Sam Chang: Hello, everyone. I have the pleasure of introducing two, actually, superstars when it comes to upper tract disease. My name is Sam Chang. I'm a urologist in Nashville and I work at Vanderbilt University. We're going to focus on the perspective and collaboration between the surgeon and the medical oncologist in a field that's actually now had options in terms of how these different disciplines actually interact. We have Gene Pietzak. Eugene is actually at Memorial Sloan Kettering. He is an assistant professor there. And we have Dr. Arjun Balar, who is an associate professor at the NYU Langone Medical Center. In all honesty, I'm going to give promotions to all of them. They're professors to me in my mind.

What we're going to do is we're going to start off with scenarios. And so, Eugene and Arjun, I'm going to throw out, probably, three different cases, and I'll ask each of you at different times to actually go first and then tell us what your thoughts are and how you would help manage when you bring in your colleagues, why you would consider certain maneuvers and that type of thing.

So, let's start off with kind of a classic patient. 73-year-old female comes in, has had some hematuria. Renal function shows an EGFR of, say, 50, 48, right on the edge, creatinine around 1.8, 2, who has a high-grade, we don't know if it's invasive or not, upper tract renal pelvis carcinoma, who doesn't have any evidence of metastatic disease. Let's start off with Dr. Pietzak. Gene, you have this woman in your office. Tell me how you counsel her and do you then call Dr. Balar down in Midtown, say, "Look, do we need to consider chemotherapy, immunotherapy, that type of thing?" How do you manage this patient, Gene?

Eugene Pietzak: Thanks Sam. I think that with the marginal renal function is a all too common situation we deal with with upper tract disease, and I think it's often nice to have clinical trial options available as well. We typically will have some IO-based neoadjuvant treatment. So, even if patients are unlikely to be able to get cisplatinum, I will still refer them to my medical oncology colleagues to at least set up that discussion, and we'll go into more detail about that with the POUT Agilent data as well. I think at least setting up that relationship before surgery only really facilitates that, and I don't think there's any harm, necessarily, in at least having that discussion.

But depending on the appearance on the imaging study, whether there's any evidence, you'd mentioned no evidence of invasion, but we know that clinical under staging is a major problem. I do think that patients do benefit from a preoperative consultation with a medical oncologist. And so, at least at MSK, our approach here is very similar to patients with muscle invasive bladder cancer, where we will typically refer them to medical oncology for a discussion of neoadjuvant versus adjuvant systemic treatment.

Sam Chang: So, Arjun, at your institution for this patient, do you routinely see them? And if you do, let's say you don't have a clinical trial available at that time for someone right on this edge of renal function that may or may not be adequate for any type of platinum-based regimen. How do you counsel these patients? And do you all see them?

Arjun Balar: We do. It's a similar model that Eugene has up there, is that it's a multidisciplinary model. And to his point, what we first try to do is assess is this a GFR that we can improve? We get a good quality urogram, CT, or MRIs. Is the 3-dimensional mass? Is there some obstruction that we can relieve? Is a stent or a PCN going to help us? And whatever GFR we settle out at, is this patient going to benefit from neoadjuvant cisplatin-based chemotherapy? And we do our best to try to do that. At the end of the day, extirpative surgery is the end goal. If we can get platinum in, we do. If we can't, we tend to send to surgery.

We don't have trials now for neoadjuvant immunotherapy in this space, at least we don't right now at our center, but if other centers do, we would certainly consider referral to those places. Then the question is, is adjuvant therapy the POUT study, I'm sure we're going to talk about it. That study showed a DFS benefit for patients receiving platinum, either GemCarbo or GemCis, but the problem is that most of that DFS benefit was really in the GemCis group. They snuck in a bunch of carbo platinum-treated patients, but if you look at the hazard ratios for the carboplatin group, that benefit really is driven by cisplatinum. So, I have not been as enthusiastic about carbo platinum, but I understand the rationale for at least considering it in the adjuvant setting.

Sam Chang: I think that's a really good point, because if you look at the forest plots, and there's always, obviously, you have concerns after the fact you do subgroup analysis, but clearly that GemCis arm, that was the arm that really showed clinical significance and statistical significance. So, let's take that patient then. She's right marginal, and I like to hearing that you said that if you can get platinum, this is when you would, because you know that once that renal unit is removed, probably there's going to be loss of renal function, so go from there.

Arjun Balar: Yep, yep.

Sam Chang: Let's make the scenario then, Arjun, someone who has low-risk, low-grade, high-volume disease. Should you be seeing that patient, or should only Gene be seeing them?

Arjun Balar: low-risk, low-grade, it depends on how you identify it. Occasionally have we seen patients with these big, bulky, very papillary looking tumors on a scan, but it has some hydronephrosis because they're big, but you do a ureteroscopy and the snippets show just low-grade tumor, the cytology atypical and you're not really sure what you got here, but you're concerned that you might have invasive disease, that's a real judgment call and you rely on your pathologist, you rely on your clinical imaging and your staging. And then, ultimately, if you feel that, listen, this is most likely low-grade noninvasive disease, you're hard-pressed to treat with neoadjuvant chemotherapy. Does it warrant a multidisciplinary discussion or even a consultation with the medical oncologist? Of course it does. But does that necessarily mean that that patient is destined to receive platinum? No, I don't think so. And so, I think a lot of times these patients should go to surgery.

Sam Chang: Yeah. I agree with that as well. Let's stick with that same scenario. Gene, someone with low-grade, bulky, you've done multiple biopsies, you're as sure as you can be that it's low-grade disease, but you haven't been able to handle it with the laser, it's to the point where endoscopic management, you're losing control, you're having hematuria, those types of things. At that point, as you consider a nephroureterectomy, have you ever seen any significant improvement in symptoms when someone gets neoadjuvant? So, switching gears, you have high bulky disease, you think it's low-grade, but you're not sure. Have you ever seen the neoadjuvant treatment actually helped symptoms? Because I have. I've seen, actually, hematuria get better, clearly make a difference. And so I wonder what's your experience with that?

Eugene Pietzak: Yeah, I, certainly for high-grade tumors, have seen people get symptomatically better. With regards to low-grade, we typically have been reserving neoadjuvant, both on the trial as well as now as our standard of care at MSK for only patients with high-grade disease, either based off biopsies themselves, ureteroscopic biopsies, but also if there's a high-grade cytology.

So, certainly at the time, if we're managing this patient endoscopically, what I like to do is take biopsies from different areas of the tumor, take multiple, five, six biopsies from different regions, because we know that a lot of these tumors have a lot of heterogeneity to them, and typically we'll take cytologies both before, as well as after the biopsies as well. Sometimes you find you stir up the cells, especially if you're lasering, get a little bit deeper down, and you uncover that. So, if we do find or uncover a high-grade cytology, more than just an atypical cytology, but truly a high-grade cytology, that would definitely be a patient we would consider for neoadjuvant.

Sam Chang: I love that as kind of a second key point. Dr. Balar talked about the impact of the ultimate renal function in the decision making regarding chemotherapy. The second point that I think is good, because you always learn from experts like you all, is the role of cytology pre and post, perhaps, treatment at the same setting and what you can do and how that high-grade cytology can really tip you over into something dramatically different as opposed to just low-grade therapy.

Let's go to patient case scenario. Number two, someone, let's take this same 73-year-old patient, let's make it a gentleman who has significant flank pain has high-grade disease and has really good renal function, but has local invasion. So, just seen someone recently, it looks like I'm worried about the liver plane, I'm worried, [inaudible 00:10:00] is definitely kind of obliterated, but has really good renal function, and he has pain. Gene, at this point, is it a slam dunk that we should do a nephroureterectomy for pain? Or because of how much involvement there may be, should we consider this patient for neoadjuvant chemotherapy for symptom relief and perhaps for better surgical extirpation? What are your thoughts regarding that?

Eugene Pietzak: Yeah, I think that's definitely a patient that I would refer to my medical oncology colleagues for neoadjuvant treatment, especially if they're able to get cisplatinum-based chemotherapy. I think, unfortunately, it's very unlikely that surgery alone would be curative, and if he's not getting chemotherapy before surgery, he's almost certainly going to need it afterwards, so it's better to give it to him upfront while he's still able to tolerate the cisplatinum.

Sam Chang: Arjun, what is your preferred platinum-based regimen for this kind of patient, and how many cycles and when do you re-emerge and evaluate?

Arjun Balar: Yeah. This is where I would probably tend to get the most aggressive, and this is akin to like T4b or node-positive disease in the pelvis from bladder cancer, where I get one shot at a cure, and so I might lean toward accelerated MVAC or triplet therapy with taxol, gemcitabine, cisplatinum, and I might shoot for six cycles of therapy, not just four. This is a one-shot on goal attempt at cure, and so I tend to be most aggressive in this setting.

The good news is, is that cisplatinum is most active chemotherapy in urothelial cancer. The palliative effect is generally pretty immediate within the first one cycle of therapy, so the symptoms, whether it's hematuria, flank pain, et cetera, should resolve. And so, you'll get a therapeutic benefit that way, and then hopefully I've helped out my surgeons by getting that surgery a bit easier. And that dose density with accelerated MVAC, in my experience, has actually, at least anecdotally, that's been my experience, so I probably would lean toward that a bit better and also gets them to surgery faster. And so, that's probably what I would do.

Sam Chang: That's an excellent segue to let's go to our last patient case scenario. 73-year-old gentlemen, this time, who has clearly a high-grade cancer, may or may not have, have local invasion, but clearly has suspicious lymph nodes. Regionally located along one of the great vessels in the retroperitoneum area, not anywhere skipped or funny. This looks like a regional disease, multiple lymph nodes, say, 2 to 3 centimeters in size. Arjun, first, does that patient need a biopsy to prove it's metastatic? And secondly, how do you treat? Similar to the locally invasive one or is there a different regimen? How would you treat? First, prove or not necessarily prove it's metastatic disease, and how do you treat?

Arjun Balar: Let me just make sure I understood you correctly. I've got high-grade cytology or known high high-grade urothelial cancer in the upper tract, and I've got bulky nodes, not just 1.5 Centimeter, not sure if it's reactive or not, but these are 2 and 3 centimeter chunky nodes.

Sam Chang: Yes. Ipsilateral side, not too distant.

Arjun Balar: Yeah. This is, I think, an important opportunity to say this is not kidney cancer, where we often see reactive adenopathy that when you do the nephrectomy, these nodes end up being negative. And so, in urothelial cancer, I would say that if these nodes aren't easily accessible by IR, I would generally feel comfortable treating if they look clearly metastatic. And so, if it's not going to be straightforward to get an IR biopsy, maybe I'll get a PET, feel a little bit more comfortable about it, but I'd probably start them on systemic chemotherapy, especially if I need to get started right away.

And again, if this is regional metastatic disease with nodes or the node dissection planes, I know, speaking to all my surgical colleagues over the years, are not very clear, but again, if my goal is cure, I counsel them about metastatic disease, but the goal is three cycles, re-image. If I've got good outcomes, we go another three cycles and hopefully I get them to surgery as well.

Sam Chang: Yeah. I have two follow-up questions. So, yeah, they shrink down, they basically have quote-unquote, normalized. Gene, how enthusiastic are you with these patients then in terms of taking him into the surgery? This is a vibrant 73-year-old, goes through chemotherapy well. It's one thing if they're not doing well and performance status has worsened. Understood. But ready for surgery, do you take this patient then to surgery?

Eugene Pietzak: Recognizing the limitations of the data in this area, we generally do take those patients for consolidated surgery. I think part of it, especially with the regional adenopathy plan, is to do a therapeutic retroperitoneal lymph node dissection, at least template-based, ipsilateral depending on what side it is. There's been some great mapping studies with some guidance on where the most likely sites of disease are, whether you're going to go [inaudible 00:15:24], take some of the common iliac lymph nodes, et cetera, depending on where the location is. But I think that is definitely something that I think the patient could potentially benefit from. And that is definitely one of our approaches here. Although, recognizing again, that there's not a tremendous amount of data, certainly in the upper tract space to say the least.

Sam Chang: This is the last scenario, which I told you three, but it's related to number three, so I'll call it three-and-a-half. Similar scenario because I'm in tumor board because this is something that's recently happened. This patient has poor renal function, was placed on immunotherapy. All right? Has had stabilization of disease now, this patient's had actually stable disease, no distant sites, tolerating the immunotherapy well. At 6 months, we decided, continue the immunotherapy. Would you guys both concur with that?

Arjun Balar: Describe stabilization of disease. The nodes didn't move at all?

Sam Chang: The lymph nodes, they initially had a little pseudoprogression, and then actually shrunk back down and now are a little bit smaller than what they were before. They haven't gone away, they haven't normalized, but if anything, are smaller, tolerating the immunotherapy well. I told them I wasn't interested in surgery, I continue the immunotherapy.

Arjun Balar: Any disease-related symptoms and how does the patient feel?

Sam Chang: Doing well. Doing well at 6 months.

Arjun Balar: This is a tough call. I'll take the baton here and say that this is, obviously, a very, very data-free zone, but I think we do need to generate the data and this is the entirely the realm of clinical judgment, and I would say that this is very much akin to what happened in the 1990s, and ultimately it was published when MVAC and other platinum-based regimens were being developed and patients were taken to consolidative surgery in metastatic disease and we had to describe those experiences. And then we understood that, okay, these are the patients that we can take to surgery in metastatic disease, and it's, hey, look, it's the node,-positive patients only.

Sam Chang: Only, yeah.

Arjun Balar: They do well post-consolidative surgery, and we will probably learn the same lessons in the era of immunotherapy, is my feeling. I'll be honest with you, a patient like this, if it's been 6 months and they've done pretty well, I would actually be okay with taking them to surgery, but I'm not the one operating. It's you.

Sam Chang: Right, right.

Arjun Balar: So, it's easy for me to say, but if you felt comfortable operating on a patient like this, maybe after a year, 6 months might be a bit too soon, perhaps a year or longer I might revisit the scenario, is probably what I would counsel the patient on. But again, it's a data-free zone. But I think once we have enough of this data, multi-institutional experiences, we need to publish this and see how these patients do longterm.

Sam Chang: Eugene, 6 months, doing great on the immunotherapy. The nodes are smaller, they're there. What do you do? I said, "Okay, let's watch a little bit longer." What about you, Gene? What would you do? Operate or watch?

Eugene Pietzak: Yeah. First off, I think we have to acknowledge just what tremendous progress we've made in the last couple of years in this disease space to even be running into this problem.

Sam Chang: Sure, yes.

Eugene Pietzak: I think this is an increasingly more common issue we're running into with both upper tract as well as bladder. And I agree with both of you, no one really knows what the right thing to do is. Our approach is generally what you do there, Sam, and you discuss in tumor boards, you get the smartest people in the room and you discuss, and it really does seem to be on a case-by-case basis. And so, sometimes we do take those patients to surgery. It's always a discussion of the timing of such. Do we wait another 3 months? Re-scan? Do we wait a full year or so? No one really knows. And I agree with Arjun, we need to work on this altogether.

Anecdotally, I feel that we've often waited a little bit closer to 9 to 12 months before taking someone to consolidate a surgery, but again, no one really necessarily knows what the right thing to do is, and the last thing you want to do is run into a surgical complication and the patient has to come off systemic therapy that they're benefiting from. So, it is among the hardest decisions that we're making these days.

Sam Chang: Right. Well, I didn't want to give you any softballs because I got the two experts here, so I'm going to end with that, because I think the last point there of individualizing care, especially when we're in an evidence-free zone, but importantly, hopefully accumulating that evidence to help guide us in the future of what we do. Because this scenario, those patients who, now for the first time for advanced disease have options, and then now we're trying to hone in on what is perhaps the best treatment option for that individual patient. So, I'll end it here, but I want to thank Dr. Pietzak and Dr. Balar so much for their time and their expertise. As always, learn much more from those of [inaudible 00:20:24], and thank you again, guys for your time.

Arjun Balar: Thanks for having us.

Eugene Pietzak: Thank you. Thank you both.