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 in 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 a Journal Club, we're going to move onto the question of the impact of delays in treatment of patients with testicular and penile cancer during the COVID-19 pandemic, as well as providing some guidance for the management of these patients. By way of brief background, some testicular cancer epidemiology. In 2018 worldwide, there were just over 70,000 new diagnoses of testicular cancer and just under 10,000 deaths attributable to the disease. A majority of these patients presented with localized disease, at least in the U.S. The 63% localized disease according to SEER data, 12% regional and 12% metastatic disease. Of note, the majority of patients who are diagnosed with testicular cancer are Caucasian, and thus the burden of this disease differs across the world.

Zachary Klaassen: So in terms of the management of localized disease, there definitely is a paucity literature on delaying orchiectomy. The surgical dogma going back decades among urological oncologists is that [5:30] the sun never sets on it on a testis mass, and certainly, there's no data to suggest that we should be delaying these patients. And so the recommendation really is to proceed with a radical orchiectomy as soon as possible.

There's a lot of data on the management of clinical stage I germ cell tumors. A recent publication, European Urology, gave a very strong recommendation for active surveillance among these patients, and certainly, this has been corroborated from studies from the University of Toronto at the Princess Margaret Cancer Center. And so active surveillance, at least during the pandemic, is a standard of care.

In terms of the role of retroperitoneal lymph node dissection... Similar to orchiectomy, there are no studies assessing the effect of delay for these patients. When we're looking at nonseminomatous germ cell tumors, certainly chemotherapy is the preferred initial approach for a clinical node-positive disease.

However, what happens in the patients, if we delay post-chemo RPLND for masses more than one centimeters unknown. Certainly, the post-chemo mass is less than one centimeter. We typically will observe. However, there is no data to suggest the ramifications of delaying a post-chemo RPLND for the patients that have masses more than one centimeter.

Looking at advanced germ cell tumors. Certainly the medical oncologist on our panel, we're strongly for timely chemotherapy, especially for these patients that have IGCCCG intermediate and poor-risk features. Similarly to that, there were strong recommendations for not delaying salvage treatment for these patients. Certainly, it's likely that stage two seminoma and good prognosis non-seminoma germ cell tumors may delay systemic therapy. The exact timing of this is somewhat unknown, so this is something that probably will continue to evolve depending on the length of the pandemic.

Christopher Wallis: When we put these data together, I think in general we can conclude despite the absence of data that surgical delays in patients with newly diagnosed testicular masses should not be undertaken. While we don't potentially have to operate on them the same day as Zach alluded to, expedient treatment, certainly within the order of a few days to a week, should be prioritized. We should also consider that the burden on the healthcare system is likely minimal from doing this as these are same-day surgeries that can be easily managed on an outpatient basis. For most patients with clinical stage I, testis cancer surveillance should be the preferred approach in adjuvant therapies certainly during the time of the pandemic can be reasonably withheld.

With respect to more advanced testicular cancer, there is a paucity of data to guide management. Patients who have intermediate poor prognosis disease were recommended to proceed chemotherapy without delay on the basis of expert opinion, but without real data underpinning any harms due to the delay.

We're now going to pivot from testicular cancer to look at penile cancer. This is an uncommon, although often relatively severe, disease. It's categorized as an orphan disease and accounts for nearly 35,000 new cases worldwide in 2018 and 15,000 deaths. The proportion of mortality here is relatively high underpinning the potential severity and often delayed diagnosis associated with this condition. It is much more common in developing as opposed to developed countries. And so, as we alluded to with testicular cancer, the burden of this disease may be disparately shared around the globe.

Zachary Klaassen: So looking at the management of the primary disease, there are no studies assessing the effect of delayed partial, total, or radical penectomy. Much like testis masses, these patients are rather expeditiously taken to the operating room and treated within a short period of time. Certainly, there is delays between the initial appearance of a penile lesion and when patients actually seek their first consultation. It's well known that there's certainly a social stigma that's common with penile cancer likely leading to these delays. There was a single center study out of Italy that looked at 113 patients and they found that there was a 53 day delay between the first appearance of the penile lesion and first consultation.

Looking at the management of the inguinal nodes, we relied on the guidance of the European Association of Urology guidelines for penile cancer from 2014, and from these guidelines, there's a strong recommendation for modified inguinal lymphadenectomy or a dynamic sentinel-node biopsy. These are for patients that are intermediate- or high-risk tumors and non-palpable inguinal nodes.

We actually did find a paper looking at the effect of treatment delay for patients that require an inguinal lymphadenectomy, and this is data out of one of the Penile Cancer Centers of Excellence in the world and Moffitt Cancer Center led by Phil Spiess. They operationalized their delay as greater than three months and less than three months. They had 33 patients that underwent an inguinal lymphadenectomy more than three months after treatment of the primary and 51 patients less than three months after treatment of the primary. These patients were followed for a median of 21 months.

You can see from there, two outcomes, recurrence-free survival at five years, and five-year disease-free survival. That early inguinal lymphadenectomy certainly was associated with better outcomes. Looking at five-year RFS, early inguinal lymphadenectomy had a 77% rate versus 37.8% in the delayed group. And similarly, for a five-year DFS, early inguinal lymphadenectomy had a rate of 64.1% compared to 39.5% in the delayed group.

Christopher Wallis: Taking this together in the context of COVID-19 with respect to the management of penile cancer, it's difficult to rely on data for the management of the primary tumor. But the group recommended avoiding delays in primary surgery given the rarity of the disease, the symptomatic burden of the primary tumor, and the high risk of metastatic progression. With respect to immoral node dissection, where it's indicated according to guidelines, there's evidence of a harm when delays more than three months are undertaken. And so the group felt that a single node dissection should be undertaken within three months of the initial diagnosis and treatment of the primary lesion.

Alicia Morgans: So thank you both again for another review, this time of testicular and penile cancer. The bottom line from your recommendations from the review of the literature seems clear and is certainly a clinical principle of both of these diseases: get these patients to the OR expeditiously. These are the patients, some of the patients that we need to prioritize. Am I understanding your conclusions correctly?

Zachary Klaassen: Yeah, definitely, Alicia. I think a lot of these patients will be seen in tertiary referral centers, particularly with regards to RPLNDs and inguinal lymph node dissections for testis and penile cancer, respectively. Other than the one study by Phil Spiess's group at Moffitt, there really it's really clinical principles that are guiding us more than anything. And basically the recommendations were based on the fact that these patients certainly have a decent amount to lose from delays of particularly when it comes to the management of advanced testis cancer and advanced penile cancer.

Christopher Wallis: I think I would highlight maybe two exceptions to that. Number one is to highlight the importance of surveillance both generally and particularly in the pandemic for patients with clinical stage I testis cancer. So while we are expediently treating the primary testicular mass, the role of adjuvant therapy should be avoided I think, in general in this setting. And then consideration of when to initiate systemic therapy for patients with good-risk metastatic testicular cancer. So those are the only two areas where I think we can entertain somewhat more cautious intervention in the remainder of the case. I think the underlying oncologic and surgical principle of moving forward predominated given the absence of data.

Zachary Klaassen: Yeah, absolutely. Good point, Chris.

Alicia Morgans: And to emphasize what you alluded to there, that those patients who need chemotherapy should proceed with chemotherapy. I definitely have had these considerations, discussions and management issues in my own practice and have moved forward every time, thankfully consistent with your guidance. But we don't actually have a lot of choice in those situations. I'm glad to see that your guidelines support that practice. And I imagine that there was pretty significant consensus among the medical oncologists on the team.

Zachary Klaassen: Yeah, absolutely. They definitely had strong consensus in this area, for sure. I think and especially these young patients for testis cancer, there's a psychological burden. I know that you and I both have similar interests when it comes to that, Alicia. And certainly, we know how these patients are and I think especially in first-line treatment for them, it's important to keep the ball rolling towards what they need.

Alicia Morgans: Absolutely. Well, I thank you both for your discussions, your review of the data in the first place, and then discussions of your consensus guidance on testicular and penile cancer. Thank you very much for your time.

Zachary Klaassen: Thanks, Alicia.

Christopher Wallis: Thanks.