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Ashish Kamat: Hello and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center in Houston, and it's my distinct pleasure to welcome to stalwarts in the field of bladder cancer to join us today, Professor Param, all the way from Edinburgh, and Professor Mir, all the way from Valencia. We're going to recapitulate a debate that we had at EAU23 in Milan this year. It was a debate on the pros and cons of organ--sparing, reproductive-sparing cystectomy, both in males and females. We had a hypothetical case at that point, which, again, we won't use today specifically because we want to have a journal discussion on the feasibility and the safety of organ sparing, both in men and in women. With that, Param, I'll hand the stage over to you.

Param Mariappan: Thanks a lot, Ashish and UroToday. I'm looking forward to this discussion. Essentially, my task is to oppose the motion of organ preservation. It's useful to put out a disclaimer that this is mainly to encourage discussion and does not really reflect a rigid clinical stance.

The premise of this organ preservation is essentially to try and preserve continence and sexual function for the patients. However, it's not as simple as that, and let's put some perspective into the equation. Neobladders, as we know, don't really happen in a vast majority of patients. In fact, in this particular age group, it's probably done in less than 15% of patients. Equally, sexual dysfunction in cancer patients is really a complex problem, and particularly in those who are young and adolescents. With this in mind, let's take a more systematic approach to this problem.

When it comes to clearing the current cancer, I give it to you that prostate cancer diagnosis is probably simple, however, prosthetic urethral cancer is a different beast altogether. Why? Although it's seen in about 1 in 3 patients, perhaps this is an underestimation, because there are at least four known mechanisms of spread of cancer to the prosthetic urethra, and perhaps conventional biopsies could actually miss these.

We are also told that prosthetic urethral or urethral cancer is more likely when the primary tumor is multifocal, situated in the trigone, or this presence of CIS. However, we really are reliant on tests and tools, which are somewhat flawed. We know this because we still find a substantial number of cancers at re-resection, carcinoma in situ is missed in up to about 50% of patients, and from looking at a molecular landscape, we now know that even in solitary tumors, there's significant field change well beyond the primary tumor. When it comes to additional information, we do make staging errors. This is not unique to all centers, and even centers of excellence have staging errors, you can see here from this graph. And what this under-staging does is it translates to not only survival disadvantage but also is associated with a higher risk of advanced disease and reproductive organ involvement, which is further subrogated by the presence of variant histology. And if we don't really look for these variant histology cells, then we are likely to miss them in up to about 40% of patients.

What about safety? Yes, urethral cancer can be found or missed if organs are preserved, but what is important is the risk of cancer in the organs that we preserve themselves. This may translate to quite an onerous follow-up and also repeat surgery, which can be quite challenging. The risk of these men developing prostate cancer is going to only increase in time, and in the female, the risk of endometrial cancer, as we all know, is on the rise and will continue to increase in these women. We also know from our gyne colleagues that they actually want us to opportunistically remove the fallopian tubes to reduce the risk of ovarian cancer.

When it comes to continents, perhaps preserving some of these organs may help. However, the data that we have is somewhat flawed, mainly because of small sample sizes and with high risk of bias. As I mentioned earlier, sexual dysfunction is quite complex and it's not just simply fixed by preserving the organs and the evidence base is really quite flawed.

Therefore, in summary, are we really going to change the goalpost because we missed the target? We have to be cautious because we might actually just change the whole game. Many thanks.

Ashish Kamat: Thank you, Param, for that very succinct stance and I'm glad you clarified what your actual stance is. But for the purpose of this debate, we're going to make you stick to your guns and fight Carmen after she's done. With that, Carmen, the stage is yours now.

Maria Carmen Mir: Thanks, Ashish, for the introduction. My role for the next 3 or 4 minutes will be to defend the active involvement of prostate-sparing and female-sparing radical cystectomy. As we looked at it and Twitter plots, it's a hard job because for females it seems to be taken on for urologists. However, for males, prostates-sparing doesn't seem to be quite embraced by urologists overall.

The rationale for prostate-sparing radical cystectomy comes mainly from underneath to avoid any to mental effects secondary to the cystectomy, either in quality of life, urinary function, sexual function, emotional health, body image issues, or psychosocial stress. Actually, prostate-sparing radical cystectomy is a controversial topic, and if you look at EAU guidelines for muscle-invasive, it does not support its use except for highly selected cases. Also, to take into consideration that several definitions of prostate-sparing have been reported and the outcomes that we have are taking into consideration that also imply open and robotic outcomes. So every cook has a different recipe, that makes it very difficult to explain.

Upfront, the requirements for prostate-sparing cystectomy are the ones we expose here. Basically, a good performance patient that does not have any involvement of perivesical fat and it has good sexual function, good continence, no issues with prostate cancer, and is willing to go through the process. If we look upfront, the only prospective data that we have so far on the topic was published over 10 years ago, approximately 75% of the cases were then open, and unfortunately did not show any results in the difference in terms of prostate-sparing versus nerve-sparing in terms of functional outcomes, urinary outcomes, sexual, or oncologic outcomes. Unfortunately, this trial was underpowered due to the lack of recruitment.

If we look a little further, the only serious long series that we have so far in the topic looking at nerve-sparing versus prostate capsule-sparing is from a single center. They have reported good outcomes in terms of urinary function, sexual function, and oncology outcomes, as we can see on the table. However, there is no report, for example, how many patients require intermittent catheterization or other diseases related to the prostate sparing.

When I think about if I'm going to offer somebody a prostate-sparing radical cystectomy, I look at three things I worry about. One would be urothelial occurrences, like my colleague Param mentioned, because they have a strong impact on overall survival. If we look on the table, we have some of the major series that we have on prostate sparing, we can see that, yes, the local recurrences exist, however they seem to be already stated. Again, if there is an up-staging of patients, for example, from cT2, that will be our profile patient. Up to pT4 it does exist, but it happens in any location.

What we also see, and I worry about, is the urothelial cancer within the prostate urethra that it can happen, as my colleague mentioned, but it can also be reported and explained to the patient. Finally the last thing I worry about is a prostate cancer incidence. As we can see on the series on the right, the rate of clinical-significant prostate cancer is quite low.

If we move to the female, obviously women are less likely to be counseled about this sexual dysfunction that we were talking about. Probably 60% or less receive any kind of counseling. Actually, non-sparing the vagina and all the sexual organs might provide a lot of grade of sexual dysfunction that is very difficult to measure. If we look again at the requirements, they are pretty similar to before. The ones that I mentioned. Basically patients with non fat-invasive, no T3, young age, good performance status, and good sexual and urinary function.

Is there any rationale for removing the ovaries? Obviously it has the advantages that it eliminates the risk of ovarian cancer and breast cancer, and also the risk of having bladder cancer into the ovaries. However, it has been shown that it increased the risk of mortality, cardiac disease, and menopausal risks. And as you can see on this well-known manuscript that was published a while ago and looked at females having had hysterectomy before 50 or after 50, as we can see in the middle, the rates of cardiovascular events are quite higher if you had it in a young age.
About opportunistic salpingectomy, my colleague also mentioned it. As we can see, it is associated with fewer than expected ovarian cancers. This is out of a population study that was over 25,000 patients that had hysterectomy alone or tubal ligation, and then they had the opportunistic salpingectomy, and they could see that actually there was a decrease on rate of serious ovarian cancers.

Again, for females we worry about three things. Local recurrence once more, unitary function, as we know one-third each, and the sexual function, that I mentioned before, is quite difficult to measure. You will look at some oncological and functional outcomes that has been presented over the last couple of years. We can see that vaginal sparing and organ sparing for female is a safe option even including histologic variance. This is on the left, one of the longest series that we have so far. And we have also functional outcomes with robot-assisted radical cystectomy that, as we can see, it shows decent functional outcomes. However, it got my attention that 50% of the patients actually got intermittent catheterization anyway.

What to take home from this? The key features is a patient selection for, we need motivated patients that want to preserve their sexual function with localized muscle-invasive and that understand the risk of upstaging and recurrence. So looking forward, we should do better in terms of selecting patients in terms of how our outcomes are measured and getting the trifecta outcomes. And also, a couple of ideas about how we should look forward. Probably bladder MRI might help in the concern for upstaging and surgical planning, and also, molecular markers might help in terms of patient selection. Thank you.

Ashish Kamat: Thank you, Carmen, for that viewpoint. Again, I know that between the three of us, we all agree that in the appropriate patient organ sparing, vaginal sparing, ovarian sparing, and nerve sparing is very, very important for our patients and we have to always factor that in. Let me ask you first, Carmen, when you are a counseling a patient and you're sitting with the patient in clinic, what are some of the points you discuss with, say, for example, you're a female patient that might be on the younger side of things when it comes to vaginal sparing and nerve sparing and reproductive organ sparing, what are some of the things that you discuss with the patient?

Maria Carmen Mir: As I mentioned in my discussion, probably the things that I mentioned is that she has to understand the risks of recurrence. That seems to be more accepted in general, it seems to be more widely known urologists, and then the functional outcomes that are related with it that are not as good as we think, in general. As I mentioned, I always say the third rule, that one-third [inaudible 00:13:45] continent, one-third incontinent, one-third okay. So you discuss definitely the need of self cut and the fact that they can be in incontinent. Those are very important things. Honestly, it is hard to counsel about sexual function because it's, as I mentioned, something that is really poorly understood, poorly reported, and the definitions are not clear. So, honestly, this is very, very hard to discuss overall. Those are the three things, definitely, that I would discuss.

Ashish Kamat: Great. Param, I mean any additional points when it comes to counseling patients that you factor in?

Param Mariappan: Absolutely, Ashish. Unfortunately in our environment we still see a substantial proportion of patients presenting with a locally advanced disease, particularly in women. And we know from a recent study that was led by Jim Cuttle about a third of our patients, sadly, at the time of presentation actually are not suitable for any form of radical treatment, either because they've got advanced disease or they're not fit enough for surgery. I think, primarily in our mind, especially with that data, our patients are very concerned about the oncological outcome. So I think the main thing that they ask from us is, "Can you cure me, doctor?"

I think sexual function, continence are secondary matters, especially since less than a tenth of our patients have some form of reconstruction to maintain continence. I'm not very familiar with trying to preserve these organs for sexual function and I don't think there's a huge amount of experience in the UK in this area.

Ashish Kamat: I think that's a very important point that both of you made, because, ultimately, if you ask the patient what's important, they'd rather be alive than not. And if we don't enlighten them and educate our patients, sometimes it becomes like an echo chamber where you hear people talk about organ preservation, organ preservation, organ preservation, which is very important, but not at the cost of the patient's life. And if the patient doesn't understand that, then clearly it's we've not done them a service.

Let me ask you both, and this time, let me start with you, Param. If a patient comes to you and says, "It's absolutely essential, I want to preserve sexual function, not that it's more important than oncologic outcomes, but that's really, really important to me." Does that change your thinking as far as offering maybe trimodal therapy over radical surgery to the patient?

Param Mariappan: Absolutely. Again, our practice in the UK is often we try to maintain equipoise, and we actually suggest that there's probably some benefit in patients who would like to preserve sexual function. But again, there's a counter-argument to that because these are more likely younger patients and probably a long-term follow-up following trimodal therapy may not be in their best interest. So there are lot of lots of elements that they need to take into account. But definitely trimodal therapy to try and preserve the organ, yes, and again, poorly understood. The quality of life that happens after that is really poorly understood as well.

Ashish Kamat: Yeah, again, you made an important point because it's the younger patient that's motivated, but it's also the younger patient that might have, potentially, the most detriment from not going into cystectomy, for example. Carmen, any thoughts as far as the culture in Spain or your personal experience with these sorts of discussions?

Maria Carmen Mir: From my personal experience, we do embrace trimodal therapy here in Spain. It's a little more embraced probably than in other areas. To me it definitely overlaps. It's the profile of patient where you would offer the organ-sparing cystectomy. It definitely overlaps, as we can see, with the patient that you would offer trimodal therapy. It would be a hard choice for me to decide how to explain to them how they would choose for it. As we said, quality of life outcomes are not clear in any of the situations.

The other thing that I think is interesting also is that there is a lot of mismatch between the reported outcomes. We said most of the data that we have on prostate sparing is based on the open era, and probably in that era it made sense to have the prostate-sparing approach or the organ-sparing. However, with robotics nowadays, we see better, we do better. So what we call nowadays nerve-sparing is probably very similar as a concept of what you would call in an open era the prostate-sparing. So I think that in terms of outcomes, it would be very hard to explain a patient how different they are and how the mismatch of data that we have can be explained. It's something that comes to my mind when I see all the data that we have.

Ashish Kamat: Now, you make a good point Carmen, as far as the data from prostate-sparing being the open era, but I don't think there's any literature, and in my series, actually, there's no difference in sexual function recovery after robotic and open cystectomy. There isn't any data on that, so I think we have to be a little cautious there. But yes, it makes sense to sort of recapitulate what we've seen in the past and try to do it in the more modern era. I know a lot of bladder cancer experts across the world are going away from robotic cystectomy because of the lack of benefit or perceived benefit other than one or two days or 90 days, as was shown in the UK study.

But let me ask you a pointed question then, because you showed data, and again you were given this stance, but what would you say to a patient if you're trying to discourage them or tell them the cons of doing a prostate-sparing cystectomy?

Maria Carmen Mir: For me, honestly, I've never done it myself, to be honest, but I follow patients that had that procedure done and what I see is that they have a lot of issues with emptying their bladders. The new bladder, because of the prostate on its own, has a lot of issues and generate a lot of problems in them. A lot of UTI issues that make them come back to hospital quite more often than you would expect without the prostate sparing. So that would be one of the real practicum reasons that I would not encourage it to for them.

Ashish Kamat: Yeah, the only patients have done prostate sparing are those that have wanted to spare their prostate for fertility, not so much for a sexual functional continence, but these are very young men who, for whatever reason, religious and otherwise, said that they could not do sperm banking and if they could not have a natural child, they would just never have kids. So I spared the prostate in some of the vesicles for that reason. Param, what's your experience with prostate sparing and how do you consider that in the grand scheme of things?

Param Mariappan: Absolutely. I think the important point here is to consider the surgeon experience, surgeon volume, hospital volume. These are highly, highly complex operations and I don't think we can put across a broad brush to say, "Well, in everyone's hands, the outcomes are going to be similar." I am a high-volume surgeon, but I have very little experience in trying to preserve prostates or reproductive organs. So I'd probably suggest a referral to someone else who's a high-volume surgeon, who's got experience in doing these operations rather than trying to take on the patient myself. Because in the end of the day, we have to do what's right for the patient.

Ashish Kamat: And I think that's a great point to end this on. We have to do what's right for the patient. I think we all recognize, the three of us and the whole field, that we don't need to jump on the latest bandwagon, whether it's for or against a particular topic, but the patient voice and the patient ultimately comes first. Once again, thank you both for taking the time. This was a great session and thank you to UroToday for allowing us to do this.

Param Mariappan: Thank you UroToday. Thank you.

Maria Carmen Mir: Thank you.