Sam Chang: Hi, my name is Sam Chang. I'm a urologist in Nashville, Tennessee. And we're quite fortunate to have actually, to me, one of the most exciting panels coming up at the AUA 2023. So, I'll have these distinguished leaders introduce themselves, and then we'll focus on the panel which they will be discussing actually, management evaluation, surveillance, follow up of those individuals with upper tract urothelial carcinoma. So, I think we'll start here.

Jay Raman: Great. Thanks, Sam. My name's Jay Raman. I'm Professor and Chair of Urology at Penn State College of Medicine in Hershey, Pennsylvania.

Sima Porten: My name is Sima Porten. I'm a Urologic Oncologist at UCSF, and I'm an Associate Professor.

Surena Matin: Hi, I'm Surena Matin. I'm a Professor at MD Anderson Cancer Center.

Tomonori Habuchi: Hi, I'm Tomonori Habuchi from Akita University, Japan. I'm doing my [inaudible 00:00:55] and robotic surgeries for urinary tract tumors.

Sam Chang: Well, thank you again for joining us. And Dr. Matin, I'm going to turn it over to you. You've actually helped put this panel together as the moderator. I think there are certain points that during the session that you all will try to emphasize, try to educate, try to illustrate. So, I'll start off with you, and tell us kind of some key points that you guys will be discussing.

Surena Matin: Thanks so much, Sam. Thanks for doing this, by the way. It's really great to be able to get some of this out. And I'm also grateful to the AUA, both for their work on the guidelines panel which was just released, and as well for my panelists here who are just great colleagues.

And so, I think we do have some important highlights from our panel discussion. Dr. Habuchi, you were telling me that you all recently completed a clinical trial on lymphadenectomy for upper tract urothelial cancer. Can you tell us a little bit more about that?

Tomonori Habuchi: We just still recruiting the patients, but we are focusing on renal pelvic tumors, which lymphadenectomy... The area for lymphadenectomy is well-defined. So, we divide it into two groups, one for lymphadenectomy, one without lymphadenectomy. But the result is still yet published. So, we are now looking forward to the results outcome.

Surena Matin: That's terrific. And this will be a randomized study?

Tomonori Habuchi: Yes, randomized.

Surena Matin: Excellent. Okay. And how many patients do you think you will need to enroll?

Tomonori Habuchi: We have already recruited more than 100.

Surena Matin: Wow.

Sam Chang: Wow. That's amazing. And your endpoint that you'll be looking at is disease free survival?

Tomonori Habuchi: Yes. Yes. disease free and cancer specific survival. Yeah.

Sam Chang: Wow, that's amazing to be able to actually... to have that type of trial randomized will help answer important questions.

Tomonori Habuchi: Yes.

Sam Chang: Dr. Matin, what other key highlights?

Surena Matin: Yeah, so the other thing that's very exciting for us and we think will be impactful is the idea of risk stratification and whether we want to consider giving chemotherapy first or proceeding with nephroureterectomy first. Dr. Porten, is this something that you can give us a little bit more detail about?

Sima Porten: Yeah, sure. So, the conundrum always is when a patient walks in the door with upper tract disease, do you actually have an appropriate clinical stage, right? And so, we have to use a lot of surrogates to figure out, is this someone who we would consider high risk? Like with traditional lower tract or bladder cancer, those are folks who have muscle invasive disease. That's really, really difficult to tell with a ureteroscopic biopsy.

So, we end up using surrogates, and these can be is there high grade cytology in the setting of a large papillary tumor? Is there clinical evidence of T3 disease on imaging? That's pretty rare. That's a difficult thing to see as well. Or is there just...

Sam Chang: Not a good thing to see, that's for sure.

Sima Porten: Not a good thing to see at all.

Sam Chang: Yeah, absolutely. Right.

Sima Porten: Or is there just high grade disease on your biopsy from your ureteroscopy? And so, there's been a lot of development into trying to figure out and create nomograms for risk stratification that will be pointed out in the guidelines.

In addition to that, there's also risk stratification as well, if you end up going straight to nephroureterectomy, what's the chance that your GFR won't be appropriate enough to get cisplatin based chemotherapy?

And there's a nice poster by Dr. Matin's group with Pat Hensley looking at how you can estimate that. And there's also readily available nomograms estimating post nephrectomy GFR in the RCC setting.

Sam Chang: And so, to help predict then if I go ahead and do this nephroureterectomy in an individual, will that individual then be able to get cisplatin based chemotherapy? Is that right, Dr. Matin?

Surena Matin: No, that's perfect. And I think one of the things we want to highlight, and I think will be highlighted in the prior session of ours that highlights... that looks at the guidelines, is this idea that we want to think ahead a little bit at that time when we're counseling patients about both which treatments we're offering, but also the downstream consequences of those treatments on kidney function now, because it will burn bridges or open up possibilities depending on anything unexpected on pathology.

Sam Chang: So, any further details regarding that? Because I think so many things come into play as a practicing urologist. Some of these systems are obstructed and upfront, and does that impact... Tell me some of the key variables that you all found then in this abstract that I'm sure you'll elucidate on the panel. Yeah.

Surena Matin: Yeah. So, age definitely plays a role. Their pre-existing GFR plays a role. And then there's a couple of other factors that do. Having a split function from either renogram or volumetric studies, which are actually pretty good now, that also can help with prediction.

Obviously, if it's a non-functioning kidney, then you already know what their GFR is going to be. And in those cases, maybe it's not quite as critical. There won't be as much of an impact with initial surgery, for example. And then the only question is do they have really bad disease or is it surgically treatable?

So, I think these are... for the other routine cases with bilateral kidneys being present, it does require a little bit more work on our end to do our diligence to make sure that we don't shortchange the patient down the line.

Sam Chang: Right. So, along those lines, Dr. Raman, the downstream effect of any treatment that we have, the realization that these patients also most of the time have bladders, there's certain areas, I think, of emphasis that perhaps the panel will also raise that you want to also discuss.

Jay Raman: Meaning you're talking about prevention of subsequent bladder tumors.

Sam Chang: Absolutely, that's one thing. Yeah, for sure.

Jay Raman: Yeah. I think there's more and more data that shows that whether you do a nephroureterectomy or whether you do some type of ablative procedure for maybe a lower risk tumor, there is some inherent risk, I think, of some downstream seeding that can occur and the resultant effect of bladder cancer.

And I think one of the things we're going to talk about on the panel is the data that's, in some case, level one for nephroureterectomy, or a little bit more circumstantial for ureteroscopy, about giving therapy in the bladder, intravesical chemotherapy, to reduce the likelihood of bladder cancer recurrence.

Sam Chang: So, along those themes of sparing, tell us something about the initiatives about sparing the kidneys in terms of treatment options.

Jay Raman: Yeah, I mean, I think this is one of the big goals of the panel on the guideline is to really understand that upper tract urothelial cancer is not one disease entity that can only be managed by one treatment approach. And so, this concept of risk and risk stratification and understanding that certain tumors that are maybe low grade, that are unifocal, maybe in older patients, can be managed by one approach, kidney preservation, while those that are higher risk, as my panelists have talked about, may need more aggressive surgery.

And I think one of our big themes is kidney preservation, and that can be done. We have so many better tools now. The ureteroscopic instrumentation is better, the percutaneous instrumentation is better, our lasers are better, and even some of our adjuvant or ablative therapies are better. And so, it's really looking in an eye of can I preserve the kidney safely, and then what tools do I have available to accomplish that goal?

Sam Chang: Dr. Matin, other highlights from the panel coming up?

Surena Matin: Yeah, I mean, I think one of the things that Jay just pointed out, probably one of the most fundamentally important things that has happened, is there's one drug that's been specifically approved for treatment of upper tract urothelial cancer. And so, we are going to talk about that a little bit and some of the concerns and some of the barriers that exist in terms of its incorporation into care. So, we'll talk a little bit about that.

And also in terms of how things have evolved with its use with mitomycin gel post commercialization. And so, it's been interesting participating but also observing how urologists, how creative we can be in terms of adapting data and existing tools in a way that can really... sometimes wasn't really initially expected. And if I sound vague, I'm doing it on purpose because I want people to watch the panel about this.

Sam Chang: I mean, along those lines, it is really important because we can't always predict what's going to be done, in what ways. And it can be techniques, it could be medications, it could be different approaches. But along those lines, we're always trying to learn from each other.

And so, Dr. Porten, whenever I'm surrounded by smart individuals, and this panel's surrounded. I mean, you look this way, smart individual, look this way, smart... You learn something. So, what have you learned? What little tidbit or pearl perhaps? And you don't have to share the most important one because we'll save that for the panel, but is there a tidbit that you'd want to share that, wow, this is a great pearl, be it technique regarding the renal orifice, be it lymph node dissection, be it whatever? Is there anything that comes to mind?

Sima Porten: I would say the technique regarding the bladder cuff. It's great. I mean, Dr. Matin was my attending at MD Anderson, and that's who I learned how to do it from. And I hear his voice in my head. And there's going to be a great slide in this talk that talks about, okay, you go medial to the medial umbilical ligament, find that ureter. And you're not done yet. You keep going, and then you're still not done yet. You still keep going. And I think that that's a really important technique in terms of as you're teaching and as you're operating and learning, hearing that in your head, and so you can deliver the best oncologic effective surgery. Right.

Sam Chang: Yeah. I think under-reported and too often seen is the remnant distal ureteral portion. I won't say small amount, I won't say the whole ureter, but it varies. And many times, unfortunately, that can be a source of residual disease. And what you do with that can be difficult, there's no question.

So, I'm going to end with a question of excitement and future, okay? As you guys put this panel together, you learn from each other. I'm going to start with Dr. Matin. Tell me what you think the next most exciting future steps are diagnostic-wise, predictive-wise, treatment-wise? What's exciting for you?

Surena Matin: So, well, my hope is that we get better diagnostics, but I'm not sure I have a great insight into that right now. But right now, what I think is exciting is more targeted and personalized precision treatment. We really haven't done that. It used to be 20 years ago, it was one knee-jerk nephroureterectomy for everybody, right?

Sam Chang: Yes. Small, tiny papillary... Boom, take it out.

Surena Matin: Yeah, kidney out. Let's do it, right? And so, now what I think what I really would like us and my team to also work on is more precision therapy. And I think some of the targeted therapies potentially may help there. Identifying those with Lynch syndrome or MSI high tumors that may have amazing responses to immunotherapy, there's that subset. And then there's the subset with FGFR3 alterations. And that is still being explored in terms of how effective that target is, in terms of how effective drugging that target is.

But I think that's going to be very exciting down the line, particularly for patients who have need for kidney preservation and multifocal recurrences, which is really one of the Achilles heel of this disease in terms of being able to manage. We can feel really good immediately laser ablating everything.

Sam Chang: Right.

Surena Matin: But when it comes back in multiples three, six months later, what have we really done?

Sam Chang: Done, exactly. And how far have we really moved the needle? But I can say with this panel, we've definitely started moving the needle ahead. We've learned from each other. The panel is going to be fantastic. Thank you, again, for contributing to the science and our knowledge, and thank you for spending some time with us.

Surena Matin: Thank you, Sam.

Jay Raman: Thank you.

Sima Porten: Thanks.