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Zachary Klaassen: Hello everybody. Thank you for joining us for this UroToday discussion. I am joined today by Dr. Rashid Sayyid, who is a urologic oncology fellow in the division of urology at the University of Toronto. Today, Dr. Sayyid's going to present a case of management of low-grade upper tract urothelial carcinoma, a case-based presentation. Dr. Sayyid, thank you for joining us today.

Rashid Sayyid: Thank you for having me, Zach. It's always a pleasure to be part of UroToday.

Zachary Klaassen: So why don't you walk us through your case presentation and we'll get off to some great talking points and teaching points on the management of low-grade upper tract urothelial carcinoma.

Rashid Sayyid: Sounds good. So I just wanted to start the presentation by noting that I have no relevant conflicts of interest, and again, it gives me great pleasure to be involved in this and thank you very much to everyone for the invitation. So we start off with the case of a 68-year-old female who presented with gross hematuria and intermittent left-sided flank pain of two months duration. She's fairly healthy, has a history of hypertension and dyslipidemia, has had a prior left hip replacement. Note her family history is negative for any urothelial malignancy. And she's a retired school teacher, a lifetime non-smoker, although we do note that she has secondhand exposure from her husband, and is on baby aspirin of 81 milligrams for secondary prevention of any heart disease.

Zachary Klaassen: So great. So we have a patient classic hematuria workup. Why don't you walk us through the next steps in this diagnostic workup that you guys did?

Rashid Sayyid: Sounds good. So if we follow the AUA guidelines and what the AUA tells us in this scenario, it's very important to assess both the upper and lower tracts. Although this is a case of upper tract urothelial carcinoma, it's important to not be fixated on just the upper tract, so we need to consider the whole collecting system. So cystoscopy obviously is very important in this setting, hers was negative for any bladder tumors. She also underwent cross-sectional imaging with a CT scan, very importantly had contrast as well with the late imaging of the collecting system in the ureter, this is commonly known as CT urogram. And if we look at the images here on the right, we know that she has about a two to three centimeter renal pelvic filling defect, which we'll see later corresponds to an upper tract tumor. And how good is CT urogram in this setting?

So it's important to know that obviously the performance is going to differ depending on the size of the lesion. Obviously the bigger the lesion, the better CT is going to be at picking it up. But overall, if we look in total, the sensitivity is about 92% and the specificity is 95%, which is obviously very good. And one of the common challenges that we see in the clinic is some patients either have chronic kidney disease or that have iodine contrast allergy, and as such it's hard to do the CT urogram. So one alternative in this situation is an MR urogram and obviously that comes with its own set of challenges, especially given the limited availability of this modality in different centers.

And if for some reason a patient also can't have an MR urogram, let's say they have an MR-incompatible pacemaker for some reason in addition to the CKD or the iodine allergy, then the AUA tells us that we can consider an ultrasound as well as a retrograde pyelogram. And that way you get both the axial imaging along with the contrast as well to look for a filling defect. So that's a good tool to have in your back pocket if you need it in those circumstances.

Zachary Klaassen: I think it's important to point out here, Dr. Sayyid, I think just because somebody has a contrast allergy to IV contrast, they can still get the retrograde pyelogram and certainly the picture that you showed on the right, this will certainly show up as a filling defect on that retrograde.

Rashid Sayyid: Absolutely, that's an excellent point. And so next, based on the imaging results, the patient underwent a right diagnostic ureteroscopy. And as we see here in the images, she had a couple of papillary lesions of the renal pelvis and we obviously did a biopsy based on these findings, with findings eventually of low grade TA disease. One important consideration when thinking about how to do the biopsy is there's a couple of techniques to do it. Our inclination usually, based on the paradigm in bladder cancer, is to do a forceps biopsy where we try to pluck as much of the tumor as we can and obviously get an in-depth assessment to see how invasive the tumor is. And it works quite well. The sensitivity, based on studies, is about 83% it's quite specific. But it's also important to consider the brush biopsy, especially in those lesions that are flat, and where for any reason it's hard to get a good grasp of the tissue and it works quite well. The sensitivity is about 91%, the specificity a bit lower, and that's probably because of the inflammation that is induced by this technique.

But it's important to consider both modalities, and in select circumstances you can consider both at the same time. We also did a selective cytology via washing. It's important to know that we also got a cytology initially, voided cytology as part of the hematuria work up. Well, why do you get a selective cytology as opposed to just relying on the voided urine cytology? It's a couple of reasons. First of all, studies have shown an improved cellular yield with a selective cytology. It also avoids contamination from the bladder and prostatic urethra in men, obviously they have to avoid it, there's a lot of contaminants. And so it's a pure sample when you get it from the specific collecting system. And also theoretically, you can get dilution from the normal contralateral renal unit when you get the voided sample. For those reasons together, it's very important to exclude the presence of high grade malignancy and this was negative for this patient. And then based on the findings and based on what we know, we proceeded with an endoscopic ablation of all the visible lesions using the holmium laser.

One important point that the AUA has emphasized in the recent guidance of upper tract urothelial carcinoma is the standardized reporting for these lesions. It's very important when discussing the case with different people or obviously when there's a transfer of care or conducting studies, that there's a standardized way of reporting these. And the AUA emphasizes that, first of all, you need to highlight what approach you use, whether antegrade or retrograde, discuss whether there were any bladder lesions. And then when you focus on the specific tumor, it's very important to discuss if it's a ureteral lesion, where was it? Was it the lower ureter, mid ureter, upper ureter? Obviously this has important implications for treatment selection afterwards. Was it a papillary sessile flat lesion? Was it unifocal, multifocal? What was the size? Was it obstructive? Did you biopsy it, yes or no? And if so, how did you do it? As well as cytology.

And it's very important to highlight these so that we get standardized reporting. And so it's obviously something that is very easy to do if you follow the checklist and something that we need to make a bit of a conscious effort to incorporate this in our standard clinical pathways.

Zachary Klaassen: That's great. I think too, Rashid, this slide leads nicely into risk stratification and certainly when we're talking about treatment of upper tract urothelial, whether it be the ureter or the renal pelvis, certainly risk and the AUA makes a very strong point about this, is going to be driving the management options. So clearly figuring out if somebody is a low risk or a high risk patient is going to be important before embarking on definitive treatment. So why don't you walk us through this risk stratification table.

Rashid Sayyid: Yeah, thank you, Zach. So the AUA makes again, a very strong point about this and as opposed to previously where we only talked about low risk and high risk disease, now we even substratify into favorable and unfavorable. So for low risk, we have favorable, unfavorable and the same for high risk. And this has very important implications again for treatment options, both local treatment with ablation and also for consideration of systemic therapy. And so the stratification depends on a couple of features. First of all, the biopsy grade, whether it's low grade or high grade. If you're low grade, you're automatically low risk. If you're high grade, you're automatically high risk. You also need to consider the cytology results, the imaging results, whether there was any invasion, any obstruction or any nodes that you see in the region. As well, the appearance of the tumor, is it unifocal, multifocal, papillary or sessile? Obviously sessile being more worrisome. And obviously it incorporates as well lower tract involvement.

And as you see down low in the therapy boxes, in terms of ablation, you see that there's a preference for ablative treatments in low risk disease, whereas in high risk disease we start talking about systemic therapy in the form of neoadjuvant or adjuvant systemic therapy. So it's also very important to consider this in addition to the standardized reporting, when we considered the next steps for our patient. And as we have seen in the case presentation so far, this patient would fit under the low risk unfavorable disease, particularly based on the findings of multifocal disease in this case. So again, very important to consider this when we talk about treatment options for our patient moving forward.

And a couple of things I want to talk about that we often don't consider or obviously don't talk about as often. Something that was very important for me as a clinical fellow right now is what do we do in these patients who've been instrumented before and have a stricture or conversely, have what we call a virgin ureter and have a tight ureteral orifice. And this can be quite challenging and frustrating in clinical practice, but it's important to acknowledge this and have a game plan going in and think about what we can do in these scenarios. And so the AUA addresses this very eloquently and recommends that clinicians should minimize any risk of potential ureteral injury by using gentle dilation techniques such as temporary stenting or pre stenting and obviously limit the use of aggressive dilation in select circumstances. And so one common question is, well how often do we leave the stent in? And so the AUA recommends one to two weeks and obviously this can be very frustrating for our patients having to have an additional one or two procedures, obviously take out the stent later on.

But it's very important that we counsel them ahead of time and do what's right for our patients. Another thing that's often forgotten about is Lynch syndrome. Lynch syndrome is a lot more common in this patient cohort than we think. So Lynch syndrome is also known as hereditary non-polyposis colorectal cancer, and it's an autosomal dominant syndrome due to a germline mutation mismatch repair gene such as MLH1, MSH2, MSH6, PMS2 or EPCAM. And in the general population, it affects one in 280 Americans. So more common than you think and then particularly in the upper tract cohort, about five to 20% of US patients have Lynch syndrome. So obviously something very important to consider and keep in the back of your mind as you're treating these patients.

Zachary Klaassen: Yeah, I think that's a good point. The Lynch syndrome is for sure something we're seeing more in the clinic. I think the awareness of it, the association with family members that have had colon cancer, multiple family members, most of our cancer centers now have genetic specialists, so maybe these patients have already visited with them. So I think your point about Lynch syndrome, particularly in these situations where we're seeing younger patients with upper tract urothelial carcinoma is very important. So let's go back to your case. So why don't you walk us through, you did the initial ablation, so what are the next steps for this patient?

Rashid Sayyid: We have to survey the patient at this point. We have to make sure she has no local regional or distant recurrences. So as a standard per the AUA guidelines, the patient underwent a repeat ureteroscopy, including obviously diagnostic cysto, because we have to keep in mind the risk of lower tract asynchronous disease recurrence three months afterwards. And at three months there was no evidence of any disease recurrence. She also had repeat endoscopy at six months, which was negative, but at one year we found a one centimeter local recurrence in the right renal pelvis. And as we see here, again, it's papillary in appearance, it's uni-focal, so not something that worries us a lot, but obviously quite frustrating for the patient and gets us thinking about the next steps. Also, in addition to the ureteroscopy, she had axial imaging, upper tract imaging every six months as is currently recommended by the guidelines, that was negative for any locoregional recurrence in the form of nodes or anything that we can see on the imaging or any evidence of distant metastases.

Zachary Klaassen: Yeah. So this is kind of a decision tree for the patient. So they've already had endoscopic tumor ablation, so certainly you could repeat endoscopic ablation with tumor ablation, probably get another biopsy to confirm this is still low grade. Other options may include chemo ablation. So if endoscopic ablation is not feasible, there's now a product called Jelmyto, which is a mitomycin containing reverse thermal gel. I know you're going to go through that data in a minute. And there's also the more definitive or more aggressive treatment, radical nephroureterectomy or segmental ureterectomy in patients with distal lesions. Obviously this patient with a renal pelvis tumor, a distal ureterectomy or segmental ureterectomy may be difficult. And this is for patients particularly those that have progression in either size or focality or grade, particularly in the high volume patients. So why don't you walk us through the treatment options that you discussed with your patient, Rashid?

Rashid Sayyid: Yeah, so great points, Zach. So I think in this scenario, obviously it's her first recurrence, it's solitary, it's papillary in appearance, looks low grade, we know she has a history of low grade TA, so obviously we want to give her every chance of avoiding having to take out the kidney. And obviously given the location, a segmental ureterectomy does not make sense in this scenario. So what it comes down to really in this scenario is one of two. Do we want to talk about repeat endoscopic ablation, which is definitely feasible, but what about other options? Obviously the paradigm has shifted a bit with the emergence of Jelmyto and I'm going to talk about that in the next upcoming slides within the context of the OLYMPUS Trial. So Jelmyto is also known as UGN-101 and is produced by UroGen. And it was recently tested a couple of years back in the OLYMPUS Trial, which was an open-label phase three trial that included 74 patients.

Very important to consider the eligibility criteria in this trial when considering the external generalizability and validity of these findings to our patients in practice. And so patients in this trial had biopsy proven either primary or recurrent, obviously this patient fits that, and also low grade upper tract urothelial carcinoma. The size criteria were five to 15 millimeters in this trial. And it's important to note if it's greater than 15, you can endoscopically downside to less than 15 millimeters. So size here is not really exclusion criteria unless you can't bring it down to the ideal cutoff of 15 millimeters. And it could be in the renal pelvis or calyces. Again, very important to consider that when talking about patients with lesions of the ureter. So overall primary recurrent, five to 15 millimeters, in the renal pelvis or calyces. And these patients in this trial had six instillations of once weekly Jelmyto, followed by monthly maintenance, only in responders obviously, via retrograde ureteral catheter.

And that's one thing that comes up in discussions all the time is well a retrograde ureteral catheter, do you have the facilities at your institution to take them into your cystoscopy suite, obviously with the x-ray and do it, or do you have to take them to? So it can be quite burdensome from a health services utilization standpoint. And one thing that has emerged over time is instillation via a nephrostomy tube, that has been demonstrated to be feasible in numerous observational studies. But in this trial per se, they only used retrograde ureteral catheters for instillations. And if we look at the schematic here, let's start on the upper left corner. How many of these patients had a complete response? 58%. So almost 60% of patients who met this criteria had a complete response. Next, if we look at the 41 patients who had a complete response, 56% maintained the response after 12 months.

So just over half have a complete response and just over half of those maintained the response beyond 12 months. And next, if we ask the question, well, did the maintenance therapy make a difference? It appears that the answer is yes. So among the 41 patients, 29 received maintenance instillations once monthly. The complete response rate that was maintained was 59%. And then if we look at the 12 patients who did not receive the maintenance, the complete response rate that was maintained was 50%. So obviously there's about a 10% difference. So this advocates for the use of maintenance instillations in these patients. What about ureteric stenosis? This is something that comes up all the time, that how can I offer my patients a treatment with 44% of them potentially having ureteric stenosis in the future? That's a very important point and something that's important to counsel our patients about.

But there's several points to consider, this 44% may be quite inflated. So if we look at the definition of ureteric stenosis in this trial, it's quite broad. It includes any hydro, symptoms suspicious of ureteral perforation or rupture, which may include prolonged localized abdominal flank pain, tenderness, etc. So very nonspecific symptoms and signs that may be related to this and may not. And so for the purposes of adverse event reporting, this had to be included within the context of ureteric stenosis. Also, another question that we need to think about is, well, is this stenosis related to the drug itself because of the inflammation it induces or is it because of the repeated instrumentation from putting the catheter all the time? So something very important to consider. And so clearly we need to assess this in the real world and real world data from Woldu et al in 132 patients showed that the overall incidence of new onset, clinically significant stenosis defined as need for a stent or nephrostomy tube, so more of a practical definition was only 23%, so it's half of the 44%.

It's important to note that almost half of these patients underwent a nephrostomy tube as opposed to retrograde instrumentation. So obviously that may also be related to the lower rate. So I think it's important when I talk to my patients that I tell them about the 44%, but I also kind of highlight that things aren't as bleak and I think the 23% is more realistic when we consider the need for a stent or nephrostomy tube as something being more practical. And so based on these results, the FDA in April, 2020, approved Jelmyto for the treatment of adult patients with low grade upper tract urothelial cancer, which is obviously great news for our patients in terms of the availability of the drug, potential or reimbursement, and so just adds to the armamentarium that we have in this disease space that historically has very limited treatment options.

Now one thing that also comes up quite often, what is the role for adjuvant therapy? And this comes from the bladder cancer disease space where we know that BCG is currently recommended for patients with intermediate or high risk, non-muscle invasive disease. And so the data is quite weak in the upper tract space, but the AUA has acknowledged this and said that following the ablation of these tumors and obviously making sure you have no perforation of the bladder or upper tract, you may instill chemotherapy in the renal pelvis or you may also consider intravesical chemo to decrease risk of the urothelial cancer recurrence. And we'll talk about why intravesical when you're talking about upper tract disease. There's a couple of ways to do this. So you can instill the drug either via retrograde catheter, you can do it via nephrostomy tube, you can also place a stent.

And we know that at least half of the patients develop reflux. And so based on that you can do a voiding cystourethrogram to confirm reflux. And based on that, if they do, you can instill it in the bladder and anticipate that the upper tract will have at least some elemental contact with the drug. You can also use Jelmyto in this setting. So Labate et al assessed the use of adjuvant Jelmyto in this setting and they demonstrated that at about seven months the ipsilateral disease free rate was 63% with only 20% of patients having ureteral stenosis, which again may be related to the underlying instrumentation as opposed to the drug itself. And so it's important to consider that chemotherapy, either the acridine solution or Jelmyto may be an option for these patients.

What about BCG? We know BCG is very prominent in the bladder cancer space. And so the AUA currently recommends that you may consider pelvicalyceal therapy with BCG in patients with high risk favorable upper tract disease after complete tumor ablation or in patients with upper tract CIS. And again, this goes back to the recent risk stratification by the AUA and you see the importance of how this is only recommended for a specific subgroup of patients with high risk favorable disease in this setting.

Zachary Klaassen: That's great, Rashid. So I think the point you brought up about the perc nephrostomy tube is really interesting, because I think in my practice this has really been a game changer just in terms of decreasing the patient burden. I basically will discuss with them risks and benefits of Jelmyto. We'll book them with interventional radiology to get a perc nephrostomy. At that point, we're able to get the interventional folks to measure the volume in the renal pelvis so that we then use the same volume for the Jelmyto. When they're doing their placement, they're able to inject contrast and give us at least an estimate, usually around eight to 10 CCs. And basically the patient just has it capped for the remainder of the six weeks, with very little change in quality of life. And I think that's really made a big difference.

Certainly, at least in my practice, it's decreased the ureteral stenosis or the ureteral stricture rate. And basically after that six weeks we get imaging, we're able to discuss next steps, whether we're going to do maintenance therapy or not. So why don't you walk us through the final slide here in terms of the case presentation, and how you treated this patient?

Rashid Sayyid: Yeah, absolutely. So we had the same discussion with our patient, talking about the approaches, antegrade versus retrograde. She felt more comfortable with the retrograde, based on the data from the OLYMPUS Trial. And so she received the six weeks of induction and then she received the monthly maintenance for one year. So she was one of the patients who was able to tolerate it quite well, again, with excellent quality of life and results. So she's been followed for 18 months since we started the Jelmyto and she undergoes repeat endoscopic evaluation every three months with ureteroscopy. And so far, knock on wood, she hasn't had any evidence of disease recurrence, her CTs to date, with contrast, have been negative for any locoregional or distant metastases. We can't forget every time we survey her, we do the selective wash and voided cytologies and these have been negative for high-grade disease. So we'll see how this patient does moving forward, but at the very least, we bought her 18 months of a disease-free interval with minimum morbidity and so far excellent results.

Zachary Klaassen: Dr. Sayyid, thank you so much for joining us today. It was an excellent presentation of your case and walking through some of the nuances in the data of the OLYMPUS trial from UroGen. Thank you very much for your time.

Rashid Sayyid: Yeah, thank you so much for having me and it's always a pleasure.

Zachary Klaassen: Thanks.