Ashish Kamat: So today, let's address a question that comes up in the minds of treating physicians that take care of bladder cancer all the time and that is the patient with muscle-invasive bladder cancer. For the purpose of this discussion, let's assume that it's not a trick patient. This patient has standard histology and is amenable to neoadjuvant chemotherapy. There's no trick imaging. It's clear muscle-invasive bladder cancer. And with that in mind, Professor James, if you would tell us why you favor trimodal therapy for this patient. And then Professor Williams, you can tell us why you favor a radical cystectomy and then we'll have a nice discussion at the end. So professor James, take it away.

Nick James: Fantastic. So thank you very much for the invitation to speak and I'll sure proceed. There's a couple of strands of this. The first is the evidence-based for bladder preservation as an alternative to surgery and I'll make some sideways comparisons to other disease sites managed by chemotherapy, radiotherapy and so on. And I'll say a little bit about optimizing bladder preservation at the end in terms of treatments.

Basically the outcomes of bladder cancer had been completely static for 30 or so years and this is a paper published by a very eminent collection of urologists trumpeting exactly that fact, that the surgery has made exactly static to 30 years in terms of outcomes. The question is, is survival better after surgery than after bladder preservation, chemo, radiotherapy, whatever. I think the best way of looking at this is cancer registry data because that gets away from all the problems of case selection and case-mix and all the problems with that.

And this you can see is a chunk of data from a large area of England called Yorkshire and you'll see a couple of things. If you look at the numbers at risk at the bottom, more patients in the UK you get bladder preservation labeled as RT here because it would have been exclusively radiotherapy and surgery. It's roughly three to one get radiotherapy compared to surgery. The median age of the radiotherapy patients is seven or eight years older than the surgery patients, but you'll see the survival going out to 10 years is identical or if anything it's slightly worse with surgery. But there's nothing to suggest that the surgeon-treated patients are doing better.

The second thing about that is there's no plateau in the survival curve and that's because patients died from metastases. So you've got two components to your treatment. You've got how you achieve local control and how you manage metastases. The question is what can we learn from other cancers?

Just quickly looking at breast cancer, you can see that right the way through the 20th century, there was a trend towards ever more radical surgery until the 1980s when combination therapy started appearing. So adjuvant radiotherapy, hormone therapy, chemotherapy, HER2 targeted therapy and so on. And what you can see is that the trend for mortality went rapidly into reverse with combination therapies, and the trend for radical surgery went into reverse at the same time. So these survivals are achieved with less surgery and more other treatments. Of course, the key here is you have to have treatments that work. Improved outcomes depend on new systemic therapies and as everybody would be very well aware, there's a sort of a revolution happening with PD-1 targeted therapies. This is Tom Powell's seminal paper in Nature.

Moving on, or moving sideways if you like, into the gut. The literature on bladder cancer quite closely parallels what's happened in anal cancer except with one huge exception. Various chemo-radiotherapy regimes are showing high activity in anal cancer from the 1970s onwards and the statement at the bottom is from the joint ESMO-ESSO-ESTRO guidelines, and they say that surgery as the primary therapeutic modality has been abandoned, which obviously hasn't happened in bladder cancer even though the literature otherwise looks pretty much the same. One of the key things, of course, is can you salvage local failures? This is data from the Christie Hospital in Manchester and this is a large number of patients, not randomized, comparing this at long-term survival with 300 or so primary cystectomies versus 239 salvage cystectomies, again over a very long time period showing identical outcomes. Again, you've got this 40% or so long-term survival rate which relates to the rate of metastases.

The question is, is there a penalty to pay in terms of surgical complications if you do primary radiotherapy with salvage surgery strategy? And again, from the same series of patients, there is no significant difference in any of the complications of surgery, primary or salvage.

Next question is, is surgery applicable to the whole population? And I think here is actually where the whole basis for the debate just falls apart. This is an age distribution of patients whose bladder cancer, for the UK, but it'll be the same in the U.S. and in most other countries. You'll see the peak age at diagnosis is in the mid-70s, but substantial numbers of over 80s. The large neoadjuvant chemo trials shown here have a median age in the mid-60s. The very large University of Southern California series of over 1,000 cystectomies is only slightly older and well below the peak.

In contrast, the chemo-RT dates I'm about to show you relate to men and women in their mid-70s, so much nearer to the peak. The data I'm going to show you is much more applicable to the whole population than actually the very relatively selected cases that get surgery.

My conclusion would be that surgery and radiotherapy relate to simply different groups of people and however you try and compare surgery with radiotherapy, you can't get away from the fact that the age distributions in these series are inherently very different.

Just to show you some quick chemo-RT outcomes, so I'll show you the data from my BC2001 5FU mitomycin trial. We've just updated this to give 10-year outcomes. This is the local regional disease-free control out to 10 years and you'll see you get very good local-regional control. That's driven substantially by the effect on invasive local-regional control, so you can see you're at or around 80% durable local control with respect to muscle-invasive disease. There are trends towards the survival benefit, and there is a statistics in bladder cancer-specific survival benefit, and also benefits on metastases-free survival and salvage cystectomy rates as you'd expect.

The other question, of course, is quality of life, and there's this widespread misconception that radiotherapy gives you a small, poorly functioning bladder. This is the toxicity data using the RTOG data from the trial I just showed you. You'll see there's very low rates of grades 2, 3, and 4 toxicity and low impact from adding chemo to radiotherapy. This is the patient-reported outcomes out to five years from the same trial. You can see you see a transient drop in some of the domains, but not all domains associated with the treatments, which is of course what you'd expect. But you can see these are otherwise stable all the way out to five years and in some domains like emotional wellbeing, they actually go up.

Can we select patients? I think you can select them either positively or negatively. There's a whole lot of patients who are unsuitable for surgery, like the elderly, the obese, severe cardiovascular chest problems, diabetes, reluctant to cope with a stoma. None of these are contraindications to radiotherapy.

There are patients you don't want to offer chemo-radiotherapy to and these are not the ones that typically crop up in the American trimodality series, which are a subset of what I've shown you here. So poor bladder function, there's obviously not much point in trying to preserve a bladder if you can operate. Extensive CIS is probably a contraindication but actually could be managed in other ways. Prior pelvic radiotherapy acting inflammatory bowel diseases certainly are, but obviously they make surgery hard as well.

I think you've got three patients. You've got fit for surgeries, fit for cisplatinum, i.e. for all options, fit for surgery, not fit for cisplatinum, which is probably quite a small category, and not fit for surgery but still fit for chemo-RT. And I'm very concerned these patients get undertreated because it's felt there's nothing that can be offered them when actually you can offer them effective radical therapy.

My conclusions would be there is no convincing evidence that surgery is superior to primary bladder preservation with salvage surgery for those only around 10% who failed with chemo-RT. Improved chemo-RT schedules with drugs like 5FU mitomycin give you very good pelvic control rates, but the key to improving overall survival is not better surgery or better radiotherapy. It's better systemic therapies, and I think we're now seeing those appearing in the shape of the IO drugs, FGFR3 targeting drugs and so on. Thank you for your attention.

Ashish Kamat: Thank you very much. You raised some very important points that we'll definitely circle back to. Dr. Williams, if you want to now tell us why you would favor surgery for this patient.

Stephen Williams: So that is a very important discussion and I would have to echo that it's deciding which treatment for this particular patient lies a large part in that patient/provider multidisciplinary decision making. As was alluded to in regards to the data, there are no randomized controlled trials comparing radical cystectomy to trimodal therapy.

However, there are several observational studies which have been performed, which have all their merits as well as their limitations but more importantly have conflicting evidence as was mentioned by Dr. James in regards to the survival outcomes, one of which that has been done in regards to looking at trimodal therapy versus radical cystectomy and it has been by our group. Largely this is because there have been no comparisons in regards to survival, but also, too, taking into account costs which are very important in bladder cancer being one of the most costly treatments. This is a very timely topic given our healthcare climate.

As has been mentioned before, trimodal therapy and radical cystectomy are good, particularly looking at survival and costs. What we found with particularly, say, this type of patient with stage 2 disease is that these patients have worse survival with trimodal therapy when compared to radical cystectomy. These are the survival curves which show those differences.

Moreover, we did sensitivity analyses and I think looking at patients that underwent trimodal therapy, only 50% underwent guideline-recommended chemotherapy. This is a study that was derived from SEER-Medicare data. It's a study to describe the treatment patterns as well as costs. What we noticed here, although survival did improve when they were receiving guideline-recommended chemotherapy or trimodal therapy, it was worse than radical cystectomy. Then importantly, when we looked at costs, there were significantly increased costs that are associated with trimodal therapy. This persisted at 90 and 180 days.

I think one of the questions and the doubts are, particularly with this type of study and other studies beforehand, is determining whether these patients are actually palliatively treated, given their median fractions are less than 18, and as I've mentioned before as well is these are observational studies and one cannot deduce or the indication for treatment decision making based on these claims' doubt.

Importantly as well is the fraction quantified was based on claims codes and there are bundled codes not accounted for in this particular study. When we look at neoadjuvant chemotherapy and radical cystectomy, there's further improved survival benefit associated with cystectomy over trimodal therapy.

Then when we looked at granularity and costs in a subsequent study, we noticed significantly increased costs associated with trimodal therapy and as one would expect, though, with radical cystectomy had increased hospitalization costs where trimodal therapy had increased costs, particularly among medication, radiology and pathology laboratory expenses. Interestingly enough, though, the medication costs, when we account for neoadjuvant chemotherapy, radical cystectomy actually had some increased costs compared to trimodal. However, this difference was about $2,000.

When we account for the intensity of treatments as well as survival, we noted persistently increased costs associated with trimodal therapy, which if you extrapolate nationally, can be up to $468 million for one year, costs associated with trimodal therapy.

Then once again in the subsequent study using inverse positive treatment waiting, we noted worse survival associated with trimodal therapy. Then once again, when we looked at the medium fractions in this particular study, accounting for those bundle payments, we noticed continued worse survival associated with trimodal therapy, albeit improved.

So in the conclusion here, as with most studies, is they're observational, have inherent selection bias. In addition, there are nuances to the evaluation of any type of study and it goes back to the data that's obtained. I think one of the most important things here is that we need to take into account, as Dr. James alluded to, variant histology subtypes. Also too, which is very important, is quality of life and then prospective clinical studies, and multidisciplinary decision-making is critical in keeping the patient first.

At my institution we are investigating this further alongside my radiation oncologist, understanding this disease in a SWOG 1806 study. So for this particular type of patient, it would be having that discussion with them, understanding the data as it presents itself and determining what's most suitable for the patient. Thank you.

Ashish Kamat: Great. Thank you so much, Stephen. With that brief background, let me ask both of you a couple of questions and I'll address it to you first, Nick. In patients that are considering the two options, radical cystectomy versus trimodal therapy, one of the questions that often comes up from the patients and the providers is the quality of life after radiation therapy in patients who might have been pretreated with intravesical therapy, for example, BCG, and then have muscle-invasive disease. How do you counsel these patients?

Nick James: There are two parts to the... I mean, that's a very relevant question, I agree. If somebody's got a very sort of angry bladder already, I would, if they've got the option of surgery and are an acceptable surgical risk, I'd generally say you should have surgery. If they've got a reasonably well-functioning bladder, I'll usually say, well it'll functional little less well. For example, we measured bladder capacity in BC 2001. It dropped on average around 50 mils at 12 months. So they're not seeing huge bladder shrinkage, but it depends how much bladder volume you've got to start with. But generally, I think I'd be guided by the symptoms they had. If they didn't have bad symptoms, I'd say you're probably fine having chemo-RT. But a lot of these patients do have symptoms and I'll steer them towards surgery.

Ashish Kamat: From my personal experience, patients who have had radiation therapy and then have surgery, we don't find any increased complication rates. And yes, the surgery is a little bit harder, but not so much so that it makes it prohibitively difficult. But Stephen, I know you have access to sort of population-based data where some have suggested that this particular issue may not apply to the urologists that are not doing these types of surgeries day in and day out. If you could comment on what you found regarding the complications of surgery after radiation therapy?

Stephen Williams: Certainly. So we at my group, our group hasn't looked particularly in regard to the complications that are associated following trimodal therapy as it was previously presented. The complications that may arise after trimodal therapy, it depends on the data and the patient selection. Then also too, the center where they're actually delivering the trimodal therapy and whether or not there are additional therapies administered after what's presumed a treatment failure.

But I think it goes back also too to the patient factors, and in America, although I don't want to be as, I guess, opinionated, but it is true, we have maybe a sicker population, increased comorbidities that may portend to different complication rates as could be compared to other populations. It also matters, I believe, in regards to the center. The center itself and the EAU actually just recently made it a part of their guidelines is high volume centers, at least greater than 10 cystectomies a year, if not greater. That would be, is greater than 20 a year. I think these have important ramifications when you're discussing complications and the severities of these complications.

Ashish Kamat: Good point and I agree with that. I do want to make one point though because people always talk about the expertise of the surgeon and how important that is, but they don't really talk about the expertise of the clinical oncologists, radiation oncologists, and I think that is just as important. Nick, what's your take on that? Can just anybody do radiation therapy for bladder cancer or should they be selected centers that are doing this?

Nick James: Obviously different healthcare systems do things very differently. In the UK, like Birmingham where I was working before, a city of 5 million people, there were only two hospitals permitted to do cystectomies by the NHS. It was all centralized. There were no guys taking out one or two bladders a year and there was only one radiotherapy center for the entire five million people with a huge number of [inaudible]. Within that, as we were all sub-specialized, so I only did bladder and prostate cancer. I didn't do anything else.

In places like the UK, that is what happens. Now if you operate in a different environment where you do a broader spectrum of disease, it doesn't necessarily matter because you will be... Say you're doing anal cancer, rectal cancer, head and neck cancer, as well. Well, they all have similar protocols using chemo-RT. So you will probably still be getting experience of managing the complications of chemotherapy and radiation, but just not in a sort of single-site setting.

It is easier to standardize chemotherapy and radiotherapy, the doses are fixed, the doses of radiation are fixed, the planning constraints are published and well-known and easy to put into your radiotherapy planning systems. Whereas surgery, I'm not a surgeon, obviously. I would imagine it is inherently much more dependent on somebody who does a lot of cystectomies I would imagine is always going to do it better than someone who does the occasional one whilst doing a whole lot of other stuff as well. I think it is easier to standardize.

Ashish Kamat: Great. So now, making it a little bit more of a topical question. We're right now in the midst of a COVID-19 pandemic and a question that has come up in multiple bodies that are looking at how we should or we could best serve our patients between radiation therapy and radical cystectomy, have each come up with their own pros and cons as to the benefits of one versus the other? What are your thoughts about this, Nick, in today's day where we have access to healthcare facilities restricted, where staff with potentially COVID-positive and may or may not know this? What do you think about the pros and cons of radiation versus surgery for our patients?

Nick James: I've been involved in the sort of pan-London emergency planning for this and the guidelines that we've put out suggest, where practical, to shift patients from surgery towards chemo-RT. I have to say not uniformly supported by the surgeons on the grounds that we felt that by and large if you are 70-something, long-term smoker and all the rest of it, being on a ward for four, five, six, seven, however many days it is was putting you at huge risk compared to the outpatient attendances for radiotherapy, particularly if you adopt practices like having patients sit in their car and get texts when their slot is available. So they don't sit in the waiting room, they come straight in and go on the machine, go out again.

We've gone to great levels at Marsden and other hospitals are doing the same to separate the known COVID from the known non-COVID patients and obviously that's going to get easier as tests get more available.

Now obviously other people, but nonetheless there are still going to be patients who have surgery. For example, we're saying, "If you're going to have surgery, you're going to have to self-isolate for 14 days pre-surgery because we're not going to want to operate on you if you're COVID-positive when you turn up." We've already seen patients turning up with clear COVID lung changes on their staging scans even though they didn't know they had it. It's going to be an evolving picture and I think we're going to have to be very careful not to harm people who are very vulnerable, basically.

Ashish Kamat: Stephen, what are your thoughts?

Stephen Williams: I mean, I would have to echo that. Our institution actually in the United States now, all elective surgeries have been canceled as we all are well aware. But also too now, for instance, all of our surgeries that we're performing, urgent or emergent, are having point of care COVID testing, but this does not always indicate, and there may be a number of false positives that come through. But I think it's important, particularly with this type of disease where there's an inherently increased risk of complications associated with radical cystectomy, that even more so we need to take under particular consideration and have a multidisciplinary discussion with the patient, as well as involving our radiation oncology colleagues, as well as our medical oncology colleagues to determine what's the most appropriate care for that patient and having that intelligent discussion.

Ashish Kamat: My sense with the way it's going and the fact that a lot of the issues with mortality are based on patients who end up on the ventilator is that with surgery if it is in a highly suspected COVID-positive region of the country, surgery seems to be a little bit taking too much of a risk for these patients when we do have a good, effective alternative, which is trimodal therapy. I do agree with the precautions that Professor James was mentioning. Again, we do have the option, obviously after discussing with the patient, to say, "Well, if the TMT doesn't work, we can then go in and do surgery when hopefully this curve will have been flattened and it won't be quite as much of a pressing issue." Again, everything's a moving target and it's hard to know what the right answer is, especially with the way everything with COVID-19 is mushrooming around the world.

As we end this debate, which has really been very informative and I do want to thank both of you for sticking to time and making it so valuable to our audience. But I would like to ask both of you to leave our audience with closing thoughts. So Stephen, if you could go first and then I'll have a Professor James close up.

Stephen Williams: Certainly. So I think what was alluded to before, I think in both of our talks and something that I've realized when analyzing this data and Dr. Kamat is well aware, is over 50% of the population in the United States and even in other countries have noticed non-curative therapy for muscle-invasive bladder cancer. And particularly in our series is these are patients actually with clinical stage 2 disease. I think this should be an eye-opening moment if you will, that we need to have an increased multi-disciplinary discussion and care for these patients. I think trimodal therapy is a valuable and effective tool when it's managed in the appropriate setting, but also too by the appropriate providers. I think having that multi-disciplinary discussion as we've seen in prostate cancer, but is even ever more important in bladder cancer.

Nick James: I would completely agree with that. I think for me one of the most important things is that at the left-hand end of the spectrum as it were, there's patients who've got a genuine choice of surgery or radiotherapy, bladder preservation, whatever. And that's one debate. But at the other end of the spectrum, which is what I'm more concerned about, I think there are patients who could have bladder preservation radical therapy with curative intent and would certainly get good palliation from it who are not getting any treatment at all. I think that's the end of the spectrum, as a urology audience, I'd urge you to consider referring far more patients for chemo-radiation with your radiotherapy department. Because I think that's the end that really stands to benefit a lot and it's low hanging fruit and it's a safe treatment that gives you good quality of life, even in an elderly population.

Ashish Kamat: Great. Gentlemen, I want to thank you both again for taking the time to put together such an interesting debate and informative session for the audience of UroToday. Stay safe in these days, and good luck.