Sam Chang: Hello everyone. My name is Sam Chang. I'm a Urologist in Nashville, Tennessee. I'm very fortunate to have Dr. Firas Petros from Toledo, who is moderating a session at this year's AUA 2022. It's a podium session that focuses on upper tract urothelial carcinoma. So thanks so much for being with us today, Dr. Petros.

Firas Petros: Thank you for the invitation, Dr. Chang.

Sam Chang: So, I wanted to ask you, as you moderate this session, are there any concepts or abstracts that really stick out in your mind, in terms that maybe practice changing or at least hypothesis generating in your mind?

Firas Petros: Yeah. There were a couple abstracts when I reviewed the sessions that are interesting. Both of them involved the use of circulating tumor DNA as a biomarker, as well as to assess the likely response to treatment in patients with locally advanced or even metastatic upper tract urothelial carcinoma. So these could be practice changing in the future.

Sam Chang: Right. So they collected circulating tumor DNA, prior to treatment?

Firas Petros: Correct.

Sam Chang: And then looked at levels after therapy, is that correct?

Firas Petros: Correct. So one of them actually involved patients with the clinically localized disease, without preoperative imaging showing metastatic disease. And in five of these patients, the level was high enough to predict they have locally advanced and later developed metastatic disease. So the author concluded that these patients probably would benefit from new neoadjuvant chemotherapy.

Sam Chang: I see. So basically, not only giving you a description of the disease process, perhaps, but also allowing us prediction of what will happen then downstream?

Firas Petros: Correct.

Sam Chang: Okay.

Firas Petros: So down the line that would be practice changing.

Sam Chang: Right. So with that, do you have any idea regarding when this can start coming into practice? Because we've heard about either circulating tumor cells, circulating tumor DNA, cell-free DNA. All these different types of descriptions. How close are we coming to actually using this in our clinical practice, do you think?

Firas Petros: I think it will come potentially. But one challenging aspect in upper tract urothelial carcinoma, as you know, it's under staging. So often times you proceed with nephroureterectomy and then the final pathology would be more clinically localized or locally advanced diseases, stages three or four. And these patient haven't received neoadjuvant chemotherapy. Then as you know, giving adjuvant chemotherapy after one kidney is out could be challenging and not all patients will tolerate. Although we have level one evidence, the POUT trial. But maybe early use of the circulating tumor DNA to identify this subset of patients, along with molecular subtyping of the biopsy specimen to know exactly if they have papillary upper tract or basal. Because, as you know, from the bladder cancer trials, the basal subtype usually respond the most for-

Sam Chang: Do better for chemotherapy.

Firas Petros: Exactly.

Sam Chang: I see.

Firas Petros: Than papillary or luminal subtype.

Sam Chang: So, people who know me understand that I have a high level of ignorance. So please excuse my ignorance here. But is there enough evidence regarding circulating tumor DNA that if I have individual A and they're circulating tumor DNA is this level, and I have patient B and they're circulating tumor DNA is this level, is there enough data out there that's basically this patient, patient A, has high-risk disease. Likely has occult, perhaps metastatic disease, they should get neoadjuvant versus this patient B? Or is it only dependent upon an individual serves as their own self-control?

Firas Petros: Actually, circulating tumor DNA, in some studies, has been correlating with mutational tumor burden. So the higher mutation tumor burden, more likely you're going to have higher stage of the disease as well as more risk for LVI and more risk for disease of progression. Probably we need level one evidence, which is lacking at this time. But also in clinical staging, when you have a patient with T1 or T0, even after the biopsy, most likely they would not have that high level. Based on the tumor burden from the imaging probably would expect these patient, they would do worse in the future.

Sam Chang: Got it.

Firas Petros: And that could also correlate to the level of the mutational burden.

Sam Chang: I see. Any other posters or podium sessions within your session that stick out?

Firas Petros: Yeah. One of them that's also sticking out was reported the phase one trial of the photodynamic therapy by the Dr. Coleman group in New York. So that also opens another arena for patients who are not willing yet to accept radical nephroureterectomy. Or if they have solitary kidney. It actually showed 94% preservation or clinical response rate. And some of these patients, I think they reported eight patients, they had partial response and required second trial. So of course this opened another arena for a larger phase study. But in this phase one trial, they reported feasibility and safety, which I thought that was interesting.

Sam Chang: Right. So give us a nutshell description of the photodynamic. Do patients receive a medication intravenously?

Firas Petros: No. They do urethroscopy and they apply this to the tumor and they had it in the abstract, the dose and the duration.

Sam Chang: Okay.

Firas Petros: And some of these patients had even failed prior intracavitary therapy, BCG and chemotherapy. And they were able to have good response with this therapy that, as you know, it has regulatory approval by the FDA in prostate cancer.

Sam Chang: I see. So then once you apply the medication, then you turn lights on, different types of things-

Firas Petros: Correct.

Sam Chang: To stimulate the action of the actual photodynamic, kind of parameters that are taken in. So does this treatment have to be repeated? Is this a one-time treatment or how did they do that?

Firas Petros: Well, they haven't specified in the abstract yet.

Sam Chang: I see.

Firas Petros: But they reported some patients, they had partial response. So they had to repeat the treatment and of course some patient progressed to radical nephroureterectomy. But of course, a larger scale trial is needed at this point.

Sam Chang: But again, another step forward for our patients.

Firas Petros: Correct.

Sam Chang: Just as you said, to help avoid the nephroureterectomy. I mean, we struggled for a long, long time. Then we had approval obviously of the UroGen medication that is able to stay, the Mitogel, that's able to stay within the renal pelvis for lower grade disease.

Firas Petros: Correct. And there was another abstract actually about the Mitogel.

Sam Chang: Yes.

Firas Petros: And the state of, as you know, in the OLYMPUS trial was given through a urethral catheter. All these patients for the induction part, they have to put under, to sleep, under sedation and anesthesia.

Sam Chang: Yes.

Firas Petros: So actually, one abstract explored the arena of giving it through a nephrostomy tube, which is kind of interesting avoiding patient anesthesia each time in the induction phase. But it's more interesting, they found a lower stricture rate [inaudible] obstruction. I think they reported 15% compared to 59% in the OLYMPUS trial.

Sam Chang: That's very eye-opening because I myself have been somewhat hesitant for exactly the reasons you just raised regarding the placement that ureteral catheters. Many times that may require anesthesia and the issue with stricture rate. But I was aware that people were trying to do the percutaneous method, but the fact that the stricture rate is actually much less and allows them to be done, I'm sure in the clinic, in terms of just an application through to antegrade nephrostogram method. It's really, really interesting.

I can say that at our institution, we've started to use Mitogel and that's the approach we've been using. Is it antegrade via percutaneous nephrostomy tube and patients have been tolerating it incredibly well.

Firas Petros: Perfectly well.

Sam Chang: So I'm really glad to hear that along with the lines of, hey, this seems to work, the stricture rate has actually greatly improved.

Firas Petros: Correct. And one more abstract reported about whether or not, as you know, there's always debate about lymphadenectomy. Whether a radical cystectomy, whether an upper tract urothelial carcinoma. But actually they reported on survival outcome if it is linked to lymph node yield. So they found that when appropriate lymph node dissection done, and you have more than 10 lymph nodes reported found by pathologist, actually this is linked to disease prog... These patients will have more progression free survival and lower chance of recurrence compared with patients with less than 10 lymph node yield. I mean, again, retrospective study, but large scale at trial. I think it was multi institutional.

Sam Chang: Did they describe the templates that were needed were done?

Firas Petros: They did not.

Sam Chang: Okay.

Firas Petros: They did not.

Sam Chang: Yeah. To me, that's always my personal struggle is, I think that lymph node removal clearly is important for staging and understanding. And the issue is in a lower tract tumor, do I need to go high up on the retroperitoneum? And for a retroperitoneal tumor in the renal pelvis, do they need to have a pelvic-

Firas Petros: Lymph node dissection.

Sam Chang: So I always struggle with that. And there are others that have defined certain templates and lymphatic drainage pattern. But we haven't had the combination of, use this pattern, these are the results that get.

Firas Petros: Correct. And I think lymph node mapping has been, as you alluded to, has been described in prior multi-institutional.

Sam Chang: Yes.

Firas Petros: One study of Dr. Matin at MD Anderson with Jonathan Coleman, they nicely highlighted the areas of mapping and the percentage of detection when you combine, for example, interaortocaval, with paracaval, retrocaval, based on the location of the tumor. Whether renal, pelvis-

Sam Chang: Of where to go.

Firas Petros: Correct.

Sam Chang: Exactly. Those mapping studies have been important to me because that's what I tend to do. But unfortunately though, much like bladder cancer, it can be a multifocal disease process.

Firas Petros: Exactly.

Sam Chang: And so, then do you put someone through the morbidity of an extended lymph node dissection? I still personally struggle with that, but there's unquestionably the impact and the importance of lymph node dissection, I think, for upper tract disease has been pretty well. Has been pretty well made clear.

Firas Petros: Correct.

Sam Chang: Well, looking at this year's AUA, I think there's at least two or three podium and poster sessions for upper tract disease. And I think it talks to kind of the explosion and interest. The explosion in actually research in a disease that we used to really have very, very little knowledge about and actually very few treatment options. So I think it represents a very exciting time. So as the moderator of this session, as you look through things, what are some key take home messages that you'd want to tell our folks?

Firas Petros: Yeah. I think germline testing also in the future for upper tract. So one of the abstract, actually the described germline testing, not only for patients with known history of Lynch syndrome or Lynch associated conditions, but actually testing all patients with upper tract. And in some diseases state like solid tumor, you will find one third of patients without even reporting family history. They will test positive for hereditary genes. And the use of circulating tumor DNA, any adjunct that would increase our ability to detect more advanced disease than imaging or even detect recurrence before showing on imaging, that actually will improve patient's outcome patient survival. So I think these are the key take points of this year's abstracts submitted to the AUA.

Sam Chang: Yeah. Sounds like a great session. So Dr. Petros, thank you for spending some time with us and really appreciate the succinct kind of points of emphasis that you've gleaned from your session. And again, thank you.

Firas Petros: Thank you. I appreciate the opportunity.