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Rashid Sayyid: Hello, everyone, and thank you for joining us today. I'm Rashid Sayyid, a urological oncology fellow at the University of Toronto. Along with Zach Klaassen, associate professor and program director at Augusta University, we'll be discussing the recently published AUA guidelines looking at the diagnosis and management of non-metastatic upper tract urothelial carcinoma.

In our prior recording, we had discussed the background, diagnosis, evaluation, and risk stratification of upper tract urothelial carcinoma. In this segment, we'll specifically discuss the guidelines pertaining to the treatment of upper tract urothelial carcinoma.
Statement 12 tells us that clinicians, as a clinical principle, should provide patients with a description of the short- and long-term risks associated with recommended diagnostic and therapeutic options. This includes the need for endoscopic follow-up, the risk of clinically significant strictures, toxicities associated with surgical treatment, and side effects from neoadjuvant and adjuvant therapies.

Now, let's start by talking about kidney-sparing management. Statement 13 tells us that tumor ablation should be the initial management option for patients with low-risk, favorable upper tract urothelial carcinoma. This is a strong recommendation with evidence level Grade B. When we talk about endoscopic ablation, this can be via a retrograde or antegrade approach with ureteroscopy and laser ablation. In this setting, specifically the low-risk, favorable upper tract cancer, an endoscopic ablative approach has similar cancer-specific survival compared to radical nephroureterectomy, with the enhanced superior renal function by sparing the kidney.

Another option, in addition to endoscopic ablation, is chemoablation. This is probably best used when endoscopic ablation is not feasible. For example, if the tumor location is in the calyx, and it's hard to reach, or if you have multifocal disease and you don't feel confident that you are able to ablate all the visible tumors. A very attractive option in this setting is Jelmyto, which is a mitomycin-containing reverse thermal gel.

Let's talk about Jelmyto specifically within the context of the OLYMPUS trial. The OLYMPUS trial was an open-label Phase III trial of 74 patients, with the following eligibility criteria: either biopsy-proven primary or recurrent, and all patients had low-grade upper tract urothelial carcinoma between 5 to 15 millimeters. If patients had a tumor that was greater than 1.5 centimeters, then you could endoscopically downsize it to less than 1.5 centimeters and you would be eligible for this trial at that time. The tumor could be present in the renal pelvis or calyces, so not in the ureter. That's very important when we're considering treatment options and candidates in our clinic for this treatment.

And so, in this trial, patients underwent six instillations of once-weekly UGN-101, which is Jelmyto, and then they had monthly maintenance in the responders via retrograde ureteral catheter. All the instillations in this trial were via a retrograde approach. However, it's important to highlight that instillation via a nephrostomy tube, meaning antegrade, is feasible, safe, and effective, as has been demonstrated by numerous subsequent observational studies.

What did the OLYMPUS trial show us? Among the 71 patients, about 60% had evidence of a complete response, and the response durability at 12 months was about 82%. Then, if we look at the 41 patients who had a complete response, out of the 41, 23, meaning approximately 60%, maintained their complete response after 12 months.

The authors then looked at whether the maintenance instillation had any efficacy in this setting. If we look at the lower panels here, we see that among those who did receive maintenance instillation, the complete response rate remained at 60%, whereas in those who did not receive it, it was only 50%. So, somewhat of a benefit in this setting.

Now, what's often brought up about Jelmyto is the concerns about ureteric stenosis. It's a real concern. It was reported in 44% of patients in the OLYMPUS trial, but there are several points to consider. It's not a clear black or white issue; the definition of this adverse event, ureteric stenosis, is quite broad. It included any hydronephrosis and any symptoms that were suspicious of ureteral perforation or rupture, such as prolonged localized abdominal or flank pain, abdominal tenderness, or acute abdomen. So, symptoms that may be related to ureteric stenosis but are also very likely not related to it. The definition was kept broad based on guidance from different entities. The other question is whether this adverse event, ureteric stenosis, is secondary to the drug itself or the repeated instrumentation that comes from placing the catheter repeatedly.

Because of this concern, there have been many observational studies since then that have tried to address it. Real-world data from 132 patients by Woldu et al. demonstrated that the overall incidence of new onset clinically significant ureteral stenosis is 23%, which is about half of the 44%. This was based on a definition of stenosis that required the need for a ureteral stent or a nephrostomy tube—a definition that's more clinically practical. So, if patients have urinary stenosis that requires a stent or a nephrostomy tube, in our practice, commonly, and when we counsel a patient, that's a definition that is more meaningful to us. It appears that the rate is 23% as opposed to 44%. It's also important to note that in this study, almost half underwent a nephrostomy tube as opposed to retrograde instrumentation. Based on the results of the OLYMPUS trial, the FDA approved Jelmyto for the treatment of low-grade upper tract urothelial cancer on April 15, 2020.

Next, statement 14 tells us that tumor ablation may be the initial management option offered to patients with either low-risk, unfavorable upper tract urothelial carcinoma, or select patients with high-risk, favorable disease who have low-volume tumors or cannot undergo radical nephroureterectomy. This is a conditional recommendation with evidence level Grade C. This approach should be particularly considered in patients with tumors less than 1.5 to 2 centimeters. That's because, for patients who have tumors greater than 2 centimeters, there's about an 80% increased odds of having invasive disease, meaning T2 with the larger tumors. Now, for patients with low-risk, unfavorable disease who demonstrate progression in either tumor size, focality, or grade, it's probably best that these patients undergo segmental ureterectomy or a radical procedure as opposed to repeat endoscopic ablation.

Statement 15 tells us that tumor ablation may be accomplished via a retrograde or antegrade percutaneous approach, and repeat endoscopic evaluation should be performed within 3 months. This is based on expert opinion. An antegrade approach is typically reserved for those patients who have had a prior cystectomy and/or urinary diversion for any reason, or if they have large tumors or those in the upper tract-collecting system that are difficult to access via a retrograde approach. One important tool to keep in your back pocket is the ureteral access sheath. It has become quite commonly used in practice, but it's also still important to bring this up. What are the advantages of a ureteral access sheath in this setting? It may decrease the ureteral stricture rate due to repeated passage of the scope, it may also improve fluid drainage that minimizes excess pelvicalyceal hydrostatic pressure from irrigation, and may also decrease the rate of intravesical recurrences in patients undergoing ureteroscopy followed by a radical procedure. A repeat look should be performed within 3 months, but could be done earlier based on clinical risk.

At this point, I'll turn it over to Zach to go over the remainder of the statements from this guideline discussing treatment options for patients with upper tract urothelial cancers.

Zach Klaassen: Thanks so much, Rashid. This takes us to statement number 16, which states that following ablation of tumors and after confirming there is no perforation of the bladder or upper tract, clinicians may instill adjuvant pelvicalyceal chemotherapy or intravesical chemotherapy to decrease the risk of urothelial cancer recurrence. There are several technical approaches that should be considered. This could be via a retrograde ureteral catheter, antegrade via a percutaneous nephrostomy tube, or reflux via stent placement. And so, all of these have been discussed previously, and most of these are based on observational studies.

As you can see here, in Galileo et al., this was a prospective non-randomized single-cohort study of 51 patients. A single upper tract instillation of mitomycin C after endoscopic ablation improved ureteroscopic recurrence-free survival to 29 months versus 19 months. Cutress et al. looked at their institution and found no difference in recurrence-free survival with adjuvant intraluminal chemotherapy. Labbate et al. examined adjuvant Jelmyto post-endoscopic ablation and found a 63% ipsilateral disease-free rate at 6.8 months following instillation, but did note a 19% ureteral stenosis rate.

Looking at statement 17, it states that pelvicalyceal therapy with BCG may be offered to patients with high-risk, favorable upper tract urothelial carcinoma after complete tumor ablation, or to patients with upper tract CIS. And this is based on expert opinion. This may be particularly important for patients who have a solitary kidney, have bilateral upper tract disease, or are at high risk of progression to end-stage renal disease if they were to undergo a radical nephroureterectomy. There have been numerous small observational studies that have assessed BCG for CIS of the upper tracts, but as expected, this is limited by small sample sizes, its retrospective nature, and inconsistency in the detection of upper tract CIS.

These studies have shown a complete response rate which varies widely, from 41-100%, and variable rates of recurrence, progression, and the eventual need for a radical nephroureterectomy. BCG as adjuvant therapy for upper tract Ta or T1 disease has been evaluated in a systematic review of nine studies. There was a 40% recurrence rate within 2.5 years, but a cancer-specific survival rate quite good at 94%. However, the majority, if not all, of these studies are hindered by the absence of a control arm for comparison.

Statement 18 suggests that when tumor ablation is not feasible or evidence of risk group progression is identified in patients with low-risk disease, surgical resection of all involved sites, either by radical nephroureterectomy or segmental resection of the ureter, should be offered. This is a Grade C recommendation. Pathologically low-grade tumors with evidence of invasion, multifocal implantation, high-grade cytology, or obstructive patterns should trigger alarm bells in these patients and should prompt concern for underlying high-grade disease. This should then lead to discussions for a possibly more extensive surgical resection.

Looking at statement 19, clinicians may offer watchful waiting or surveillance alone to select patients with upper tract urothelial cancers that have significant comorbidities, competing risks of mortality, or are at a significant risk of end-stage renal disease with any intervention that may lead to dialysis. And this is based on expert opinion. We do know that complication rates following radical nephroureterectomy range from 15 to 50% with a 30-day mortality risk of 1%. I think it's important in these patients that we understand that the pathophysiology of our muscle-invasive bladder cancer patients is very similar to those patients that have aggressive upper tract urothelial carcinoma. So, really understanding the comorbidity profile of these patients is important.

Let's talk about surgical management. Statement 20 suggests that clinicians should recommend radical nephroureterectomy or segmental ureterectomy for surgically eligible patients with high-risk upper tract uro carcinoma. There are certain techniques to radical nephroureterectomy that we'll discuss, and one of them is complete bladder cuff excision and lymphadenectomy. In 2023, robotic, laparoscopic, and open approaches are all acceptable for performing radical nephroureterectomy, and when we talk about the bladder cuff excision, we can either do this via extravesical or transvesical approaches. It's important to note that the transurethral endoscopic approach is less favored for removing the bladder cuff due to a high bladder cancer recurrence rate and limited ability to instill post-nephroureterectomy intravesical therapies if the bladder is not fully closed.

Looking specifically at ureterectomy, whether this is segmental or distal with ureteral implant or ureteroureterostomy, these are acceptable approaches in well-selected patients. So, we can consider a distal ureterectomy when tumors are in the lower third of the ureter and less than 2 centimeters, and we should have sufficient mobility of the bladder with the capacity to facilitate reimplantation, or if necessary, a Boari flap. With regards to segmental ureterectomy, this may be considered for small unifocal tumors less than 1 centimeter in the proximal or mid ureter requiring resection of less than 2 centimeters of ureter to allow for a primary ureterostomy.

Looking at statement 21. For surgically eligible patients with high-risk and unfavorable low-risk cancers, endoscopically confirmed as confined to the lower ureter in a functional renal unit, distal ureterectomy and ureteral reimplantation is the preferred treatment based on expert opinion. Endoscopic-assisted tumor ablation has recurrence rates of roughly 23-76%. Thus, distal ureterectomy is preferred when technically feasible.

Looking at statement 22. When performing nephroureterectomy or distal ureterectomy, the entire distal ureter, including the intramural ureteral tunnel and the ureteral orifice, should be excised, and the urinary tract should be closed in a watertight fashion. This is Grade B evidence. Again, a formal bladder cuff excision, whether extravesical or transvesical, is preferred over an endoscopic approach with secondary healing via long-term catheter drainage. This is going back to, again, concerns about improper removal of the transmural tunnel, and this is a distinct concern with ureteral excision with the pluck technique, given that there are concerns about urinary extravasation when watertight closure is not performed. This also delays the potential administration of intravesical agents with an open cystotomy.

Statement 23. When patients are undergoing radical nephroureterectomy or segmental ureterectomy for upper tract disease, a single dose of perioperative intravesical chemo should be administered in eligible patients to reduce the risk of bladder cancer recurrence. And this is a strong recommendation with Grade A level of evidence, and we'll go through several of these trials.

The first trial looking at this was the ODMIT-C trial published in 2011. This was an RCT of 284 patients without bladder cancer undergoing radical nephroureterectomy. Patients were randomized to a single post-op dose of mitomycin C at the time of catheter removal or standard management. And in the per-protocol analysis, recurrence was decreased from 27% to 16% with this single post-op dose of mitomycin C. We can see the Kaplan-Meier curve here to the right showing the benefit of mitomycin versus no mitomycin.

The second trial was the Ito trial published in 2013. This was 77 patients randomized to pirarubicin versus no instillation within 48 hours of nephroureterectomy. Pirarubicin instillation decreased recurrence rates at 1 year from 32% to 17% and at 2 years from 42% to 17%. And we can see this Kaplan-Meier curve here on the right. What's important is that gemcitabine has not been prospectively evaluated in this setting, but this is the most popular agent given its effectiveness in lower tract urothelial carcinoma and the lower cost and risk of peritonitis compared to mitomycin. In talking to folks around the country, gemcitabine is quite commonly used in this setting.

Let's talk about lymph node dissection to conclude this discussion. Statement 24 says that for patients with low-risk upper tract disease, clinicians may perform lymphadenectomy at the time of radical nephroureterectomy or ureterectomy. However, there are no randomized trials comparing lymph node dissection versus no lymph node dissection at the time of nephroureterectomy or segmental ureterectomy. There have been two systematic reviews demonstrating no difference in oncological outcomes, and this may be performed if there are intra-op or radiographic findings concerning for regional lymphadenopathy.

Statement 25 suggests that for patients with high-risk disease, clinicians should perform a lymph node dissection at the time of surgery. However, again, there's no level 1 evidence to inform this recommendation. But systematic review and analysis of the SEER data suggests a cancer specific survival benefit for lymph node dissection, particularly for patients that are T3 or T3. We can see here to the right, this is the lymph node dissection template that's recommended for tumors of the renal pelvis. This is a regional lymph node dissection based on right or left disease. For tumors of the upper or middle ureter, this is a regional lymph node dissection with a little bit more extension down to the iliac vein and artery. And we can see for tumors of the lower ureter, this is the lymph node dissection including the common iliac, external iliac, and internal iliac.

In conclusion, kidney-sparing management and well-selected patients as safe and feasible. And this includes endoscopic ablation and Jelmyto. For higher risk tumors, patients should undergo a radical nephroureterectomy or a distal or segmental ureterectomy based on the tumor location. And at the time of the expert surgery, patients should receive a single dose of perioperative intravesical chemotherapy. Finally, for patients with high-risk disease, surgeons should consider performing a regional lymphadenectomy. We thank you very much for your attention and we hope you enjoyed this UroToday discussion of the AUA guidelines for upper tract urothelial carcinoma.