG's six-month toxicity outcomes. So purple is chemoradiation, and blue is radiation therapy only. And you can see the majority of patients at six months in the clinician assessment are reporting no toxicity and I will show you the patient-reported outcomes in a second. Of those that report toxicity to the clinician, the majority is grade one or two. There's no suggestion that adding chemotherapy to radiation makes it worse. Exactly as for BCON as Ananya already showed you. Toxicity is not so then a reason to not add chemotherapy to your radiation.

These are the patient-reported outcomes from the same cohort of patients. And this is the pooled data from the whole trial. There were no significant differences between radiotherapy and chemoradiotherapy. This is the entire population, in the dotted line is the baseline. This is physical wellbeing, which takes a dive whilst you're having the chemoradiation. But by the time you come back for your post-chemo RT checkup, you're back to baseline and then it flatlines. Social wellbeing is the same, functional wellbeing again, you've got a drop during your treatment. Emotional wellbeing goes up even during treatment. You're having a treatment that's preserving your bladder, that is an outpatient treatment. All of the asterisks are statistically significant. There's a significant drop in your quality of life during chemoradiation, not very surprisingly, but rapid recovery and all of these other ones are at baseline or were [inaudible].

The other thing I'd just like to make the point is that we tend, or people use chemoradiation and trimodality kind of interchangeably. But in my view, I think this is slightly sloppy wording and we should not do this.

This is what's normally defined as trimodality therapies. You have a maximal TURBT, concurrent chemotherapy, with your radiation as the third component. These are the three components of it. Now it's very important to emphasize, in BC2001 this is not how we selected our patients. This is not who went into the trial.

This is a typical trimodality therapy format. And the second feature of trimodality therapy is that you have an initial induction period where you get the option to go to cystectomy if you do not get a good response to your initial chemoradiation. The course is split into two halves. Typically in 40 gray or so and then a further 25, 26 gray or so in the older versions but you don't necessarily, only a minority of the patients, around two-thirds, go the whole course with chemoradiation. A significant minority, about a third end up with a cystectomy as part of their primary care. It's a very different format.

There are other selection criteria that get put in the typical TMT mix. So maximal TURBT, no CIS, no hydronephrosis, good bladder function, which I would agree is essential if you want to do bladder preservation, and a good response to the first part of therapy, which is not at all what we do in the UK, you get the whole course of therapy and then assess afterward. It does ensure that the patients in the trimodality therapy series are low stage and it excludes the poor responders because they get surgery. You will get good results with trimodality therapy, pretty reliably because of the way we select it but it does not address then the problem of what we do with older, less fit patients.

And so if you look at the Mass General series going to trimodality series, these are typically a similar age to the surgical series and younger than the patients we put into BC2001. And Americans tend to view this as an alternative to surgery and cystectomy fits most of the younger patients, rather than an alternative to no treatment in older, less fit patients, which is the other way of looking at chemoradiation. This is clearly a valid thing to do but it doesn't cover the whole spectrum that we treat in the UK.

What we do in the UK is that we will do a TURBT if indicated but there is no requirement for maximal debulking. The data from BC2001 and BCON did not include maximal debulked patients 100%. There will be no mixture. We will tolerate CIS because you can manage that with intravesical therapy, as long as it's not too extensive because you are going to end up losing the bladder anyway, sooner or later, if you have that. So you may as well just cut to the chase and remove it. We would not view hydronephrosis as a contraindication. We will stent people, give them chemo, neoadjuvant chemo if they're fit, and then manage the stent. It's a poor prognosis factor, but it's a poor prognosis factor for surgery as well. We give it as a single block of therapy with no midpoint assessment and salvage cystectomy is for local relapse or non-response. And we would view this as the mainstay of therapy for older patients, plus as an alternative to surgery in younger patients. So we've got two different kinds of categories if you like to shade one into the other.

Now, just to show you how this pans out. This is from BC2001. This is looking at the impact of neoadjuvant chemo. Now, this was not randomized but about a third of the patients got neoadjuvant chemo, two-thirds did not. It was the younger, fitter patients who got neoadjuvant chemo. These patients do better because they are better patients, not necessarily, but may well be because of the neoadjuvant chemo. But the point I want to make here is that if you like, these are the TMT patients in here, the ones who've been completely debulked with no residual mass but we also had all of these ones who had a residual mass. And of course, they do worse because they are bigger stage patients.

The surgeons don't go at it to suboptimally debulk or leave the tumor behind, whether there's a residual mass, it's a bigger tumor, it's a T3 tumor, or whatever. What you can see is the uplift from adding chemo in these patients in absolute terms is bigger than in the TMT patients. And they are all benefitting, their hazard ratios are all broadly the same. You get a benefit from adding chemo to radiotherapy, even in patients who you couldn't debulk. And we've got this broken down by different age groups as well.

Coming back to the need for TURBT. This was a radiologically assessed stage in BC2001. T2, T3-4 do worse. This is the size of the tumor at TURBT or at cystoscopy. So the cut points here are three centimeters, small tumors do better than big tumors. This is the interesting thing though here, these are patients who are completely resected. This is incompletely resected ie. it's a surrogate for the stage. These patients only had a biopsy. They have no resection at all. And they sit somewhere in between. And this is residual mass post-resection, which again is a separate thing to the radiological stage. And again, it's a surrogate for the stage. Now, all of these things will predict a poor outcome for surgery. They don't tell you that you should have surgery, not radiotherapy.

This sums that up. It doesn't follow that for radiotherapy, you should only do the ones who have been completely debulked. They are going to do badly with surgery as well. Also, therefore it doesn't follow that TURBT is even needed. Now I realize I'm getting beyond myths into controversy here but I think it's worth airing this.

One of the things that always gets said when I say this is that you need a TURBT for a variant histology definition but actually it turns out that the TURBT is not very good at this. If you think variant histology should affect treatment, which I think is a debatable point, then you need better ways to identify it other than a TURBT.

And just to make the point, this is just, this is a recent paper looking at the discrepancy between the stage at TURBT and the stage of cystectomy. These are patients at TURBT who were staged as non-muscle invasive, 44% of them were concordant, a substantial minority were understated. TURBT obviously is not very good at assessing muscle invasion. These are patients who had CIS only at TURBT but who then went on to have a cystectomy, only 31% had CIS only. These are patients who are muscle-invasive at TURBT. Now here it's much better. And I guess you could argue, the ones that weren't muscle-invasive, they should have already removed it at the TURBT stage.

But this is also important coming back to the histology. Of patients who were assessed as pure urothelial carcinoma at TURBT, 79% of them were concordant, 21% had other differentiations apart from just pure TCC. Of the ones assessed as pure variants at TURBT, the concordance rates are about 74%, 75%. So again, you've got quite a big mismatch. It's really not a very good way of doing it.

One of the things my group is very interested in, I've taken the slides out in the interest of time, is looking at whether you can profile the mutations in cancer from the urine. And the short answer is that you can and I think we need to be looking at smarter ways of doing staging like MRI instead of a TURBT, taking a biopsy to confirm the diagnosis, and looking at things like sequencing the mutations from the urine DNA or from the pellet's DNA, rather than doing a big resection. You'll get a much clearer picture. This is how we do most cancer staging. We don't debulk with a [inaudible] team or that I can think of.

And that is my last slide so I'll stop there so that we can have a bit of time for discussion.

Ashish Kamat: Great. I want to thank both of you for really addressing that head-on. There's a TV show called MythBusters, which I'm sure you are familiar with and you guys were perfect there. I had a whole list of questions but you addressed them in your slides already but for the sake of our audience and just because we do want to discuss this, let me bring one point to the forefront. And that is, I've been a big believer in bladder preservation and obviously focused on the noninvasive state and with the BCG, BCG unresponsive, and even the muscle-invasive bladder cancer, trying to get these patients to in some way or the other spare their bladder. I agree with all the points that were raised because if a patient has a small tumor, we can often not even do a radical cystectomy. We just do a TUR and it's gone and you just monitor the patient and do well.

I sort of am believing what you are saying about the bulk of the tumor being a surrogate for the seriousness of the disease. That being said though, and again I'll throw this back out to you and it might be a North America versus a UK thing. Oftentimes when I refer patients to my radiation oncology colleagues, and if the patient has not had a complete TUR, they are sent back to me with the recommendation, please remove all the tumor otherwise radiation therapy would be pointless. Now I know you showed the data, but what would be kind of your top-level message to your radiation oncology colleagues that still believe that the urologist needs to remove all the tumors before sending the patient to them?

Nicholas James: In essence, this was criteria that Bill Shipley made up in order to ensure that he got referred good quality patients. It's not underpinned by any data. It is a prognostic factor for sure. Nobody is showing that it's necessary. And the puzzling thing for me is that we don't do this in other tumor types. If we're going to go down the radiation therapy route, we biopsy, we image and then we treat. We don't take half of the tumor out, piecemeal, and stir everything up first in any other tumor site. It is a puzzle to me that radiation oncologists won't extrapolate into other tumor types and just do it. Ask them to speak to me, I'm happy to chat.

Ashish Kamat: Well, but one of the things is even when you're looking at neoadjuvant chemotherapy, and there was an FDA workshop that we held last year and there were the findings, and the white paper was just published, where even for neoadjuvant chemotherapy trials and even the FDA surrogate markers, they are recommending that the tumor is completely removed or debulked as much as feasible before the patient goes on to get neoadjuvant chemotherapy. It's possible that some of that paradigm is trickling over into the design of a trimodal therapy or radiotherapy so I can see where they are coming from but I'm glad you said what you did because I might actually have them contact you so they could talk to you about that.

Nicholas James: I'm very happy to talk to them about it. I would view it as much more important to ... I think if you need to resect, do it at the end when there is much less tumor if you really think that it's got a role but you'll mostly find there will be no tumor. And therefore we've done the matter in operation.

Ashish Kamat: That was one of the questions I was going to ask either one of you to kind of address. And Ananya you could maybe address that. After radiotherapy, when we evaluate the bladder after you're done with their course, and I know you showed the two different courses and you could even talk about that a little bit. How often do you expect to see the residual tumor, visible tumor? And if you do not see residual tumor but you see necrotic tissue, do you need your surgical colleague to go in and resect that to look for microscopic disease, even if it's not visible to the naked eye?

Ananya Choudhury: A lot of the data out there shows that three months cystoscopic response rates are very high. They are sort of 80% to 90%, and therefore it's actually rare that I have a patient who at the three months stage still has a tumor there. And obviously, for those patients who still have tumors there, we don't wait another three months to see if it will go away eventually, those patients get assessed for cystectomy there and then. But the vast majority of patients have no residual disease at that point. If they have any sort of necrotic areas or areas that look unusual, then my urology colleagues biopsy them, and invariably at the MDT, they often get reported as showing no evidence of tumor. We do not advocate anything more than a biopsy if there is no evidence of a tumor. We certainly don't advocate TURBT or anything at that point.  I think as an MDT, we make the decision, is there cancer there or not? If there's cancer, they go for cystectomy.  We don't feel the need to go and try and resect lots of tumors, lots of tissue, certainly in a patient who's potentially still got a reaction from the radiotherapy.

Just picking up on what Nick was talking about before, about the whole sending patients back for TURBT. I think one of the things that hopefully the fractionation meta-analysis has shown is that treatment time is important. For a long time, certainly, I was brought up being told that there were some cancers in which overall treatment time is absolutely crucial to the outcome for that patient. And bladder cancer, I believe is one of those cancers. So any sort of fluffing around that you do upfront with trying to work out whether you've done enough of a TURBT, even before that if you haven't done a TURBT, which there is muscle present, so you have to go back in before you're able to make the diagnosis, prolongs the overall treatment time. And actually, regardless of what treatment that patient ends up having probably is detrimental to the final outcome.

Again, I think it's really important. And if colleagues want to talk to Nick and then want to talk to me to get a second opinion about it, that's absolutely fine. But I think there is quite a lot of evidence out there to suggest that rather than doing any sort of completion TURBT, getting the diagnosis and putting the patient through their radical treatment, whatever radical treatment that is, is far more important.

Nicholas James: Yeah. The NHS just did something very interesting in that, just to pick up on that as well, which is that we have to treat patients within time limits from their presentation in the hematuria clinic or whatever. So we have 30 days to do their definitive treatment. Now until not that long ago, TURBT counted as definitive treatment for muscle-invasive bladder cancer but actually, after a long campaign, led jointly by surgeons and oncologists, it has been removed. If you re-TURBT, you are guaranteed to miss the 30-day thing and I trust you will not get paid for the treatment. There was quite a strong consensus amongst all flavors of uro-oncology that the TURBT did not count as being a useful thing to do in the treatment pathway for bladder cancer. You just get on with the treatment, either do a cystectomy or do something else, chemotherapy, radiotherapy, it doesn't matter, but don't just go and do another TURBT.

Ashish Kamat: Well, that's good to hear because we were always puzzled as to why TURBT was considered in the UK as definitive treatment and that was your benchmark.

Nicholas James: Yeah, it's gone.

Ashish Kamat: I'm glad you made that point, but I do want to take upon the point that you just made because that is something that I'll often hear people throw about as a downside of this whole paradigm and I'll phrase it this way, the thought process as well.  If I look in the bladder at three months and the patient hasn't responded to radiation therapy, I wasted three months and now the patient presents actually with metastatic disease. And again, there's a whole body of literature showing that if a radical cystectomy is delayed beyond 12 weeks, those patients have half the survival of those patients that have an expeditious radical cystectomy. Not in the radiation therapy literature but just waiting, this is access to healthcare, things of that nature. But how would you address that sort of criticism that is ingrained in the minds of many people?

Nicholas James: Well, mainly with the slides that I showed, the data I showed you from The Christie, looking at survival from primary versus survival from salvage cystectomy, it's identical. And the survival of all of these patients is, you're right, it's driven by metastatic disease. But I'm not sure, but yes, there must always be the odd case for which that is true. You can't deny it but on average it's not true.

Ashish Kamat: Right. And the data as you show shows that it's not true. That's the point I just wanted to drive home. And another myth that I often hear thrown about by people and again, I'm a little bit biased because I get referred these patients. I see a lot of these and I am a believer in this myth and I would love for you to set me straight, is that the patients who do respond to radiation therapy to the bladder when they have non-muscle invasive recurrences down the road, they're not able to tolerate intravesical BCG or intravesical chemotherapy, as well as if they hadn't had radiation therapy. Now, clearly, it's a small price to pay because they still have their bladder and yes, we can manage their tumors. But more so than dispel that myth, any tips or tricks that you have learned over the years to help these patients with their subsequent non-muscle-invasive recurrences?

Nicholas James: I don't hear British urologists saying what you've just said. I guess I couldn't cite your data but our urologists do not seem to have much of an issue about managing noninvasive recurrences as for patients who haven't had prior radiation. I don't know what you hear from your urologists, Ananya.

Ananya Choudhury: Yeah. That isn't something that I get challenged within the MDT. I think certainly over the course of my years of practice, there has been a move I think in the right direction of urologists now offering patients the opportunity to have nonsurgical treatment for their non-muscle invasive bladder cancer recurrences. And I think that is due to the data that has been published by the likes of Bill Shipley in Boston and also Klaus Riedel in Germany. I think people now are more willing to accept that they do not lose anything by trying BCG or intravesical chemotherapy. And then if that fails, then the patient goes on to cystectomy. But I've not heard surgeons tell me that the patients who've had radiotherapy prior to that get more toxicity. I don't know, Ashish, is there actually data for that or is that entirely anecdotal?

Ashish Kamat: No, there is. There is. In patients who've had radiation therapy, obviously, we see radiation-induced cystitis and hematuria and you can't give BCG when there is hematuria because you could cause BCG sepsis. And that is a real issue. It's not as much of an issue as is advertised. And I was again, you seem to have a lot more data in this than most of our North American colleagues. I was hoping you might have some nuggets somewhere hidden that you could share with us.

Ananya Choudhury: I guess certainly I think part of the whole thing about bladder preservation, as with so many parts of medicine, is it's down to experience. One of the things I think we have in the UK is right through training a lot of us have been exposed to and have the experience of looking after patients who are having their bladders preserved both during treatment and also then during follow-up. And certainly what I hear from some of my colleagues outside of the UK is as the number of patients having bladder preservation has decreased in their practice, the experience of their junior colleagues has decreased as well. And so going back to something you said, Ashish about either you have radiation oncologists that you work with who say, "I don't feel comfortable giving this patient bladder preservation, go and do more TURBT". That probably is related to that, isn't it? And similarly, a lot of this anecdotal concern about having more toxicity after radiotherapy with intravesical cycle treatment is probably related to reduced experience.

Ashish Kamat: And that's exactly why we have this, today with the two of you here, sharing your wisdom and busting the myths. I could go on chatting with you forever but in the interest of time, we do have to wrap up. Maybe some high-level thoughts from your perspective that you want to share with the audience so they can kind of leave this with some top-level thoughts. Nick, start with you.

Nicholas James: Yeah. I'm very keen that people start thinking critically about why we are doing TURBTs at all as a staging test when in pretty much every other cancer we biopsy and scan. And so we've got trials running based around MR as an alternative. And I think we should be putting a lot of sauce into getting rid of TURBT from the management of muscle-invasive cancer completely. I think it should just purely be for non-muscle invasive tumors, for resection would be my plea for the things that you guys should be looking at in your practices and your research.

Ashish Kamat: And Ananya.

Ananya Choudhury: I think what I would like, and I'm really pleased because I think this is happening, is for patients to be empowered to be able to make the right decision for treatment for themselves. Again, whether to have neoadjuvant chemotherapy or not, whether to have surgery or bladder preservation, these are life-changing decisions that we are asking our patients to make. And I think they will make the right decision for them if we help them by giving them the proper information and that I suppose is what this myth-busting is about, is making sure that we are all clear as to where the data comes from, what we know to be the truth, and if you like, where we need to focus the research for the future.

Ashish Kamat: So well said. Once again, Nick and Ananya, thank you so much for taking the time. I know it's late in the evening where you are. I truly, truly appreciate this. Thank you so much.

Nicholas James: A pleasure.

Ananya Choudhury: Thank you.
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