Impact on Bladder Cancer of Treatment Delays During the COVID-19 Pandemic - Zachary Klaassen & Christopher J. D. Wallis
Zachary Klaassen and Christopher Wallis join Alicia Morgans to discuss the management guide released by European Urology on how to best optimize the care of patients with GU malignancies during the COVID-19 pandemic. In this Journal Club, Dr. Klaassen and Dr. Wallis assess the impact of delayed treatment of bladder cancer.
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center
Christopher J.D. Wallis, MD, PhD, Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee
Alicia Morgans, MD, MPH, Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
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.
So, the objective of this Journal Club was to assess the impact of delayed treatment of bladder cancer during the COVID-19 pandemic and provide guidance for triage and management of these patients.
By way of brief epidemiology for bladder cancer in 2018 would be 549,000 new diagnoses worldwide leading to 199,000 deaths. Looking at the SEER data for stage in the United States, 47% of these will be stage I patients, 11% of these will be stage II, and a handful of these will be a stage III and IV. Certainly, with regards to patients that are at risk of COVID- 19 these are very comparable to the bladder cancer population in that they're often male, hypertensive, and patients with multiple comorbidities.
Christopher Wallis: As with the other disease sites, we took an approach based on tumor stage and grade. And in prostate cancer looked at low-, medium- and high-risk. In kidney cancer, we looked at a localized, locally-advanced, and metastatic. And here we looked at low-grade non-muscle invasive, high-grade non-muscle invasive, muscle-invasive, and then advanced bladder cancer. And we were fortunate to have the risk-adaptive management of low-grade bladder cancer tumor recommendations from the international bladder cancer group, which were published just as we were putting together our review. And so, this was a scoping review of randomized controlled trials, previous reviews, guidelines, and meta-analyses. The key takeaway from this paper, and I think our view of how we manage low-grade non-muscle invasive of bladder cancer is that this disease has a relatively indolent natural history and long-term bladder cancer-specific mortality for these patients is very, very low.
As a result, we can consider a more expectant management approach and Dr. Soloway was among the first to describe this with expected management of small Ta or T1 low-grade bladder tumors. In observing 32 patients, he found no evidence of disease progression that is no muscle invasion with observation.
With respect to high-grade non-muscle invasive bladder cancer, this is certainly a different beast. And so, we initially formed our background views on this on the basis of a recent, systematic review looking at a T1 high-grade bladder cancer. And this systematic review showed that rates of progression in bladder cancer-specific mortality are significant in this population, even without muscle invasion and therefore we felt that a more invasive investigation and treatment was warranted in these patients than in those with low-grade disease.
And I think all urologists know the pioneering work of Dr. Morales looking at intravesical BCG and the treatment of bladder cancer. Certainly, the rates of recurrence and arguably progression are improved with BCG. And so, this is now the Lamm paper, which is similarly famous looking at maintenance BCG and showing reductions in recurrences, and somewhat less profound improvements in survival.
When considering the treatment of patients with high-grade disease, we also need to consider the surgical questions of re-resection. And so, this is a recent systematic review published in European Urology assessing the role of re-resection. And so, certainly, the initial pathology can give us some guidance on how informative and how necessary re-resection is in a residual tumor, depending on the primary literature cited, is present in somewhere between 17 and 71% of all re-resections with some variation on the basis of the underlying disease. Slightly lower rates in patients who have Ta and slightly higher and those who have T1. But more notably muscle invasion is detected in 8% of patients who were initially deemed to have Ta disease, and 32% of those initially deemed to have T1 disease. And notably, if muscle was not included in the initial resection these rates go even higher. Independent of the pathology, re-resection has been associated with lower bladder cancer recurrence rates.
Zachary Klaassen: So, the non-muscle invasive disease summary is quite extensive in the sense that this is a large proportion of the bladder cancer patients that we see on a daily basis. And, certainly, having a way of stratifying these patients is important. So, we find that the management of low-grade non-muscle invasive bladder cancer may be safely deferred, especially during the time of the pandemic. And I think that's important, not just because it's safe, but also because we need to save these resources for the higher risks patients. And, certainly, patients with high-grade non-muscle invasive bladder cancers should receive at least induction, and one maintenance course of BCG. And, certainly, this may be a fluid recommendation as the pandemic may drag on, or we see second waves of the pandemic. But at least for this initial triaging of patients, this is the recommendation of the panel for our paper.
And, finally, re-resection can be considered on a case-by-case basis. What is particularly valuable in those patients with pT1 disease or no muscle in the original specimen. So, similar to non-pandemic times when you have a T1 patient without muscle in the specimen, particularly a re-resection should be considered.
Christopher Wallis: We then moved from non-muscle invasive disease to consider muscle-invasive bladder cancer. And this is one of the areas in which the data on delays to treatment are relatively robust and while there's obviously no randomized controlled trials here to inform us there's a wealth of observational data. And, relatively recently, Dr. Russell and colleagues published a systematic review in European Urology Oncology assessing 19 studies in 17 and a half thousand patients. And they asked the question, what is the association between the time to cystectomy and survival outcomes in patients with muscle-invasive bladder cancer?
And so, they operationalize time to cystectomy in a few different ways. And this is the first way looking at time from the initial diagnosis to radical cystectomy. And when they included three studies and pooled these results, they found a significantly worsened survival rate for patients who had longer delays.
They then operationalized this as looking at the time from TURBT to radical cystectomy. And, conceptually, these may overlap somewhat, but studies have operationalized it a bit differently. So, in order to decrease heterogeneity, they pooled them separately. And among the five studies assessing this question, again, we found a significant worsening of survival in patients who had longer durations between their TURBT and their radical cystectomy.
And finally, among patients who underwent neoadjuvant chemotherapy, they looked at the duration of time from the end of neoadjuvant chemotherapy to radical cystectomy. And here there were three studies they drew upon, and the effect was much smaller than in the other two pooled analyses. And in this time was not significant. Taken together, the literature I think would suggest that there's harm that may befall patients when we delay radical cystectomy, certainly, more than 90 days following the diagnosis of muscle invasion.
Now, those studies predominantly focused on patients with urothelial histology. And so, relatively recently a paper has come out looking at the impact of time to cystectomy for patients who have a variant histology. And this paper from USC looked at 363 patients, who had a clinical T2 to T4 bladder cancer, who underwent radical cystectomy without perioperative chemotherapy. Approximately 80 of the 360 patients had variant histology, and among those patients, after accounting for other patient factors, as well as disease factors, delays beyond 12 weeks from diagnosis to cystectomy were associated with worse survival in patients with variant histology.
Zachary Klaassen: So, much like non-muscle invasive bladder cancer there's a lot of nuances to muscle-invasive bladder cancer. And, certainly, this is a cohort of patients across the GU oncology spectrum that when we're talking about triaging patients, and prioritizing patients for the operating room this is arguably one of the most important groups of patients. So, our recommendations, in summary, was that delays of up to 12 weeks before cystectomy may be safe for patients with muscle-invasive bladder cancer. And secondly, the oncological principles, including the importance of neoadjuvant chemotherapy, should be considered at this time while acknowledging the risks of neutropenia. And finally, not specifically addressed here, but similar to the resources for cystectomy and the waiting period we've seen lots of data over the last five or six years looking at tri-modal therapy and this may be considered based on patient and hospital factors as well.
Christopher Wallis: Then, moved to advanced and metastatic bladder cancer. And, again, we had no real data to draw on to guide whether delays here would be safe, but relying on the principals from the treatment of patients with muscle-invasive disease, the group felt that proceeding with first-line treatment was warranted during this time. And cytotoxic chemotherapy remained the preferred approach for the majority of patients. A number of members of the panel felt that a regime comprising gemcitabine-cisplatin should be preferred over MVAC due to the lower risks of neutropenia. Immune checkpoint inhibitors, certainly, can be considered, particularly, in patients with PD-L1 positive disease, although there is the risk that was discussed in the kidney cancer session on immune-related adverse events that should be considered.
Anecdotally, some of the medical oncologists in our group noted that there was some reticence on both the part of the patients and healthcare professionals to start immune therapy during this time, but evidence really to speak against these approaches is lacking. And so, the group felt that an individualized approach should be used, weighing the risk of cytotoxic chemotherapy and associated neutropenia against the toxicity of immune checkpoint inhibitors.
Alicia Morgans: So, thank you both for that. Quite another long, and quite comprehensive review of what we need to think about when we see patients with urothelial carcinoma. Just starting with those patients with non-muscle invasive disease, I think it's really good for everyone to feel like the data's been reviewed and that there is some safety in really kind of looking at those patients with low-grade non-muscle invasive disease and observing them. And when we get into high-grade disease, I think that it can be, obviously, observation is not something that we want to do, and the data doesn't suggest that's the right thing to get to do. So, again, really important that the group was able to come forward with recommendations on that.
Similarly to the way we've talked about other sections, how do you operationalize this if you are moving forward with induction are there specific concerns about BCG in the era of COVID-19? Is that something that the group discussed and reviewed in this consensus paper?
Christopher Wallis: Oh, I think, it's interesting unlike most of the oncology treatments we're considering there's actually some suggestion that BCG may enhance an antibody response to COVID-19. And so, there may, in that respect, be some benefit from the use of BCG. And, certainly, there are ongoing trials assessing systemic treatments with BCG on whether these may be beneficial in patients either with COVID-19 or at risk of COVID-19.
I think it more fell to a question of a resource utilization rather than any harms of the treatment. And that's where the group felt that the induction course of BCG and the first maintenance course was the most beneficial, and provided the greatest incremental gain. Whereas ongoing maintenance after that, while guideline concordance certainly recommended under most circumstances probably provided a smaller incremental gain. And so, we should be, where necessary, prioritizing that upfront initial BCG course.
Zachary Klaassen: And I think from a surgical standpoint there is arguably no patients that can suffer harm more than the under staged or the poorly staged urothelial carcinoma of the bladder patient. And I think from a practical standpoint when we're looking at utilization of resources there's something to be said for a cystectomy patient that may be in the hospital for five to seven days. But if you're trying to accurately stage and, essentially, prepare for treatment a high-risk non-muscle invasive patient a TURBT, or a repeat TURBT are often performed on an outpatient basis. And so, I think taken together these high-risk non muscle invasive patients, certainly, are some of the higher priorities in terms of stratification of OR utilization.
Alicia Morgans: Great and important for everyone to understand. And as we think about OR utilization, I'm very glad too that the group reviewed the need to go back for re-resection because this is something that's a key principle of understanding muscle-invasive bladder cancer, if you go in and have a specimen that does not actually have muscle on the specimen it's really important to go back, even in the setting of COVID-19. And so, again, I think that's really important that was pointed out and that the data was reviewed. Was there a lot of controversy on that particular issue? Or that seems like something there would be quite a bit of consensus around?
Christopher Wallis: Yeah, I think the question of re-resection was fairly clear. I think most of the group felt that the re-resection was warranted, particularly in patients with T1 disease and those without muscle. Where patients had high-grade Ta with muscle in the specimen the group felt a little less strongly that re-resection was I warranted. But, overall, I think the idea of reaffirming the underlying oncologic principle here came through for most people.
Alicia Morgans: Great. Well, the other thing that was touched upon, but I imagine there might have been more controversy than the last issue is the idea of neoadjuvant chemotherapy. So, certainly, acknowledging the risks of neutropenia, also acknowledging, I think, the risk of making sure that we take adequate care of the cancer, timing, whether it's neoadjuvant or whether it's adjuvant, was this an area of discussion within the group?
Christopher Wallis: Yeah, it definitely was. And so, some members of the group felt that we should be prioritizing the single treatment, which offered the greatest incremental benefit and, obviously, surgeons in the room felt that that would be radical cystectomy. In the end, most of the group felt that we should be offering the best oncologic treatment to these patients given that they're high risk of progression and bladder cancer-specific mortality. And so, that's why we reaffirmed the overarching oncologic principle in the management of bladder cancer being the neoadjuvant chemotherapy where possible, and reasonable based on histology and patient factors should be often qualitative cystectomy.
A number of the medical oncologists in the group felt that adjuvant chemotherapy, given the lack of proven survival benefit, and risks of neutropenia, and infectious-related complications, should not be undertaken during this pandemic period. But that neoadjuvant did remain a strong consideration where feasible.
Zachary Klaassen: Yeah. I think one of the big things that we're going to have to look at going forward, especially if the first wave of the pandemic continues, or we get a subsequent wave in the fall is really the cystectomy patients. These are resource-intensive patients, they're all high-risk for no only perioperative complications that we all know about but, certainly, COVID-19 infection risk. And so, I think these patients during a downtime, let's say, in between waves of the virus are going to be probably expedited for the operating room just because of them the implications of delaying cystectomy. But also, when resources are a little more available, really making use of those resources.
Alicia Morgans: Well, again, I thank you for this extensive review. I think this really underscores, particularly in muscle-invasive disease and in more advanced disease, the importance of multidisciplinary care that we need to get ourselves together in our virtual tumor boards. Or, at least, have our conversations with our colleagues, whether we're in-person or not. And, certainly, appreciate the guidance that you and the team have put together for this particular issue on bladder cancer. Thank you.
Christopher Wallis: Our pleasure.
Zachary Klaassen: Thanks.