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Sam Chang: Hi, my name is Sam Chang. I'm a urologist in Nashville, Tennessee, and we are quite fortunate to have a well-known superstar and a rising superstar from Indiana University. We are very fortunate to have Dr. Chandru Sundaram and Dr. Courtney Yong, who will be actually discussing their collaboration with other investigators in the ROBUUST registry, looking at actually surgical techniques and impact with nephroureterectomy with upper tract urothelial carcinoma. So Vanderbilt is one of the UroToday's Sites of Excellence, and we have a focus on upper tract disease. And so we really like to highlight important research that's been going on. So Courtney and Chandru, thank you so much for spending some time with us, and we really look forward to the presentation. So I'll turn it over to you guys.

Courtney Yong: Great. Thank you so much for having us. I'm Courtney Yong. I am from Indiana University. This is my mentor.

Chandru Sundaram: My name is Chandru Sundaram. I've been at Indiana University for over 20 years, but we are here to highlight this multi-institutional study that Courtney will speak about. She's our Assistant Professor in the Department of Urology, and we worked together on this multi-institutional study. Upper tract urothelial carcinoma is not a common condition, and so the value of having 17 institutions across the world is fantastic to study various aspects of how robotic nephroureterectomy and other treatment options are used to manage this condition. Courtney will talk more about this, but I must also recognize all the investigators, Dr. Riccardo Autorino, and various others from institutions across the world who have participated in making this possible. Courtney?

Courtney Yong: Absolutely. Many people making this possible. So we're going to present one of the many different papers that have come out of this ROBUUST registry. This one was titled "The Impact of Bladder Cuff Excision on Outcomes After Nephroureterectomy for Upper Tract Urothelial Carcinoma." It'll be myself and Dr. Sundaram presenting this, but again, we collaborated with many people, so many people get to take the credit for this.

So the outline of our presentation: we're going to be talking about what the ROBUUST collaboration is and then tell you about how bladder cuff excision affects outcomes after radical nephroureterectomy. We'll also talk about future directions and other studies that we're hoping to perform in the future.

So the ROBUUST collaborative, it's actually, like Dr. Sundaram had said, 17 tertiary referral centers that are international, so across the US and parts of Europe and also in China. And it's a retrospective database that studies only upper tract urothelial carcinoma, and specifically we're extending it to distal ureterectomy and ureteroscopy as well, but primarily we're looking at patients who underwent a radical nephroureterectomy for this disease. We have studied the patients from 2015 to 2023 in order to get a wide range of time for this.

So we wanted to know: does bladder cuff excision affect the outcomes for upper tract urothelial carcinoma after nephroureterectomy? And we had around 1,700 patients, and 90% of them had formal bladder cuff excision as expected according to the guidelines. Four percent had other techniques such as the pluck technique or the intussusception technique, and then 6% did not undergo an excision. There wasn't a specific reason listed in our database, but 6% of them did not have an excision. And our median follow-up was 24 months.

And as you can see in these Kaplan-Meier survival curves, we had significant differences in recurrence-free and bladder recurrence-free survival. Mostly the recurrence-free survival is driven by bladder recurrence-free, so I'm showing both of the curves here, but they kind of overlap clearly. So patients who underwent a bladder cuff excision, regardless of the technique, had better recurrence-free survival, mostly driven by bladder recurrences, compared to those who did not have any removal of their bladder cuff. But again, the technique did not matter in our series.

So recurrence-free survival, mostly driven by bladder recurrence, and it is improved with excision of the bladder cuff. That's really important that we get the ureteral orifice out, so the entire ureter has to come out. But we did not notice any difference in metastasis, cancer-specific, or overall survival. So I'll go through the curves really quickly, but there was no difference in the survival curves or in the techniques of excision. So all of the different survival curves showed no difference in metastasis, cancer-specific, or overall survival. Those are all the curves.

So our take-home message is that bladder cuff excision during radical nephroureterectomy for upper tract urothelial carcinoma does improve recurrence-free survival. That's mostly driven by decreased rate of bladder cancer recurrence. There's an unclear benefit for metastasis, cancer-specific, or overall survival, but our future directions are to look for longer-term follow-up. We only had 24 months of follow-up in this series, so continuing to follow these patients, seeing if there is an effect on those other survival curves on bladder cuff excision.

And so I think really for this study, what we wanted to do is study something that we kind of take for granted already in urology. This is already part of our guidelines, it's already considered the gold standard to remove the bladder cuff, and I think it's always good for us to check and make sure that we're doing the right things and that our guidelines are saying the right things. So we were very encouraged that this data has shown that really what we're doing is what we should be doing because it does actually improve patient care. So thank you so much, Dr. Chang, for the opportunity to speak with us today.

Sam Chang: Perfect. That was great. So Dr. Yong, Dr. Sundaram, I think at this point, taking out the bladder cuff makes sense, people understand that. Let me ask a couple of questions. I don't think they'll be too difficult, and you may or may not know the answers. So question number one, and it may be more than a couple of questions, but the first question is, other than not removing the bladder cuff, was there anything else that you found that increases the chance of bladder recurrence separate from already having a bladder tumor? What about location of the tumor? What about multifocal upper tract tumors? Were there any other risk factors, high-grade, low-grade, etc., that increased recurrences within the bladder?

Courtney Yong: That's a great question. For our study, we were a little bit limited on how many variables we could look at, so we really wanted to get things that we kind of knew were going to affect bladder recurrence, so things like higher pT stage and high-grade and things like that, like neoadjuvant chemotherapy, adjuvant chemotherapy, things like that all did affect the outcomes, that all of the survival curves were affected by them, but we didn't specifically look at multifocal disease, or I don't think we looked at size of tumor or anything like that.

Sam Chang: Along those lines, I would think, and this is just a personal bias, I would think that perhaps there would be a difference with location of tumor. Obviously a mid or distal ureteral tumor more likely, but that's just a guess. I don't know. So I was wondering if you had that.

Can you all describe then classically, or not classically, but what do you guys do most commonly, Chandru, in terms of your technique when it comes to the bladder cuff? I think people will always love to hear from experts regarding how they do it robotically, etc.

Chandru Sundaram: Yeah, the robotic approach allows us the opportunity to do an extravesical excision of the distal ureter and include the cuff of the bladder as well as the entire intramural portion of the ureter very efficaciously without much contamination. I think that's the difference between robotic and the open approach where we used to make a much bigger incision in the bladder, and we sometimes would have to go transvesically as well. And so we are able to do that robotically very efficiently, and by doing so, we ensure a watertight closure of that cystotomy and are able to provide the patient with intravesical single dose of chemotherapy to further reduce the risk of bladder tumor recurrence.

Sam Chang: Excellent points. I was just going to bring up the classical where we used to bivalve the bladder and core out and never made much sense. We know this is a tumor, we know it can implant, and this is what we used to do. And then there was a trend then to let's try to not do that, and laparoscopically, when we weren't as skilled, we did some of these intussusception and pluck techniques or whatever, but I agree with you very much, Chandru, regarding the ability, extravesical, pour out, drain, treat with perioperative chemotherapy. We actually place it intra-op, but then being able to have that watertight closure I think is fantastic.

Tell me, what is, as you all look at the different investigators and their techniques, you talked about that 90% plus did a bladder cuff. Is that by far the most common technique you found, Dr. Yong, in terms of it tends to be an extravesical resection, etc.? Was that by far the most common?

Courtney Yong: That was by far the most common. Yep. That was basically the entirety of the 90%. I would say, I don't know how much we studied re-docking and whether or not they did it if they were doing it like laparoscopic or hand-assist or they went down to the pelvis, so I don't know how much they did single dock versus re-docking and things like that, but yes, they were for sure doing extravesical.

Sam Chang: I don't want to steal any future fire because this registry has really helped identify risk factors and techniques and that type of thing, but what's up next? I was able to find this, because I mean this just came out in Urological Oncology just a couple months ago or even more recently than that, but what's next? What's next from what should we expect from the registry?

Courtney Yong: I'm hoping actually that we're going to be submitting an abstract to AUA about intravesical therapy right after nephroureterectomy. We were just talking about that. It's something that most of us I think will do, and we believe that it helps. But of course with this disease being so rare, we haven't studied it really well. So having this multi-center study would be great to see if what we're doing actually helps.

Sam Chang: Great. And so although a little bit off-topic, but importantly for upper tract, describe to me what you all do at the time of nephroureterectomy with that intravesical instillation, dose, timing, etc. What do you all tend to do?

Courtney Yong: Great question. It sort of depends. If our closure is completely watertight, so we have a little bit of limitation at our institution, oftentimes we'll want to get a cystogram before we put the instillation in if we're going to do it post-operatively. Sometimes it's not available if it's the weekend or after hours or something like that. Oftentimes, yes, if it's completely watertight, we will put it in intraoperatively like you said that you do, so we will absolutely do that. Otherwise, we like to wait one day and just get a cystogram afterward. And then if that's negative, then we'll put it in.

Sam Chang: Yeah, if you look at the Omit data and other data, looking at the advantage, it's up to seven days afterwards. What we've done, and there was actually some folks at Mayo were trying to do this but never actually published the data, what we do now is actually at the time of the dissection, we'll put an early clip on as soon as we can to try to prevent distal migration. But we'll actually put the chemotherapy medication with the Foley catheter after we dock, and we time it for an hour, and that's where we put it in. We'll put either one or two grams of the gemcitabine and to hope to decrease at that point spillage or seeding of the bladder from dissection. And the other thing too is we're also hopeful at that time then we drain it. We try to avoid obviously spilling any gemcitabine into the peritoneal cavity, but we drain it.

And then that's been our technique. Is that as good? I don't know. So very much look forward to the future manuscript and abstract that will be forthcoming to give us an idea of the techniques and the findings, etc., because I think it really will make a difference.

While I've got two experts, so Chandru, when you do your ureteroscopy on these patients, either biopsy, laser, are you giving perioperative chemotherapy at that time as well? Because more individuals, not universally, but more individuals I talk to will say following the biopsy, and we can talk about pros and cons of biopsy, but following manipulation, evaluation, etc., that they'll then also put, following that procedure catheter is in, they'll put—tell me if you do that or have you thought about doing that?

Chandru Sundaram: We have not done that routinely, and obviously, and that certainly is a good idea. It makes sense because you are going to stir up cells there, especially when you do biopsies. And then the question then becomes when you have a distal ureteral tumor, do you contaminate the upper tracts with the ureteroscopy? Clearly, I think the guidelines say it that on the contralateral side, you certainly should not do a ureteroscopy.

Sam Chang: Yeah. Really good points. And I really don't know the answers. There's data regarding maybe we shouldn't be doing biopsies at all. And so it's definitely a field that's getting more attention. AUA guidelines just out last year, and I think the work that you all have done and helped to organize with these other institutions is really, really fantastic, and we look forward to highlighting future work again on UroToday, and thanks for spending some time with us.

Chandru Sundaram: Thank you very much, Dr. Chang.

Courtney Yong: Thank you.