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Rashid Sayyid: Hello, everyone, and thank you for joining us today. I'm Rashid Sayyid, a urologic oncology fellow at the University of Toronto, and along with Zach Klaassen, an associate professor and program director at Augusta University, we'll be discussing the recently published AUA guidelines regarding the diagnosis and management of non-metastatic upper tract urothelial carcinoma that were published in May of 2023.

In our previous recordings, we had discussed the statements pertaining to the diagnosis and evaluation, risk stratification, and treatment of upper tract urothelial carcinoma. In this recording, we'll be discussing the statements with regard to neoadjuvant and adjuvant chemotherapy and immunotherapy use in these patients. We'll also be touching on the statements regarding the surveillance and survivorship aspects for these patients.

So starting off with neoadjuvant/adjuvant chemotherapy and immunotherapy, Statement Number 26 states that clinicians should offer cisplatin-based neoadjuvant chemo to patients undergoing a radical nephroureterectomy or segmental ureterectomy with high-risk upper tract urothelial carcinoma, particularly in those patients whose post-op estimated GFR is expected to be less than 60, or in those who have other medical comorbidities that would preclude platinum-based chemotherapy in a post-op setting. This is a strong recommendation with Evidence Level Grade B, and this recommendation is based on strong positive data from single-arm phase two trials that we'll discuss in a bit, also with consistent evidence from systematic reviews and meta-analyses.

There's also an analogous paradigm in the muscle-invasive bladder cancer space where neoadjuvant chemotherapy is standard of care; and so given the similarities, there's a lot of high-level analogous evidence from that disease space. Also, there are increased challenges with administration of cisplatin-based chemo in the adjuvant setting post a radical nephroureterectomy. Given the expected decrease in the estimated GFR and the elevation of creatinine, it is more challenging to administer the cisplatin-based chemo, and, as such, it becomes more attractive to give this chemotherapy upfront.

So there have been recently two major phase two studies that have looked at the role of neoadjuvant chemo pre-radical nephroureterectomy. The first was the ECOG 8141, published by Margulis et al. in the Journal of Urology, whereby patients received four cycles of accelerated MVAC in those who had high-grade upper tract disease of the renal pelvis or ureter without evidence of local regional metastatic disease and who were planned for a radical nephroureterectomy. These four cycles of accelerated MVAC were associated with a pathologic complete response rate of 14%, and the ypT1N0 or lower rate, meaning either no evidence of disease or only T1 was present, was 62%. And as referenced, the pathologic complete response rate is closer to 40% in the neoadjuvant bladder cancer trials. So we see that the pathologic complete response of 14% is significantly lower in the upper tract space.

Importantly, the four cycles of accelerated MVAC were well-tolerated, with about 80% of patients completing all four cycles and none of the patients progressed prior to surgery. This is a common concern of our patients: "Well, if I just treat with chemo, first of all, will my disease progress to unresectable?" So that was not the case for any of the patients. It is very important to reassure our patients.

And what's very nice about this study, they also looked at renal function at different stages during the treatment. So pre-op, the median creatinine clearance was 82. After the patients received chemo, but before they underwent surgery, 20% had creatinine clearance less than 60, which is often used as a cutoff commonly to administer cisplatin-based chemo. Then, post-op, 70% had a creatinine clearance less than 60. So we see that jumped from 20% to 70%, which again highlights the importance of trying to get chemo early on in these patients.

More recently, Dr. Coleman published in the Journal of Clinical Oncology another phase two study that looked at four cycles of split-dose gem-cis for high-grade upper tract patients who had no evidence of nodal metastatic disease and who were planned for a radical nephroureterectomy. The pathologic complete response rate here was a bit better at 19%, and the rate of patients having either pT0 or T1 was 63%. So the results are quite similar to those by Margulis et al. The two-year and five-year progression-free survival rates in this single-arm study were 89% and 72%, so quite good compared to historical series. Again, importantly, none of the patients progressed prior to surgery. The four cycles of split-dose gem-cis were also well-tolerated, with 90% of patients receiving three or more cycles and 50% receiving all four cycles. So again, strong evidence in this setting, albeit single-arm with no control arm for comparison.

For Statement Number 27, the guidelines say that clinicians should offer platinum-based adjuvant chemotherapy to patients with advanced pathologic stage, meaning pathologic T2 to T4, or if they had nodal disease N1 to N3 without evidence of metastases, for patients with upper tract cancer after a radical nephroureterectomy or ureterectomy who have not received neoadjuvant platinum-based chemotherapy. This is a strong recommendation with Evidence Level Grade A.

This statement is based on results of the seminal POUT Trial that was published in the Lancet in 2020. This was a phase three RCT that randomized 261 chemo-naive patients with either, and it's important to consider when seeing these patients in clinic, patients who have muscle-invasive disease, so T2 to T4, and they can have any nodal disease but importantly, no evidence of clinical metastases on imaging; or if they have N1 to N3 disease, it doesn't matter what their T stage is as long as they don't have metastases. So again, T2 to T4, no mets, or N1 to N3 without any mets. Patients in this trial were randomized to either four cycles of gem-cis or gem-carbo if they had a poor estimated GFR within 90 days of their surgery and patients received no adjuvant therapy beforehand at the time of trial enrollment. The four cycles of gem-cis or gem-carbo were associated with an improved disease-free survival with a hazard ratio of 0.45, and a lower risk of either development of mets or death with a hazard ratio of 0.38. It's important to note that the completion rate of four cycles of adjuvant chemo was relatively lower in this setting, at 58%. And this again speaks to the difficulty of administering adjuvant chemo after taking out one kidney, given the expected drop in creatinine in this setting.

For Statement Number 28, the guidelines state that adjuvant nivolumab therapy may be offered to patients who received neoadjuvant platinum-based chemotherapy and who have evidence of T2 to T4 on the surgical specimen, or they have node-positive disease, or in patients who are ineligible for or refuse perioperative cisplatin, and who have pathologic T3 disease, T4a, or node-positive disease. And this is a conditional recommendation with Evidence Level Grade B.

The evidence for this recommendation comes from the CheckMate 274 Trial of 709 patients, of whom about 20% had upper tract urothelial carcinoma. In this trial, patients received one year of planned adjuvant nivolumab 240 milligrams every two weeks or placebo, and we saw that one year of nivolumab improved disease-free survival from 11 months to 21 months, and also improved metastasis-free survival with a hazard ratio of 0.75. But when we look at the forest plot, there was no disease-free survival benefit for patients with renal, pelvic, or ureteral cancers, and we see the hazard ratios are anywhere between 1.23 to 1.56, and so there's a higher hazard of these events. But given that the approval was given based on this CheckMate 274 Trial, and it included 20% of patients with upper tract cancer, these patients were bundled within this approved regulatory process, and so nivolumab was approved for patients with both upper and lower urinary tract urothelial carcinomas. But, again, the evidence specifically in this cohort is not that convincing, but given the regulatory approvals, the guidelines do recommend that this is an option for patients, obviously after we counsel them extensively regarding these subgroup analyses.

With regards to Statement Number 29, in patients with metastatic upper tract urothelial carcinoma, a radical nephroureterectomy or a segmental ureterectomy should not be offered as initial therapy. This is based on an expert opinion. To date, there's no evidence for cytoreductive radical nephroureterectomy or segmental ureterectomy in this setting. And even worse, the nephroureterectomy may delay or even preclude administration of cisplatin-based chemo, which should be the pillar of any treatment approach in this setting.

For Statement Number 30, patients with clinical regional node-positive, meaning clinical node 1 to 3, M0 upper tract cancer, should be initially treated with systemic therapy. Then you may consider consolidative radical nephroureterectomy or ureterectomy with lymph node dissection in those patients with a partial or complete response, and this is based on expert opinion.

The evidence in this setting comes from systematic reviews that demonstrate that giving neoadjuvant chemo followed by radical nephroureterectomy, as opposed to radical nephroureterectomy alone, in patients with clinical node-positive disease, M0, is associated with improved overall survival, improved cancer-specific survival, and improved recurrence-free survival.

For Statement Number 31, patients with unresectable upper tract cancer, including those who are ineligible or refuse surgery, should be offered a clinical trial or best supportive care, including palliative management, meaning radiation, potentially using a systemic approach, endoscopic, or ablative, for refractory symptoms such as hematuria, and this is based on expert opinion. And it's very important that we adopt a multidisciplinary approach in these patients and their families, with preemptive discussion about goals of care and palliative measures in this setting. Meaning, do patients want a stent or nephrostomy tube in case of any obstructive symptoms? If they are bleeding from the upper tract cancer, would they be okay with embolization? So these are very important discussions that are to be had early on in order to provide the appropriate, timely, and goal-oriented care for our patients in this setting.

At this point, I'll turn it over to Zach to go over the surveillance and survivorship with regards to surveillance after kidney-sparing in this setting.

Zach Klaassen: Thanks so much, Rashid. So this is the section where we'll talk about surveillance both after kidney-sparing and more aggressive TURP therapy. The next five statements are quite dense, but we will summarize it nicely in a table highlighting the rate of imaging, cystoscopy, and evaluation for these patients.

So Statement 32 suggests that low-risk patients managed with kidney-sparing treatment should undergo a follow-up cystoscopy and upper tract endoscopy within one to three months to confirm successful treatment. Once this is confirmed, these patients should then subsequently undergo continued cystoscopy of the bladder at least every six to nine months for the first two years and then at least annually thereafter. Endoscopy should be repeated at six months and one year. Upper tract imaging should be performed at least every six to nine months for two years and then annually up to five years. And surveillance after five years, in the absence of recurrence, should be based on standard decision-making between the patient and the clinician. This is based on expert opinion.
Of course, the intensity and frequency of surveillance should be tailored to the inherent disease risk, and chest imaging should be obtained at baseline but is not required thereafter. So this is for low-risk patients managed with kidney-sparing treatment.

When we switch to high-risk patients that are managed with kidney-sparing treatment, they should undergo a follow-up cystoscopy and upper tract endoscopy with cytology within one to three months. Patients with no evidence of disease should then undergo cystoscopic surveillance of the bladder and cytology at least every three to six months for the first three years and then at least annually thereafter. Endoscopy should be repeated at least at six months and one year, and upper tract imaging should be performed every three to six months for three years and then annually up to five years.

Finally, surveillance after five years, in the absence of recurrence, should be encouraged and based on shared decision-making between patients and clinicians. So we see for these higher-risk patients that had kidney-sparing treatment, the intensity of follow-up is certainly more stringent.

This is based on numerous retrospective studies demonstrating that metastasis-free survival, cancer-specific survival, as well as overall survival is worse for high-grade patients when endoscopic nephron-sparing treatment is performed. MR urography or retrograde pyelography plus non-contrasted axial imaging may be utilized in patients for whom iodinated contrast is contraindicated, so those patients that may have worse kidney function after treatment, and chest imaging with chest x-ray or CT is recommended every six to 12 months to evaluate for intrathoracic metastases.

Looking at Statement 34, we see that patients who develop urothelial recurrence in the bladder or urethra, or positive cytology following treatment for upper tract urothelial carcinoma, should be evaluated for possible ipsilateral recurrence or the development of new contralateral upper tract disease. And this is based on expert opinion. We know this based on the risk of metachronous contralateral upper tract disease after radical nephroureterectomy is approximately 2.2% after four years but may be as high as 7% in some series. So we cannot forget about the contralateral kidney, and this is certainly important when we're evaluating these patients in follow-up.

So let's switch over to surveillance after radical nephroureterectomy, and this is based on basically their pathological stage after treatment. So after radical nephroureterectomy, patients with less than pT2 or N0M1 disease should undergo surveillance with cystoscopy and cytology within three months after surgery and then repeated based on pathological grade. So for patients that have low grade, less than pT2, this should be repeated at least every six to nine months for the first two years and then at least annually thereafter. For patients that are high grade, less than pT2, this should be repeated at least every three to six months for the first three years and then at least annually thereafter.

Due to the risk of metastasis and an estimated 5% probability of contralateral disease, cross-sectional imaging is also important and should be done within six months after surgery and then at least annually for a minimum of five years. Surveillance after five years, in the absence of recurrence, should be encouraged and based on shared decision-making between the patient and the clinician. The main concern for these patients is the risk of intravesical recurrence, and this is approximately 30%, with a median time to recurrence of six to 12 months. So close evaluation of the bladder is important for these patients. As we see here, it's going to happen within the first year for the majority of patients and usually within two years but rarely after 10 years. For patients with unifocal Ta-T1N0 disease, the risk of regional or distant metastases is roughly 10%, which is 7% for low grade and 13% for high-grade and multifocal tumors.

Statement 36 suggests that for patients who have undergone radical nephroureterectomy for greater than pT2 disease, a clinician should perform surveillance cystoscopy with cytology at three months after surgery, then every three to six months for three years, and then annually thereafter. So, more intense than the patients with less than pT2 disease. Cross-sectional imaging of the abdomen and pelvis with multiphasic contrast-enhanced CT urography should be performed every three to six months for years one and two, every six months at year three, and then annually thereafter to year five. A clinician should perform chest imaging, preferably a CT, every six to 12 months for the first five years, given the higher risk of thoracic metastases. Beyond five years after surgery, in patients without recurrence, ongoing surveillance with cystoscopy or imaging may be continued and again should be considered in a shared, informed decision-making between the patient and the clinician.

Going back to the risk of intravesical recurrence, this is higher in patients with a higher pathological T-stage as you'd expect. This may be as high as 53% compared to 30% in patients with Ta-T1 disease. In a meta-analysis, the risk of retroperitoneal or pelvic recurrence was 5%, and distant metastases were 16% within three to four years. In a large Canadian study by Kapoor, et al., the risk of local, regional, or distant metastases was 24%, with a mean time to recurrence of eight months, and 90% of these occurring within one to two years. So one of the themes of surveillance, particularly in these higher-risk patients, is that the majority of events will happen within one to two years. Finally, patients may consider a PET CT in select cases if patients are not able to undergo a contrast-enhanced CT or MRI.

This is nicely summarized in this table. As you can see here, we've talked about kidney-sparing low-risk, kidney-sparing high-risk, post-nephroureterectomy less than pT2, as well as post-nephroureterectomy greater than or equal to pT2. And so as you work from the top of the table at low risk to the highest risk at the bottom of the table, the surveillance intensity increases based on disease characteristics.

So let's talk about survivorship. Statement 37 suggests that for patients with reduced or deteriorating renal function following radical nephroureterectomy or other interventions, clinicians should consider a referral to nephrology, and I think this is important as we talk about multidisciplinary care in the survivorship setting. So we should strongly consider a nephrology consult for patients that have eGFR less than 45, those that have confirmed proteinuria, those that are diabetic with preexisting CKD, and whenever the eGFR is expected to be less than 30 after an intervention. CKD is important, and we know that it increases the risk of osteoporosis, anemia, cardiovascular disease, hospitalization, and mortality.

Statement 38 suggests that clinicians should discuss disease-related stress and risk factors and encourage patients with urothelial cancer to adopt healthy lifestyle habits, primarily smoking cessation, exercise, and a healthy diet. And we know that these patients, again, are very similar to our muscle-invasive bladder cancer patients with regard to their pathophysiology. The majority are in less than ideal health, and at the forefront of this is smoking cessation, which we know affects recurrence and cancer-specific survival but also worsens CKD progression. And certainly, weight control is important as well, as we know that obesity leads to worse cancer-specific outcomes, as well as CKD. Managing comorbidities is vital in these patients. The silent killers of the remaining kidney are diabetes and hypertension. We must promote healthy lifestyles, and it's important to have early referrals to appropriate providers and to provide continuous communication with our primary care providers for these patients.

There are several current gaps for clinical practice and future directions, and we'll highlight some of these to conclude our session today. Certainly, biology-driven biomarkers are important. We know that FGFR3 mutations are much more common in upper tract urothelial carcinoma compared to lower tract urothelial carcinoma. There's also the importance of noninvasive genomic biomarkers, which may allow for earlier screening for patients with Lynch Syndrome and other high-risk cohorts, and this may allow for precision medicine and pathway-directed treatment.

Other urinary biomarkers are out there, including DNA methylation assays, RNA panels, cell-free DNA, and this may have improved accuracy compared to cytology and may have implications with regard to screening, surveillance, and evaluation of these patients.
Certainly, instrumentation is a huge issue with upper tract disease, and it's challenging to get appropriate tissue. We have the BIGopsy forceps. We have the new robotic endoscopy snake instruments, which may allow for improved sampling. But this is certainly a huge area of unmet need for the engineers out there, with improved instrumentation certainly helping with our staging and diagnosis of these patients.

We've talked about ablative techniques, and there's lots of research going on in this setting as well. Jelmyto is approved for low-grade upper tract disease. The Thulium:YAG laser has also been approved for thermal ablation. There are also Phase 3 trials that are currently evaluating photodynamic therapy.

I think this is an important slide because this disease really has become multidisciplinary. This includes the urologist, the medical oncologist, medical genetic specialists, particularly for those who are seeing our patients for consideration of Lynch Syndrome, as well as nephro-oncology because these patients are all at risk of renal function decline. So bringing all of these specialties together to allow clinical trial collaborations and just excellent patient care is certainly important.

So in conclusion, patients with pT2 to T4, PN0 to N3, M0 upper tract urothelial carcinoma after radical nephroureterectomy should undergo adjuvant platinum-based therapy based on level one evidence from the POUT Trial. Follow-up will be tailored based on the treatment received, whether this is kidney-sparing versus non-kidney sparing, and generally includes cross-sectional imaging, cystoscopy surveillance, and urine cytology. Referrals should be made to nephrology for those patients at risk of having or developing chronic kidney disease, and all patients should be counseled regarding the importance of smoking cessation.

We thank you very much for your attention. We hope you enjoyed this UroToday guideline discussion of the AUA's recently published Upper Tract Urothelial Carcinoma Guidelines.