Ashish Kamat: It gives me great pleasure to welcome Dr. Vitaly Margulis here today. Vitaly's a colleague and a good friend, a Professor of Urologic Oncology, and Director of Urologic Oncology up in UT Southwestern in Dallas. Welcome, Vitaly.

Vitaly Margulis: Thank you. Good to be here with you, Ashish.

Ashish Kamat: There's a lot of activity going on in the urothelial cancer field and you've been very active in all aspects of it. But I wanted to pick your brain a little bit on upper tract disease. It's like a little bit of an orphan disease. There's not too many people who are truly focused on it and you are. Could you share with us and the audience what you would think would be the top three developments in this field in the last several years?

Vitaly Margulis: Maybe the way I should start is through starting with localized disease and moving onto more advanced disease. I think with localized disease, exciting things are some of the intracavitary therapies. As you know, the problem with upper tract disease, it's difficult administering. Unlike the bladder where there's dwell time, it's very difficult to have anything hang in the upper tract so there are several things we'll probably discuss that have to do with intracavitary therapies. I think, looking at more advanced disease, some of the genetic changes that we know are more prevalent in upper tract compared to the sort of bladder are interesting, potentially targetable. And finally, sort of utilization of systemic therapies in locally advanced disease to improve outcomes. I think those three things would be sort of on top of my list.

Ashish Kamat: With the cavitary application, with the localized upper tract disease, there's clearly been a lot of work being done with stent delivery, with gels. You've been involved in a lot of those. Could you expand on that a little bit?

Vitaly Margulis: Again, unlike the bladder where we extrapolate all the findings, in upper tract, the dwell time or exposure of the urothelium to the agent or therapy of choice is difficult because everything just drains through. And so, it's exciting finally to have some tools available to us to actually improve on that, and really try to deliver appropriate doses of drugs for appropriate amounts of time to the upper tract. Probably on the forefront of these treatments is something called MitoGel™, which is a reverse polymer, as you may know, that is basically liquid when it's frozen but becomes gel-like at room temperatures. And so the substance can be delivered into the upper tract, and as soon as it warms up basically creates a cast which then releases the drug of choice. In this case, it's mitomycin.

Ashish Kamat: And it's kind of like a reverse Jell-o, as I call it, right?

Vitaly Margulis: Reverse Jell-o, exactly.

Ashish Kamat: Now, the studies that were done looked mainly at patients that had a low-grade disease that was not considered amenable to complete resection. And the results were, of course, presented last year. One of the things that the critiques of that study pointed out were the stricture rates. Personally, I didn't think that was a major issue. What are your views on the complications associated with MitoGel™ in upper tract?

Vitaly Margulis: Yeah. Again, my experience, I agree with you. In my experience, we have not seen strictures with this agent. I think it's difficult to assess the stricture formation because I think a lot of it is driven actually by what you know. So one has to try to resect as much of the upper tract disease as possible using endoscopic techniques. And I wonder if the strictures are actually coming from endoscopic management versus attributable to the agent itself. Again, in my experience and talking to other people, the strictures have not been as much of an issue.

Ashish Kamat: Okay. If you had to kind of talk our viewers through your paradigm right now for managing patients with upper tract disease, the patient presents to you as a small tumor in the ureter or renal pelvis, how would you go about in a stepwise fashion, figuring out what the best treatment for an individual patient is?

Vitaly Margulis: I think one has to start with the risk stratification. And so every time we have concern for upper tract disease, we perform an evaluation at the bladder, upper tract endoscopy, cross-sectional imaging to make sure we know exactly what's involved. I think an endoscopic biopsy is possible, removal of as much of the tumor as possible at the time of endoscopy. I think is probably the first step. Subsequent steps or subsequent steps of management dependent sort of what the pathologic findings tell us. For low-risk disease, that mainly will be low-grade disease, unfortunately. The problem with upper tract disease, we don't have as many tools available to us for risk stratification as we do have in bladder cancer. But for low-grade disease, which essentially equates to low-risk disease, I think we're shifting more and more to organ-preserving strategies. For high-risk disease, which tends to be an invasive and high-grade invasive disease, we are switching more to multimodal therapies.

Ashish Kamat: When you do a uroscopy, do you recommend that everybody always should perform a biopsy or is visual recognition of the tumor alone sufficient?

Vitaly Margulis: Yeah, I guess our field is in my opinion, is moving away from just visualization to actually understanding if you have low-grade disease, ie. low-risk, versus high-grade disease because that really changes your management. And so I think the biopsies are crucial. In fact, not only the biopsy but if it's possible I would recommend removing as much of the tumor as possible.

Ashish Kamat: Right, right, right. And then do you use any nomograms, I know you've been involved in constructing a lot of those, but in your daily practice, do you use nomograms to try to predict which patient should get more aggressive therapy versus conservative therapy?

Vitaly Margulis: Yes, nomograms are useful. They're more probably more useful for paper publishing and maybe pain patient counseling so they can be useful. But essentially with the tools available to us now, I think the grade is the main predictor of what is going to happen to these patients. Other factors for risk stratification such as multifocality, size, some of the findings on the radiologic imaging, cross-sectional imaging that may play into it. But I think grade remains probably the most important predictor and we have to remember that unlike the bladder, it's very hard to get a representative specimen and really assess the depth of invasion. We have to rely on grade as probably the most reliable predictor at this point.

Ashish Kamat: Sure. If you have a patient with high-grade disease, what's your primary recommendation for upper tract high-grade disease? Say, papillary lesion?

Vitaly Margulis: Again, if it's small papillary lesion, if it's possible to manage this endoscopically effectively, in select cases one can consider conservative management. This would require at least repeat endoscopy and rebiopsy followed probably by adjuvant therapeutic of your choice, intracavitary therapeutic of your choice and very careful surveillance. Most patients with high-grade disease probably will be directed towards extra operative surgery plus or minus systemic options.

Ashish Kamat: Right. Let's assume that the patient you deem necessary for a nephroureterectomy, are you a believer in the data from the POUT study or do you recommend neoadjuvant therapy for these patients?

Vitaly Margulis: Yeah, so now we're getting into the management of, although I would say high-risk, possibly locally advanced urothelial cancer. I am a full believer that platinum works in the space. But the issue is that if one proceeds with surgery upfront, half the time you're not able to give treatment after surgery because your renal function is declined to the point where platinum was not an option. The POUT, the careful evaluation of the POUT data suggests that carboplatin, which could be given at lower GFRs is not as effective as cisplatinum. And so I'm a full believer in the neoadjuvant paradigm because that's, unfortunately, may be the only opportunity to give cisplatinum.

Ashish Kamat: And an at your center, if someone can't get cisplatinum are you taking them straight to surgery? Are you offering them IO therapy for example?

Vitaly Margulis: We are, but under on the clinical trial basis.

Ashish Kamat: And let's assume the patient has a solitary kidney, high-grade disease, what are your options for topical therapy? Do you go for BCG? Mitomycin? Route of administration? To some practical tips for our listeners.

Vitaly Margulis: For CIS, I think so upper tract, imperative indications I guess for the preservation of the upper tract. If there is CIS, I think BCG probably would be my choice of an agent to use. One has to remember there are several ways to deliver intracavitary therapy. I would just caution to say that placing a stent and placing the therapy to the bladder, hoping for appropriate reflux and exposure is not the way to go. And so if one were to do this, I think either antegrade infusion through nephrostomy tube or retrograde infusion through some sort of a ureteral catheter would be the way to administer any of these agents. But for example, for CIS only, I think BCG would be my preferred agent of choice. As an adjuvant to management of high-grade lesion, either invasive or non-invasive post-therapy as an adjuvant agent, we have switched the gemcitabine instilled, again either through antegrade prostate or retrograde through a catheter.

Ashish Kamat: Yeah. And you make an important point because you know there's always been this talk amongst a select group of people that you can just put a stent in the bladder and hope that the agent goes up and that's clearly not accurate and it's a very important point that you brought up. Lastly, sort of in the last couple, few minutes that we have, there's been a lot of activity in typing, subtyping upper tract and bladder, and FGFR3 et cetera, and clearly there are trials that are directed against FGFR3 pathway therapy. What's your view in whether the FGFR difference between the upper tract and bladder's actually true? Or is it a sampling issue? Number one, and number two, where do you think we're headed with these targeted therapies?

Vitaly Margulis: Well, I think this is the right, again, ultimately time will show, but I think this is the right direction. Multiple studies show consistently that the prevalence of FGFR mutations in the upper tract is higher than what we see in bladder cancer. I think it's a very interesting therapeutic option. I think it needs to be explored further. I think looking at sort of DNA repair mechanisms is also important because there are treatments available to target those pathways. But ultimately again, like anything in urologic oncology, hopefully, it will be a more pathway-driven therapy.

Ashish Kamat: Absolutely. This has been great. Thank you again for taking time from a busy GU ASCO schedule. It was a pleasure having you.