Webinar: Understanding Upper Tract Urothelial Carcinoma

April 25, 2022

With Drs. Surena Matin, Kate Murray, and Matthew Campbell

You can read the entire Understanding Upper Tract Urothelial Carcinoma (UTUC) webinar transcript at the bottom of this page.

Year: 2022

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Part 1: Understanding Upper Tract Urothelial Carcinoma

Video (14 min) | Transcript (PDF)

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Part 2: Urologic Treatments of Upper Tract Urothelial Carcinoma

Video (19 min) | Transcript (PDF)

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Part 3: Oncologic Treatments of Upper Tract Urothelial Carcinoma

Video (15 min) | Transcript (PDF)

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Part 4: Question and Answer

Video (17 min) | Transcript (PDF)

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Full Transcript

Morgan Stout:

Urothelial cells make up the lining of your bladder and urinary system. Cancer can occur in those cells. Upper tract urothelial carcinoma, or UTUC is a rarer form cancer that impacts the urothelial cells in your kidneys and ureters. It is like other forms of bladder cancer, but UTUC can present additional challenges for treatment because of the location and functions of the upper urinary tract. Beacon is delighted to welcome MD Anderson urologist, Dr. Surena Matin and medical oncologist, Dr. Matthew Campbell and urologist Dr. Kate Murray from the University of Missouri Medical Center for this discussion on how UTUC is similar and different from other forms of bladder cancer in its diagnosis and treatment. With that, I’m going to hand it over to Dr. Matin.

Dr. Surena Matin:

Hello everybody. I’m Surena Matin. I’m very pleased to be here. Thank you for that introduction, Morgan. I’m also very pleased that my terrific colleagues, Dr. Matthew Campbell and Dr. Katie Murray are able to join us as well. I think you should be able to see my screen at this point. What we thought we’d do for today is first of all, keep it conversational. You’d hopefully hear the three of us chatting a little bit, asking each other questions. I’m going to give you a brief introduction and overview, including the anatomy and some disease aspects. Dr. Katie Murray will talk to us about some of the surgical and endoscopic treatments that we have available. Then, Dr. Campbell will talk to us about the role of chemotherapy and immunotherapy for this disease.

Basically, when we talk about upper tract urothelial carcinoma, we’re referring to everything being above the bladder. In this figure, you’ll see the bladder at the bottom there, and you can see everything that’s in yellow essentially reflects the urinary tract and the lining of the urinary tract, as Morgan mentioned, is where these cancers arise. As I’ll show you in the next slide, the majority of the urothelial cancers arise in the bladder and we call it bladder cancer for short. Technically, it’s a urothelial cancer because it’s arising from the lining of the urinary tract, which we call the urothelium. That same lining extends up the ureters and as you can see the ureters go all the way up to the, what we call the upper retroperitoneal area. Then, these divide up into these multiple channels within the kidney.

That’s still all the urinary tract, and it’s still lined by this urothelium. Cancers that arise in the ureter or in the renal pelvis or in what we call these calyces, all of these are considered urothelial cancer, but because they’re occurring above the bladder, we call it upper tract urothelial cancer. These are some pictures from endoscopy that show you what these look like sometimes when they’re smaller. This bottom picture shows you the view from when we’re doing ureteroscopy. Now, one thing that I frequently find myself doing with new patients is that I have to explain that this is not kidney cancer. Patients get confused, and quite honestly, even doctors get confused because these cancers, since they’re arising within the renal pelvis, which is inside the kidney, people mistakenly think that that might be kidney cancer, and so they look up on the web and get all this information on the internet about kidney cancer, and then they come see us, and then we’re telling them all this information that they have not heard and that they’ve not read about. Then, we have to explain where the confusion may be arising from.

As probably most of you who are tuning in are aware, but some of you may not know, kidney cancer is a completely different cancer that arises from this fleshy part of the kidney. It’s genetically completely different and the treatments that we render are different and the way it behaves biologically, also it’s very different. Dr. Murray, is there anything here that you want to highlight based on conversations you’ve had with patients that you think our audience may want to know?

Dr. Kate Murray:

Yeah. I think that you made a great point. Sometimes what I will talk to patients is describe the outer part of the kidney as being the meat of the kidney, of a traditional kidney cancer versus this inside lining. The inside lining of the ureter, the inside lining of these, he was pointing at these yellow calyces in the kidney looking like your fingers would be looking like this. Then, that’s also the inside lining of the bladder, and so that’s really what we’re talking about when we’re talking about this upper tract cancer.

Dr. Surena Matin:

Matt, anything from your end?

Dr. Matthew Campbell:

Yeah. I just like to draw it out for my patients, and I basically say that you have this … the kidney serves as the filter and then you have your funnel system that connects to this tube. This is the delivery system, the bladders, the storage system and the urethras, the elimination, and it’s just a waterproof system not intended to secrete or absorb, but just a delivery storage elimination system is how I explain it, and normally, and then I stress again, this is a very different cancer than kidney cancer, which I see in my clinic as well.

Dr. Surena Matin:

Yeah. Thank you both. Great comments. There are some unique aspects about this disease. It is not very common at all. Of all the urothelial cancers we see, of course, most of them are bladder, 5% to 10% are in the upper tract. Overall incidence is two per a hundred thousand in Western countries and I think that one definition of a rare cancer is four in a hundred thousand or less. This meets most of the criteria for being a rare cancer. There’s already been a question about whether it can start in the bladder and the answer is yes, and you can see with some of these other boxes. We see them happening, what we call synchronously or at the same time about 17% of the time. On the other hand, about 2% to 4% of bladder cancer patients can develop upper tract disease, so it’s not very common, but there are some bladder cancer patients that may be at higher risk than others. In patients who do have upper tract cancer and whom we treat it, there is a higher recurrence rate in the bladder. Mostly, if it helps to think about it, I guess, because the bladder is the most downstream and things can trickle down and seed, but also, the disease can start anew in the bladder as well. Now, this says 22% to 47% with some of the newer methods that we have, which involves giving chemotherapy washes in the bladder during, or excuse me, after treatments. We’re able to reduce this to less than 20%, but still have not gotten to a point where we can completely eliminate that risk. Then, one other thing that’s different than bladder is that most of these, when they present, are invasive a diagnosis, which is the opposite of what happens with bladder, which is most of them are not invasive.

Then, this table summarizes some of the major differences between bladder and upper tract cancer. In many ways, they’re very similar. If you ask a pathologist to look at them under the microscope phenotypically, as we say, or by visual inspection, they look very similar. But when we get down to practical levels and then when we start probing more molecular aspects of it, we find that there actually are some differences. With bladder, we have, for example, tons of evidence and lots of high level data, with upper tract disease, we don’t. The other interesting thing is that we do see a higher proportion of women with upper tract disease. You’ll see with bladder, it’s 4:1 male to female ratio. With upper tract, that’s 2:1, so it’s still mostly males, but overall many more females proportionally than with bladder.

Dr. Surena Matin:

We do see Lynch syndrome, which is an inheritable genetic syndrome, is strongly associated with upper tract cancer and much less so with bladder. We think, overall, maybe about 4% of patients with upper track cancer may have Lynch syndrome, but this is an area that we’re still exploring. When we deal with bladder cancer, we can reasonably stage it between a TURBT, which Dr. Murray’s going to talk to you about, examining patients under anesthesia or UA and then with CT scans. It is much more imprecise when we’re dealing with upper tract disease, because we’re looking at such smaller resolution, much smaller organs. Current imaging is at the limit of being able to tell us sometimes things that are happening at the millimeter level, which is sometimes what’s going on with this disease. Intra cavitary therapy is treatments that we drip in like for the bladder, and that’s essential in a management of bladder cancer like with BCG or chemotherapy. A bladder is perfect because you put something in it, it’s a storage organ and it’ll sit there. Well, the upper tract is not meant to be a storage organ, it’s meant to conduct as Dr. Campbell so nicely worded it and it’s a funnel. Things don’t necessarily stick around to do their treatment job and that makes it challenging.

We think removing lymph nodes for upper tract disease is important, but there’s controversy. If you come to our meetings, you’ll hear people argue strongly one way or another, and the role, so the role is still unclear. Then, as I mentioned, from a molecular perspective, what’s really interesting is this molecule called FGFR3, which plays a very minimal role with bladder cancer, but in upper track cancer, the majority of them, at least with low grade cancers, have this mutation. Then there’s some other details about this that we’re finding out in terms of their molecular subtypes, but this is still an evolving area. Matt or Katie. Did you have anything you wanted to add to this? I didn’t mention tobacco. That’s very similar between both of them. That is, of course, our single, strongest risk factor for both. I didn’t include that. It’s not necessarily different, but that’s still also a risk factor for both diseases.

I wanted to show this guideline from the NCCN, because as you’ll notice here, it tells you if it’s non-metastatic, you don’t see staging. Again, staging for this disease is very difficult. We don’t necessarily work hard to talk about staging, although we do more and more talk about risk stratifying patients. But nevertheless, what a lot of people do is really think about it in terms of low grade or high grade disease. The grade is assigned by the pathologist when they look at the cancer under the microscope. Essentially, what I tell patients is that it’s a measure of its aggressiveness. Low grade is low aggressiveness and high grade is high aggressiveness. From that, we can make some assumptions about the possibility of what the stage is. Low grade, for example, almost always is not invasive in its low stage. High grade, on the other hand, has about a 2 out of 3 chance of being invasive to some degree.

Dr. Surena Matin:

As you can see, the treatments are somewhat different. With low grade, we can look at kidney preservation and you’re going to hear a little bit more about that in a few minutes. Sometimes, if it’s a lot of tumor, we’ll have to still do surgery to remove the kidney and the ureter. On the other hand, if it’s high-grade, kidney preservation is really not a good option, and not only are we looking at surgery, but sometimes we’re also looking at having to add chemotherapy before or after. I just wanted to mention that and the reason for that, again, the grade being such an important part of it is reflected in these charts, which just broadly, if you look all the way to the left, the grade one or low grade, these curves are overall very favorable. Then, if we look over for here for grade three or high grade disease, you can see that the curves, especially the red ones indicate patients who had kidney preservation and endoscopic management, and high grade disease does not do well for that at all. That’s why we have to treat these very differently. You’re going to be hearing about that over the next several discussions from Dr. Murray and Dr. Campbell. From that, I am actually going to turn it over to Dr. Katie Murray, unless one of the two of you has some comments that you wanted to add at this point.

Dr. Kate Murray:

I think that’s great. Dr. Campbell, anything that you want to throw in before I start talking about the urology portion of treatment?

Dr. Matthew Campbell:

I think that’s a great start, and I’m sure there’ll be additional questions that will emerge that we can address and definitely looking forward to talking about the treatments that we use from the medical oncology standpoint.

Dr. Kate Murray:

Great. I think everybody can see my slides now, or I hope so. Right. Just a couple of disclosures here before the presentation. I think Dr. Matin set this up perfectly as a setup to talk about what’s next. When I see patients in clinic, this is absolutely what I do, and we do this for all the cancers that we treat. But I think, as we noted, this grade is extremely important to help us risk stratify. Then we say let’s talk about risk for patients with UTUC. A big part of that comes in these gradings. We talk about low risk patients. These are the patients that as we go along here, I’m going to talk about trying to save kidneys and not have to do radical surgery on. If these are patients with bladders, we’re talking about bladder cancers where we’re just removing the tumors and doing things like that. But this low risk for patients with small tumors throughout the ureter or renal pelvis, anything above the bladder, as we talked earlier, a smaller sized single tumors, we do a biopsy, which I’m going to talk about here in a little bit, some of the implications and the difficulties of doing those biopsies. When we look at these patients and we look at CAT scans, we don’t see any evidence of invasiveness on it as CT scan for staging. Again, a reminder here is that we always say how important biopsies are. Tissue is so important for us to pass on to our pathology colleagues for them to grade these tumors for aggressiveness and potentially grade these tumors for invasiveness as well. What about these patients that don’t fit the criteria? What about these tumors, I should say, that don’t fit the criteria for those low risk disease? We’re talking about patients with high risk disease. These are patients who already, they may have swelling of the inside lining of their kidney. We call that hydronephrosis, meaning there’s a tumor in that funnel that’s blocking off the drainage of the kidney in some way, so urine is not funneling its way out as it would normally. A larger tumor size in the kidney that we may see when we do a biopsy and the pathologist tells us it’s high grade, so very aggressive or more aggressive looking tumors, as far as looking at the cells, the tumor cells under the microscope. Multi-focal, meaning this is a tumor that’s not located in just one spot in the ureter or just not one spot in the upper, up in the kidney, but maybe in multiple locations up and along that ureter or patients who have had other variants of bladder cancer or have had aggressive interventions or invasive bladder cancer are also patients that we think of as higher risk for upper tract disease.

Dr. Kate Murray:

Dr. Matin mentioned this a little bit, and this is something in the daily life of a urologist that we think about and we talk about with our patients, because getting a diagnosis, a true pathologic diagnosis, that’s reliable for grading and risk assessment for a patient can be quite difficult. I say this in contrast to bladder cancer, which is urothelial cell carcinoma of the lower urinary tract of the bladder of that urothelium. We do things called, we call it a TURBT, or a trans urethra resection of a bladder tumor. On these pictures here that you can see is, when we see a tumor in the bladder, we have this little hot instrument through a cystoscope when we’re looking inside that we’re able to scrape that tumor out, as well as some of the muscle wall and some of the bladder wall at the same time, that allows us to have a larger piece of tissue for the pathologist to give us a reliable diagnosis. Upper tract or working in this ureter tube, we often use what we call a ureteroscopy. This is very similar to what urologists use or exactly what urologists use for patients who have kidney stones or obstructing ureteral stones. It’s a very common procedure for urologists, where we’re taking this scope similar to a cystoscope, but very small. I tell people, as big as the end of my ink pen when it’s open and we’re going, and we’re putting that camera all the way up these ureter tubes up into the kidney. Now, what does that allows us to do? It allows us to directly see that. Dr. Matine had some pictures as well of what these tumors might look like. Here’s a picture here of a tumor blocking off a ureter tube. Then, we have to figure out a way to get a biopsy and get it pulled back down that little tiny tube and enough of a biopsy for us to reliably look at under the microscope and say, “This is slow grade, this is high grade, and is it an invasive tumor or not?”

Dr. Kate Murray:

It can be quite difficult, over here on my far right hand side picture, we use these little baskets oftentimes to do a biopsy of trying to grab a piece of this tumor off, so that we can look at it under the microscope, and so our pathologist can look at it under the microscope for us. We get a diagnosis and I think, one thing that we talk about and Dr. Matine mentioned this as well, is staging as important more so for our patients, obviously, who are high risk with high grade disease. Oftentimes, patients come and they’ve already had some sort of cat scan or an MRI, or there’s a way that we’ve found this cancer in the first place, but other imaging can be important for staging, looking at the chest, along with that CT of the abdomen, and then, obviously, we’re also looking at kidney function and other things that play into what our treatment options may be down the road. I say this as treatment should be based on risk, and this is true for anything that we do. Low-risk disease or low-grade disease should not equal aggressive interventions. Instead, we should save what we call nephrons. Those are … that’s what makes up a kidney. We’re wanting to spare kidneys, high risk disease equals aggressive interventions. We need to be doing operations or therapies with curative intent for these individuals, well, but there is some question of maybe there are options for patients that we can still spare nephrons in patients with higher risk disease. Without going in too much detail of high and low and all these different gradings are, in a nutshell, what are our treatment options?

A little bit of this. I flip to the very bottom of this slide first and say, I’m going to rely on Dr. Campbell to answer some of our still unanswered questions about chemotherapies for upper tract disease before and after surgery and now in the era of immunotherapies. Some of our treatment options are things aggressively, such as a nephroureterectomy with a lymph node dissection, a nephroureterectomy is in contrast to a nephrectomy, which would be nephro means kidney, so removal of the kidney. What’s important, when we’re talking about upper tract disease, is that we remove that entire system. Here’s a pathology, gross picture of a patient’s kidney, their ureter, their funnel draining all the way down here into the bladder and there’s even a small cuff of bladder that’s removed at the same time. There are options for patients to do what we would call ureterectomy if a tumor is located or isolated to a solitary place within the ureter.

Then, we talk about endoscopic ablations, and that is very similar to what, again, we do this via a ureteroscope that a urologist would use for stones oftentimes, and on my right hand side here, I have a picture of the inside of a kidney. This is in the calyces in one of those fingers of the kidney and there’s a tumor here on the bottom, and you can see this blue with a red light on the end of it being a laser fiber and we’re ablating or lasering off this tumor. Then, of course, discussions of chemotherapies that are put intra-cavitary or directly into the kidney similar to what we’ve historically thought about putting BCG or chemotherapy into the bladder. Then, of course, I’ve not put on their option of a clinical trial for patient for treatment options.

Dr. Kate Murray:

I’m going to just show a couple of more pictures for each of these different treatments that we would be doing for patients that come to see us for these disease process. Therefore, ureterectomy is, I have the same picture showing that it’s the kidney, the entire ureter tube that comes out. It can be done in many different ways. It can be done in an open approach through an incision in the abdomen done robotically. It can be done laparoscopically just as long as that kidney, that ureter, that little piece of bladder is removed all at once, and then a lymph node dissection as well. Here’s some pictures of what that would look like robotically and then really, what you’re seeing here is this circle on the bottom is our bladder. We’re seeing a ureter tube that’s coming in and have taken just enough of a piece of bladder to get that entire ureter out and not leaving anything behind, and then we sew up that small hole in the bladder that we’ve made for a nephroureterectomy.

Next, I’m just going to focus on little bit more on saving our kidneys and the ablations, the biopsies, the chemotherapeutics that we may use as urologists in today’s world of 2022. Why do we want to save kidneys? Why? Because, Dr. Matin showed us in that one of his very first slides that recurrence rates happen. We’ve talked about the risk factors of smoking and other risks for upper tract disease and disease can come back metachronously. That means at a later time. That can happen in the same kidney, it can happen in another kidney, it can happen within the bladder. Taking out kidneys can impact a patient’s overall life, so that is impactful in potential future therapies. It can be impactful for, removing kidney also have a great part in blood pressure control in our diabetes, and so we’re really trying to help with that.

I say, when do you save kidneys always is a good answer if possible? That always comes with a tongue-in-cheek “if possible”, and how do we do that? We do that often with these ablations, as I showed you in the first picture, and in now since 2020, talking about some chemoablations at the same time. I showed you those pictures, ablations with or without chemotherapy that can be done in today’s world. We talked about this intraluminal chemotherapies and how the bladder is a storage location. It makes sense that you can put a chemotherapy in there and it stays. The kidney, on the other hand, it doesn’t stay. Everything drains right back out of the kidney, but there is, newly in 2022, an approval for what’s called Jelmyto. It uses a reverse hydrogel technology for installation of a mitomycin C chemotherapy within the upper urinary tract within the renal pelvis.

Dr. Kate Murray:

It’s very, very well-known to urologists. It’s six weeks of a weekly installation is what it’s FDA approved. The dosage is dependent on what we find at the time of a patient’s ureteroscopy when we’re looking and doing that biopsy. The reminder that I have here is this is for patients with low risk disease. One of my final slides is I really like to save kidneys if possible and some of these things can be done in multiple settings, in clinic settings and operating room settings. It’s familiar to us as urologists. It’s quite tolerable for the patients, and it can avoid repetitive surgeries, repetitive anesthetics for our patients, if possible.

My last take home point from a urology aspect is based on one of those first slides that recurrences happen and they can occur in the same kidney, if it’s still there, it can happen in the other kidney and it can happen in the bladder. I think that’s something really important for us, is that we definitely need that ongoing management, documenting so that up to 40% of patients could have a bladder cancer after a urothelial of the upper urinary tract, and so we do need ongoing management of the bladder. We need it of the upper urinary tract, we need it of the lymph nodes of everything else, and of course, we’re monitoring a patient’s kidney function at the same time. Any comments from Dr. Campbell, because he sees these patients after, often after their seeing us as urologists or Dr. Matin if anything different that he does in his practice, or any good points.

Dr. Matthew Campbell:

I’m just very lucky to have a chance to work with Dr. Matin with a lot of these patients, because I think best care really is a team effort for a lot of patients and trying to figure out best strategies to help maintain kidney function as much as possible and to give patients every chance to treat cancer while it’s still localized and before it has spread. Again, I really lean on Dr. Matin’s expertise in helping understand when treatments are best given locally versus when I can Linda helping hand with a treatment to make surgery either more feasible or more reasonable for patients.

Dr. Surena Matin:

Thanks, Matt, for those comments. The only thing, I guess, that I would add is, and it’s something that I think we, even in our very detailed conversations at our conferences, we sometimes don’t really talk about at all, which is how much disease is there? Kidney preservation is so easy when there’s very little disease. On the other hand, when there’s a high volume disease and there’s a lot of it, even if you think it’s all low grade, it’s a real challenge. As someone who is and still eager to preserve kidneys when you can, I think there’s still indications for surgery to remove the kidney in the ureter if it’s a low grade, because it’s just so much to put the patient through sometimes to get all the disease and preserve the kidney when there’s a lot of it there. Quite honestly, I’m not sure it’s really worth it. Hopefully, they have a normal opposite kidney that’s going to function well. Of course, in those cases, we have a conversation about that, but I do think it’s something that we need to start highlighting a little bit when we go to conferences and have these conversations and maybe even in the guidelines trying to be a little bit precise about how much disease is actually there, because there’s just, it’s just that practical factor of there’s only so much we can do with our kidney preserving techniques.

Dr. Kate Murray:

Great points. I think now it looks like we’ve got a screen share from Dr. Campbell and we will pass it on to him.

Dr. Matthew Campbell:

Thank you very much. I really enjoy how active that the question and answers are going. I think that that’s tremendous to see a lot of questions for this cancer. I’m going to discuss, and really the focus today is patients with cancer localized to the urinary tract, not speaking as much about metastatic, though I’m happy to discuss in the chat as we move forward. These are my disclosures. There’s a lot of questions that always come up about best management, and so the way that I think about how and the analogy that I like to use for urothelial cancer in general, whether we’re discussing neoadjuvant chemotherapy, which is before or adjuvant therapy, which is after, is my treatments with chemotherapy largely do a good job in killing worker bees, but they can leave queen bees behind, and my colleagues in surgery are able to remove both. If you have cells that are in a resting state, chemotherapy has a hard time of working. Those are more of the queen bee cell types. I think there’s a clear role of oftentimes doing both. What does the word adjuvant refer to? It’s one that helps or facilitates, if you look in the Webster dictionary. When we use that in regards to chemotherapy for adjuvant, it’s something that enhances the effectiveness of medical treatment, so chemotherapy after surgery. Neoadjuvant is just referring to using this prior to that intervention, so to enhance prior to treatment, which would be surgery. Let’s start where we have currently the most evidence, which is in the adjuvant setting, which is adjuvant chemotherapy. This was a trial that was done in the UK called the POUT study.

Dr. Matthew Campbell:

On this study, they looked at patients that had had surgery that was done for upper tract disease and they received either adjuvant chemotherapy with two drugs, gemcitabine plus platinum and the platinums could be a drug called cisplatin or a drug called carboplatin. When you look at the patients that received chemotherapy in the adjuvant setting, they did what appears to be much better with adjuvant chemotherapy. What you can see here is that there’s a significant improvement in terms of time until cancer came back and we’re waiting to see if this is going to translate to overall survival, meaning that patients live longer with this approach. There are some interesting things here and I want to point out. We call these analysis when you look at papers, forest plots. This is where we’re trying to see if there are various groups of patients that tend to benefit most.

What we were very interested in is, in bladder cancer, there is a sense that carboplatin is not helpful if you give it prior to surgery or after surgery at preventing a recurrence. When we look at this, anything above the one line means that the surveillance would be better. It appears that all of these groups tended to benefit from the chemotherapy, whether they had nodes that were positive or negative, whether they received cisplatin or carboplatin, whether they had positive or negative margins, no matter their tumor status. While we look at this and say, “Well, it appears that the cisplatin potentially had more benefit, this little dotted line here is where the benefit seemed to, for all patients, tended to be, and because this crosses this line, we can’t say as a group, that carboplatin is less effective here. My takeaway is that adjuvant platinum-based therapy can and be beneficial.

I do strongly feel because patients that, in bladder cancer, we have such strong evidence with cisplatin, if patients are cisplatin eligible, then my preference is to give them cisplatin. Quality of life is always a very important consideration for patients and there’s a lot of concern about the toxicity with chemotherapy. Here, I think what this study does show is that patients do have a diminished quality of life while receiving chemotherapy, but you can see compared to patients that were on surveillance, quality of life is identical at six months. As a treatment trying to prevent recurrence of disease, most patients go through a period where their quality of life does suffer, but it does recover back to baseline and I think that that’s important. I thought that this was a nice slide that was shown at the GU symposium this year and this is one of the concerns that we have.

If you do surgery and then are trying to see if a patient is going to be cisplatin eligible after surgery, the majority of patients who would’ve potentially been cisplatin eligible prior to surgery is greatly diminished. Each of these little figures represents two patients, and so basically, 58% of patients would be eligible for cisplatin prior to surgery, while only about 15% of patients would be eligible after surgery. This number may be closer to 20% to 30%, it just depends on which literature you’re reading, but you’re clearly losing patients who would potentially better tolerate chemotherapy by going to surgery first.

Dr. Matthew Campbell:

Dr. Matin has done a tremendous amount of work in this area over really the last decade and longer, but looking at how patients, how can we look at the benefit for potential a neoadjuvant approach? In this quick diagram, this is looking at the staging of patients with similar stages at baseline, what was found at the time of surgery, should they go to immediately to surgery? What you can see here is a good portion of patients with T3 tumor or T4 tumors. These are more aggressive tumors as compared to patients that receive chemotherapy with a higher chance of finding no evidence of tumor, which would be T0 carcinoma only or T1 disease with less patients with more aggressive presentation.

Looking at how do patients do with neoadjuvant chemotherapy, and so this was one of the initial efforts, which was showing that at MD Anderson, there was, in our looking back at patients who had received chemotherapy versus initial therapy, there appeared to be an improvement in terms of overall survival, as well as disease-specific survival. Why do we look at both? Patients that are diagnosed with upper tract cancers are also at risk of having other health conditions, including high blood pressure, heart disease and others. We always try to trace and see are these potential deaths related to cancer or are they related to other reasons?

Dr. Matthew Campbell:

We’ve recently updated this series and this was published earlier this year, where we looked at 5 and 10 year outcomes. What we basically saw was that, if patients received chemotherapy, if we follow them out to five years, the risk of death was really less than 10% from the cancer itself, but there were competing risks of death and after 10 years, the risk of death was about 15% while there are other competing risks as well for patient’s health. Going back to the slides that were, or the presentation at ASCO. Dr. Yep is a urologic oncology fellow at Memorial Sloan Kettering, and they showed their study results which included 57 patients who were treated with neoadjuvant chemotherapy on a prospective clinical trial. What they were looking at is how well did they respond to the cisplatin chemotherapy? Pretty similar to what we found in a retrospective series, the vast majority of patients did have a response and were downstaged, and in terms of not having invasive cancer, this number approached 50%, which was extremely promising compared to historical evidence. There were patients that did not respond and we’re also interested in identifying patients less likely to benefit from this type of strategy.

How about, where do we stand with immunotherapy? Immunotherapy has become a mainstay in the treatment of metastatic urothelial cancer. It’s used in for the majority of patients, either as part of an initial therapy strategy, where chemotherapy is often given first, followed by a switch to immunotherapy. Patients who are not eligible for chemotherapy will often start with immunotherapy. It’s become a mainstay for us. But we have not had an understanding, can we use immunotherapy to try to prevent a cancer from being initially muscle invasive to having recurrent or metastatic disease later? This important study, Adjuvant Nivolumab was published late last year. What we basically saw on this study was the vast majority, as in most studies, were patients with bladder tumors and about 20% or so involved what we consider upper tract, so renal pelvis or ureter. On this study, looking at all patients that participated, there did appear to be a benefit for patients that received nivolumab, and this was statistically significant. When they looked at a pre-planned subgroup, which involved patients who had PDL1 expression, there appeared to also be benefit and perhaps a more substantial benefit in the subgroup, though that is something that we are following longer and we are continuing to wait for the overall survival data from this study. The way that I describe how these drugs work to patients, PD-L1 basically serves as a camouflage for these tumor cells. When you have a T-cell that is basically trying to kill a cancer cell, it puts PD-1 on its surface as a safety flag. When PD-1 interacts with PD-L1, it causes that immune cell to die or to hibernate. When we use a drug like nivolumab that blocks PD-1, that actually rejuvenates these T-cells to be more effective at killing cancer, and they don’t care about this camouflage anymore.

Dr. Matthew Campbell:

These drugs have had a huge change for us in the metastatic setting. This is now FDA-approved. If patients are not platinum eligible, I will consider this as an option for patients and I discuss with them the pros and cons of both approaches. In terms of side effects, the side effects with chemotherapy and immunotherapy are very different. With immunotherapy, there can be, at times, rare or extremely serious side effects. Though on this study, about 10% of patients had significant side effects and I quote patients a risk of death of 1 in 200 with immunotherapy. With that, I thank everyone for their attention and more than happy to answer questions and happy to hear Dr. Matin and Dr. Murray’s thoughts on this topic as well.

Dr. Kate Murray:

Great. Thank you so much, Dr. Campbell. I think that was a great overview. I’m just going to reiterate what you said earlier of how lucky you are to get to work with Dr. Matin and really use his guidance of what he sees in the patient and the discuss that he’s laid out up front. On the flip side of that, there’s so many patients that I see and that we see as urologists that we’re weighing out this chemotherapy or not chemotherapy and what are our things? It absolutely goes the opposite direction as well and I think, especially with patients with high-risk disease and patients that were worried about having both a urologist and a medical oncologist on board in your case for urothelial cell carcinoma is so important.

Morgan Stout:

Thank you so much, everyone. That was so insightful and wonderful presentation. We do have some questions that have rolled in, and I know that they’ve already been answered in the chat, but for the sake of those, maybe just listening in, I’m going to ask one or two of them out loud. The first one has to do with recurrence, which is something on everybody’s mind, especially with those nephroureterectomies is, how can we prevent recurrence? What is the recurrence rate for the folks in the different grades? If you can just talk about that very quickly.

Dr. Kate Murray:

Sure. Yeah. I think we’re talking about, if you have a nephroureterectomy or you’ve had an upper tract cancer, and so much of this is based on age, but I’m just going to throw out some general rules. The follow up is so important. Up to 40% of patients will end up with a tumor in their bladder at some point in time and up to 5% of patients can end up with a tumor in the other kidney or if you have a kidney remaining in another part of the ureter or something. So often, many of these patients maybe have had a history of bladder cancer and so they’re quite familiar with that bladder cancer follow up of having to look inside the bladder in clinic and do those routines. But there also are many patients who are found to have a tumor of the upper tract of the kidney or of the ureter based on an episode of blood in the urine and they’ve never had anything in their bladder, and so explaining that risk of recurrence in the bladder is so important, in that it’s a very similar cancer in some of our treatment bases are based on the similarities based on that urothelium, but as was noted at the very beginning, it’s also maybe not the same cancer as we’ve always historically thought about from a molecular level. There is so much more to come from us in the world of urology from that aspect.

Morgan Stout:

Thank you so much, Dr. Murray. Dr. Matin, Dr. Campbell, anything to add on that?

Dr. Surena Matin:

That was a really good summary of it. I think the one question about the follow up for this, at least in terms of what you read in the papers, it’s, in my opinion, a little too intensive. A lot of these papers we write that you have to, we have to do ureteroscopy or the upper tract endoscopy every three months in the first year. Gosh! That’s a lot. It’s a lot to put the patient through. It almost always requires anesthesia. There’s always a lot of symptoms afterwards because we have to put a stent in. Patients hate stents, I can’t blame them. We don’t love them either, but the alternative is worse. Anyway, I’ve actually gotten to the point where I modified that. I don’t feel … I will modify my follow up for patients depending on what the risk of disease is. Basically, I generally don’t do that intensive of a follow up, as you might read in some of the papers. I don’t know. Dr. Murray, do you modify? Is your follow up modified for those types of things or are you still pretty dogmatic in terms of how you follow them?

Dr. Kate Murray:

I think that you’re absolutely right. I think even if you want to be dogmatic and you want to be the most strict surgeon and say every three months, I have to be looking, we also are putting that into patients lives. It’s hard to come in for surgery every three months. Every time you go under an anesthetic is impactful. You have to take off work or your children have to take off work, there’s lost revenue, lost income, and so I really, if it’s somebody I really am worried about, I’ll stretch it and I’ll do try to get four months, so I get one less a year even. Or if it’s somebody who you can see on a scan, I’ll alternate it with a CT scan and assuming I don’t see a big, large tumor on a cat scan, I’d probably have enough time to wait another three months thereafter, so alternate cat scan and endoscopic direct visualization.

Morgan Stout:

Thank you. We did have a couple of really good questions submitted prior to the program, and they talked a lot about the genetics and gene expressions in upper tract tumors. As the experts here, how important is it to get those genetic screenings and look at just the genetic biomarkers that come off of these tumors? Is that something you recommend for everyone or is it pretty specific?

Dr. Surena Matin:

Yeah, I think, the truth is in terms of, it’s really, no, we’re not there yet. I actually do it, but that’s also because we have a program and we have a clinical trial going on, so I’m trying to see if some of my patients are eligible for the clinical trial. Having said that, outside of that, there really is not a role for a patient with localized disease at the current time for us to look at the tumor genetics. I do want to clarify that I think the question is specifically about the genetics of the tumor and whether they have mutations. The other genetic test is to look at the patient’s own germline, and that’s different. That’s when we’re looking for an inheritable syndrome. I just want to clarify that because sometimes it can be confusing about which one we’re talking about. In this particular case, we’re talking about having obtained a biopsy of the tumor and doing a mutation profiling, looking at the, seeing if there are genetic mutations there.

I don’t think we’re quite there yet, at least for localized disease. I’ll give Dr. Campbell a minute to answer for patients with metastatic disease, they will actually, there is probably some role for that. It may be changing a little bit in those with patients with Lynch syndrome, because there is actually a provision to treat those patients with immunotherapy, even if they don’t have metastatic disease. It’s very slowly changing, but bottom line is there really is not a role if we’re looking at it in an everyday type of case that we might see.

Dr. Matthew Campbell:

Yeah, I would agree. We, for all of our metastatic patients, and I have not gotten in trouble for this yet, but if patients are node positive, I look as well at their molecular profile looking for particularly FGFR3 mutations, since we do have FDA-approved targeted therapy. But to me, it gives me a roadmap of potential clinical trial opportunities and a potential better understanding of how their tumor is behaving. I completely agree with Surena. I think if we could have all patients screened for lymph syndrome with upper tract, that would be ideal. But I understand the concern about potential cost and that we do have the luxury of the ability to do that here that may not be covered in the community though. I think the immunohistochemistry test that we use as a screening tool are relatively inexpensive. Though the ramifications are immunotherapy is extraordinarily active for patients that have this, but it’s also important for families to understand risks to relatives, including siblings and children that as this is part of a syndrome that also increased risks of colon cancer, uterine cancer, pancreas cancer, and others, and so it’s ideal if we can try to identify that as early as possible.

Morgan Stout:

Absolutely. Thank you so much. I believe we have time for just one more question and Dr. Campbell already wrote the answer, but I want to ask it out loud. What’s the protocol for screening for upper tract in patients that have already had a radical cystectomy?

Dr. Matthew Campbell:

Yeah. In general, we’re following patients that have had a cystectomy most often for muscle invasive disease, but can be for non-muscle invasive disease with cross-sectional imaging, which is going to be CT scans or depending on kidney function, can be MRIs of the abdomen and pelvis. Depending on how those are done, as long as they’re done with contrast, we’re able to see the upper tracts reasonably well, and so that tends to be the way that we monitor for recurrence or a new development of an upper tract disease.

Morgan Stout:

Great. Thank you so much.