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Ashish Kamat: Hello everyone, 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 my distinct pleasure to welcome today three experts in the field of bladder cancer, Professor Peter Black, Jens Bedke, and Hugh Mostafid. We are going to replicate today something we did at the EAU this year. And we had a nice crossfire panel discussion on the choice of urinary diversion in patients undergoing radical cystectomy. And today we are going to have the opportunity to not only hear what was said there but also expand it a little bit with a little bit more extensive discussion. So with that, Peter, I will flip the stage over to you.

Peter Black: Perfect. Thank you, Ashish. I'm going to get the session started with the presentation of a case on which we will base the discussion. So the question is, "Ileal conduit or continent diversion: which is a better choice for a patient with a GFR of approximately 60?" so normal kidney function. So I'm going to present what I would consider a relatively straightforward case without any hidden traps or problems. This is a 74-year-old female with a BMI of 26. She is relatively healthy, just some hypertension, on a single antihypertensive. She has very little in the way of past surgical history, just an appendectomy. She previously smoked but quit 15 years ago. She lives independently with her husband and remains active, at least socially, if not particularly physically. She initially presented with gross hematuria and was found to have a muscle-invasive tumor of the bladder, conventional urothelial carcinoma. There was right hydronephrosis which justified it as a clinical T3 tumor, but no nodal or distant metastasis.

She required percutaneous nephrostomy placement. And after this, had normalization of her kidney function with an estimated GFR of 65. She went on to receive neoadjuvant cisplatin-based chemotherapy, four full cycles of GemCis. She had a good clinical response based on imaging, and she is now proceeding to radical cystectomy.

And the question is what would be the preferred form of urinary diversion in this 74-year-old female. And so I'm going to invite Hugh Mostafid to give us his opinion on this, making the case for an ileal conduit. Mr. Mostafid is a urologic consultant at The University of Surrey in the UK.

Hugh Mostafid: Great, thanks, Peter. And it's a great pleasure to join in with this interesting debate. So the fact is that I think we need to consider when choosing a diversion for this lady, are the general factors that relate to her life expectancy and the likely changes in her mental function and frailty over her future life expectancy. There are also the issues of quality of life and this concept of decision regret, whether you ever regret the decision that you made with the operation.

And then there are organ-specific considerations to do with renal function after diversion, sexual function, the potential complications, not just around the time of the operation, but looking into the future, and then whether you might need to re-operate on these patients.

So this lady who is 74, she's an EU citizen, and we think that she could reasonably have a life expectancy of about 20 years. And this puts her in risk of developing chronic health conditions going right into her 90s. We know she already has got hypertension, she's an ex-smoker, so she probably has atherosclerosis. I think one of the things that we need to consider is not just a one-year outcome with a diversion, but potentially the 20-year outcome.

And I think we really need to consider not just counseling her, but her future carers, which are likely to include her children, because this is something that she is going to have to live with for the rest of her life. And I think we need to bear in mind that this healthy lady who's sitting in front of us, probably exercises, cycles, and so on and so forth. She is at significant risk, as you can see, with increasing age of developing dementia. And we know that worldwide, about two-thirds of patients with Alzheimer's in the elderly are female. So ladies are far more susceptible to developing dementia than men are, unfortunately.

And so this healthy lady that we can see now, what we have to think is, what is going to happen to her over the next 10, 15, 20 years. Is she going to be needing round-the-clock nursing care and might she even end up in a wheelchair? You can imagine the difficulties of trying to deal with a continent diversion if you are wheelchair-bound, frail, and in a nursing home.

On the other hand, if we focus on the specific issues around the diversion itself, we know that multiple studies have shown no difference in global quality of life between an ileal diversion and the continent diversion. And you can see here examples that pretty much every single physical activity has been successfully carried out with an ileal conduit.  And we certainly have never come across any kind of activity that any of our patients have managed to do that was made much more difficult by having a bag on. We also know from various studies that continent diversion is associated with increased bother from incontinence, particularly nighttime incontinence, and also sexual dysfunction.

Decision regret is quite an interesting concept, which people are looking at more and more. In this study, what it really showed was that patients do not regret having the conduit that they've had. And certainly, I'm not aware of any patients who have ever had an ileal conduit and wish that they'd had a continent diversion. Interestingly, we have seen a few patients with a continent diversion that we have converted to ileal conduit, but not the other way around.

If we look at one of the main concerns, renal function, we know that over the long term, renal function is exactly the same for an ileal conduit as with a continent diversion.  We know that renal function deteriorates with age, but the question that I would say is that if you have a patient with end-stage renal failure, which diversion would you prefer to manage? An ileal conduit is, by definition, incontinent and therefore is relatively easy to manage. Whereas the continent diversion has two sites of potential obstruction and therefore requiring this obstruction, the supravesical site, which obviously is the same as an ileal conduit, but also the infravesical area.

Other long-term complications, about 30%, and I accept that that is the same, whether it's an ileal conduit or a continent diversion. And the complications tend to accumulate over time. So the longer you have any kind of diversion, the longer you will be susceptible to having complications. We know that just under 10% of patients get a uretero-ileal stricture. But again, around 10% can get a vesico-urethral stricture, and 22% of patients with a continent diversion also have long-term problems with nocturnal incontinence.

So to sum up, I think personally, the biggest factor in this woman's decision is the life expectancy of the next 20 years. And unfortunately, she may well be susceptible to increased frailty, reduced mobility, and mental function. And this will place a big burden of care on her family and also society, in general. And so I think there is really only one choice for this patient, which is an ileal conduit. So with that, I'm going to hand it over to Jens to present the case for a continent diversion.

Peter Black: Thank you, Hugh. Let me introduce Jens while he is pulling up his slides. So Jens Bedke is a Professor of Urology at the University of Tubingen in Germany, and he is going to make the case for continent diversion.

Jens Bedke: Yeah. Thank you so much. It's a pleasure to be here with you today. And well, after we have heard in the last minutes that the conduit is not inferior to the neobladder, let's just stick now to the continent diversion. So I think, first of all, what is special in this case, and there are some properties which are unique. Well, it's a young lady, 74 years old. She lives independently with her husband and is socially active. The pathology is probably clinical T3 with right hydronephrosis and she received neoadjuvant chemotherapy, which all three points should be discussed. But there are a lot of unknown facts. Currently, it's a preoperative continence situation that we had a clinical downstaging to the neoadjuvant GemCis chemotherapy, what exactly is biological age, frailty and her attitude, her personal attitude towards catheterization, and heterotopic pouch, and of course, what would be her personal decision.

So, first of all, if you have a look at the age, she lives independently at 74 years old and she has a cT3 with right hydronephrosis. So what exactly is her life expectancy, which is limited due to the TNM stage. And if you have a look at the T3 tumors, the green Kaplan-Meier analysis, five-year overall survival is 65%. And we can split that up in this pT3 group to the overall survival and disease-specific survival rates. And what we do observe is that the overall survival rate is in contrast to the disease-specific survival rate. So patients tend to die of other causes, not of bladder carcinoma, and this gap is widening, and let's say, live long and live well until you die, not of your tumor.

Well, what about the post-operative complications and the preserved quality of life with an ileal neobladder?  So there are some comparisons, first of all, in patients of the other category and which is probably patients who received a potential neobladder, we observed that the neobladder compared to an ileal conduit have a lower rate of short-term complications. And the quality of life after radical cystectomy using these validated questionnaires and putting all this data together in a meta-analysis demonstrated that the neobladder is favored, in terms of this questionnaire's assessed quality of life. Well, there are some special issues with the pathology, with the hydronephrosis and this leads us to whether there is any bladder neck involvement, and is it still possible to do a neobladder in patients where the neobladder is not far away from the potential tumor site?

Well, first of all, urethral recurrence in female patients is a rare factor. Risk factors, of course, include trigonal involvement, but we know that the frozen section is a reliable method. So we observed here on this table, the recurrence rate in the urethra after the neobladder is a rare event. And on the other hand, we have a high accuracy of a frozen section analysis, if performed intraoperatively, we could rely on the result, which we get. And if the frozen section is negative, well then the bladder neck, and the urethra is free.

What is the impact of neoadjuvant chemotherapy? There is some limited data for a matched-pair comparison of cisplatin-based neoadjuvant chemotherapy on the 30-day and 90-day late outcome comparison to neobladder and an ileal conduit and there is no... well, let's say inferiority of the neobladder.  I would not say due to this limited data available, that this is a superiority even of the 90-day late morbidity and mortality [inaudible] should imply this in the Kaplan-Meier analysis, here on the far right. And don't forget, the field is moving forward with immune checkpoint inhibitors.

And we have the first data from Andrea, and looking at the PURE-01 trial that we can do immune checkpoint inhibition as a neoadjuvant approach in these patients. Well, the patient has a BMI of 26. We have several unknown facts. And well, is an ileal conduit always the better choice? We know that an ileal conduit is not always an operation surgery performing well in the long run. On the other hand, a neobladder can be done with small scars, which can be, well, diminishing in their pants. Not to forget costs, here, a calculation based on the German DRG system. Don't forget, for conduits, you need the stoma plates. For the neobladder, you do not need any additional devices.  In the long run, the neobladder is superior in terms of cost, compared to the ileal conduit.

Well, to take home; life expectancy in muscle-invasive bladder carcinoma is different and should be taken into account. You have an improved quality of life, of neobladder compared to the ileal conduit. You have no negative impact of neoadjuvant chemotherapy. The negative frozen section of the urethra is reliable and has good accuracy. And, of course, we have lower costs favoring the neobladder and therefore the right choice for this patient is clearly the neobladder. Thank you.

Peter Black: Excellent. Thank you, Jens. Maybe I'll start off the discussion with, you've both focused on age. This patient is 74 years old. You both highlight that she's actually relatively young at 74 and has a long life expectancy.  Yet, Hugh, you are concerned about the potential for frailty and cognitive decline, which makes me think you must be concerned about that in every patient since this patient has a good 15, 20-year life expectancy. So do you have an age cutoff in practice where you say, "Okay, I am not going to do a continent diversion because I worry about these issues, frailty, cognitive decline?" That's the first question. And the second question is, do you actually see that in your practice? Do you see patients and their caregivers struggling with the management of diversion based on age-related factors?

Hugh Mostafid: Yeah. So what I would say is that we would never turn down a patient who wants to have a continent diversion purely because of their age, but we have very rarely done one much over the age of about the late 70s, somewhere around 77. We have done a few. So I think a lot of it has to do with how fit the patient is rather than their numerical age. I think the other little bit of insight that I have had is that I've visited a couple of centers in the US that are specialized in doing continent diversions, including USC, and the one thing that struck me is that there is quite a difference in the patients in the United Kingdom. Because we are a National Health Service, we see everyone from the lowest socioeconomic class to the top socioeconomic class. And so we are dealing with, generally, frailer patients than, maybe, some of the centers that have always historically done a high proportion of continent diversions.

And so that leads on to the final bit of your question, which is yes, we have seen a modest number of patients, who were done by my predecessor, who are now in their mid-eighties, having had a pseudo patch done probably 20, 25 years ago. And some of them have had very problematic issues to do with their cognitive function, which has been difficult to deal with.

Peter Black: I worry, especially about the Indiana pouch in that context or other continent diversions, where the patient really has to reliably catheterize, as most patients with the neobladder, and will be emptying okay. And I don't think that age and cognitive function is as important in a lot of patients.

Hugh Mostafid: Yeah.

Peter Black: Jens, can you comment on how you use age in your practice?

Jens Bedke: Well, Peter, I agree with what you have said. And I mean, there is no clear cut-off age, but I think in the late 70s, you will get careful in recommending continent diversion. On the other hand, you should never deny what... I mean, our patients are usually older than the patient or the case presented here. So on the other hand, maybe we should not forget that if a patient has a very favorable course of his or her disease of bladder carcinoma, and we know that bladder carcinoma has a high risk of recurrence and the ones that we cured, that the cure is a rare event.

Well, except for the... since now, we have the immune checkpoint inhibitors. But anyway, we should not forget if we have done once a neobladder and even if you would like to avoid secondary surgery, if there is anything in the long run, which goes wrong, that you have the chance of undiversion to do an ileal conduit out of the neobladder. And while this should not be the reason for the first choice, that you have in your mind that you can do a second surgery and do an undiversion of that. But in patients who have had five, 10 years and they get older and are living longer, this might be an option not to be focused on, but It should be in our minds.

Peter Black: An important message is that it's important that we are able to offer the patients all options. And we shouldn't be steering them towards the diversion that best suits our needs based on our skill sets, which is just to say some places do not do a continent diversion, and it will be important to be able to offer that to the patient. Now, Jens, you've commented on sort of the extent of disease around the bladder neck and urethra, and that that would be a reason not to do a neobladder in a female, and I think that no one would debate about that. You also presented some data that neoadjuvant chemotherapy does not affect your choice. I would ask you to... or is there anything about neoadjuvant therapy and/or the extent of disease that impacts your choice of diversion? And I'm thinking here, for example of node positivity.

Hugh Mostafid: Yeah. I mean, that's a good question, quite tricky, the issue of node positivity. I think we can all probably agree that if the patient is node-positive, first of all, you're looking for a significant response to the neoadjuvant chemo. And the second thing is that I think we probably all agree, it's unlikely that we are going to cure the patient by taking their bladder out even if you do a reasonable lymph node clearance. The only exceptions to that are that sometimes when we see very young patients in whom, really, even if there is a very small chance of cure, they are willing to take a chance, then that's the one time we would consider it. But I'd probably say if you are 74, certainly in our practice and you've got lymph nodes, we would probably have a chat with the patient, but not be that keen on doing the cystectomy, anyway. The second thing with the bladder neck involvement is that I think we'd be worried about possible issues with bladder neck involvement. And we would probably look at the very least doing some biopsies around the bladder neck to see if there is still any residual disease there.

Ashish Kamat: These are great points that you guys are bringing up, the disease characteristics and obviously the pros and cons and contra-indications from a pure oncologic standpoint. I like the statement that Peter made because we do see nowadays where there are certain practices that, whether it's because of the use of the robot or not, is another matter to discuss, but some places will not even offer a neobladder or continent diversion to the patients saying, "Well, we are going to do this all endoscopically or robotically, and the conduit is the only way to go," which clearly is not fair to our patients. One of the things that struck me when I started getting involved with patient groups, is a statement that I heard from more than just one patient saying that when they met with their surgeons, it seemed like their surgeon was trying to sell them a neobladder as though that was the best model in the latest Ferrari.

Whereas the patient just wanted a simple option, which is a conduit, and they actually moved surgeons to find a surgeon that would do a conduit on them because the center that they had gone to was only pushing neobladder. So that was a unique perspective that I heard from more than one patient many years ago, which really stuck with me. This is a great discussion and we can go on and on, but in the interest of time, let me flip it back to the three of you and ask you each, leaving aside, pure oncological considerations, such as tumor at the bladder neck, potential positive frozen section, those sorts of things. Which is in your mind, the ideal candidate for a conduit versus a neobladder? Just purely from a patient characteristic. Is it that patient who has a history of prior prostatectomy or a patient who has no access to good healthcare in terms of supplies? I mean, what would you advise our listeners and our audience to consider from a pure patient perspective, leaving aside the oncological edge. Peter, maybe I'll have you start.

Peter Black: Yeah, I think it's a good question, Ashish. I think so much depends on what the patient wants and it's difficult for patients to get a really good understanding of what they are getting themselves into. They do not really know what life is like with a neobladder or a conduit, for example. And so I think it's important to portray that to a patient. Ideally, they would talk to peers and have written and perhaps video information online, for example. And then I think it really depends on exactly what the patient wants, and different patients have different needs.

A lot of patients, you might think, that they are in their early 50s, they are active, of course, they're going to want a neobladder. And when they have a good understanding of what's involved, they say, no, I want an ileal conduit. And so I think our job is to educate and then the patients have to decide. But certainly, the main factors are just a younger, active patient, often a more sophisticated patient, who is really looking to avoid a bag and that understands the intricacies of a neobladder or continent diversion, that is often tied to better access to healthcare, better engaged in their own health. There are a lot of sort of social aspects like that, that I think is important.

Hugh Mostafid: Yeah. I mean, I think Ashish and Pete, you make really good points. And I'm aware that there are some instances where a patient has been really sold on a neobladder. I think you're really kind of making a rod for your own back to try and push a patient into having a neobladder. And with regards to how I pick, I think, first of all, it's impossible to make that decision on one single consultation. So we always allow the patient to go home and bring them back shortly afterward to see whether they've had a chance to mull it over. And I think one thing about, particularly neobladders, is you've got to really be able to trust the patient that they... You've got to have this sense that they really know what they are getting themselves in for. And if they really do appear to be fully informed with realistic expectations, then I don't have an issue with it. But on the other hand, sometimes as you say, younger patients will just say, I want an ileal conduit, and equally, you just go with what they have decided.

Jens Bedke: Ashish, I totally agree with what Peter and you have already said. I mean, you made a very, very important point that we are not sellers. We do not sell neobladders. Our task is to give advice to the patient. And if the patient decides for an ileal conduit and we think they should receive a neobladder, it's not our task to convince the patient. I think, all in all, with this process, we need time. And this is, I think an important message. We have to take time, time for our patients. And as you said, we have to counsel them twice or even three or four times. Because even if the patient receives the diagnosis of muscle-invasive bladder carcinoma and the advice that the bladder has to be removed, usually this is such a huge burden that the patient cannot really decide.

Then the next step is to do neoadjuvant chemotherapy or to do what type of diversion should be done. So we always do secondary counseling, second appointments. We always send the patient to the stoma care nurse where there they will get excellent advice. We always put the stoma back on the place where it will be just for simulation and just to get an impression. And Peter, you said, to get the peers or try to get them in contact with other patients who have a neobladder or an ileal conduit. And in the end... so this takes time, then we will have the final decision. This decision should be there prior to the admission to the hospital to do the surgery.

Ashish Kamat: Great point. Yeah. The patient should not be burdened with the decision right in the morning, prior to surgery, which again, I have heard from certain patients where they met a nurse or someone in the recovery or holding area, right before surgery, who convinced them to switch their diversion. But anyway, we could go on chatting about this for a long, long time, but I really want to thank each and every one of you for taking time from your busy schedule to spend with us and our audience today. And it's been very informative. Thank you again.

Peter Black: Thank you, Ashish.

Hugh Mostafid: Thank you.

Jens Bedke: Thank you.