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Ashish Kamat: Good morning and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urology at MD Anderson Cancer Center in Houston, and it's my distinct pleasure to welcome a friend, colleague and an expert in bladder cancer, Professor Fred Witjes, from Nijmegen in the Netherlands, to talk to us today on the EAU Guidelines, focusing on muscle-invasive bladder cancer. Dr. Witjes can talk to us on multiple different topics when it comes to bladder cancer, but today, he's going to focus on the guidelines, certain highlights, and then we'll have a brief discussion towards the end. Fred, take it away.

Fred Witjes: Okay, Ashish. Thanks for the invitation, also, UroToday, to be able to discuss the guideline on muscle-invasive bladder cancer. I have done some conflict of interest, but they're not relevant for this lecture. And as you can see here, I'm actually not talking only on muscle-invasive bladder cancer, but also metastatic bladder cancer because that's in the same guideline. There is some news in that respect, which I will discuss at the end of this lecture.

So I'll just pick out a few highlights, which I think are relevant for a 2020 bladder cancer treatment or a guideline discussion. One of the things that we see is more relevant and more prevalent in the last few years is variant histology, used to be only urothelial carcinoma and a bit of squamous cell and a bit of adenocarcinoma in the bladder, but you'll see all kinds of variant histology more and more reported these years.

You see on the upper right side, that with the bladder cancer guideline, we have done a nice systematic review on that, which actually has shown us that mostly these variant histologies are a little bit more aggressive. You see in the lower part, that it doesn't really influence your treatment still for most invasive variant histologies. Radical cystectomy is the way to go, except for small cell carcinoma, as Ashish already mentioned on a paper in 2013, that you should treat systemic disease. So you really should start with chemotherapy to get downstaging and then you might consider surgery or maybe try modality treatment. But for the rest, it's still treated as a urothelial carcinoma with radical cystectomy, but do keep in mind that this is going to be mentioned more and more depending on your pathologist.

Then pre-surgery, what shouldn't you do, and I guess most people don't do that anymore. I've been trained still with preoperative radiotherapy, but strong recommendation not to offer preoperative radiotherapy. What you should do — and that's again, a strong recommendation and guideline — is offer preoperative chemotherapy. That should be cisplatin-based. If patients are not cisplatin eligible, then you should try something else. And that is a problem because a lot of those patients are cisplatin-ineligible. As you can see here, again, a nice study from Memorial Sloan Kettering, you'll see that around 50% or even more of these patients have an impaired renal function, which means it cannot be treated with cisplatin-based chemotherapy.

Apart from that, most of those patients are not in a very good condition. They have an impaired performance state. Most of them have been smoking or are still smoking. As you can see at the lower part on the right, the average age of these patients is around 70, 75. So again, also, age is usually a problem in these patients and prevents us from giving adequate chemotherapy. And even if you start with chemotherapy, you'll see that in this nice study, it's a SEER-Medicare analysis that nearly 30% of the patients, which actually were fit to get cisplatin-based chemotherapy, are not able to complete the regimen. So in all, a lot of those patients do not get adequate neoadjuvant chemotherapy. That's the reason that you see also, a very recent study, again from National Cancer Database, but still, you'll see that in real life, neoadjuvant chemotherapy apparently doesn't have a lot of advantages. You have a higher pT0 rate, but the overall survival benefit is not as we thought it would be in the study status, 5% to 7%, but in real life, that is absolutely less. You see in the lowest line, the bottom line, that the reason is quite simple, that there are important baseline differences between trial patients, like in a SWOG trial or in the RC trial, and the patients you and I see in daily practice, again: age, smoking, performance status, et cetera.

The second thing that you have to keep in mind is that most of the studies that have shown a survival advantage for new regiment chemotherapy are often done with MVAC or MVC. We are used to giving gemcitabine cisplatinum nowadays, which is less toxic, but also a little bit less effective. As you can see, one of the few studies that have addressed that quite recently. So, apart from the fact that the patients are probably worse than we see in studies, also, the regimen with chemotherapy is a little bit less effective.

Let's go to surgery. We are urologists, so that's something that we do every day. What about the extended lymph node dissection? So again, with the guideline, we have done systematic review a few years ago and in spite of all the limitations of the studies that we have used for the review, extended lymph node dissection seems to improve survival. You see that has been translated in a level three recommendations, so it's not very strong recommendation that you should do, an extended lymph node dissection together with your cystectomy.

There are two randomized control trials: The SWOG trial is still ongoing, so we hope that we, this year or next year, we will have some results of that and the German trial has been registered and published last year. Here you see the results. You see that adjuvant chemotherapy has been offered to patients with invasive bladder cancer. They randomize between an extended node dissection and the limited node dissection around 200 patients in every group. You'll see that even the limited node dissection were on average, 90 nodes, which means already I think very thorough surgery. The extended node dissection were 31 nodes, and you see that actually there is no survival benefit in the patient group with an extended node dissection. The only exception is to subgroup analysis in pT2 tumors, which, to my opinion, does make some sense. If you have a limited tumor, then the few nodes you might have, if they are dissected, that might be a difference. Although, of course, this trial was not for the sub-analysis. This trial was not designed to show this difference in this small sub-analysis of patients with the pT2 tumor. So it still is out there, whether an extended node dissection really does improve survival.

What about the way that you do your cystectomy, robot-assisted, or open cystectomy? Well, this is a systematic review of the five randomized controlled trials that have been published until very recently. It's a publication of this year. So of course the randomized controlled trials are not very large. The trials in all had 550 patients that were treated and you'll see actually no difference in complications. Robot has a little bit less blood transfusion and blood loss and marginally shorter hospital stay, around one day, longer operative time, but in all areas, a very, very limited difference between the two ways of surgery. So the surgical approach doesn't really have a considerable impact on oncologic safety or quality of life outcomes.

So I do support our own recommendations in the guideline and you can see them here. So you have to inform your patients about the advantages, but also the disadvantages of the different forms of cystectomy. And I guess more important is to select an experienced urologist or an experienced center instead of just choosing for a way of doing that. And both recommendations as you can see, are strong. What about diversions? So my main choices are uretero-cutaneostomy, I do that a little bit more than a few years ago because you avoid the bowel part. And especially in older patients that really helps to avoid a lot of those complications.

Then you have the ileal conduit, and for me, if I do an orthotopic diversion, that's the Hautmann neobladder — which diversion is better? Well, actually, if you inform your patients, I don't think there's a large difference. The neobladder, if you don't inform your patients well, even score less in the first month after surgery, because it's of course more time consuming and labor-intensive for a patient if he has neobladder. If you have a conduit, you just put on a back and that's it, if you inform your patients well, I think in the end, the outcome of neobladder might be a little bit better, but in all, the differences are very limited. Also, a good ileal conduit is a very, very nice diversion.

What about bladder sparing treatments for localized disease? Again, that is something that almost was not mentioned five to 10 years ago, but it is getting more and more popular in the current years. You should not offer as monotherapy for curative intent a TUR, or radiotherapy or chemotherapy. Of course, there are reasons to do so. For example, radiotherapy, if there is hematuria, or TUR, if you still also have hematuria, but for curative intent, I think multimodality treatment is something that is really gaining popularity. And multimodality treatment means a good radical TUR, in two stages with a re(TUR) radiation and chemotherapy as a radiation sensitizer.

And here, you see in blue, the two recommendations in our EAU guideline from 2020, there you see that you can do offer multimodality treatment as primary curative therapeutic approach in select patients. And that's something that you really have to do, select your patients well, and inform them very well.

Reasons not to do this, is, for example, carcinoma in situ, that's one of the reasons not to consider radiation therapy. Hydronephrosis is a reason not to consider radiation therapy. And if you are going to do a multimodality approach, then you really should try to do a good and radical TUR. So let's say, debulking surgery. So the last part you see, table seven, six, four, two is from a very large EAU-ESMO consensus meeting that we had in 2019 to amongst others, address multimodality treatment. I advise you to go to that manuscript. It gives you a lot of information.

And then finally, my next to last slide is metastatic disease. Of course, you still have there our good friend chemotherapy, which is again, like we already said, cisplatin-based, but we now have immune checkpoint inhibitors, and that's first-line in patients that are unfit get cisplatin. So that's better than start with carboplatin combination therapy. And of course in second-line treatment patients that have had chemotherapy with cisplatin, if they get a recurrence and checkpoint inhibitors is the first choice as second-line treatment. And you see that all these recommendations are strong recommendations.

Reasons why this is important: Bladder cancer, you know, of course, that [inaudible] in bladder cancer is very high. And just like in melanoma and lung cancer, bladder cancer is a good candidate for immunotherapy. And in most of the trials, you see that, let's say around one-fourth of the patients do respond well on immunotherapy. And a big advantage is that if you do respond to well, you respond for a very long time. And this is one of the things that was new, or at least that was addressed again during the virtual EAU meeting of this year. And a lot of those trials are still going on, and outstanding in different indications in bladder cancer, even in higher-risk non-muscle invasive bladder cancer.

Summarizing my presentation: Know the options in variant histology, know that it is mentioned more and more and might have some consequences for your treatment. Use neoadjuvant chemotherapy, that's the guideline advice, but know the limitations, not all patients can have that. Do good surgery, which means an extended node dissection. I think that's still something you have to do. The surgeon counts, not the method. So also an open cystectomy still is a valid way of treating a patient. And immunotherapy is developing, is there to stay, and certainly in bladder cancer, I think this is going to be one of the things that we have to use in current practice.

Ashish Kamat: That was excellent, Fred. You've covered a lot of very, very important points in a short time. And I want to compliment you on being able to do that in such a concise manner. If I might, I will ask you some questions that may be going in reverse order, maybe starting with the bladder preservation first. As you mentioned, in the guideline statement, and of course, that's something that I agree with as well, that TMT works best in patients who do not have CIS, who do not have hydronephrosis, and where a tumor debulking is performed by the urologist. But there's a lot of discussion in more recent times, both from the Mass General group and from the UK group from [inaudible] for example, that you can treat patients with CIS, you don't need to do a TURBT, you just a biopsy is sufficient. Could you comment on some practical points that you've come up with when it comes to this evolution in trimodal therapy?

Fred Witjes: Yeah. So I guess we've been doing that in the Netherlands already for a few decades. The group in Rotterdam started with that in the sixties. So we are a little bit used to trimadolity treatment in bladder preservation in Holland. And in spite of all the things you read from UK, from the US, I still think that a good transurethral resection, which for me also makes sense, is an important starting point for trimadolity therapy. And of course, if there is carcinoma in situ, you can also treat that with intravesical therapy after trimodailty treatment, but I still would like not to select those patients for trimodality treatment, and certainly not a patient with hydronephrosis, you will run into trouble. So I would think that the consensus statement that we had in 2019, and that's really very recent, we did that last summer, for me, it's still valid. So I wouldn't select CIS. I wouldn't select hydronephrosis. And I would really like to do a good TUR.

If you look at the outcome and there is no randomized control trial comparing cystectomy versus trimodality treatment, and I guess that will never happen, you'll see that initially, maybe five to 10 years, the outcome is more or less the same. Of course, you have to do still bladder cancer followup in the bladder in the patients at that trimodality treatment. But you see, after let's say 10 years or more that there is a slight decrease in survival after trimodality treatment. So there are some differences, although I think it is a good initial treatment and certainly for an older patient that wants to preserve his bladder.

Ashish Kamat: In patients that choose to have a trimodality therapy or bladder preservation, when they develop an intravesical recurrence, assuming it's non-muscle invasive and has all the other characteristics where they could ideally have been treated with intravesical immunotherapy BCG, do you modify your intravesical regimen use because they've had radiation, any tips for the audience there?

Fred Witjes: Not specifically, or not only when they had radiation, only of course, when they have a lot of bladder problems, which you do see in 10, 20% of the patients, they will have some urgency or lower urinary tract symptoms. Then of course you have to train your schedule, maybe start with a lower dose or give anticholinergic drugs. So it's not only based on the fact that they had radiotherapy there but more on how their bladder is behaving at the time point that they have a recurrence.

Ashish Kamat: Yeah. And that's an important point for the people to keep in mind because often times I'll see where patients are not offered BCG simply because they have a history of radiation, whereas they have almost near normal bladders and could have had BCG therapy.

Fred Witjes: Yeah. That's not a specific contraindication. I agree with that.

Ashish Kamat: All right. Keeping with the radiotherapy theme, you mentioned that preoperative radiotherapy should not be recommended to patients. And I do agree with that general statement, but one particular situation, do you still consider that we should not offer pre-operative therapy for patients with bulky squamous cell carcinoma? And if you don't offer pre-operative therapy in these patients, do you consider intra-operative radiotherapy when there's a suspicion for margin positivity?

Fred Witjes: Well, you'll see if you look at the literature, that preoperative radiotherapy with stream cell carcinoma does improve the maybe, local operability. What we do usually is do the cystectomy and then offer adjuvant radiotherapy. We don't do simply because we don't have that here. We don't do intra-operative radiotherapy. And what I just do [inaudible] cystectomy. I try to put clips there where I think there is a positive surgical margin, and then offer adjuvant radiotherapy because if you don't mark the spots where you want to have radiation, it's difficult for radiotherapists to choose a radiation field when the bladder is out. So we don't do pre-op, but we do maybe post-op.

Ashish Kamat: Do you take any precautions during surgery to keep the bowel out of the pelvic field in patients that you feel might require postoperative radiation, or do you rely on your radiotherapists, who are obviously experienced, in order to avoid pelval toxicity?

Fred Witjes: Actually both. So I think with the current imaging techniques, radiotherapy is much more directed and less toxic than done 20 years ago, but I also then try to put momentum in this lower pelvis or try to get the small bowel out of the small pelvis. So I actually try to do both.

Ashish Kamat: Great. Moving on to chemotherapy. You raised some important points about the limitations of the role life data compared to clinical trial data, et cetera, et cetera. But when you have a patient that sits in front of you and has the need to go for a radical cystectomy, what are some of the variables that you use other than just GFR or performance status in counseling a patient on whether they should consider chemotherapy, go straight to surgery or perhaps even consider immunotherapy, even though it's early days now?

Fred Witjes: Well, to answer the last part, I don't think outside of a trial that pre-operative immunotherapy currently should be offered. And I guess we have seen some results during EAU and AUA that might be something that is going to be very effective in the near future, but let's first wait for the trials. And if I see a patient in front of me with an invasive bladder cancer, we look at the pictures, you see the pathology result. Sometimes I'll look in the bladder again, and I don't basically offer adjuvant chemotherapy. If it's very limited, so and the t2 tumor, if it's a t3b, or t4 [inaudible], because we've also seen some studies which have shown that in limited invasive bladder cancer, you don't even have an advantage in chemotherapy, but you even have a disadvantage because you postpone, of course, effective therapy. So basically it's a small t2, I don't offer neoadjuvant chemotherapy. And I explain to the patient why I don't do that. If it's a clear t3 on the pre-TUR scan, I do.

Ashish Kamat: You're echoing my sentiments. That's almost exactly what I do. And of course, if the patient has small cell carcinoma or something like that — 

Fred Witjes: That's different.

Ashish Kamat: That factors in as well. You raised important points about surgery and I absolutely agree. I think there's too much time and debate on robot versus open. I think the surgeon and the quality of the resection matters a lot more than whether you use a knife or a robot, but then that brings us to the question of the lymph node dissection. And again, you summarize the trial really well and the nuances between the limited and extended and so on and so forth.

As a practical matter though, if you leave out the designation of limited extent, what template would you recommend that a surgeon performing a radical cystectomy should perform at a bare minimum? And then in patients who require a more extended, what is the template that you would recommend? Because node counts, as you know, are very variable and people label things differently. So what's the template that you would recommend?

Fred Witjes: Well, that's actually a good remark, Ashish. I don't think the count is important, but the template that you use is important. And I basically have a reason to go higher up, which that might be after chemotherapy in young patients where you really want to try to get the most out of it. But otherwise, I would go to the crossing of the ureter and the common iliac artery, then, of course, down between the obturator nerve and the external iliac artery down to the pelvis. So for me, the node dissection template is already more or less the same for a long time. Again, unless I have a specific reason to go up, which basically shouldn't be there because if you have nodes [inaudible], then basically I think from a surgical point of view, you can't cure those patients, but sometimes you have an exception there.

Ashish Kamat: You know, again, I want to emphasize that, and it's almost like you and I have rehearsed this, but we haven't, but we agree on this point again, the crossing of the ureters should be the bare minimum that is performed in a patient that's undergoing a radical cystectomy.

Too often I'll have patients who undergo radical cystectomy somewhere, and they have a quote-unquote limited dissection, which is a node plucking from the obturator fascia. That's not what we mean by limited. We mean the crossing of the ureters, and that should be the bare minimum. That should be standard. We should do away with limited extended and just say standard lymph node dissection should be where the ureters cross. And anything more than that, like you mentioned, should be on a needs basis. So on a case basis in selected patients.

Fred, this has been a wonderful discussion, and you and I could chat forever, but the interest of time I do have to wrap up. I do want to thank you for taking time off from your busy schedule to share your thoughts and updated guidelines with our audience. Stay safe and stay well.

Fred Witjes: Okay. Thank you very much.