Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of medicine at Northwestern University in Chicago, Illinois. And I am so excited to have here with me today, Dr. Christopher Wallis, who is an Instructor and Fellow in Urologic Oncology at Vanderbilt University Medical Center in Nashville, Tennessee, as well as Dr. Zach Klaassen, who is an Assistant Professor in the Division of Urology at the Medical College of Georgia. Thank you so much for being here with me today, gentlemen.

Zachary Klaassen: Our pleasure, Alicia.

Alicia Morgans: Wonderful. So, guys, I wanted to speak with you about an incredible tour de force that came out on April 21st, e-publication, in European Urology, a real management guide for how we should think about taking care of patients with GU malignancies during the COVID-19 pandemic. Can you tell me a little bit about why this was so important and how you brought it about?

Christopher Wallis: Absolutely, and I think the credit here goes to Dr. Catto who, as the Editor-in-Chief of European Urology, really coordinated getting such a team together. But the goal here was to acknowledge the rapidly changing environment of medical practice around the world as a result of the COVID pandemic. And how we can best optimize care for our patients with GU malignancies during this time. And so, in order to do this, we had to forgo a little bit of the formality of a standard systematic review and rely on previously published reviews, as well as a scoping review of the primary literature in order to identify studies that could guide us on the impacts of delays in treatment, predominantly designed to inform the research community and practicing clinicians about what we may expect from delaying treatment for patients with urologic malignancies. The goal here, of course, being to inform case triage, so that we can identify those patients who are likely to come to harm if we delay their treatment, and distinguish those from the patients who can have delays without any adverse events.

Zachary Klaassen: Thanks, Chris. So, just a little bit of background on the COVID-19 pandemic. So there is, certainly, heavy demand for resources across the country and across the world these days. And this is exacerbated by limited health system capacity and overwhelmed hospitals. And, certainly, this may be different even within certain countries and, certainly, in different regions of the world. What is exacerbated in Europe may not be what is exacerbated in the US and vice versa. So, because of this, medical governing bodies across the world have recommended re-prioritizing surgical cases. And in the United States, certainly, the Surgeon General and the American College of Surgeons have given guidance with regards to prioritizing which surgeries should be done. And, certainly, at the epicenter of this is balancing the risk of COVID-19 infection versus the risk of delayed surgery. And I know in both of our experiences there are certain oncology cases that should wait and should not wait. And this is part of the surgical aspect of this article in European Urology.

So, it seems like almost daily there are new data coming out, whether it's from China, whether it's from Italy just as to terms of how these patients have done, how they presented. In one particular paper that came out a couple of weeks ago, published in JAMA from Lombardy, Italy, which is one of the first hard-hit regions, was looking at baseline characteristics and outcomes of patients admitted with COVID-19 to ICUs.

And so, one thing that comes to mind here is that a lot of these patients, if you look at it closely, really mirror our patients that have GU malignancies. So, in their 1,591 patients with COVID in the ICUs had a median age of 63 years, 82% of these patients were male, and 68% of these patients had more than one comorbidity and most commonly this was hypertension. At the time of their data cutoff, the mortality rate of these patients in the ICU was 26%, and unfortunately, with longer follow-up, that number will probably go higher.

Christopher Wallis: In this Journal Club we're going to discuss the impact of delaying treatment in patients with upper tract urothelial carcinoma in the context of the COVID-19 pandemic, and hope to provide some guidance for the triage and management of these patients. By way of background and for a little bit of context, we can review some of the epidemiology of this disease. It's a relatively rare subset of urothelial carcinoma comprising only five to 10%, while the remainder of urothelial carcinoma obviously is in the bladder. There's an annual incidence of approximately two cases per every 100,000 patients in Western countries. And potentially as a result of its rarity or asymptomatic presentation, a relatively large proportion of upper tract diseases invasive at the time of diagnosis. As with the presentation of severe COVID disease, the peak incidence of upper tract diseases in the elderly, and is again more common in men.

Zachary Klaassen: So with regards to upper tract urothelial carcinoma management, whether this is pandemic or non-pandemic times, this is usually guided by the disease grade in terms of low- versus high-grade, and as always with these elderly patients, their co-morbidity profile. Numerous studies including the EAU guidelines suggest that the endoscopic management of low-grade upper tract urothelial carcinoma is safe. However, the impact of delayed radical nephroureterectomy for those requiring intervention is less clear. And this was really what made up the majority of our section in our paper with regards to the management of these patients that require a nephroureterectomy.

So we found four single-center studies that looked at the impact of delaying radical nephroureterectomy for diagnostic ureteroscopy, plus or minus biopsy. And it's important to note that predominantly these patients were low-grade patients, and only one-third of these patients amongst these four studies were high-grade. One of the studies looked at the impact of delayed treatment with regards to multiple ureteroscopic interventions and they found that undergoing two ureteroscopic treatments prior to radical nephroureterectomy increased the risk of intravesical recurrence for those with high-grade disease, but did not impact more downstream oncological outcomes.

So there were two studies that looked at the impact of a radical nephroureterectomy delay for three months. This first study was published in BJU International in 2010 and it was a multicenter study that operationalized the timing of radical nephroureterectomy as greater than three months after diagnosis and less than three months. There were 41 patients that had their surgery more than three months after diagnosis with a median time to nephroureterectomy of 110 days. And there were 146 patients that had their nephroureterectomy less than three months after diagnosis at a median time of 33 days. And when you looked at the delay in radical nephroureterectomy for more than three months, there was no difference in risk of disease, recurrence, and cancer-specific mortality, so really hard oncological downstream outcomes. However, these patients that had to delay more than three months were associated with worse pathological stage, lymph node involvement, LVI, tumor necrosis, and infiltrative tumor architecture.

A subsequent study in 2012 from the groups at MD Anderson, Hopkins, and UT Southwestern also looked at the impact of delaying radical nephroureterectomy and also operationalize this as waiting more than three months versus less than three months. You can see here that there were 54 patients that had their surgery more than three months after diagnosis and 186 patients had their surgery less than three months after diagnosis with a median follow-up of 29 months. So their outcomes were a little bit different than the previous study. They looked at five-year cancer-specific survival rate and five-year overall survival rate. You can see here that early and delayed radical nephroureterectomy were almost comparable in terms of five-year cancer-specific survival, at 72% and 71%. And also very five-year overall survival rates of 60% for early nephroureterectomy and 69% for delayed nephroureterectomy.

This has also been looked at the population level, looking at the delay of radical nephroureterectomy. The group from Penn looked at the nationwide cancer database and looked at 3,581 patients that were stratified by surgical wait time, and you can see here how this was categorized. Less than 7 days, 8 to 30 days, 31 to 60 days, 61 to 90 days, 91 to 120 days and 121 to 180 days after diagnosis. You can see that the majority of these patients fell in the 8 to 30-day range or the 31 to 60-day range. Interestingly, there was no difference in overall survival except in those patients that were delayed 121 to 180 days, as compared to the patients undergoing nephroureterectomy 8 to 30 days after diagnosis. And this was associated with a hazard ratio of 1.61. So it seems like there is a safety net with regards to delaying treatment, but when we get to the 121 to 180 day time period, these patients ultimately had worse survival.

With regards to perioperative chemotherapy, the much-heralded POUT trial was presented at GU ASCO in 2018 and subsequently published earlier this year in Lancet. And this trial looked at patients that had a radical nephroureterectomy and had pT2-T4 lymph node status any, or a pTany and pTN1-3 upper tract urothelial carcinoma, and they were randomized to surveillance versus adjuvant chemotherapy in a one-to-one fashion. You can see here that for disease-free survival, the hazard ratio was impressive at 0.45 favoring chemotherapy. And when we were considering how this would parlay into the COVID pandemic, looking at the trial protocol, chemotherapy was mandated within 90 days of radical nephroureterectomy. So it seemed reasonable that patients can wait a period of time to get their adjuvant chemotherapy if they were eligible for it.

Christopher Wallis: So when we put together this data, we need to start at the beginning of the disease trajectory. And when we look at patients with suspected upper tract disease, the group felt that even though there was no strong data for this, that the classic investigations of urinary cytology and CT urogram would be sufficient in this time. We could forego diagnostic ureteroscopy to avoid an additional procedure with a hospital visit and resource utilization. For patients with low-grade disease, these are often managed with nephron-sparing approaches pre-pandemic and are likely to have minimal risk due to a surgical delay.

However, in patients with a higher grade disease, there is some data to actually inform this guidance, and the evidence suggests delays up to 12 weeks may not be associated with adverse survival outcomes. Although, there is some evidence that this may affect pathological outcomes adversely with higher stage disease. In the setting of metastatic disease, first-line treatments should be commenced whenever possible and though POUT has shown a benefit to the use of adjuvant chemotherapy, it's likely feasible to delay this at least for a period to allow us to better assess the burden that the pandemic will place on healthcare systems.

Alicia Morgans: So thank you both for putting together all of this data and your thoughts. So really it sounds like taking a thoughtful approach upfront, particularly if what we see is just suspected and then hopefully could be low-grade. Taking a thoughtful approach to making sure we get that definitive diagnosis is the way to go, and we may have a little bit of time to do that. And it sounds like, too, thinking about using cytology and urograms are part of that way of using a thoughtful and noninvasive approach. Is this something that's been challenging to implement in your practices or is this something that seems like it's really part of what you would normally do anyway? What are your thoughts on that?

Zachary Klaassen: Yeah, I think that certainly a lot of these patients, once they come to you as a tertiary referral center, they've had a workup. And I think, as we discussed at the outset, it's really important regardless of the timing, pandemic versus no pandemic, to triage these patients into low- versus high-grade as the management will often drastically differ based on those criteria. And I think, for low-grade, definitely the delay in management is feasible, especially with a known diagnosis.

I think where, at least from my standpoint, from a personal standpoint, I was surprised of the delay of three months for radical nephroureterectomy. I guess my premonition coming into this sort of work that we've put together was that these patients would be urgently operated on. But it seems like from several studies, two multi-institutional and one population level, that at least a period of a delay seems relatively safe. So as we've mentioned before, how we stratify these patients going forward depending on the length of the pandemic and subsequent waves of the pandemic, I still think these patients will be prioritized much like muscle-invasive bladder cancer will be.

Christopher Wallis: I agree. I think the nuance in upper tract disease is less about the definitive management and more about the workup and investigation, as Zach alludes to. At a tertiary care center, many of these people come having already been worked up. And so we've seen in the last couple of weeks a number of patients referred in who've already had their ureteroscopy, and certainly having that histologic diagnosis is helpful. Some of my mentors in training have talked about the idea of two out of three if you have cytology, imaging, and you ureteroscopic biopsy. If you have convincing results on two or three you can likely forego the third.

So if you have a patient who presents with hematuria, you have a urogram showing a lesion, you have a cytology that's high-grade. I think most urologists are relatively confident that that is high-grade disease. In the setting where we're not resource-constricted, many I think would still prefer to do a ureteroscopic biopsy, get some tissue before moving forward, but the panel felt that wasn't absolutely necessary in this setting. And we could conserve resources by foregoing that diagnostic ureteroscopy and move forward with intervention.

Alicia Morgans: So this is a question that may not have been addressed specifically in your article and if not, feel free to demure. But in the United States at least, there are a number of institutions that actually favor neoadjuvant chemotherapy for upper tract urothelial disease, rather than adjuvant, which is what was, studied in the POUT Trial as you presented. And as you've reviewed, is that something that came up at all in your conversations? Because I think the medical oncologists on the panel were predominantly European, if not all European, right?

Christopher Wallis: Yeah, we didn't discuss it in a lot of detail. When we did discuss it, I think there are principles that I think are in a bit of a conflict, but the idea of neoadjuvant chemotherapy fits with giving the chemotherapy at a time when renal function is maximized in order to hopefully get patients the cisplatin, and get cisplatin as opposed to giving them carbo. And so that increases the likelihood that a patient will have renal function sufficient to get optimal chemotherapy. And sort of the push to that pull is that our staging for upper tract disease is often quite poor. Unlike bladder cancer where TUR gives quite a good distinction between invasive and noninvasive disease. Often in upper tract disease, it's less clear when we're relying on the interpretation of the CT urogram to try and decide invasion versus noninvasion.

So giving neoadjuvant is, especially given the context of difficulty with staging, going to put you at risk of overtreatment of patients with noninvasive disease. And so to me, those are the push and pull of adjuvant and neoadjuvant in this setting. And I think given the absence of strong data for neoadjuvant and the proven survival benefit of adjuvant, and in POUT, carbo was used quite routinely and retained a progression-free survival benefit even in the subgroup analyses. I think the group felt that there wasn't evidence, particularly given the context of the pandemic to support a strong push towards neoadjuvant.

Alicia Morgans: Great. Well, really important and helpful information. Thank you so much for putting this together and walking us through it. Thank you both.

Zachary Klaassen: Thanks, Alicia.

Christopher Wallis: Thanks.