The Impact of Treatment Delays on Prostate Cancer During the COVID-19 Pandemic - Zach Klaassen & Chris Wallis
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 is a Urology Resident at the University of Toronto. He obtained his Doctor of Medicine from the University of British Columbia and his Doctor of Philosophy in Clinical Epidemiology and Health Care Research from the Institute of Health Policy, Management, and Evaluation at the University of Toronto.
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. 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. 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.
In order to do this, we had to forego 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. Just a little bit of background on the COVID-19 pandemic. There is certainly a heavy demand for resources across the country and across the world these days. This is exacerbated by limited health system capacity and overwhelmed hospitals. 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 exacerbated in the US and vice versa? Because of this medical governing bodies across the world have recommended re-prioritizing surgical cases. 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.
Certainly at the epicenter of this is balancing the risk of COVID-19 infection versus the risk of delayed surgery. I know in both of our experiences there are certain oncology cases that should wait and should not wait, and this sort of is a part of the surgical aspect of this article in European Urology. It seems like almost daily there's 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've presented. 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.
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. In their 1,591 patients with COVID in the ICUs, had a median age of 63 years. Eighty-two percent 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%. Unfortunately, with longer follow-up, that number will probably go higher.
The objective of this Journal Club today discussing this paper in European Urology was to assess the impact of delayed treatment of prostate cancer during the COVID-19 pandemic and to provide guidance for triage and management. Just with regards to a brief epidemiology review of prostate cancer, in 2018, almost 1.3 million new diagnoses of prostate cancer were made worldwide resulting in 359,000 deaths. In terms of stage distribution coming from the SEER database in the US, localized prostate cancer makes up 78%, regional 12%, and metastatic 5%. Certainly, as we've mentioned before, patients at risk of COVID-19 are very comparable to the prostate cancer population and that many are male... Excuse me, all of them are male. A lot of them are hypertensive and more than one comorbidity is quite common.
Christopher Wallis: When we look to provide both an assessment of the literature and guidance to clinicians, it's clear obviously that prostate cancer is not a homogenous disease. We took this in a standard risk-adapted approach and first focused on low-risk disease. We'll review here some of the seminal studies that informed our thinking and then go over the conclusions and how we integrated these. Active surveillance has become the standard management of patients with low-risk prostate cancer based in large part on the work from Dr. Klotz in Toronto.
This is a long-term followup with his cohort of nearly a thousand men with low or intermediate-risk prostate cancer who underwent surveillance. The key here is that over long-term followup, over 15 years, rates to metastasis and prostate cancer-specific mortality are very low. As a result of that, the American Society of Clinical Oncology clinical practice guidelines have recommended accuracy as the recommended approach for all patients with low-risk disease. Given that this is a conclusion that's valid prior to the COVID pandemic, there's no reason why we would change it during this time. If anything, it reinforces the importance of non-interventional management in these patients. However, going back to Dr. Klotz's paper, we can see that metastasis-free survival is much lower among patients with intermediate-risk disease. It tells us that we need to think differently about these patients.
Moving forward, we have a number of informative studies. This one coming from Johns Hopkins looked at the effects of delays between diagnosis and radical prostatectomy in patients with intermediate and high-risk disease. In their cohort of 2,300 men, they compared those who received radical prostatectomy in the first three months following their diagnosis to those who were treated between three and six months after diagnosis. Very few patients in this cohort were treated after six months after diagnosis and so they didn't include those in their analysis. Of note: all patients in this cohort were treatment-naïve at the time of radical prostatectomy, that is they didn't receive any neoadjuvant treatments.
The authors looked at pathologic outcomes, including margin status and T stage, as well as recurrence and metastasis. When they stratified their analysis according to the histologic Gleason grade, they found no differences in pathologic outcomes, biochemical recurrence related outcomes, and in metastasis-free survival, whether patients were treated with radical prostatectomy in the first three months after diagnosis or whether they are treated between three and six months after diagnosis.
Looking at even longer intervals, the group from San Raffaele in Italy looked at just over 2,600 patients that underwent radical prostatectomy at their institution. Here, rather than categorizing it as the Johns Hopkins group did, they looked at a more linear approach and assessed the association between the time from diagnosis to radical prostatectomy and both biochemical and clinical recurrence outcomes. You can see in these figures, first in the top left, this is the overall population, and then more informatively, fields B, C, and D give you the relationship between biochemical recurrence following time from diagnosis to radical prostatectomy on the basis of risk strata. B and C both demonstrated that for patients with low- and intermediate-risk disease, there's very little relationship between the duration between diagnosis and surgery and final recurrence outcomes.
There is however a relationship as you can see in the bottom right for patients who have high-risk disease. The inflection point here appears to be around 12 months. Right around here we see an upward inflection of the curve indicating that patients who waited more than 12 months between the diagnosis and treatment of high-risk disease had an increased risk of biochemical recurrence and outcomes for clinical recurrence mirrored these.
I alluded to this before but in both of those studies as well as the remainder of the literature we reviewed, patients who were characterized on their time from diagnosis to radical prostatectomy did not receive any treatment in that time. We know that a number of randomized controlled trials have assessed the role of neoadjuvant androgen deprivation. For the most part, this has been not utilized on the basis of no difference in survival outcomes. In the absence of the pandemic, we view these data suggesting that delays to surgery with ADT in the meantime do not improve outcomes. However, I think in the current practice environment we can view it a little bit differently. We can potentially see these data as indicating that the use of androgen deprivation can lead to equivalent outcomes with surgery three or six months down the road even for patients with high-risk disease. However, I need to emphasize that the role of neoadjuvant ADT was a relatively controversial topic amongst the consensus panel with some members feeling that it was inadvisable on the basis of this data presented for you right here and others utilizing this quite routinely in their practice.
We then moved on to the question of what do we do for patients with biochemical recurrence? The new evidence from RADICALS and RAVES, which has been presented but not yet published, demonstrates that early salvage radiotherapy is at least equivalent to adjuvant radiotherapy. The role of adjuvant radiation is diminishing in general and certainly in the time of this pandemic should not be prioritized.
Finally, wrapping up our section on localized prostate cancer, we assess the question of the use of radiotherapy at this time. One of the more informative studies is this recent systematic review of prostate hypofractionation and assessing just over 8,000 men across 10 randomized trials. They found that compared with conventionally fractionated regimes, oncologic and toxicity outcomes are equivalent. This suggests that especially in a resource-strained environment and when we're trying to reduce our patient's exposure to the healthcare system, prostate hypofractionation may give equivalent outcomes for our patients from a prostate cancer treatment perspective while diminishing their risk of infectious complications.
For patients opting for radiotherapy in the tumor, they're localized prostate cancer, there's also good evidence, and this is one of many studies, demonstrating that neoadjuvant ADT provides a benefit. In the 9601 trial, six months of neoadjuvant ADT had improved distant progression, prostate cancer-specific mortality, and overall survival compared to radiation therapy alone, while three months of neoadjuvant ADT did not give such a large benefit.
Zachary Klaassen: Great. To summarize localized prostate cancer from our paper in European Urology, patients with low-risk prostate cancer should not receive active surveillance. As Chris mentioned, this is standard of care in non-pandemic times and certainly should be during the time of the COVID-19 pandemic. Second, patients with intermediate-risk and high-risk prostate cancer may safely defer treatment for three to six months. Finally, patients optimizing for radiotherapy should receive neoadjuvant ADT, as well as hypofractionated regimens.
Christopher Wallis: We then moved from localized prostate cancer to consider the management of patients with metastatic prostate cancer. Unlike the data we've just reviewed, there's very little here to guide decision-making. This is based more on clinical principles than on underlying data. However, the group felt that androgen receptive targeting agents, including abiraterone, enzalutamide, apalutamide, may be preferable to docetaxel due to two factors. First, the oral administration, which avoids the need for hospital visits, as well as the decreased risk of neutropenia. In considering the question of how to administer ADT, the group felt it was clear that longer formulations, three-, four-, six-month formulations of ADT, will be preferable to monthly injections were feasible at the present time.
Alicia Morgans: Great. Thank you so much for reviewing all of that data. I think it would be good just to dig into a couple areas and to see how you really bring this into practice. If you have a patient with say high-risk localized disease, you are sure from your imaging that the patient does not appear to have any metastatic disease, and you are in a setting where there is a current shortage of operating rooms because the COVID-19 pandemic is really hitting hard in that particular area at this time, it does sound like it's safe to go for three to six months before having to move forward. Can you comment a little bit on that and how that may evolve as we potentially are going through wave one and maybe a wave in the future?
I mean, how are you thinking about timing this and how this would work in terms of operationalizing it? For those high-risk patients, are you using neoadjuvant ADT at this point? Is that something that there's a soft recommendation as you mentioned, or is that people are doing more regularly?
Christopher Wallis: I think the question of neoadjuvant ADT varies, but I think you take a step back and first have the same discussion you'd have with your patient with this new diagnosis regardless of the pandemic. That's to consider the treatment options. We know that primary ADT is not the way forward, but local therapy should be considered. We need to prepare our patients for the idea that this is likely a multimodal treatment approach that's going to be required and either surgery or radiation can play the sort of core foundation in that. The standard discussion we have regarding the role of radical prostatectomy or radiation with androgen deprivation as the initial treatment of patients with high-risk localized disease I think needs to form the basis of the discussion.
Then when patients have sort of formulated their feelings on which treatment approach seems most suitable for them, we can then potentially add the nuance of how to manage that within the COVID pandemic. I do think that there's perhaps a slight preference for radiotherapy at this time, especially in places where there are OR resource limitations. Although it isn't entirely clear to me, especially in prostate cancer where radical prostatectomy is a one-day hospital stay, how the overall balance of healthcare resource utilization lies between radical prostatectomy and radiotherapy, which will require at least five fractions if extremely hypofractionated and potentially many more.
The question of neoadjuvant ADT I think varies geographically. I think the British associations have come out with some soft recommendations in favor, others have come out against, essentially reemphasizing the absence of data that we discussed or the absence of benefit in the data that we discussed before. But I think it's a case by case basis and I certainly don't think that there's a clinical principle that should tell us that if we're considering neoadjuvant ADT before radiation that a patient should suddenly no longer be eligible for radical prostatectomy just because we're initiating ADT in order to delay their local therapy.
Zachary Klaassen: I think to dovetail off of Chris' excellent explanation, I think as you mentioned, Alicia, we may be in phase one or wave one, possibly another wave coming in fall. I think the overarching theme with stratifying patients and utilizing resources is if a certain area gets into a position where there are resources available, really prioritizing those patients. I've certainly seen that in my own practice whereas we hopefully go into the summer months at least here in the Southern US and hoping for a little bit of a reprieve, really looking at the patients that would benefit from being moved up and utilizing that time for these high-risk patients.
Certainly what Chris said about at least at this point the unknown risk-benefit ratio of a one-day hospitalization stay after radical prostatectomy versus several visits to the medical facility for or hypofractionated radiation therapy. I think these are all things that will continue to evolve, especially if we move into a second wave down the road.
Alicia Morgans: But really helpful I think to examine the data and put some folks' mind at ease that even intermediate and high-risk patients may have similar outcomes if they are in need to defer for three to six months. I think that is really important to know. Of course, we always encourage those patients who are potential candidates for active surveillance to go that route as well. In terms of metastatic prostate cancer, it's good for us to have some guidance on that too. I think that in the medical oncology community, at least, we talk a little bit about trying to avoid treatments that cause neutropenia in the instance where we have a choice.
We don't always have choices, but I think it's really important to put into print and put into guidelines that this is something that has been considered by an expert panel and is the recommendation that avoiding cytotoxic agents that may cause neutropenia and increase the likelihood that a patient is not going to be able to potentially recover from a COVID-19 infection as rapidly as they normally would. That's an important piece. Any comments there on putting that together? I bet that was hard given the lack of data or maybe it's not because it's pretty common sense too?
Zachary Klaassen: Yeah. Both Chris and I being urologists we had some excellent medical oncologists on our panel and I think we derived a lot of the recommendations from an excellent table that we've included put together by Tom Powles and Silke Gillessen who are co-authors and really sort of looking at several instances of should we delay first-line therapy and generally the answer was no, we shouldn't if we can avoid it. Certainly specific to prostate cancer, if there's an equivalent oral medication that may be replaced or at least not replaced, but defer docetaxel or cabazitaxel at this point in time, as you mentioned, with the neutropenia and everything else that goes along with chemotherapy.
Certainly, those were more expert opinion than guideline just because we don't have data on delays in these situations because we usually don't delay. I think it's the beauty of having a multidisciplinary panel for these situations.
Alicia Morgans: I completely agree. Just as we wrap up, any closing thoughts or just sort of summary for the entire prostate cancer section that you'd like to leave the audience with?
Christopher Wallis: To me, reviewing this literature was actually very reassuring. I think making a prostate cancer diagnosis, making any cancer diagnosis is not anything that a physician takes lightly and is certainly often associated with a significant burden of anxiety for patients, but I think the literature and prostate cancer, in particular, is quite reassuring that we can both reassure ourselves and our patients that delays are reasonably safe and we can give ourselves a window to sort out how things are going to evolve and proceed with the COVID pandemic without compromising the long-term outcomes of our patients with prostate cancer.
Alicia Morgans: Great. Well, I agree with you. I appreciate the guidance that your team has put together and put together so quickly. I appreciate your time today. Thank you.
Zachary Klaassen: Thank you, Alicia.
Christopher Wallis: Thanks a lot.