Sam Chang: Hi, I'm Sam Chang and one of the urologic surgeons in Nashville, Tennessee at Vanderbilt University, and we are quite fortunate to be joined with Dr. Phillip Pierorazio. Dr. Pierorazio is at the University of Pennsylvania and is really one of the leaders when it comes to kidney cancer and to actually urothelial carcinoma. And we are fortunate here, as he will highlight, actually a recent Journal of Urology article looking at the long-term effectiveness of UGN-101 reverse polymer, correct, I think, Phil? It's a hydrogel that is actually used to treat the upper tract. So Phil, thanks so much for being with us. And if you could just give us some highlights of that article.

Phillip Pierorazio: Yeah, Sam, always a joy to be with you and to talk about upper tract urothelial cancer. We don't get a lot of the spotlight. So it's nice when we do. And relatively rare disease, relatively nuanced management. And a few years ago, the AUA guidelines, I think did a great job in really highlighting some of the nuance points here, but it's still challenging for a lot of people. And one of the new strategies is really for patients with low-grade upper tract urothelial cancer.

These are non-aggressive tumors. They're highly unlikely to be invasive. The treatment paradigm has shifted where we should be trying to spare a lot of these kidneys and using ablative strategies. And whether you're using a laser and a ureteroscope or adding or using one of these novel agents, this is really the paradigm moving forward and trying to spare kidneys.

So UGN-101, as you mentioned, is this reverse polymer hydrogel. What does that mean? Well, it's a really cool technology. This liquid is actually liquid at room temperature, and when it warms up in the body it solidifies and then dissolves as urine runs over it. And you can instill a variety of agents into it. And for the treatment of upper tract urothelial cancer, they use mitomycin. And we know that's a great drug for decades in treating urothelial cancers in the bladder, and so it's great for the upper tract here.

So this is basically a long-term analysis of the initial trial, which was called OLYMPUS, that was published back a few years ago now and was a total of 71 patients. This is long-term data from that study. So the first thing people look at, they go, well, there were 71 patients in the initial study. How come there's only 42 in this one? Well, first thing is we're looking at the patients who responded. So yeah, not everybody's going to respond to every treatment we offer them. So these are the patients who responded.

So 42 patients received a complete-- had a complete response in the initial trial 4 to 6 weeks after their initial treatment. So you looked up there, 4 to 6 weeks later, no evidence of cancer. And what we see now long-term is these patients do incredibly well. So for the people who respond, they do really well. 75% of them, in fact, had no evidence of recurrence at the last follow-up, which is now almost five years later.

So not everybody's going to respond to this product. But if they do respond, they tend to have a really durable long-term response. And I think that's reassuring for people who are kind of new to the upper tract realm or new to thinking about ablative strategies for upper tract disease.

Sam Chang: Yeah, I think I was really impressed with the fact, the median follow-up in the article that you reported was more than two years. And just as you said, there seems to be a tail of the curve for Jelmyto. That's the trade name of the product, UGN-101. And in looking at that, tell me if you have an idea, Phil, it was up to the investigator regarding maintenance versus non-maintenance. I don't know if you all had the breakdown of how many of these received monthly maintenance after their complete response.

Phillip Pierorazio: Sam, it's a good-- I don't know the exact number, but I will tell you the answer is very few, to be honest with you, which I think is actually reassuring and it speaks to the biology of this disease. We see this in the bladder too. There are patients with low-grade disease you treat once, you get rid of that low-grade tumor, and they're fine for the rest of their life. They're the patients we all shrug our shoulders and go, why are we doing surveillance cystoscopies?

But there's a significant number of patients who are going to have progressive, recurrent, low-grade disease, and a small amount who will progress to high-grade disease. So that's why it's so important to keep an eye on these patients, both in the bladder and in the upper tract. But I think it tells us in the upper tract it's a similar phenomenon. 75% of the patients who respond will have a long-term response without new tumors.

Sam Chang: Yeah. So currently in your day-to-day practice, how are you instilling this? Are you doing it retrograde via the ureteral catheter or are you placing an ostomy tube and treating it antegrade? Tell me the nitty-gritty of you see a patient, tell me the patient you choose to treat with this. Obviously, we focus on low-grade disease, papillary disease, but tell me the disease evaluation of your patients and then how you actually then proceed with therapy.

Phillip Pierorazio: Yeah. So the first point here is doing a really good diagnostic ureteroscopy and getting good tissue. You want to grab as much tissue as you can for your pathologist to give them the best chance at making a good diagnosis. Also, get a barbotage cytology after you do your biopsies. When that renal pelvis is full of as much cellular kind of debris as possible, that gives them the best chance, really, at confirming that there's not high-grade disease because you don't want to treat somebody with high-grade disease with this drug. Not that it's going to harm them, but that high-grade disease isn't really going to be treated by this. So you want to rule those out.

So there's lots of techniques to get good biopsies. I love a basket when you've got those really pedunculated papillary tumors. Otherwise, you get a Piranha forceps, and you take as many biopsies as you can until the renal pelvis gets a little bloody and you can't see anymore. I've moved towards lasers. The new laser technologies are really nice for upper tract urothelial cancer, so I do try and ablate mechanically or with a laser as much as you can.

If you can get them visibly disease-free with a laser, bring them back in a few months, and get an idea of where that disease is going. If you can't get rid of it, or if you're back in three months and now there's tumor there again, in my mind, ideal patient for this treatment strategy. You're treating the entire renal pelvis. You're treating the entire upper tract urothelium. And it's a great way to do it.

So technically, Sam, we do it both ways. And part of this has to do with the finances of the drug. And it's not a cheap drug by any means, but it is covered by insurance. Some insurances will allow us to do it in the ambulatory surgery center, where we could do it with retro caths. I love doing it that way. I think it's a little bit easier on patients. I think it's kind of a nice way to instill it, and they can be relatively mildly sedated, to be honest with you. You just have to get a urethral catheter up the kidney, make sure you're in the renal pelvis, and then in retrograde.

Most of the time with insurance coverage, it's more favorable to deliver in clinic through a nephrostomy tube. So we're probably about 80% of our patients are getting it in clinic. Nephrostomy tube goes in by our wonderful interventional radiologist. You give it at least a week to mature that tract. You don't want to do it within the first week. A week later, you start their first of six treatments, and then once a week they come in.

What is nice about the nephrostomy tube is that the patient's awake, and they will tell you when their renal pelvis is full of the product. As you slowly inject it in, they'll say, yeah, I'm feeling a little fullness. That's the time to stop. And then you just cap the nephrostomy tube, let the drug dissolve. They'll be urinating purple because the drug is impregnated with a purple dye, just so people can see when it's cleared. And they'll be peeing purple for about six hours. And it does a great job.

Sam Chang: We have a very similar track record. We've definitely, the vast majority have been given actually in the office antegrade. I love that sensation from a patient standpoint. We've also-- we ask our interventional radiologists when they placed a nephrostomy tube to give us an approximate volume that fills the renal pelvis. And what we've been doing, although we may not have to do this, is after that last sixth treatment, Phil, we've been leaving the nephrostomy tube in an additional week or so, and prior to removal, we've been just out of precaution just because of possible concern of UPJ strictures.

We have been doing the nephrostogram and making sure things are patent. Knock on wood. We haven't had anyone at this point. And we've treated, I guess, in the teens now in terms of number of patients, have not had one with strictures. But we obviously are concerned about that, and patients are made well aware of that possibility as well. Tell me what you do now in terms of follow-up? Imaging versus ureteroscopy, a combination, alternating. Tell me what you do now with these patients in terms of follow-up. They've gotten the six weeks, the nephrostomy tube. Tell us how long you leave it in or out, and then tell us where you go from there?

Phillip Pierorazio: Yeah. We take the nephrostomy tube out a week later. We have not been doing an antegrade nephrostogram. But you know what, Sam, that's a great idea. We have the capability in clinic, and now that I think about it, there's no reason we shouldn't. We have not had much issue with strictures, and I was part of the original trial, and I saw them on the original trial. And I think part of the reason we saw it at the 40% rate in the initial study was that this product was brand new and we didn't know what to expect, and we knew our protocol said, you give drug every six weeks no matter what.

And patients were telling us I feel a little tightness on that side. Or we were putting up the retro caths, and they definitely felt different in week four than they felt in week one or two. Now, we've learned. If somebody is complaining of a little bit of inflammation, or maybe they feel like they're a little obstructed, just back off. Give them a week or two. Just let the inflammation go down. Mitomycin is incredibly caustic; that's why it works. And sometimes you just need to give those ureters some time to rest. And I think that's why we're seeing in clinical practice the stricture rate go way down, because we're just not pushing as hard because we know more about it now.

You can also use steroids. Some people have talked about using a prednisone pack. I haven't used any steroids. I haven't needed to, to be honest with you, just giving people ureteral rest for a week or two. It doesn't necessarily have to be six weeks in a row, but great, great point there. In terms of long-term follow-up, we take that nephrostomy tube out a week after treatment, and then the plan is ureteroscopy basically three months after that.

And I think that's the right cadence for this disease until we have more data. So depending on the patient, depending on their tumor burden, we want to do something every three months. I don't like bringing patients-- I don't like doing ureteroscopy every three months if we can get away from it. We know that just doing ureteroscopy can increase the risk of strictures, and we're putting up access sheaths, we're manipulating them.

So I like to do a ureteroscopy at three months. If that's clean, MRU has become my go-to. Penn loves MR. When I was at Hopkins, we used a lot of CT scans. I've come to really like MRIs for upper tract urothelial cancer, but I think either one is reasonable. You want some kind of axial imaging in the upper tract where you can really see the urinary system. So if no evidence of disease, I stagger and alternate the ureteroscopies and MRIs at this point. If you see disease, I think you're obligated to go back in three months and put another ureteroscope up.

Sam Chang: Have you yet-- and I'll be honest Phil, those that we've had respond, which has been honestly, more than half, more than actually two-thirds, we've not had to retreat. Have you retreated anyone with a repeat induction course?

Phillip Pierorazio: I haven't in a while. So part of the initial study actually, I can't remember if it was one or two of our patients on the initial study. We retreated. About two or three years later, they had recurrence of disease. We retreated them and once again, they had a response of about 2 to 3 years. And then it came back a third time. But once again, I think it speaks to the biology of that individual.

So once again, there are patients who you treat. They never come back. There are patients who are going to have a prolonged course, and there are patients who you treat, and they're going to come back in 3 to 6 months. And I think that tells us very clearly that nephroureterectomy is a reasonable approach for those patients.

Sam Chang: Yeah. Well, Phil, thanks so much for enlightening us regarding the long-term efficacy of this medication and a treatment alternative for patients as they-- we were limited before just to surgical options. And there's no question that laser ablation is an important part of treatment for these tumors.

But I think your point regarding treating the whole urothelium, treating the whole renal pelvis, clearly there are areas we don't visualize well. Just as you said, things get bloody. Lower pole areas, difficulty in terms of access. We want to be careful in terms of not going too deep, et cetera. So the ability to cover the whole urothelium, I think is a really important point. The last thing actually, for that we'd love for you to contribute, Phil, is any specific tips or tricks that you have as you've seen these patients and treated them, anything that you'd say, hey, we had an "aha" moment here and we found this to be really helpful.

Phillip Pierorazio: Yeah, it's a good question, Sam. I think the most important thing with this-- a couple of important things. One is being really persistent with diagnosis. There's a fair amount of time we do a ton of these that we get a non-diagnostic ureteroscopy and don't jump to a nephroureterectomy or don't jump to conclusions about treatment. This disease is nuanced. Tissue diagnosis is hugely important.

So take your time. Bring patients back to the operating room. Diagnosis really drives all of this. And if you look at the kind of risk stratification paradigm from the AUA and the EAU as well, you're really trying to select out the patients who you can spare kidney versus those who have really bad systemic disease in that high-risk population. So take your time, get a diagnosis. And the second thing I would say, my mantra for low-grade disease now, particularly for the trainees, but other people when I lecture about this, is radical nephrectomy is still the gold standard for upper tract cancer, but for low-grade disease it should be our last resort. We have a growing laundry list of treatment options for these patients to try and keep their kidneys around, and that's the way we should be thinking about it.

Sam Chang: Well, Phil, that was awesome. Thanks so much for spending some time with us. And thanks so much for all your contributions, your role on the guidelines for the AUA. I think that really helped set a new paradigm in terms of treatment strategies for patients with upper tract disease. And as always, we look forward to your future contributions. Thanks again.

Phillip Pierorazio: Thanks, Sam. Always fun sharing the morning with you.