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Sam Chang: Hello everyone. My name is Sam Chang. I am at Vanderbilt University, Nashville, Tennessee. And I am fortunate enough today to be joined by Dr. Doug Scherr. Doug is a Professor of Urology at Weill Cornell Medical School and is actually the Director of Urologic Oncology in New York. I've known Doug for many, many years, and I really consider him a superstar. And he is going to be focusing on how he evaluates upper urinary tract strategy from a risk stratification standpoint. Good morning, Doug.

Doug Scherr: Morning, Sam. Thanks for allowing me to participate in this really great agenda. This morning I will be discussing, as Sam had mentioned, how we risk stratify patients for upper urinary tract cancer. And I think when looking at these, there are many things we like to predict, obviously, survival. Also dictating how we are going to treat disease. But one of the most important factors we look at as well, given that oftentimes the kidney or ureters are removed, how do we predict bladder recurrences? Because this occurs in upwards of 30% of patients.

And there are several things we tend to look at. There are patient factors, there are tumor-specific factors, and there are treatment-specific factors. And of course, we will get into these in a bit more detail in discussing how I approach things.

But in terms of patient factors, I think it's understood that male patients often have higher rates of bladder recurrences than female patients, perhaps because they retain urine. Smokers, particularly active smokers, have higher rates of recurrences. And patients with underlying kidney disease will also have higher rates of bladder recurrences.

In terms of tumor-specific factors, a positive urine cytology or a history of bladder cancer will predict bladder recurrences, where the tumor is located in the ureter, whether it's a multi-focal tumor or a high T stage, the presence perhaps of necrosis.  And then interestingly, treatment-specific factors can have a role as well, whether surgery is done laparoscopically or open, whether you do an extravesical or intravesical bladder cuff removal, margin positivity at the ureter, and whether you have done diagnostic ureteroscopy prior.

In terms of focusing on some of the patient factors, many people initially thought age and gender were real considerations in predicting high versus low-risk urothelial carcinoma in the upper tract. And I think there is some evidence to suggest that older patients may have a higher risk, but by and large, I think we treat these patients the same. Active smokers, particularly those with a long smoking history, are certainly considered at higher risk. But if you do smoke, I think if you quit more than 10 years ago, this can have significant mitigation of this effect.

Surgical delay can put a patient at high risk. I think if you're performing a radical nephroureterectomy, to me it should be done within 12 weeks from the time of diagnosis. There are certain preoperative lab factors, some that predict inflammation such as the neutrophil-to-lymphocyte ratio, sarcopenia, or obesity. And there is now a new phenomenon known as sarcopenic obesity. These are obese patients who have muscle wasting as a result of chronic disease. And we will speak a little bit more about interventions of ureteroscopy prior to nephroureterectomy.

In terms of classifying tumors at risk and patients who are considered high risk for upper tract disease, again, the stage is probably our most important predictor. And we see here that the five-year survival for patients with low-stage disease is more than 90%. So upper tract disease can and often is a curable disease. But if you look at patients with advanced disease, T4 disease, very few of these patients will live beyond five years, less than 20%.

How do we stage patients? I still think at this point in time, CAT scan. CT urography is the best staging device that we have right now. And you can see the sensitivities and specificities there. Certainly, something to focus on is the presence or absence of hydronephrosis. I think this is a very important phenomenon in looking at high-risk diseases.

Multifocal tumors, we know are definitely high risk. Large tumors can put someone at high risk. I think it is pretty well understood that ureteral disease, stage-for-stage, can have a worse prognosis than renal pelvic disease. And there is a higher rate of tumor bed recurrence after surgery for ureteral disease.

Lymphovascular invasion, we always have a hard time getting our pathologists to comment on this on ureteroscopic biopsies. But certainly, it is a predictor of bad disease at the time of nephroureterectomy. Carcinoma in situ has a higher risk of disease at the time of nephroureterectomy.

When you are looking and doing a ureteroscopy on a patient, it's important to distinguish between sessile and papillary tumors. Sessile tumors tend to do worse. And I think getting negative margins is critical at the time of surgery.

More and more data now is arising on the role of lymph node dissection. And although we don't have any well-done randomized prospective trials, I think there is ample evidence, both from the retrospective standpoint, that performing lymphadenectomy at the time of radical nephroureterectomy is very important. And any evidence of local regional nodal disease at the time of diagnosis, I think neoadjuvant chemotherapy is critically important.

There is now mounting evidence looking at some of the immune checkpoint markers. Interesting, there is some data such as PD-1 expression having the worst prognosis, but PDL-1 expression may have a more favorable prognosis.

And now we're seeing a growing body of literature on genomic biomarkers, we have a lot of stuff in other diseases. We know about the Oncotype and Decipher scores in prostate cancer. And I think in the future, we are going to be relying more on these in upper tract and bladder cancer as well.

Very briefly, this is sort of what I've already spoken about, but looking at guideline management, this is how we distinguish between low-risk and high-risk disease. And I've commented on most of these, so I'm not going to spend a ton of time on them. But risk stratifying in this disease is, unlike many others, we have a lot of algorithms that are fairly well delineated in terms of how we treat disease based on risk. And low-risk disease, and again, I'm going to get into this in more detail in terms of how I approach things. But by and large low-risk disease, I think you have a gamut of treatment options extending from just local resection of small papillary tumors, laser ablations of larger tumors, nephroureterectomy can be used for low-risk disease in large cases, segmental resections.

And now, and I'll speak more about this, we have some upper-track instillations of chemotherapy agents in a new FDA-approved drug called JELMYTO. High-risk disease, I think the gold standard and cornerstone of treatment is radical nephroureterectomy. I think nowadays we are looking at more and more patients getting neoadjuvant treatment for this disease. And now we have some well-done randomized trials looking at the benefit of adjuvant treatment after patients with radical nephro-u who fit into the high-risk categories.

Again, I'm not going to go into this in any level of detail right now, other than to say, when approaching these patients, it's important to have as a backdrop sort of, what are the guidelines and where you fit into this, and location plays an important factor.  Where in the ureter is it located, if this is a calyx or in the renal pelvis? These can dictate different approaches to how we look at this disease.

So I tend to use predictive nomograms and there is a variety of those out there. This is one that we have created at our institution. And although it has been validated internally, we have yet to validate this in a larger external cohort. So I say this with some degree of a caveat here. But it is very helpful for us, particularly in counseling patients to who we want to give neoadjuvant chemotherapy. So we do go through these nomograms. They are based on simple clinical factors that you can get from your scans and ureteroscopic biopsies. And it gives us a general sense of the risky nature of these patients. And we try to make a great effort, particularly in patients with normal kidney function, to put into the neoadjuvant setting because I think it's really difficult to give chemotherapy after surgery. And I think it's important if they need it, I think it is much easier to give it beforehand.

I will now pause for a moment and just go into a sort of how I approach things. And again, I think the first element I look at to stratify risk is the grade of the tumor and the stage of the tumor. So grade is something we are going to get off of the ureteroscopic biopsy. I'm not someone who typically operates on someone who has a filling defect and positive cytology. I still like to get a ureteroscopic look at these tumors to get a better idea of where we stratify these patients. I want to know if it's in the ureter or the renal pelvis. I want to know how large it is. Oftentimes, if it's a low-grade tumor, we're able to perform some laser ablations or even electrocautery ablations of these tumors. And in patients with compromised renal function or very low-risk disease, I do think segmental resection has a big role.

For example, if I see a low-grade distal ureteral tumor in the lower ureter, if I can't ablate this completely, I would consider a distal ureterectomy. I think there are some patients even with higher levels of risk disease who have compromised renal function, I feel like I'm very proactive in pursuing distal ureterectomys and re-implants. Radical nephro-us, even for low-grade disease, I think are not an unreasonable factor. I think it still should be in your armamentarium. And I will say over the last several months with the FDA approval of this gel-based mitomycin C, I have been making liberal use of this in patients in a variety of settings, and I've been mostly using it in the renal pelvis. I have not used it yet for ureteral disease. But in patients with low-grade disease in the renal pelvis who are beyond necessarily the ability to ablate, or even as an adjuvant setting after ablation, I've been using JELMYTO. In the study of the OLYMPUS trial that was done and published, there was a 59% CR response with an 11-month median follow-up.

So the downside to this is there were some significant side effects. We did see upwards of almost 40% of the patients had some ureteral stricture disease or UPJ obstructions following treatment. So I think you do have to be careful with that. I think nowadays we are taught to let the gel sit there before we pull the stent out to try and diminish ureteral instillations. But it is something I definitely use in my armamentarium.

High-grade disease, as I mentioned earlier, I do try to have liberal use of neoadjuvant chemotherapy. I'm a big fan of it, particularly for those that have a local regional disease or just extensive T2 or T3 disease that you see at the time of ureteroscopy. I think downstaging these tumors is very helpful prior nephro-u. Even in patients with nodal disease or low-volume metastatic disease, instead of giving three to four cycles of neoadjuvant chemotherapy, we will maybe give six cycles of chemotherapy for the metastatic state. And if they do have either a CR or partial response with some residual disease, either in the nodes or the kidney, I also tend to be proactive in consolidating treatment with surgery. Because I think the data does suggest getting a CR, whether it's through combination therapy of surgery plus chemo, or chemo alone, I think these patients tend to do better than leaving disease behind.

I think now we have, as I mentioned earlier, some real good randomized data confirming the benefits of adjuvant chemotherapy. So I think these patients do need to refer for adjuvant chemotherapy for these high-risk T2 patients and above. In terms of very high-risk patients locally advanced or metastatic disease, again, chemotherapy is important and now we have a variety of clinical trials. This is just a list of some of the ones we have open. And most of these are either chemo plus immunotherapy-based in the neoadjuvant or adjuvant setting. And now there is also a body of evidence looking at FGFR receptor alterations,  and I think most of these trials require about a 10% expression of FGFR to enroll in these trials. But I think upper tract disease, there is some really good growing body of clinical trials that I think we need to start enrolling patients in, either in the adjuvant or high-risk setting preoperatively.

So I'll leave it there. And I would love to have a back and forth with you, Sam, and sort of see where I differ or may not differ from some of the things you may do.

Sam Chang: Doug, that is absolutely fantastic. I want to ask a couple of questions first that were some things that I find incredible as I do this and talk with experts, I always learn something. Tell me a little bit more about the differential response or favorability associated with PD-1 versus PDL-1 expression. I'm not as familiar with that data. So is that only expression or is that actual treatment derived as well?

Doug Scherr: No. Well, it's a couple of things. It's both.  Most of us understand that in predicting response to checkpoint inhibitors, there is definite evidence to show that higher expressions of these receptors correlate with an improved response. I think we also know that tumor heterogeneity or the greater mutational load in these tumors tend to have better responses. But there are now interesting data looking at just immunohistochemistry of tumors, that there is some prognostic information. It is a little unclear as to why that may be the case, but there is mounting evidence to show that there is a sort of distinct difference between PD-1 and PDL-1 expression in terms of worse. This hasn't been validated in large trials, but there is some early evidence to suggest that. So it is something we look at. I think we tend to look at it more from a predictive to treatment, but I think prognostically, it also may have a role.

Sam Chang: I think it's really interesting. I think people continue to try to figure out why some of the adjuvant urothelial trials have had different response rates-

Doug Scherr: Correct.

Sam Chang: And different significance versus lack of significance. So I think that is, at this point, definitely provocative and definitely, things that we will learn more and more about, obviously, with the checkpoint inhibitors and what their expression is versus, vis-a-vis, their response to therapy, and their prognosis upfront, and as you were saying.

Doug Scherr: I think we're going to ultimately move in a direction, if we look at prostate cancer, we have all these genomic risk scores associated with prostate cancer, Oncotype, Decipher, etc. We're starting to see some of it in the bladder and I do think ultimately, we're going to have better prognostic genomic risk scores for upper tract disease as well. We're just not quite there yet.

Sam Chang: I want to follow up on that. So with risk stratification, I agree with you totally regarding the importance of grade, really, at this point, kind of dictating what we do. I've asked this question before, but how do you sample, how do you determine grade? Just like you said, there's the heterogeneity, it's difficult to biopsy these tumors. I have the most difficulty, I think, with those tumors that tend to carpet the ureter, that does not have a big papillary area, but clearly, there's a fair amount of disease. Tell me a little bit about how you determine that risk for these tumors.

Doug Scherr: Sure. That's a great question. I think looking at grade and stage, stage, of course, is very difficult to ascertain ureteroscopically. But grade, based on the biopsy you take, we could access and assess grade. The issue becomes a sampling error of large, more heterogeneous tumors. And I think it's very, very common where I'll get a low-grade biopsy based on my ureteroscopic biopsy. But based on the appearance, the architecture, and the size of the tumor, I'll make a determination to remove that kidney. And I say more often than not, we do find high-grade disease that wasn't detected on the ureteroscopic biopsy.

So I think looking at grades in isolation can and often is misleading. And I think you can't take it in a vacuum. I think it's really important to look at the architecture of the tumor, meaning sessile versus papillary, the size of the tumor, the multifocality of the tumor, and sort of that need to be taken into the context of your grade biopsy. The grade is incredibly prognostic, but you also do not want to be fooled into the fact that you are just dealing with a low-grade tumor, when there can be underlying elements that are high-grade, which we often do see.

Sam Chang: So at this point, let me just ask you two kinds of clinically based questions that I think are practical kinds of everyday situations. You have a gentleman or a female patient with an upper tract tumor on the right side, nothing that you know of on the left side. You're planning on doing a nephroureterectomy on the right, what do you do on the left side? Do you just say the CT urogram is enough? Do you do a ureteroscopy on the left side? Do you do a retrograde? What do you do with the contralateral side in terms of valuation prior to nephro-u?

Doug Scherr: Sure. It's a good question. So it's interesting, in the general population, and I qualify that by saying we do see a fair number of Lynch patients here, in which they do get upper tract disease. So in the general population, the non-Lynch population, I'll do a retrograde pyelogram of selective cytology on the contralateral side at the time of my diagnostic ureteroscopy. And assuming that is negative, then I leave the other side alone. I don't scope it, per se, and assuming that the CAT scan is normal. So I approached the ipsilateral tumor-like I would any other tumor.

But I do tend to get a selective washing or cytology of that side to ensure we're not seeing contralateral disease, which is quite rare. The issue with that is you do have to be careful of contamination from the bladder if you're getting positive cytologies in a patient. Number one, you don't want to contaminate the contralateral side. So I'm very careful in making sure it's a distinct 5 French stent, etc. I go through a whole slew of iterations to ensure that. And be certain that you're just not getting contaminated urine from the bladder to give you false positive cytology on the contralateral side. In the Lynch patients, it's probably overkilling, but I tend to scope the contralateral side to be sure that we are not missing anything. But that's sort of how I approach things.

Sam Chang: Oh, that's good to know. I am a big believer in the CTU, a really well-done CTU being better than, I think, retrogrades in the operating room. But in all honesty, nothing replaces, just like you're saying, evaluation with ureteroscopy. And so for those that I have the slightest worry on the contralateral side, I'll look. If there's no genetic predisposition, I just go with the CTU. And I tend not to instrument the contralateral side.

Doug Scherr: Absolutely.

Sam Chang: But it's the first time I've asked that question, but it's a question that our residents ask all the time. Well, what do you do on the other side? And I think it's a good thing to kind of consider and evaluate. So Doug, the last practical question I have for you is, in these patients that now you've had either a high-grade or low-grade upper tract cancer that you removed with a nephroureterectomy, does the outcome or the results of that upper tract influence how you evaluate the bladder and/or the contralateral side? So in other words, for high-risk cancer, do you tend to do cystoscopies more often. For multifocal disease, do you tend to do it more often? Tell me a little bit about your follow-up regimen.

Doug Scherr: Sure. It's a good question. So, obviously, overall numbers, about 30% of patients with upper tract disease will get a bladder recurrence over the course of their lifetime. I, obviously, on all patients make use of an adjuvant dose of mitomycin C or gemcitabine in the bladder before the catheter is removed. I think there are two randomized trials supporting that, but then I follow these patients sort of independent of stage and grade like I would any other bladder cancer patient. So they are getting cystoscopies every three months for the first year, every six months for the second year, and yearly thereafter. There is some evidence that perhaps some people can start using some of these bladder tumor markers, the NMP-22, there's a whole slew of these. I don't think any has necessarily been truly validated to replace cystoscopy at this point. So I still rely on urinary cytology, cystoscopies, and yearly upper tract imaging to evaluate these patients.

Sam Chang: Doug, I follow a very similar pattern. I think that with these patients, especially, I think the data suggests the early recurrence pattern, very similar to a bladder cancer primary, it tends to be early as opposed to later. And I think you obviously need to keep an eye on that contralateral upper tract as well. So I follow a very similar regimen. I don't use the urinary markers currently available. I do use cytology, honestly, as a screen for a higher-risk disease that it might be missing.

So, Doug, that was very, very useful, and really appreciate your insight, as always. I've always found your clinical management one that always has evidence backing, but is also based upon your experience and your expertise. So thanks again for your insights.

Doug Scherr: Thanks, Sam. Thanks for having me. It is definitely a humbling disease, but I think one that we are learning more and more about every day. So thank you.

Sam Chang: Great.