Sam Chang: Hello, everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee and work at Vanderbilt. And we're quite fortunate today to have two investigators that have looked at the current practices regarding chemotherapy and radical nephroureterectomy. And so, I'm going to let them introduce themselves. They're true leaders and they've worked on a project together that's recently been published. I'll start off with the senior author, Dr. Chung.

Benjamin Chung: Sam, thanks so much. I'm Ben Chung. I'm the senior author of this paper and I'm an associate professor here at Stanford. My specialty is urologic oncology and my practice is essentially focused in on kidney cancer and prostate cancer and the robotic treatments of that. Also have some research as you can see that has been kind of focused on outcomes research, but as of late, I'm beginning to change some of my focuses as far as my research is concerned, looking more at kidney cancer and urologic cancer epidemiology.

Sam Chang: Oh, fantastic. Francesco, I'll have you introduce yourself and then I think you have some slides to share.

Francesco Del Giudice: Yeah, sure. Thanks, Dr. Chang. Thank you for the opportunity to be here today for UroToday. And basically my name is Francesco del Giudice. I am urologist and currently a PhD student at the University of Rome Sapienza in the Department Of Urology. I have been spending one year as post-doctoral reserve scholar at Stanford. And I am currently an international collaborator with Stanford and I'm working in Ben's lab. I had a pleasure and privilege to be mentored by Ben Chung, over my, let's say, study career. And this is one of our result. One of the latest publication that we'll be today sharing with you. Once again, I would like to thank you for the opportunity to present our outcomes from our recently published research. The topic of the presentation will be focused on a large insurance claim data set from the United States and we'll be addressing the contemporary trends in the systemic neoadjuvant chemo as well postoperative intravesical chemo for upper tract urothelial cancer in patients who have ultimately undergone minimal invasive or open nephroureterectomy.

We do not have any conflict of interest to disclose, but please let us do share the full title of our presentation and publication, which has been recently accepted by Clinical Genitourinary Cancer, and is available in Open Access. You can download the PDF and eventually reach out if you have any questions, so we would like to positively cite our work. Thank you for eventually doing that. And once again, so the idea from this paper came from the EAU Guidelines, which are yearly updated and I am currently working in Europe, in Italy, Rome. And basically guidelines on UTUC on the neoadjuvant chemo have been presented data that are associated with significant pathologic response and down staging in a consistent percentages of nephro U cases. Moreover, the adoption of neoadjuvant chemo has been shown to be associated with some series, which unfortunately are mostly retrospective and limited series with lower disease recurrence and mortality when we compare to nephro U alone.

As a second point of interest, EAU guidelines strongly recommend the adoption of post to parity or let's say perioperative bladder installation of chemotherapy to lower the intravascular recurrence rate associated with the procedure. So our primary aims actually was to move the idea to review this score of patients who undergo nephro U and secondly to address these outcomes that we have been showing. So we perform our retrospective board analysis on this big data from the Optum informatic [inaudible 00:04:05] database. And the primary outcome of the study, which was just a temporal outcome let's say, was to assure the trends in the utilization of minimal invasive approach versus open Nephro U in terms and the comparison in terms of perioperative outcomes and healthcare costs. The secondary outcome, which means that actually just needed to be after our selection court, was mainly related in the trend of the adoption of neoadjuvant chemo and postoperative intravascular chemo and their contribution on perioperative complication resorts use.

And finally on direct hospital cost. So the date of surgery was considered as the index date in order to describe temporal trends in the approach adoption and with identify type and the timing for neoadjuvant chemo and peri-intravesical chemo schedules. So patients who have received the neoadjuvant before Nephro U were searching subsequently they were included if they underwent an appropriate intravenous regimen within a six months before the surgery date. Also, the number of neoadjuvant chemo cycles when then manually recorded for each eligible participant and what's further than the last. So the use once again of the adjuvant post-intravesical chemotherapy was then searched through the database up to 72 hours following the surgery date. So a total cord of 2,110 patients were treated with elective laparoscopic robotic assisted or open nephroureterectomy between 2003 and 2018.

So 15 years. Out of these, what was really surprising in terms of [inaudible 00:05:55] statistics, only 3.8% and less than 2% of the patients receive a neoadjuvant chemo and or post intravascular chemo respectively. So the adoption of minimal invasive surgery for nephro U as you can see from our graphs, and this is probably not really a new outcome, however, was a dramatically increase from 2007. And also this was associated with reduced risk of any type of complication, lower imagine hospital total cost and in particular minimal invasive surgery was widely associated with lowering the risk of developing intra events and three months postoperative sequelae. I'm saying that because obviously to address our secondary endpoint, we needed to create a surgical curve and obviously we wanted to report what actually we figured out on this kind of comparison. In order to make the paper even more broadly in closing. But if we focus on our secondary outcome, we explore it on a multivariable adjusted effect of neoadjuvant chemo administration for the similar endpoints of complications, length of stay and total hospital course in our court.

So the patients treated with neoadjuvant chemo before nephro U, regardless of the surgical approach, we associated with a higher risk of postoperative complication and in particular for postoperative blood transfusions. So similarly, the risk was also increased with regard to the total hospital costs in the neoadjuvant chemo group but not for length of stay. What was a subs aim of our secondary outcome was also looking at the higher number of neo-adjuvant chemo cycles and there wasn't any association with the outcomes. What we were able to determine is that there was an increased probability of a higher hospital cost and longer hospital stay for patient who received higher number of chemo cycles of neoadjuvant chemo cycles while its effect was not that consistent with the probability of developing any intra or postoperative sequelae. So as a conclusion for sure, our study has several limitations.

First, the data set has administrative nature, which relies on accurate coding and diagnosis and procedure. So additional procedure done prior to the access to insurance may have not been captured in our database. And finally what I would think is the most important probably is that we did not have access to any staging neuropathological information from the nephro U procedure. And this definitely may limit our ability to assess the indication for neoadjuvant chemo in this patient with upper tract disease and that also the oncological outcomes. However, as a conclusion we might say that nowadays in the United States of America, minimal invasive approach is certainly the option of choice for providing nephroureterectomy and according to EAU guidelines, even if the postoperative intravascular chemo would be highly recommended. And a neoadjuvant is only suggested that this moment, neither neoadjuvant nor postoperative intravascular chemo have been routinely incorporated into clinical practice of patient with UTUC over the past several years in the US. And finally, what is probably last sentence I would say, and most importantly, even if there is a growing body of evidence suggesting that the neoadjuvant chemo improves survival outcomes in patient with UTUC, somehow like it has been done for muscle-invasive bladder cancer, however, research suggests the possible existence of an increased perioperative risk and help cost profile for those patients who receive neoadjuvant chemo. And probably these observations should definitely be for your address in other subsequent emphasis. So thank you so much for your attention and my presentation.

Sam Chang: Francesco. Thanks very much. This study, like any study evaluating these larger databases, the best part, it starts to get people thinking about certain questions, certain points that are brought up. So I'm going to start off with some questions about your findings. Let's look at the transfusion risk associated with those patients that got neoadjuvant chemotherapy versus those who didn't get neoadjuvant chemotherapy. Do you know, based upon this data, you may not have the data, that these patients in fact also had a higher estimated blood loss, or was it associated with just the fact that they had a lower preoperative hematocrit to start? Were you able to tease that out in terms of transfusion risk associated with neoadjuvant chemotherapy?

Benjamin Chung: So I think I can start answering that we don't have intraoperative type of data because it is an administrative data set and obviously the receipt of neoadjuvant chemotherapy was low. You know, of course, our data set precedes randomized trials like the POUT trial that showed obvious benefit to adjuvant chemotherapy. But I think at least in our practice here, what I noticed that even preceding the POUT trial, we were giving neoadjuvant chemotherapy because of the same concerns everyone else had about not giving the optimal chemotherapy regimen because of lack of GFR and nephron clearance. But I think that the way I looked at it is that without the absence of some of this data, interrupted data, the patients who got neoadjuvant chemotherapy probably undoubtedly had a higher stage risk cancer. And as you know, when they have that, a lot of times they have bulky node disease which you want to see shrink away before you attempt surgery.

And obviously, if you're going to attempt surgery, obviously they had a response. But still with that in mind, as you have personally seen as many others, even when that nodal shrinks away, it still could be a very difficult surgery because of a scar tissue that forms almost like doing a post-chemo RPLND at time. So I have to imagine that the neoadjuvant chemotherapy surrogate is a marker of higher risk, higher stage diseases. And also potentially you're right, they could have hematologic manifestations of their chemotherapy as well, which could potentially increase their risk of complications. And that's I think what we're seeing here with more cycles as well that kind of correlated to higher complications. And that's not surprising that they're getting more cycles. That means that they didn't respond initially.

Sam Chang: That all makes sense and you know would hope, as you looked at this 15 year time period, I was struck with the lack of perioperative intravesical therapy. I mean less than 2%. So give me a little hope and please tell me that at least in the last few years there was a temporal increase in the use. We've had more recent studies showing the benefit perhaps wasn't as clear in the early 2000s. You didn't have a lot, but just tell me at least that there was an uptick over the past few years or could you see that or not?

Benjamin Chung: Remember? Francesco, do you remember if there was, I think there was a higher rate of perioperative intravesical chemotherapy as the study period went closer to 2018. Is that right?

Francesco Del Giudice: Right? Yeah, the trend of the logistician grew up a little bit over the years. I mean these numbers were very little. We actually were not able to display this numbers because of the possibility of basically breaking the de-identified protection of the data there itself. But what I think is an important lesson is that it has been transferred probably from bladder cancer. So post to peri-intravesical chemo and bladder cancer is widely adopted both in Europe and I am sure also in the US is something that has a medical compliance with the insurance overall. And I think there is somehow temporal trends. I mean these are basically grown over the years and now it's probably present in almost every OR across the states, and I would say also across other countries. So this is a little bit different in the guidelines for upper tract, the time you can rely for basically to undergo the chemo is wider, so it's more than 48 hours, it's up to 10 days or something like that. Obviously, this has probably been done even because obviously you have somehow a [inaudible 00:14:58] bladder after nephro U, which is removing of a bladder half and obviously administrating a few days later, chemo, it might be obviously a little bit more safe, I don't know. But however, I think that that has been a transition as well for bladder cancer. And this could be as well done for upper tract as long as the message goes away, the good landscape, the strong recommendation, and I think this is a great point on this topic.

Sam Chang: Yes Francesco, I think you raised really important points. One, the difficulty in tracking when it may be given a week later, eight days. It's not really, at least in these datasets, may not be perioperative or difficult to capture, really good point. And secondly, you're right, it's taken some time, but for bladder cancer really that's going to been increasingly, at least in the states and I think in Europe as well and across the world. It is starting to get baked in regarding the role of perioperative treatment. And then I think the third point that you brought up, which I think is important is safety always comes first. If there's a concern with a resection, not everybody should get intravesical chemotherapy after A TURBT and perhaps it was a really large resection or a really big kind of ureteral defect that you've left and you're not going to necessarily treat those patients.

So I don't think, I agree with you. It's increasing, there's no question and there's no way that a hundred percent of patients should get it. But I hope like you that we're getting increasing traction and that type of thing. So from this data, Francesco, you're in Italy, you're in Rome, busy city, big center, a patient comes in now with an upper tract tumor that's being considered for nephroureterectomy and let's make it a high grade cancer. So there's no question they should get a nephroureterectomy. Everything is negative on the scan, their renal function is good. What is your center's practice in terms of perioperative chemotherapy? Do you proceed with nephroureterectomy? Do you do neoadjuvant, has this data help guide what you guys do? What is your practice and what is your institution's practice?

Francesco Del Giudice: Oh, I think that is a very good question. It's somehow really complicated. Give a broad reply in the sense that nowadays in Europe, this has only been suggested by guidelines. So there is nobody that is basically doing that routinely in their clinical practice for sure. There might be the chance that this is definitely being tested more in clinical trials or at least dedicated prospective longitudinal studies in order to assess the outcome, which obviously in the end you rely on overall survival. I think that right now in the moment, I would say we do not do that. Except that there is some important indication in staging, I would say [inaudible 00:18:10] disease that have been detected by MRI or CT scan. But what I think is important, in my opinion is that every one of these patients should be, is somehow [inaudible 00:18:20] been down for bladder cancer discussed in a mood to the [inaudible 00:18:23] team.

There are noble important option even eventually for adjuvant therapies considering also immunotherapy related and eventually the combination of chemo regarding, as you mentioned, on renal function, that obviously may have an impact on their choice. I would say yes. And I would say that if I could be in the decision process of this patient, I would probably address a patient for at least two or four cycles of neoadjuvant. But this is probably, I must be biased by the muscle and invasive bladder cancer story. That definitely over there here is a demonstrated some survival outcome. So this is an open question for sure. We do not have to forget about opportunity for adjuvant therapists as well in the later for the patient who has a good renal function at baseline. But right now I would not be able to give you the reply that I would like to do. And this is probably been also done by the level of evidence on deadline, which unfortunately right now is still a little bit low.

Sam Chang: Yeah, Ben, I thought that was really, really well stated. Any differing thoughts or do you feel like I do, I think Francesco's spot on in terms of his evaluation interpretation. What are your thoughts?

Benjamin Chung: Yeah, so I mean I find that when patients get referred, probably when they get referred to you what upper tract disease, there's kind of a knee direct reaction to get it out surgically. And I think their local urologists kind of emphasize that as well. So when I talk to them, I say, Look, let's get some more staging studies, let's try to get a better idea of the grade of tumor of their high risk features and you may need chemotherapy up front. And they're kind of like, why do I need that? Well, it could definitely help you because we don't want to hamstring ourselves by giving you self optimal chemotherapy regimen if we find that you actually, in other words, need chemotherapy and we could have given to you up front rather than give you a lesser regimen. So these are patients that we try to stage better and then I almost always sent them to a medical oncology just to make sure that they have vetted the patient and made the decision whether or not they feel it's necessary for neoadjuvant chemotherapy. And sometimes they do, sometimes they don't. So that's how it's being done here. And actually that was how it was being done even prior to the POUT trial. But I understand that this is why we're having a discussion about this. Practice patterns are different and hierarchical systems and medical systems, the academic systems, they can all be different in how they function.

Sam Chang: Yeah, I think that's a really important real world point because it's easy for us, as we've all said about the importance of multidisciplinary care in many clinical settings. It takes a real effort to actually have that done. It takes an effort on the physician's part, on the patient's part, on the whole healthcare system part in terms of coordination. But I agree with all of you that effort should, if anything, continue to be emphasized. And I think we've done a really good job when it comes to advanced prostate cancer. I mean, we never would include, medical oncologists really would include radiation oncologists. And I think that that paradigm has changed. I think with muscle invasive bladder cancer, the paradigms change. And I think increasingly with efforts like you all have done with this paper, I think we are working on improving our inclusion of all the multidisciplinary efforts. So Francesco and Ben, thank you so much for spending some time with us. I knew it would be enlightening and we look forward to future projects from this powerhouse team and when we get them, please touch base with us and we want to make sure that we discuss them.

Francesco Del Giudice: For sure. Thank you so much. I'm delighted to be participating and obviously we look forward to be here once again.

Sam Chang: Great.

Benjamin Chung: Thanks so much Sam. Really appreciate it.

Sam Chang: All right.