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Zach Klaassen: Hello, my name is Dr. Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. And I'm joined today for a UroToday case presentation with Dr. Kyle Rose, who is an assistant professor of urology at the Ochsner Clinic in New Orleans. We're going to talk today about the treatment of low-grade upper tract urothelial carcinoma. Welcome, Dr. Rose.

Kyle Rose: Thank you so much, Dr. Klaassen, for having me. Great to see you again.

Zach Klaassen: Fantastic. So let's start with your case presentation. Why don't you walk us through and we'll have some discussion as we go through the case?

Kyle Rose: Yeah, absolutely. And just going over what we'll cover today, the idea was really to gear this towards fellows in training about the workup, treatment options for these patients, and sort of how to think outside the box in some ways for this type of tumor.

This is actually a patient that I saw a couple of weeks ago. He's a 69-year-old male with upper tract urothelial carcinoma. He actually presented to one of our partners on the North Shore, just north of the lake here. He had gross hematuria after exercise. A CT scan was done that showed a filling defect from the UPJ down to the UVJ just above the bladder, about three centimeters. And at the time, he had great performance status. His GFR has historically run between 54 and 60, depending on the day that he was sampled.

And then you can see in the top left this coronal, he has what appears to be a blown-out kidney with a very small amount of parenchyma and starting just below the UPJ, he has significant filling and tumor effects here going down towards the bladder. We'll get to his intraoperative findings, but you can see there's a significant defect here in the ureter. This open-ended catheter is just past the area of the tumor, but you can also see in the upper tract here, there's not a lot of supporting kidney tissue surrounding the collecting system. One of the things that will come up here is to question everything and be focused when taking care of these patients. I think this is such an interesting disease space and tumor, and I very often go back to when I'm seeing these patients is to stay disciplined and think about what they presented with and go through it in a step-by-step fashion.


Case in point, this gentleman presented with gross hematuria, and it's very easy for us as surgeons to get excited about what surgery this gentleman might need and forget the fact that we need to work that up first. And extremely importantly, he has a contralateral kidney that needs to be evaluated with a CT urogram, not necessarily looking up into that kidney, but at least to rule out contralateral tumor. He will need a cystoscopy, which we'll get to, but is a great opportunity as well to get a voided cytology, which will come into play when we start questioning his staging. Ultimately though, this patient with such a large volume of tumor, if I know he needs to go to the operating room to look up, I won't do a flexible cystoscopy in the office. We can do that at the time of his scope. So obviously, direct visualization and sampling is always preferred.


If we do see bladder tumors at the time, those should be resected and an attempt to clear out the bladder should be made. And there's also a great opportunity if we can't look up or if we're concerned about the viability of our biopsy, to obtain a cytology from that side or from that kidney. And so now that the patient has a pathologic diagnosis, we have to continue his staging, continue to question things. We prefer to obtain a CT chest, especially for patients with upper tract or even aggressive types of bladder cancer, just because some of the factors that they may have been exposed to also predispose them to pulmonary disease. And then as always, this will be a theme that we constantly ask is how confident are we in our staging at the end of his workup and the end of his staging?


Zach Klaassen: Yeah, that's great. Great outline. And I think you're right, being dogmatic in our workup is always important. And we know, upper tract staging is difficult. The instruments don't give us a depth on our biopsies. We can be fooled into under-staging or over-staging patients with CT or MR urograms. And I think that's part of the challenges of considering even neoadjuvant chemo versus waiting till adjuvant chemo. And just take us through some of the challenges of staging and how you did it with this patient.

Kyle Rose: Absolutely. I think the single biggest challenge is the instruments that we use and the ability to get a good biopsy sample. There's also just the ureter itself; it does not have the same anatomy as, say, the bladder, where we can take a divot of muscle with a stethoscope. And some people would argue, if you can diagnose T2 cancer through a scope, you've probably perforated the patient.

Zach Klaassen: That's right. That's right. Absolutely.

Kyle Rose: And so when we look at studies in terms of accuracy and the histology match between the ureteroscopy and a FU, there's only about a 66% grade match between the two. And not that a percutaneous biopsy is the standard of care, but that's an option for patients who may have an upper tract tumor in the kidney. There's a question of renal cell carcinoma versus upper tract, or an upper tract tumor that we biopsy looks suspicious and it comes back low-grade. There's certainly a role for percutaneous biopsy in those patients. And in studies that have reported these, they have not observed a risk of seeding after biopsy. In these patients, I really just quantify what we know and how we know it in terms of what; he's had a voided cytology, which was negative for high-grade disease, he's had an upper tract cytology, which showed atypia, but again, no high-grade disease.

And we had two good samples of a biopsy from the scope itself, which showed low-grade disease. But again, even after all of that, we still have the question: could we be missing something because this disease space is so unique that we have a therapeutic window to give a patient cisplatin-based chemotherapy? And unlike other tumors, we are planning to take out a kidney that could then make them ineligible for that chemotherapy. And so if they are a candidate, if we do have suspicion, it is really important to get this staging correct, which is very difficult to do at times. Now, there are adjunct tests that we've used in the past, and there are some coming up in the future that are very promising. FISH is not currently supported for routine use for upper tract disease. There are some concerns for the accuracy of that testing as opposed to some that there's probably better evidence for in the bladder.


Other imaging studies include MRIs, but there's also a concern that that could then over-stage the patient. Then we could be giving chemotherapy to patients that won't necessarily benefit from it and putting them at undue risk. And then on the horizon, ctDNA has shown tremendous promise for upper tract disease in predicting patients with muscle-invasive tumors, showing a 90% sensitivity and a 100% specificity in our recent studies. And then we're very fortunate that this year, in this last calendar year, our own AUA has come out with guidelines for this and how to manage these patients and how to risk-stratify them. And so I've sort of circled here how I think of this patient in terms of what categories he falls into. And this ultimately leads me into not only selecting a therapy but also how am I going to counsel this patient. And I think this is important to know; patients come in and they're educated, and they have read this stuff previously, and so this really does help me to label them and show them where they fit within the standard of care.


Zach Klaassen: Yeah, I think this slide is fantastic because if you look at the guidelines, which are excellent, we actually just did a couple of recordings which will also lay out this risk stratification. I think this is one of the best tables in that guideline because it really delineates based on the features on the left of the table and delineating them to low versus high risk, low versus high-grade, and then favorable or unfavorable, and more importantly, at the bottom, figuring out what therapy is appropriate for each of these patients. So I think it helps us explain it to the patients. And I like how you basically outlined where your patient stands. So take us through how you treated this patient.

Kyle Rose: So again, just considering everything that we know about him so far as we currently stand, I would consider him to be clinically TaN0, low-grade to our knowledge. And then going back to the guidelines, it's not just is it possible to do it endoscopically, but is it feasible? Can we manage him endoscopically? I would say with this type of tumor burden, the answer would be no. And then the following question is, is there a role for nephron-sparing surgery? And to flip that question, is this renal unit worth saving? In this patient specifically, he had a blown-out kidney. I did not do a nuke-med scan, but I would anticipate the function would be 10% or less.

And so in this situation, I would not opt for nephron-sparing for that reason. And then finally, are we confident in our staging? And we had multiple biopsies and cytologies confirming low-grade tumor; there's always a chance that it will come back higher-grade, but at least by the standard of care testing that we have available and according to that standard of care, I do feel confident in our staging. So we took him to the operating room for a robot-assisted FU and perioperative chemotherapy after bladder closure. We opted not to do a lymph node dissection at that time because again, he was low-grade with no clinically positive nodes, and his path actually came back a couple of days ago. It came back low-grade TA.


Zach Klaassen: Outstanding. So I totally agree. I think that that renal unit looks like it's completely blown out. You've got high volume, low-grade disease, and I think, let's flip the script just a little bit. Let's say you had a 1.5-centimeter renal pelvis tumor, biopsied low-grade, when are you using endoscopy? We've got Jelmyto now. Tell us about your experience with maybe both of those. If the script was flipped and you had a solitary tumor, that may be amenable to either one of those options.

Kyle Rose: Right, and I would also stress too that it would have to be a different-looking kidney, right? It'd have to be a kidney with parenchyma contributing good function to the total body.

Zach Klaassen: Absolutely.

Kyle Rose: And so if there was a solitary papillary lesion that I could manage endoscopically, absolutely. Because when we consider this man at his age, what conditions are ultimately going to lead to him potentially dying in the next five to 10 years? It's CKD, kidney disease, stroke, and having functioning renal units is extremely important in those patients.


Zach Klaassen: Yep, absolutely. How about Jelmyto? When would you consider Jelmyto in a patient like the one we just discussed? Not your case, but the good functioning unit? Maybe 1.5 to 2-centimeter tumor.

Kyle Rose: Right. I think in patients that have a lower volume tumor that is low-grade, patients that we can manage endoscopically or also in patients who we cannot fully resect or ablate endoscopically, those are good candidates. Now, depending on what you can or can't do, we also have some newer evidence that came out after the OLYMPUS Trial that we believe that the ablative effect or the adjuvant effect is better if we can resect or ablate completely prior to Jelmyto. There's also newer data coming out on some of the real-world experiences on tumors in the ureter itself and not just in the renal pelvis. And then comes in the question of how would you give it? Would it be retrograde or antegrade?


Zach Klaassen: Are you using an antegrade approach or are you using a retrograde approach in your patients with Jelmyto?

Kyle Rose: We are currently using an antegrade approach. We have found observationally, again, not very strong level evidence, but observationally that those patients have a lower rate of stricture compared to the clinical trial.

Zach Klaassen: Yeah, absolutely. That's a great case, Dr. Rose, thank you so much for bringing this to our attention and sharing it with our UroToday viewers, and we appreciate your expertise and your discussion today.

Kyle Rose: Absolutely. Thank you so much, Dr. Klaassen.