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 section, we'll be discussing the impact of delayed treatments of patients with kidney cancer during the pandemic and hoping to provide some guidance for the triage and management of these patients during the few forthcoming months. Just by way of context, we'll go over a little bit of kidney cancer epidemiology. Globally, this is the sixth most common cancer in men and the tenth most common in women. The majority, nearly two thirds present with localized disease while about 15% present with regional disease and another 16% present initially with metastatic disease. As with many other urologic malignancies, patients with kidney cancer parallel the demographics of those at risk of both getting COVID-19 and severe complications in that there's a preponderance of males often hypertensive and with multiple comorbidities.

Zachary Klaassen: So to break this up into sections. We'll discuss the localized kidney cancer data first and provide recommendations. So this first study was five-year analysis of a multi-institutional cohort from the DISSRM registry. And these authors looked at 497 patients prospectively enrolled with small renal masses defined as less than four centimeters and they divided these patients into basically what they chose. So primary intervention was 274 patients compared to 223 patients that initially chose active surveillance. In terms of their outcomes, they looked at overall survival and cancer-specific survival. And you can see that the two-year primary intervention overall survival rates were 98% for primary intervention and 96% for active surveillance, compared to 92% for primer intervention at five years and 75% at five years for active surveillance. So I think what this does in the five-year data, it shows that the active surveillance patients probably were an unhealthier cohort and thus we see the difference in overall survival at the five-year mark. In terms of cancer-specific survival, not totally surprising in that for these small renal masses at five years primary intervention was 99% hence active surveillance was 100%.

A similar study looked at the growth kinetics and short term outcomes of cT1b in clinical T2 renal masses under active surveillance. So this is interesting because these are not typically patients that we will survey, but at the Fox Chase Cancer Center where they have a huge kidney cancer database, they were able to tease out several patients that had growth kinetics on their clinical T1b and T2 renal masses. So they looked at 45 patients that only had active surveillance and they looked at 23 patients that started on active surveillance and subsequently underwent intervention.

You can see here that the growth rate was different between those that were on surveillance and stayed on surveillance versus those that eventually underwent intervention. And you can see that the growth rate for surveillance was 0.37 centimeters per year compared to 0.73 centimeters per year for those that underwent intervention. And over a follow-up of just over three years, 13% of patients of all-comers died of other causes and none of these patients progressed to metastatic disease.

Christopher Wallis: So I think when we look at the available data for clinical T1 and T2 kidney cancer, it's pretty clear that surveillance of small renal masses is safe. And when treatment is generally necessary due to growth kinetics or other factors, it may be safely deferred during this current pandemic taken together, certainly, in patients with larger localized renal masses, delays of three to six months appear safe. And so we can let the pandemic evolve before we need to worry about intervening on these patients.

Zachary Klaassen: So we're moving on to locally advanced kidney cancer. So these are the T3 and higher kidney cancers. And really the impact of delayed intervention for these patients is unknown because typically we expedite these patients for surgery. As part of this collaborative review we didn't identify any patients that had data on delay, but we relied on some of the preoperative imaging for assessing obviously tumor thrombus progression. And so we sort of use this as a guide for urgency. So in one study from the Mayo Clinic, they always obtained imaging within four days of surgery, whereas in Berlin, Germany, they obtained imaging within 16 days of surgery. So I think the main take-home from this is that we need updated imaging, but more importantly, we still need to expedite these patients to the operating room mostly because we don't know what the outcomes are for delayed treatment.

Christopher Wallis: So I think Zach summarizes well but the absence of data here shouldn't be reassuring to us. And patients with locally advanced kidney cancer both due to the risk of oncologic progression as well as other complications including bleeding and potentially caval obstruction thrombus patients. These patients should be prioritized for surgical intervention.

Zachary Klaassen: We then looked at cytoreductive nephrectomy in the setting of metastatic kidney cancer. And looking at the SURTIME trial that was published in JAMA Oncology in 2019 they had 99 patients that underwent cytoreductive nephrectomy followed by sunitinib versus sunitinib followed by cytoreductive nephrectomy and their outcome was a 28-week progression-free rate. In the nephrectomy followed by sunitinib arm, this was 42% with a very comparable 43% in the sunitinib followed by cytoreductive nephrectomy arm.

The study that we're all familiar with, the CARMENA trial randomized 450 patients 1:1 to cytoreductive nephrectomy plus sunitinib versus sunitinib alone. And you can see here the median overall survival for the sunitinib alone group was 18.4 months compared to 13.9 months for cytoreductive nephrectomy plus sunitinib. And you can see the hazard ratio of 0.89 for sunitinib alone versus cytoreductive nephrectomy plus sunitinib was non-inferior. So this was a non-inferior trial suggesting that sunitinib alone may be reasonable in select patients.

Christopher Wallis: So taking together these two studies tell us that in patients with cytoreductive nephrectomy upfront systemic therapy should be prioritized over surgery and certainly, in the times of this pandemic we should be reserving cytoreductive nephrectomy for symptomatic patients in the setting of a more palliative approach with surgery rather than oncologically intended cytoreduction.

Zachary Klaassen: We then looked at metastatic renal-cell carcinoma and we did not find a consensus for optimal therapy during the COVID-19 pandemic. And basically the conclusion from our panel was that it's always advisable to rely on guidelines. And certainly, we can see here these are the most up to date European Association of Urology guidelines published in 2019, and for IMDC favorable-risk patients, sunitinib or pazopanib are reasonable. For IMDC intermediate and poor-risk disease, a combination of ipilimumab and nivolumab, or cabozantinib and sunitinib and pazopanib open are all reasonable first-line therapies. So certainly where there's a lack of data, it's always advisable to rely on guidelines, and this is one of the recommendations that we made.

So when we look at metastatic renal-cell carcinoma, IO regimen certainly had outperformed sunitinib with regards to overall survival, but certainly, there may be more severe treatment-related adverse events. Looking a little bit closer at the CheckMate 214 study, this was 1,096 patients randomized 1:1 to nivolumab plus ipilimumab versus sunitinib. And if you look into the details of the adverse events, 436 patients that had nivolumab plus ipilimumab had immune-mediated treatment-related adverse events, and 35% of these patients received high dose glucocorticoids. So really the question is when we're giving these patients nivolumab plus ipilimumab, is this also leading to an increased risk of hospitalization? And is this something that we should be concerned about during the COVID-19 pandemic?

Christopher Wallis: Well, we didn't discuss the data in finer detail, but there's some evidence from single-arm Phase II trials that surveillance of some patients with metastatic renal-cell carcinoma can be considered. And this is particularly in treatment-naïve patients, the favorable- or intermediate-risk disease. However, for patients who do need treatment, there was no strong consensus. Some members of the group felt that VEGF targeted therapies, tyrosine kinase inhibitors, should be preferred at this time due to both the combination of their decreased risk of toxicity related hospitalization as well as their ease of administration with an oral regime as opposed to infusion requiring visits to an infusion center.

Alicia Morgans: Great. Thank you both for another really impressive summary of the data and the group's consensus recommendations. Let's focus on the localized disease patients and put that into context. It sounds like as we might expect, those patients with smaller localized masses can safely wait, but certainly, those patients who have larger masses, it's time to think a little bit more again with scant data in that setting. Now, if you face these patients in your practice, can you give an example, how would you kind of go through this decision process? How do you apply this piece of your recommendation?

Zachary Klaassen: Yeah. I think as you mentioned, there are excellent data out of Toronto, Fox Chase, several centers that surveillance is safe, and particularly in the pandemic setting, this is a strong argument to continue that. And even as we've seen in some small studies, even the clinical T1b and T2 can probably wait a period of time. I think when it comes to prioritizing OR resources across the board for GU oncology, I think a personal recommendation, as well as probably the feeling of most urologic oncologists, is that these T3 IVC renal vein thrombus patients, these are the ones that need to be expedited probably as high as anybody that we operate on a daily basis. So I saw a patient with a renal vein thrombus several weeks ago, just kind of at the beginning of the pandemic. And I had him on the operating table within about two weeks. And I think that's a reasonable and safe recommendation in the sense that we're balancing the risk of delayed treatment with the risk of COVID-19 infections. So I don't know if Chris you want to elaborate on that anymore.

Christopher Wallis: Yeah, so our current practice is that essentially large kidney masses and muscle-invasive bladder cancer make up the majority of what we're operating on right now. And so these patients fall into the category where most urologic oncologists want to proceed with surgery in part due to the sort of fear of the unknown and the risks that we don't really have an ability to counsel these patients on what may happen if we don't proceed.

Alicia Morgans: True. And we also don't know when things are going to get dramatically better from the COVID-19 situation. And so we do have to select those patients who need to be treated now, prioritize them, get them in because their opportunity may even be more challenging or there may be fewer opportunities in the future. So really good to have a strong recommendation to monitor those small lesions, and to use your best judgment and really prioritize for surgical procedures as T3 and those patients with the thrombus.

So thinking about metastatic disease a little bit, I'm grateful to know that the CARMENA trial has helped to inform this and really seems to have informed your guidelines. Just thinking about that, are you at this point still operating on patients with metastatic disease outside of COVID? Has that changed in really implementing the CARMENA data now that COVID is here, or is that something that changed and was really part of your practice before COVID-19 came into play?

Zachary Klaassen: Yeah, I think that certainly be for the COVID pandemic, and definitely now, these are always ... or they've become multidisciplinary discussions for each patient that we get. And whereas before CARMENA, we may have just said, "They are at good performance status. They're 55 years old, we're going to operate on them, and then we'll treat them subsequently." These have really become multidisciplinary discussions for each patient. And I think that's even more apparent going forward with the current situation.

Christopher Wallis: I would say that I think the role of cytoreductive nephrectomy has diminished as a result of the publication of the CARMENA trial. I would say it's less frequently done, but I would say that across all of GU oncology certainly, but I would say probably across all of health care, the current pandemic has really led to some soul searching about how we prioritize and who we prioritize. And so I think it's potentially helpful in helping us accelerate the movement towards non-interventional approaches for patients who are likely to derive minimal benefit from intervention. So this goes in small renal masses, this goes in low-risk prostate cancer, but I think it also applies in these patients with metastatic kidney cancer.

One thing I would note, and we have certainly performed a number of nephrectomies individually in metastatic disease in the last little while, is that within the CARMENA trial, there's a relatively large proportion of palliative nephrectomy in the arm that was not randomized to cytoreduction. And so I don't think that's going to go away, especially in patients with larger masses and or some degree of thrombus. The need for a palliative nephrectomy without real cytoreductive intent will remain.

Alicia Morgans: That's a great point and it's certainly something that should still be considered in the care of these patients for sure. And then just one final point as we move on, I think it was really interesting the comment that the group of expert opinion put together regarding using ipi/nivo strategies or these immune-related strategies versus VEGF targeted therapies and the thought about the need for potential hospitalization and high dose steroids. And I recognize that that was not a strong recommendation but it was really something that I think we should all consider. And I'm just curious if you have any comments on that because I do think it's important for people to think about that as they're making these decisions that include so many different facets.

Zachary Klaassen: Yeah, I think that's a great point, Alicia. I think when you look at such a broad scope for a paper like this when there's not a lot of evidence, you rely on your expert opinions and you rely on digging into the nuances of data and basically the experiences of medical oncologists. And I think specifically with the targeted therapy versus immunotherapy regimens where there may be a little bit of a ... where there is a decrease in efficacy, perhaps that's maybe traded at least during this time, during the pandemic versus your risk of adverse events. And I think that's where some of these discussions and recommendations play out here.

Alicia Morgans: Great. Well, thank you for that explanation and for that tour of renal-cell carcinoma. I appreciate the time that you've both given today. Thank you.

Zachary Klaassen: Super. Thanks, Alicia.