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Sam Chang: Hello everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, and I work at Vanderbilt. We are very fortunate today to have Dr. Phil Pierorazio join us. Phil has recently been named the Chief of Urology at Penn Presbyterian Hospital in Philadelphia, PA. I've been fortunate enough to know Phil when basically he was in diapers, just a few years ago, maybe even now. But, he has really become quite a superstar, and you all, I'm sure, are very familiar with his really important work when it comes to kidney cancer, really important work when it comes to testes cancer. But we've been fortunate enough today, to have him talk about upper tract disease. And he is going to focus actually, in the last few minutes on nephroureterectomy, which is where I'll definitely have some questions for him. So I'll turn it over to Phil. Phil, thank you again.

Phillip Pierorazio: Thanks, Sam. Great to be with you, as always.

The easiest place to start is just with some basics about upper tract urothelial cancer. We know this is a relatively rare disease, and while it's similar to bladder cancer, it obviously has some unique differences. Right? It's more related to environmental exposures. There is a Lynch syndrome predominance. And as we think about treatments, we're really going to focus on radical nephroureterectomy today, but we know that the treatments can be highly variable for this disease.

Recurrence rates are high in the low-risk early-stage population, and we are worried about bladder recurrences. And in advanced, or high-grade disease, we are worried about systemic recurrences. And because of that, survival is hugely dependent on stage. It's excellent for those patients with early-stage, low-grade disease, but really poor for patients with high-grade, or advanced disease. And there are a lot of risk paradigms.

But the easiest way to think about this is in terms of histology. Low-grade tumors, in general, are non-invasive, they're unlikely to spread, and they are slow-growing. And there, we've got a number of treatments available to us, including nephroureterectomy. But for high-grade disease, these are rapidly growing tumors that can locally invade. They can metastasize. And so nephu is really, our standard of care. And we are going to talk about why systemic therapy is also really important there.

So just to break it down further, I love this analogy for understanding upper tract urothelial cancer. I love to ski. I would not say I'm a great skier, but I certainly can make my way down a mountain. This is one of my favorite places. This is Snowmass, in Aspen. And the analogy I love is, that low-grade diseases are really your greens and your blues, at the bottom of the mountains. You've got lots of options to get to the bottom of the mountain. You are very unlikely to get into trouble, and you can usually make your way safely down the mountain.

And so, here are your greens and blues. Our management principles for this disease are really then, treat the primary tumor, manage the recurrences, and recognize that we really are not going to progress to high grade or metastatic disease. So we have lots of management options available to us.

In this setting, radical nephroureterectomy is the gold standard, but I also say it's the last resort. You really do not want to take out a kidney that you don't have to. And obviously, we will talk about strategies for nephu as we progress through it. We do have endoscopic management for well-selected patients, and we are starting to learn more about intracavitary and chemoablative technologies, but that's going to be beyond our talk today.

So as we get back to the ski mountain, now, as we think about high-grade or high-risk disease, we've made ourselves, we made our way to the top of the mountain. We are now looking at blacks, we may be looking at that bowl over to the far left. Even if you're a good skier, these are treacherous. This is treacherous terrain. Even if you do everything right, you could still end up in trouble, and that is high-risk, high-grade disease. And so the management principle here is, this really is a systemic disease. So just like we think about bladder now, it's chemotherapy and cystectomy, we are really moving towards a paradigm where we're thinking about nephroureterectomy and systemic therapy, for high-grade upper tract disease.

And so we will talk more about nephroureterectomy, but there are really some important components to the contemporary nephroureterectomy. I think the first thing is systemic therapy. We obviously know there are randomized data to show that adjuvant therapy affords a survival benefit for high-grade, invasive, upper tract disease. But now there's a growing body of literature, that is saying neoadjuvant chemotherapy is probably the way to go. So we really need to be thinking about giving chemotherapy up front to as many patients as we can, in my opinion.

As we proceed with surgery, there is a surgical approach, and I think robotics has really offered a tremendous benefit for nephroureterectomy. The kidney itself is the relatively easy part of this operation, but it's managing the distal ureter and the bladder cuff that I think the robot gives us a small advantage. And really important in this disease, is the lymph node dissection. And we know that lymph node dissection is really mandatory, and affords not only a staging but potentially a therapeutic benefit for patients with low-volume, node-positive disease. We should not be using endoscopic management, except in those patients who cannot tolerate a nephu.

And the last part is, how do we manage bladder recurrences now that we're treating patients with systemic chemotherapies? And obviously, surveillance and surveillance cystoscopy is a part of that, but now using a lot more intravesical chemotherapy at the time of nephu and ureteroscopy to prevent those bladder recurrences. So I'll just kind of, ....yeah, go ahead, Sam.

Sam Chang: I may be stealing a clap of thunder from your next slides, but let's take just a couple of minutes, and let's go over specifics regarding each of these.

Phillip Pierorazio: Yeah.

Sam Chang: So, management of the bladder cuff, what do you do? How do you do it?

Phillip Pierorazio: Yeah. I do the entire thing robotically. I make sure that we are making a bladder cuff, we're making an incision into the bladder, and we are closing it. We'll get back to that in a sec, but the literature says it really doesn't matter how you handle the bladder cuff, as long as you're getting the entire ureter out. So there are people who will do a minimally invasive kidney, and then open to do the bladder cuff. There are people who do a cystoscopic or endoscopic bladder cuff and resect the end of the ureter.

The literature says, there is a slightly higher risk of bladder recurrence if you endoscopically manage, or cystoscopically manage, the distal ureter, but no effect on overall or systemic survival. So I think the key is really, get the whole ureter out. I like doing it robotically. I like making that cuff as small as possible. When we do that robotically, typically, the catheter comes out one or two days after surgery and those patients go home without an issue. Obviously, if you've got a big distal ureteral tumor, you have to make a bigger cuff, and you may want to keep your catheter in a little longer, but that's generally how I manage it.

Sam Chang: Yeah. I agree with you. I think that key is the endoscopic resection, the robotic resection, the open, whatever you do, to assure that you have gone all the way through that intramural tunnel, down to the trigone, and make sure. And early on, as our trainees are going through this, I'll actually have one of the juniors, actually put a scope in as they are doing the dissection. I drain the bladder. I actually put intravesical chemo in during the dissection, but then I'll drain the bladder as well as possible. But I want them to see what's happening to the ureteral orifice, at the upper levels. And now with the robot, it's so nice. Everybody can really see what's going on. That's great. I didn't want to interrupt, but your next slide is great. Thanks, Phil.

Phillip Pierorazio: No, that's great. I feel the same way. When I first started doing this, I would make open bladder cuffs, and I transitioned to completely robotic. And I'll tell you what's nice, you do their surveillance cystoscopies, and the bladder looks like a normal bladder, except the UO is missing. Right? Because you've done a relatively small cuff. They've done well. They have little morbidity from that approach. So I think it is a really nice advantage to that approach in these patients.

Sam Chang: Agreed.

Phil Pierorazio: Yeah. So we will just summarize high-grade, high-risk disease here, and then I would be happy to talk through some of this stuff, and answer questions.

So, as I said, it is a systemic disease, you want to consider surgery with systemic therapy. I prefer, and I think a lot of people are starting to prefer, the neoadjuvant approach, rather than just adjuvant.  I think robotic technology is changing the way we do nephroureterectomies, and certainly, there are costs associated with robotic technology, but I think we are seeing the balances that we have in other disease states with improvements in perioperative outcomes. But I think we are seeing a small, but tangible, oncologic benefit, because we're increasing the number of lymph node dissections we're doing. It's much harder to do a quality lymph node dissection laparoscopically, and maybe that's just my skillset, but I think that's true. And I think a lot of people were not doing lymph node dissections for a long time.

As we said, you've got to manage the complete distal ureter. And as long as you get it excised, that's okay. And consider intravesical chemotherapy. You mentioned you do it at the nephu. I do the same thing. When the patient goes to sleep, we put the chemotherapy in their bladder. We let it sit there for an hour, or until we have the kidney out. And then, once you start manipulating the ureter, we drain the bladder to let that chemotherapy out.

I was not impressed initially with the literature on this, but we started looking at our own data when I was at Hopkins. 40% of our patients were recurring in their bladder within the first year. And that's a little different from the literature, and the ODMIT-C randomized trial. But I think it's because we're a referral center, where patients were getting multiple, multiple, multiple ureteroscopies and manipulations, we had way too many bladder recurrences within the first year. And the use of intravesical chemotherapy, gemcitabine now, has really dropped that recurrence rate, and I think it's beneficial.

And then obviously, systemic perioperative chemotherapy does improve survival. Once again, the data is in the adjuvant setting, the level one data is in the adjuvant setting, but the retrospective and single-arm studies are really growing for neoadjuvant chemotherapy.

Sam Chang: This is fantastic. Let's look at this slide, and let's go from the bottom and go up. With that perioperative chemotherapy, I agree with you totally, regarding our bias, it continues to still be neoadjuvant chemotherapy, despite level one evidence. Are there are those individuals that you really push for neoadjuvant? A larger tumor, smallish nodes. Who are the ones, to be honest, if it seems localized or smaller, if it's high-risk, if their kidney function is normal? Then our medical oncologist, and I'm fine with it, let's follow the level one data, let's remove the kidney and the ureter. Let's see what the final pathology shows, and then discuss with the patient, adjuvant disease. Because there are some people who are non-invasive high-grade that we would watch. But tell me the characteristics that really push you to give neoadjuvant.

Phillip Pierorazio: Yeah. My thought process here is, the study data, the adjuvant data, were invasive tumors. It is really hard to know that pre-operatively. Right? We know, at least 60% of high-grade tumors are invasive. Upper tract urothelial cancer will even present with invasive carcinoma in situ, which is kind of an oxymoron. Right? But CIS can invade in the upper tract. So it's really hard. Our staging in the upper tract is poor. I think we under-stage a lot of patients. So absolutely, big tumors, any signs of invasion on CT scan, I really push towards neoadjuvant chemotherapy.

The other patient is the patient with a borderline GFR. You're talking about a patient with two healthy kidneys. Well, we see a lot of patients in this elderly population, that if we get rid of a kidney, we know their GFR is going to drop, somewhere in the range of 30%, if not more. And then all of a sudden, they can't get platinum-based chemotherapy. Carbo's ineffective, we know that. And we're still trying to figure out the checkpoint inhibitors in this space, so cisplatin-based chemotherapy is really potentially lifesaving.

So I often say to patients, we are hedging our bets a little bit, and we maybe keep giving you chemotherapy that you don't need if you have a non-invasive tumor, but we're hedging our bet that when we take out your kidney, you can not get life-saving chemotherapy. And listen, I don't twist anybody's arm into chemotherapy, nor do our medical oncologists, but it's certainly worth that conversation, before going to the operating room.

Sam Chang: I agree. Any subset stratification is always a bit unfair, but if you do look at the PAL trial, and you look at the adjuvant arm that got the gem and the carboplatin, it mirrors what you just said, regarding the ineffectiveness of carboplatin.

The last question I wanted to ask you about is lymph node dissection. I personally, struggle with what lymph nodes, if there are any areas of suspicion, that, to me, that template, that area I resect, and I've tended, somewhat simplistically, a distal ureteral, or distal lower upper tract tumor, I tend to do a pelvic lymph node dissection. When it's the renal pelvis and upper tract, I tend to do along the great vessels, but I don't go across the midline of it. I don't know if what I'm doing is really correct. I hear so many different views. What's your lymph node dissection template and algorithm?

Phillip Pierorazio: Yeah. I think the best data comes from Surena Matin and the MD Anderson group, as well as the Japanese kind of mapping studies. I think, exactly what you said, if you've got a renal pelvis tumor, you are very likely to find them in that perihilar space.

Sam Chang: Perihilar, yeah.

Phillip Pierorazio: Yep. Whether it's paracaval or paraaortic, so I will follow that node packet down to where the ureter crosses the iliac. A distal ureteral tumor, pelvic lymph node dissection is completely adequate. That is where the vast majority of those are going to go in a unilateral fashion. The mid-ureteral tumors, unfortunately, you got to do both. You've got to do your paracaval or paraaortic packet, as well as your pelvic lymph nodes because it can go in either direction. And I think that's just a function of where your lymphatics get obstructed, potentially, with cancer.

In terms of crossing the great vessel, the data says, about 20 or 25% of patients, with node-positive disease, will have cancer in their intra-aortocaval space or cross over to the other side.  The data also says, patients with more than one positive lymph node, are highly unlikely to benefit from a lymph node dissection.

Sam Chang: Yeah.

Phillip Pierorazio: So it's unlikely that cancer is going to skip that primary landing zone. So I do the primary landing zone. I think you increase your morbidity. I think you increase your time in the operating room, with minimal benefit by crossing the great vessel. So unless I see something specific that I think we need to go after, I basically stay in the paracaval, or paraaortic space, without crossing midline.

Sam Chang: Well, Phil, thank you so much for spending some time with us and going over your real-world practice, what you do practically. Because I think, for those who see these patients, and treat these patients, we really appreciate that. Because I think, you see what people say, but in reality, what they really do, is what really will benefit those treating these patients.

So thanks again, and good luck with your future move. Actually, you've started, it sounds like, and I know your practice will grow incredibly quickly. And we look forward to hopefully, talking to you again about other situations when it comes to upper tract disease.

Phillip Pierorazio: Thanks, Sam. Have a great day.

Sam Chang: Absolutely. Take care.