Preventing Recurrence of Urothelial Carcinoma in Patients with Upper Tract Carcinoma - Aditya Bagrodia
July 4, 2022
Aditya Bagrodia, MD, Assistant Professor of Urology, Urologic Oncologist, UC San Diego
Sam S. Chang, M.D., M.B.A. Patricia and Rodes Hart Endowed Chair of Urologic Surgery Professor Department of Urology at Vanderbilt University Medical Center
Sam Chang: Hello everyone, my name is Sam Chang. I'm a urologist in Nashville, Tennessee. And we're very lucky today to have Dr. Aditya Bagrodia, who is an associate professor at UCSD and is the leader of their GU Oncology program. Today Dr. Bagrodia is going to be focusing on, actually, a problem that many of us face as we treat upper tract disease, which is helping to prevent bladder recurrences as we deal with the bladder cuff and the distal ureter and do things that we try to do to actually try to prevent bladder cancer from recurring. So, Aditya, I'm going to turn it over to you and I know you'll have some actually very important clinical tips for our physicians.
Aditya Bagrodia: Thanks, Sam. I really appreciate you having me. It's really a wonderful series that you've put together. And an honor to be on with the esteemed guests that you've had. So I'll just jump into it. And I do think that this is a bit of an under-recognized and under-appreciated problem that can have some serious impact here. Ultimately if patients have bladder recurrences that can often mean multiple anesthetics if they're high grade, they may require intravesical therapy, even cystectomy. And if they're particularly offensive, lead to worse clinical outcomes with respect to cancer-specific survival and overall survival.
So we'll just jump off with a case. This is a 69-year-old female in generally good health, presents with hematuria, well-controlled diabetes, hypertension, remote history of smoking, and importantly, no history of upper tract urothelial cancer in the family or other Lynch syndrome-associated malignancies. Physical exams, fairly unremarkable and she received a CT scan. I'll just quickly run through that video. And you'll notice as you move towards the lower pole that there is a fairly infiltrative lesion in the renal pelvis extending towards the lower pole. And on the coronal images, you can also appreciate this fairly significant upper tract mass. Upper tract urothelial carcinoma to me is a fascinating disease, and we'll get to the various options here. But for the sake of completeness, overall, her kidney function is good, no evidence of metastases, in-office cystoscopy without any lesions, and notably, she did have a high-grade cytology that was taken at the time of cystoscopy.
So next steps. I'm guessing if you polled folks that think about and do a lot of upper tract urothelial cancer work, you'd get a whole gamut of options, including going straight to surgery and quite possibly adjuvant chemotherapy based on the POUT trial. I think you could make a compelling argument for neoadjuvant chemotherapy followed by surgery, and then of course, there's the diagnostics. I won't spend a lot of time on the pros and cons of doing a biopsy, versus ureteroscopy, versus is the cytology enough? But if we were to move to ureteroscopy, I think, there's some actual point of care options for us as a urologist to help maybe mitigate the likelihood of having a lower tract recurrence down the way. We'll specifically talk a bit about access sheaths, the use of stents, and then post ureteroscopy intravesical chemotherapy.
Of course, upper tract urothelial carcinoma is a rare disease, it's a heterogeneous disease, and to systematically study these in a randomized control trial is difficult. But I thought this was a very nice study from our colleagues out at USC, where they looked at their radical nephroureterectomy database. Just to orient everybody, the blue is patients that did not receive a ureteroscopy, the red is a ureteroscopy with a sheath, and the green is a ureteroscopy without a sheath.
So a bit of background, there's fairly good data out there, typically, retrospective or multi-institutional reviews that indicate that a ureteroscopy is associated with higher rates of recurrence. When you look at the data from this particular study, you can see that the patients that had no ureteroscopy in blue and those that had ureteroscopy with a sheath essentially are superimposed rates of intravesical recurrences. This to me, conceptually makes sense. You have this sheath, which is essentially a conduit from the renal pelvis leading outside of the patient, the introitus in a female, the meatus in a man. Once you've done your manipulation, your biopsy, your fulguration, you've used your biopsy, your paronos, your lasers, et cetera, all those tumor cells that have been manipulated and now are floating around, I think, all of us appreciate and recognize when you're done with your intervention you see these particles, they're immediately being taken out of the patient's body as opposed to coming into the bladder and dwelling there for some bit of time.
The authors also noted that within each of these subgroups, when they used this stent, there was no real impact on the lower tract recurrences. And to me, this conceptually makes sense. We're manipulating this tumor, we're essentially allowing cells to enter into the bladder. And when we think about bladder cancer, there's some intriguing data that if you use a stent and now you're converting this one-way valve to a two-way valve that you see higher rates of upper tract recurrence, of course, urine that's made in the kidney and travels down to the bladder is doing that regardless of whether your ureteroscopy is performed or not, and regardless of whether a stent is placed or not. So, I think, it's a little less logical that stents can be associated with the higher rates of intravesical recurrence. So what can we do? When you complete your biopsy, your ablation, your endoscopic management, a very simple thing, I think, is just to aspirate the fluid in the renal pelvis and maybe, slowly irrigate and aspirate this to get these cells out of there. And then you can also consider intravesical chemotherapy.
So, again, conceptually, we use intravesical chemotherapy to reduce recurrences after TURBT. I typically will use this in solitary, low-grade tumors, less than three centimeters. And we have some fairly high-quality data that indicates that intravesical chemotherapy actually reduces bladder recurrences if used around the time of radical nephro U. Somehow surprising, there's a complete lack of literature regarding the use of intravesical chemotherapy, the type of endoscopic management. For all the reasons that we just talked, tumor manipulation and an opportunity of seating to the bladder, it makes. And there's actually a randomized control study taking place in China, where they have 200 patients that are going to be randomized to either no installation versus pirarubicin at the time of diagnosis.
So, if I had to summarize for ureteroscopy, I think that access sheaths make sense, I think at the conclusion of your diagnostics or therapeutic intervention, gently aspirating any particular matter tumor cells. And actually, we'll send that off for a cytology to help out our pathologists. The access sheaths, again, they're going to decrease the amount of dwell time of urine with these cells potentially in the bladder. And that also creates a low-pressure system where you're maybe less inclined to have higher rates of pyelovenous backflow, potentially increased circulating tumor cell burden, and worse cancer-specific outcomes. And then finally, I think that using intravesical chemotherapy can actually makes sense, that's my opinion, and there's no really high quality data surrounding that. Then let's say we're moving on to surgery, whether this is after neoadjuvant chemotherapy or upfront. I think again, there's several opportunities for us to minimize the chances of having intravesical recurrences. And these would be the use of perioperative chemotherapy, early clipping of the ureter and bladder cuff management.
So we'll start out with chemotherapy. And so what I'll do at the time of surgery is get the patient position, the catheter goes in sterilely, and the first thing is just to instill some gemcitabine. That's the chemotherapy that I use, we set the clock for an hour and then in an hour we drain it right out. And there's actually some really compelling data from two randomized control trials that are almost about a decade old. If you use Mitomycin C within about a week postoperatively, the bladder recurrence rates decreased approximately 11%. And I saw the earlier postoperative installation had a bit more of a market improvement on the order of about 25%. So to me, high-quality level one data, and this would be considered a standard of care. Going back to our case just briefly. So this patient actually got a percutaneous biopsy, confirming high-grade cancer, T3 invading into the kidney. We proceed with chemotherapy and surgery.
And at the surgery, this is always something I hammer home to the residents and the fellows. These are opportunities for us to really help, I mean, lymph node dissection, I think, that would be considered standard of care. Then early clipping of the ureter and management of the bladder cuff along with the intravesical gemcitabine. So believe it or not, there's actually been a randomized control trial, relatively small, 85 patients. And the authors noted recurrence rates within the bladder of around 15% in those that had early clipping and approximately 35% in those that had no clipping. And that's about a 20% decrease intravesical recurrence rates, and again, that could lead to multiple anesthetics and worse outcomes for patients. Including many times in these elderly patients, the mental impact of repetitive anesthetics. So this is a no-brainer to me, find your distal-most tumor, put a clip on it, and then get about with your case.
And then the management of the distal ureter. I actually think this is one of the more technically challenging parts of the case, a lot of things that have been described over the course of radical nephro U for upper tract cancer, going in with the Collins knife, coring out the ureter, and plucking it out, that always made me nervous from both the oncologic perspective as well as a potential source of predisposing the complications. You basically have a cystotomy and you're relying on your catheter in an area that's been extensively cauterized to heal. I don't love it, but there's intravesical, there's transvesical approaches, there's extravesical approaches. I think it's easy to convince yourself, let me take it down as low as I can and put a clip or a suture, et cetera. And when within the EAU guidelines, there are several options that are available uretal stripping, which is actually to, another option is discouraged according to those guidelines.
So when I think about bladder cuff management, again, this going to be one of those nuanced things. In my opinion, supported by data, a transvesical formal bladder cuff removal would be the gold standard. And here's a nice study born out of the upper tract urothelial carcinoma collaboration, which basically shows that's likely superior to extravesical endoscopic management. And in terms of how to do it, so what I'll typically do is get some traction on the ureter. I'll generally divide the middle umbilical ligament to really have that posterior bladder, accessible and released if you will. Then spend quite a bit of time splitting the fat anteriorly and posteriorly until you're to the detrusor, and still about 100 to 120 CCs to really help you identify when you're getting down to level of the mucosa. You have to place a stay suture, otherwise, the nearly certainly once you're completing your bladder cuff it's going to retract and hence be hard to see. Then an anterior cystotomy is made, and these are not my pictures, but this is exactly the way I do it.
And you're absolutely visualizing the ureter orifice and removing it. There's no question here, have you left a stump in, have you left a bit of the intramural ureter in. And then finally it's a two-layer closure, it's tested with 180 CCs. I will leave a drain in and typically leave a catheter for three to five days upon discharge. So despite all of this, my patient had her first set of scans and a cysto at three months, and she had a little low-grade recurrence. This was biopsied in full grade in the office and found to be a low grade, Non-muscle Invasive Bladder Cancer on surveillance for that.
And with that, I think this case just highlights that there's complexity and nuance to upper tract management. We do see a lot of intravesical recurrences, and this can absolutely have a negative impact on patient health and cancer outcomes. And there's multiple opportunities for us to intervene at the point of care, if you will, with the judicious use of ureteroscopy, liberal use of access sheaths, potentially, consideration of intravesical chemotherapy at any endoscopic trip into the patient's collecting system. And then at the time of surgery, one on one early clipping of the ureter, meticulous technique for bladder cuff management, and then the use of perioperative intravesical chemotherapy. So hopefully, there's something useful to the listenership, and Sam, take it from there.
Sam Chang: Aditya, as I knew you would, tremendous job and obviously raises, I think, some key points as we diagnose, treat, and then hopefully, prevent future recurrences for these patients. So let's start with helping at the time of diagnosis in the use of the ureteral access sheath. For those patients with, say, a distal or mid ureteral tumor, what's your recommendation for those patients? Do you, even for those patients try, to put a ureteral access sheath or do you use ureteral access sheath really mainly for renal palliative tumors?
Aditya Bagrodia: Yeah, I think it's a great question. So I typically like to clear the ureter, actually, with the semi-rigid, first thing's first, just to make sure there's not some small papillary multifocal tumor that wasn't picked up on the imaging, that I might just shear off by popping up an access sheath. So I'll actually get into semi-rigid, basically have a wire, just a tip out beyond my semi-rigid. And if I come across a tumor in the distal ureter, I'll generally go beyond it, try to clear the rest of the ureter, and then come back and manage it.
And to be quite frank, Sam, it's tricky to actually have an access sheath in place a where you want it, in my hands, for something very distal. If it's mid or proximal, I think you something along the lines of a 28 centimeter, 11, 13, 12, 14 French access sheath to that level. And if it's a larger tumor, I think it makes sense. I mean, obviously, the bulk of these are renal pelvic tumors and if I've cleared the ureter, and I'm getting into the pelvis access sheath every time. And also, because I know I'm going to make 50 trips up there to get adequate specimens for a pathologist.
Sam Chang: Great. So for those patients that don't have a diagnosis, so this is the initial, you've made a decision to evaluate with your radioscopy, you're unsure, you're trying to determine low grade, high grade, for whatever reason. Do you routinely then prior to the diagnosis, give perioperative chemotherapy? Because I'm starting to do that now after honestly, talking to experts like yourself, understanding, really, the minimal morbidity makes sense of vis-a-vis, the real chance in decreasing recurrence. So I was wondering if you're doing that now routinely?
Aditya Bagrodia: I am, and it's not trivial. I don't know how it is at Vanderbilt, but every institution I've been involved with, the attending has to order the gemcitabine, it's got to be prepared. If the pharmacy doesn't have a bit of a heads up, it's not going to happen. And of course, if you don't think about it, forget it. So if I'm suspicious, the scan is pretty compelling for a filling defect consists with upper tract, I'll go ahead and order it, worst case it's not going to happen. I'll go about my either diagnostic or therapeutic ureteroscopy, and then at the conclusion of the case, I've irrigated the renal pelvis. I've really made sure I've emptied the bladder, then instilled the gemcitabine leave it in for an hour and half, and have it drained out before the patient leaves and go about it. Any trip that I'm making into a patient endoscopically for upper tract or suspected tract cancer, I've got gemcitabine ready to go.
Sam Chang: I love that. I similar to you, even before the data's come out from the Mayo, multi-institutional trial, about giving the chemotherapy at the time of nephro U, direct me, I'm doing it and I'm glad to see that you're doing it as well. It makes me feel better that I'm following a course of action. And very similar to you, I'll place a catheter, put the medication and we set a timer for after an hour, we drain it. As you go through that dissection, can you tell me a little bit about clipping early? Are you finding the ureter basically first thing, once you get access and just placing a humalog, are you doing something less? I mean, to be honest, what I've been doing is doing it like I would with any nephrectomy or any kidney surgery where early on, I tend to find the ureter to help elevate and expose the hilum. At that point, I've just been placing a humalog there. Are you doing anything different or specific when you dissect for a nephro U?
Aditya Bagrodia: Yeah. Excellent point. So I feel lucky that I'm able to use an XI, which allows you to really get fairly down into the pelvis. So to start with is typically just [inaudible 00:19:48] the colon and sizing the whitewater tote, getting access to your gerodes and so forth. Obviously, that free tale of gerodes thins out as you start crossing your cromaniliac, I think, it's a nice way to find the ureter. So what I'll try to do is go as low as I can-
Sam Chang: I see.
Aditya Bagrodia: ... and pop a clip in. If it's a more distal tumor, what I'll sometimes actually do, so the way that I position these patients is a slight bump on the lateral side, the pelvis is flat rotate, have them secured, obviously, rotate the patient. If it's very distal, I'll actually, start well into the pelvis, pop a clip in. I like doing the kidney part of it first, my lymph node dissection first, and then the bladder cuff last for a variety of reasons. But you don't have to read doc, you can actually just bring your camera, slide it inferiorly one spot. And I think it's pretty easy to find the ureter as distal as you want as if you're doing a cystectomy or so forth. But yeah, it's basically just popping on a clip and I think lower is just easier. If it's an obese patient, as was oftentimes a case in Texas, and I'm sure in Tennessee, sometimes just digging out the ureter from within gerodes can be a bit of a to-do. I like it over the cromaniliac just to kind of summarize.
Sam Chang: Oh, that's great. And we're going to end with your technique regarding the bladder cuff and dissection. And, if I had a dollar for every different way, I personally have taken the distal ureter, I would be making David Pinson money. Because I don't know, I've gone through all the different endoscopic iterations and this goes all the way back to doing in open, basically, anterior cystotomy, open, and doing the kidney lap. This was all before the robot and different things. And so the way that I've settled it is a bit of a modification of yours, and I want to hear what your take is and pros and cons. So one of the things I'm always concerned about is obviously urine and bladder or urine spillage at the time of opening the bladder for an anterior cystotomy because it's always made me concerned.
I know I want to make an opening because I'm not as comfortable with just basically looking at the mucosa and just stapling across or clipping across, which honestly I've done that as well in the past. So what I've been doing most recently is not making the anterior cystotomy doing an extra VESL approach, but actually having a resident or assistant actually have a scope into the bladder and then distend it to help the dissection part. And then actually suck out as much of that urine and maybe a little bit of the chemotherapy, and draw that out and empty as much as possible, have the sucker's ready actually have assistant replace it with a large-bore sucker, anything that's there. And I irrigate actually with water, I'm doing all these things trying to prevent recurrences. But similar to you, I put a stay stitch actually on the top of the bladder, on the anterior as well as one on the posterior to try to stretch.
And the system will have one, one arm will have one and then I'll be pulling on a clip that I've had a tie on to retract on my ureter. And I've been then just incising. And when I make my first cut, I'll have with a scope, have them look to see if the scissors are basically around, above, and actually into the bladder and mucosa and then I core out. I really like your way because of the visualization, you're basically doing the same thing, but coming from anterior and looking down. But I'm wondering, tell me tricks regarding trying to avoid urinary spillage, positioning that type of thing with what you've described.
Aditya Bagrodia: Absolutely. And I think it's a wonderful point, Sam. I mean, tumor spill, if I'm ever doing like a partial cystectomy for an ad no where you recall, I'll dissect it, I'll staple out the specimen, immediately bag it, I'm paranoid, then I'll come back and everything's way up in the air. I cut out the staple line and sew it again. And I feel like like that seems like a lot and it's some degree of paranoia. And before I jump into my technique, so once you've gotten your ureter, visualized your cystopically looking at it, do you exclude it with a clip or are you actually making a cystotomy? How do you actually complete that intramural ureter [crosstalk 00:25:00]
Sam Chang: I'm making a cystotomy. Basically, what I'll do is, when it's thinned out, I'll have the assistant actually put the scope above, mark around, and then I'll poke and say, okay, are we around it? Do you see my scissors poking? Because I've learned, it looks like we've got it all, but the intramural tunnel is much bigger and much longer than you think. And so I'll be poking and with the points of my scissors, the light will be shining from the scope. I think we're around it. And to be honest, I'm also paranoid about the contralateral ureteral orifice. I mean, I've made some some big divots. And so I do that and honestly, this is just to show my paranoia. After I do all this I'll give fluorescein or something while I'm closing just to make sure urine is coming out from the other side. Anyway.
So I didn't really want to make this episode about changed paranoia, but I'm glad that you pointed out some of my concerns because I think it really is an area of you hate to see recurrences along in a stump that you are much longer than you thought, or along a clip that you placed, and all those things I've just said are things that I've seen in my own patients. So I really appreciate you telling me nuances of the technique you described by pictures. Any other key points in Aditya?
Aditya Bagrodia: Yeah. I know, you're spot on and I'm always freaked out about the contralateral ureter as well. I always have anesthesia mark to ureteral output. And if it's not what I want, call in the indigo carmine and the fluorescein and all that kind of stuff. And 100% been burned, 90-year-old patient renal pelvic tumor. Let's take it down as low as possible, pop a clip in, fast forward and they've got some gangbusters. It doesn't even make sense to me, why would they have a recurrence there, but it happened and it's terrible.
Sam Chang: Yes.
Aditya Bagrodia: So I'm so that this has got to happen. So I think absolutely, maybe the early clipping of the ureter plus having the chemotherapeutic in there should or conceptually should use the likelihood of having live cancer cells that could essentially go into the pelvis.
So what I'll do when I take that middle umbilical ligament, and actually some of that anterior bladder pedicle, you can really have that trigone and that posterior bladder floating in the breeze, really have it up and facing. And when bring it anteriorly, it's gravity working for you. And I think you're spot on, you've got to really convince yourself unequivocally that you're at the [inaudible 00:27:54] mucosa because if you get in or you make your cystotomy in a uncontrolled fashion, I do worry about tumor spill. And I'll get with water as well and the whole licensed thing is probably ridiculous. [crosstalk 00:28:08] But anyways, I do it.
Sam Chang: Yes.
Aditya Bagrodia: But I think, when you've got that fourth arm pulling interiorly, you've got your bladder up interiorly and when it's on stretch, you make your cystotomy all the urines been drained.
Sam Chang: As you go down.
Aditya Bagrodia: I do try to make sure that the bladder's not distended or anything along those lines. Having that posterior stitch also retracted anteriorly gives you a bit of a lip almost so that you've got a ramp going down towards the bladder neck instead of coming back towards your cystotomy. If that makes sense.
Sam Chang: No, totally. It's almost like a sausage that you've lifted up. And you've kept everything shelved up and that hopefully will go down towards the bladder neck. Aditya, you thank you for spending some time with us. This is really, I think, nuts and bolts regarding areas where we can just like you said in your talk, where we can make a difference. We can make a difference in terms of decreasing the chance of an intravesical recurrence.
We may not be able to make a difference for development of metastatic disease, for someone who has very aggressive disease. But if we can prevent tumor spillage, if we can decrease the chance of bladder recurrences, if we can better stage with the lift of a section [inaudible 00:29:36], those are all things that we can do. And so I really appreciate you spending some time with us and going over your techniques and your expertise when it comes to dealing with the distal ureter and helping to prevent bladder tumor recurrences. So thanks again for spending some time with us. And I look forward to another discussion that I'm sure we'll have in terms of discussing upper tract urothelial carcinoma.
Aditya Bagrodia: Thanks, Sam. As typical, I'm positive. I learned more from you than anything I would've offered. Great to see you and thanks for having me on. Really appreciate it.