Sam Chang: Hello everyone, my name is Sam Chang, I'm a urologist in Nashville. We're quite fortunate to actually have a dynamic duo, who will actually be presenting some of their work. Evaluating the treatment, the cost, outcomes, what's actually going on in the United States for patients with localized, upper tract disease. So, we're fortunate to have Katherine Fero, I've known Katherine since she was actually visiting Sub-I at Vanderbilt, and as a result, we've joked a little bit. But she's currently now a Chief Resident, PGY-6 at UCLA and has been quite active in the academic circles.

She's joined with the senior author of this paper, Stephen Williams. You all know Dr. Williams but his titles are numerous. He's the Chief of the Division of Urology, he's the Medical Director of High-Value Care. He is a tenured Professor, he's a Robert Earl Cone Professor, his accolades continue. I think, importantly for the next generation, he's the Director of Oncology Research, as well as the Director of the Urologic Research Program there. As a result, we're quite fortunate to have both of them. I'm going to turn the talk over at this point to Katherine and Dr. Williams. And both Dr. Fero and Dr. Williams will go over their paper and their highlights and I'll ask them some questions afterwards, so Dr. Fero?

Katherine Fero: Thanks so much for having us and for the warm welcome and introduction. So, this was a project that Dr. Williams and I discussed, he really spearheaded with his excellent team. The second author did a lot of the analytics, so I need to make sure that credit where credit is due there. As you know, as people who treat patients with upper tract urothelial carcinoma, it really is a heterogeneous group of patients and a heterogeneous disease. Based on how aggressive the tumors are; grade, location, size, the various treatment options are diverse. We sought to look at it and see how contemporarily patients are being managed, with a real world study sample. Treatment patterns, how patients were doing, and then the cost associated with the care.

And these are patients who have localized upper tract urothelial carcinoma. So we looked at a group of patients diagnosed over a 10-year period, identified through the SEER database with non-metastatic upper tract cancers. And just to summarize here for those not as familiar with the SEER database, you can link the SEER database, which is a cancer registry to Medicare claims data. And that allows you to get some more granular details about timing and sequence of treatments and also costs associated with both inpatient and outpatient care. So it's a huge sample from the entire country. So we screen patients in based on their age, whether or not they had variant histology, they have to have Medicare coverage over the full study period and be non-metastatic at the time of diagnosis.

So, we then adopted the EAU risk stratification, high versus low risk to discern two groups of patients, to compare to one another. And this is a busy table but just to hit the high point here, we looked at whether patients had any surgical intervention, if they did, whether they were getting endoscopies, maybe one, maybe two. Are they getting multiple ureteroscopic interventions? Are they getting laparoscopic or open interventions on their kidneys or ureters?

And we found that a large number of patients continue to be managed with radical nephrectomy, despite all of the endoscopic advancements we've had in endourology over the recent years, so that was one interesting take home point. I think it's nicely depicted here, this is just a cumulative incidence function of patients in either the high risk or the low risk group and their time to receiving an upper ureterectomy. So, there is a significant difference in the high risk patients, in the low risk patients, high risk patients were more likely to undergo nephrectomy but it's a high percentage in both groups within the one year after diagnosis. And you see that for most of these patients it's happening pretty early on in their treatment course.

And then, we didn't want to neglect the cost associated with care for these patients. So as we know, surgery is expensive, adjuvant therapy, chemotherapy is expensive, hospital stays are expensive. And these are total costs for a time period after diagnosis, so this also does include cost of care that are not specifically related to their cancer. But you're treating the whole person and surely this new cancer diagnosis is touching all aspects of their health. And here, I really just want to highlight that these numbers aren't small and they do tend to go up, you see in this bottom half of this slide, the second table, we kind of chart it out.

Okay, are people getting a diagnostic ureteroscopy? And then maybe one more ureteroscopy and then they're getting enough ureterectomy after that. How does that cost compare to someone who gets enough ureterectomy upfront? Maybe based on imaging study, for example. And you do see that more interventions are associated with more costs over time and that those costs do grow in the year following diagnosis. So, hopefully, I did justice, a little synopsis of that work and I have my boss here to back me up, if there are any specific questions.

Sam Chang: I guess the first question is I was going through this analysis, I always look at the title, I look at the authors, I look at the institution. So, maybe Dr. Williams, you can chime in, how did this consortium get together? Because everybody can poke holes at Medicare shared data. But at the end of the day, this is kind of real world data, I mean, this is what's happened, this is how people are treated, we have an idea. So how did this get together to start?

Stephen Williams: Dr. Chang, I think this is a pivotal example of team science and collaborative efforts. And one of the co-authors Karim Chamie reached out to myself because of our team that we've developed. And as you know, with our bladder cancer research that we've done and developed this program and saw upper tract urothelial carcinoma to have a potential opportunity for some collaboration and further investigation. As you can see from the title and as you mentioned, really, it's coming to just gain some knowledge in regard to treatment patterns, the outcomes and costs of this disease. Because really it's largely unknown and a very exciting time and upper tract urothelial carcinoma, where we're having newer agents investigated trials, a trial including the POUT trial being conducted, which many thought can never have.

So to inform us for the future, we sought to embark and involve various investigators at various levels of their training. Which is very exciting for myself to not only and I call it sponsorship, not mentorship, where you're sponsoring the individuals, helping them grow, learning from them. And Dr. Fero is very humble but really helps spearhead this project. Of course, I call it servant leadership with guide rails. So, providing the necessary guidance and investigation but not eliminating really the inquisitiveness nature. And she's been brilliant and was worked extremely hard in this investigation. And really we proposed the hypothesis, is that high risk patients have worse survival outcomes, overall cancer specific. But also there are substantial costs and that is, could be different as it related and as we showed according to risk stratification.

Sam Chang: Dr. Fero, with this data, should we be telling clinicians, "You guys are doing too many nephroureterectomies for a low risk disease." Is that a reasonable statement? Or, I mean, part of this where we don't have the granular data to understand why they could be having symptoms, there could be a lot of different things. But to me, the take home is, we might be overtreating some of these patients. What do you think?

Katherine Fero: I mean, my experience is much more limited than both of yours. But even in my short time in the field, I've found diagnosing and like, well staging upper tract urothelial carcinoma to be a really difficult challenge. I mean, diagnostic ureteroscopy, sounds like, "This will be a quick little case." But it's not always straightforward and it depends on where you're practicing access to great GU pathology, depending on how much specimen you're able to biopsy.

It's not always easy to say, to your patient, "I'm confident that this is a low risk lesion and I can manage it with a laser." I think Dr. Williams alluded to various agents that are coming forth and we have JELMYTO® and whatnot, so for specific locations of tumors. So, maybe in another 10 years or even 20, this will trend will look different, kind of naturally. But I do think I empathize with people sometimes, the more extra care definitive surgery is in some ways the easier one to do.

Sam Chang: Stephen, she shows wisdom well beyond her years with that statement and explanation. Because I try to be provocative but in reality, everything that Katherine said really makes sense. We've got these overall numbers but we're not there for the individual patient as he or she is being evaluated by the clinicians, what the decision tree is, what the analysis is. I guess, my only hope is that this helps to educate regarding, a lot of patients with lower risk disease are getting nephroureterectomies and the next thing is we have options, just like Dr. Fero stated. So Stephen, Dr. Fero pointed out some of the key issues and concerns regarding risk stratification, tissue sampling, evaluation in terms of treatment. As you see these patients, tell me a little bit about how you evaluate, do you always repeat sample, is radiographic imaging as much as, tell me a little bit about how you evaluate an upper-tract patient?

Stephen Williams: Absolutely. Well, before we get into that, I think also too, a subsequent study that we ended up publishing is also, we analyze or stratified by renal preservation versus nephro U. Because that exactly as you alluded to was a big question that we had, are what are those outcomes? And really to come down to that and that publication was renal preservation had improved survival, particularly in the low risk patients when we stratified by risk low versus high. In addition, had decreased costs as compared to high risk, so thus far one would hypothesize or deduce that this could be a high value option, particularly for low risk patients in renal preservation. But as you mentioned, in regard to the diagnostic pathway, usually a CT urogram, cystoscopy, ureteroscopy diagnostic. But quite often the sampling, right, that ends up being a challenge when you use traditional biopsy techniques in so much, it depends on the bulkiness of the tumor. Even I use a stone basket to actually grasp tumor versus a biopsy or other tools but really it's a collaboration.

The one thing I love about right now, oncology, is that it's multidisciplinary. So we have a wonderful team that we've set up here, particularly at our institution, I know it's at most institutions. But between medical oncology, radiation oncology, GU pathologists, GU radiologists, really coming together because more often, right, we can have patients that have non-diagnostic ureteroscopy. But really having our interventional radiologist, it's possible to get some sampling if needed but more importantly, just really having that shared decision making with the patients so that we can appropriately risk stratify them. And then also delineate the treatment options, which now fortunate or unfortunate are our multitude but we really want to provide most value to the patients.

Sam Chang: That's fantastic. I think, you know to me, kind of the most interesting graphic of your study, the curves that Dr. Fero showed regarding, within this time period, 80% plus of the high risk, within a year had a nephro U and a 70% plus of the low risk. But when they actually had it, it was basically the vast majority with within the first couple months. So implying to me that, "Okay, the decisions made will be definitive." You would think that over time, the low risk would slowly rise, that we can't control the disease. But it looks like upfront, the decision was made. Just like both of you guys mentioned, I'll be interested to see what happens in a few years over time as we have more options. So, as we close, any last bits of advice? Or exciting next steps? Or where we want to go next? I'll start with you, Stephen, anything else that's really exciting you? What you want to do? Points that you want to emphasize for the group?

Stephen Williams: Well, I think the first point is collaboration and respecting all collaborators and their genius that they have, including from the medical students to senior authors. And being open to ideas, suggestions improvements, more often I've garnished and some of the publications, including this one and high impact journals are often the result of their genius, not my own. But like I said before, as a servant leadership model, providing and allowing others to achieve their goals and obviously providing your input where it's necessary in the infrastructure.

Our next schools in and do so, actually one of the co-authors of this paper Vidit Sharma were working collaboratively with our Mayo Clinic colleagues. So it's actually quite a beautiful transition, where we're a fellow that was, I guess, mentoring or sponsoring, now has gone on to attending and then his fellow, I'm also now sponsoring or mentoring. So we're expanding this into the metastatic disease space to really pivotally understand this disease. And one area as well, of course, is end of life care, impact, costs, utilization. So, the story is unfolding but once again is another, just a wonderful example of, tapping in and leveraging the innate talent that we have across all levels. So, it's been a wonderful collaborative effort and I'm excited to see our program grow nationally and internationally.

Sam Chang: Well, Stephen that's great and it's exciting and that definitely gives me a chance to obviously give you kudos, in terms of how much you've done individually but then within your institution and obviously within neurology as a whole. So Katherine, you've managed to survive a month, or at least some, a bit of time with me at Vanderbilt years ago. And despite that, you've been able to achieve a lot. From kind of your perspective, what excites you? What's the next step in terms of research? What do you think would be important for audience in terms of upper tract disease?

Katherine Fero: I was really drawn to this project in particular because of the cost aspect. I think that it's going to be more and more important as we go on and continue to, I mean, we spend a lot of money on healthcare in this country. And I think knowing what sort of high value interventions we're actually offering to our patients, what we're doing that helps them and at what cost is going to be, is going to be important going forward. And I think for a long time, it's been an effort or kind of maybe an excuse, we will try to separate church and state? And make clinical decision makings in a silo separate from cost implications? And I think, unfortunately, we've just reached a point we're doing that is not really tenable. And maybe that's just because I have a small child now, so I'm like thinking about the future all the time. But I think the cost piece of this is really what motivates me.

Sam Chang: Well, I think that's so true. I mean, obviously we're starting to make attempts for price transparency within hospital, et cetera. Will we ever get the cost transparency? A different question. But I agree with you, absolutely understanding or at least revealing a little bit of what's been at least spent or at least charged so that individuals know what to expect. And honestly, it will impact, I think patients' choices as it should. We go beyond a service industry but we're a service industry. And so, I think all those points that you all have made I think are essential. And I want to thank both of you guys again so much for your collaboration, your sponsorship Stephen, your active integration and taking this step forward. Katherine and I look forward great things from both of you, so thanks again.

Katherine Fero: Thank you.

Stephen Williams: Thank you so much, Dr. Chang.