Read the Full Video Transcript

Zachary Klaassen: Hello, and welcome to this UroToday discussion of the NCCN Clinical Practice Guidelines in Oncology, with a focus on prostate cancer. And specifically today we are going to be discussing Observation and Active Surveillance. My name is Zach Klaassen, I'm an Assistant Professor in the Division of Urology at the Medical College of Georgia. And joining me is Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto. Today, we're going to discuss Observation and Active Surveillance. The Active Surveillance Section of the NCCN Guidelines includes an introduction, the rationale, patient selection, confirmatory testing by discussion of an Active Surveillance program, as well as reclassification criteria, which is quite a big section in the NCCN Guidelines. So specifically today, in terms of Active Surveillance, we'll discuss the introduction, rationale, and patient selection.

So first with observation. Observation is defined as monitoring the course of prostate cancer with the expectation of delivery of palliative therapy, for several scenarios, including the development of symptoms, or change in the clinical exam, or a PSA that suggests that symptoms are eminent in the future.

The goal of observation is to maintain a quality of life by avoiding noncurative treatment, and this we know in clinical practices is typically applicable to elderly or frail men with multiple comorbidities that will likely out-compete prostate cancer for cause of death. One of the Seminole papers, looking at observations from Sweden published in JAMA in 1997, looked at 642 men that were initially untreated for prostate cancer, including 300 that were diagnosed with localized disease defined as up to stage T2. Among those patients with initially localized disease, only 13% of men developed metastases 15 years after diagnosis, and only 11% of these men died from prostate cancer. Based on this, the panel recommends monitoring, which should include a PSA and a physical exam no more than every six months, but will not involve surveillance biopsies or radiographic imaging. Importantly, when symptoms are developing or are imminent, the patients should receive palliative androgen deprivation therapy.

Next, we will switch over to Active Surveillance, specifically with some background, and an introduction to Active Surveillance. Active Surveillance is defined as actively monitoring the course of the disease with the expectation to deliver curative therapy if cancer progresses. The goal of Active Surveillance is to defer treatment and the potential side effects of local therapy. Several big studies, including those out of Toronto and other big centers, have shown that 2/3 of men avoid treatment at five years and up to 55% of patients avoid treatment up to 15 years from diagnosis. Thus delaying treatment does not appear to impact cure rates, and Active Surveillance is a safe modality of monitoring prostate cancer.

The ProtecT study was a large study published now 5 years ago in the New England journal of medicine, which randomized 1,643 men with localized disease to either Active Surveillance, radical prostatectomy or, radiotherapy with a primary outcome of prostate cancer-specific mortality. At a median of 10 years of follow-up, there was no difference in prostate cancer-specific mortality amongst these three groups. As you can see here on the right with a completely overlapping Kaplan-Meier curve between surgery, radiotherapy, and active monitoring. However, there were higher rates of disease progression and metastases in the active monitoring group. However, this was likely secondary to 23% of patients having Gleason 7 to 10 disease with 5 out of 8 deaths in the active monitoring group in this subset, so perhaps these patients based on their higher Gleason score were inappropriately managed with active monitoring in the first place.

There are several studies that have highlighted men with low-risk prostate cancer choosing active surveillance in terms of uptake of Active Surveillance. A study from the VA published in 2018, looked at the uptake of Active Surveillance from 2005 to 2015, and men less than 65 years of age, 4% uptake in 2005 and up to 39% in 2015, and in older men more than 65 years of age, 3% in 2005 and 41% in 2015.  A similar study from the SEER database, looking at the uptake of Active Surveillance from 2010 to 2015 showed 14.5% uptake in 2010 with an increase up to 42.1% in 2015. And finally, an international hospital-based retrospective analysis from 2010 to 2014 showed a 7% uptake of Active Surveillance in 2010 and a 20% uptake in 2014.

The NCCN panel believes there is an urgent need for several items, including clinical research regarding the criteria for recommending Active Surveillance, secondly, criteria for reclassifying patients on Active Surveillance, and third, the schedule for Active Surveillance, especially as it pertains to multiple prostate biopsies and this poses an increasing burden, particularly as it relates to infection risk, and patient aversion to having subsequent biopsies.

Next, we are going to switch over to the Active Surveillance rationale, and I'll turn it over to Chris to discuss the rationale as well as key aspects of patient selection.

Christopher Wallis: Thanks, Zach.  As Zach alluded to in the discussion of observation, the underlying principle of deferred treatment of any kind for patients with prostate cancer is to avoid the risks of overtreatment. And so when we use widespread prostate cancer screening with PSA testing, there is a substantial risk of overtreatment of men with clinically insignificant disease. And as a result, we see that the context of Active Surveillance arises in the debate regarding the need to diagnose and treat every man with prostate cancer. And we know that there is a high prevalence of prostate cancer at the time of autopsy and relatively high biopsy rates in men with normal digital rectal examinations and PSA levels suggesting that there is a large burden of clinically insignificant disease. Now, this is further highlighted by the contrast between the incidents and mortality rates of prostate cancer with substantially higher incidents in mortality when viewed in the context of other cancers.

Additionally, we know that we need to treat nearly 40 men with screen-detected prostate cancer to prevent one death. Thus, we should do our best to save treatments with associated toxicity for those who are most likely to benefit. And when we look at the Goteborg randomized trial of population-based prostate cancer screening, we can see that screening increases the diagnosis of prostate cancer. However, we can reduce the risk of prostate cancer-related death with an absolute difference of 0.4%. When put into context, this means that 293 men need to be invited for screening, and 12 need to be diagnosed to prevent one prostate cancer-related death. This study has been updated and now up to 18 years of follow-up, and as we might expect, the number needed to be screened or diagnosed is dropped and so the number needed to diagnose is now 10. And we can see from these data, that population-based prostate cancer screening can reduce prostate cancer mortality and we need to now weigh that these potential benefits against the risks of treatment and so we now consider prostate cancer surveillance and selecting the appropriate patient.

So the definition of clinically significant prostate cancer coming from Epstein is all of the following criteria, clinical stage T1c, biopsy grade group 1, that's Gleason score six, disease in fewer than 3 biopsy cores, less than 50% cancer involvement in any individual core, and a PSA density of less than 0.15. The NCCN panel states that for patients meeting this definition of clinically insignificant disease, especially when detected early based on PSA screening, there is little risk to men with a life expectancy of fewer than 20 years.

However, we can expand our inclusion for surveillance somewhat beyond this and this NCCN panel recommends Active Surveillance for all men with low and favorable intermediate-risk prostate cancer with a life expectancy of fewer than 10 years, as well as treatment consideration for men with low and favorable intermediate risk of prostate cancer and longer life expectancies. The most recent update that is as of September 2021, the NCCN guideline panel removed the preference for Active Surveillance for men with low-risk disease. And this led to quite some consternation among the Twitter group of urologists and this is a relatively controversial decision given the relatively overwhelming evidence as to the safety of surveillance in this population.

And when we consider moving beyond just a low-risk group into favorable and intermediate-risk prostate cancer, we can look at a number of different data points to help guide us. So first, I would like to highlight the PIVOT trial here.

This was a comparison of radical prostatectomy and observation in men with clinically localized prostate cancer and 120 men in this study had intermediate-risk disease and were randomized to observation.  Of these, 13 men died of prostate cancer. In contrast, among 129 men with intermediate-risk disease randomized to prostatectomy, only six died of prostate cancer. While these numbers are small, there is a suggestion of worse survival for men with intermediate-risk disease who are undergoing observation. And when we look at the Toronto Active Surveillance Experience, we can see that intermediate-risk disease confers an inferior metastasis-free survival and so we have it here stratified according to both Gleason score and PSA. And you can see that particularly driven by Gleason score, men with grade group two or grade group three disease, have a much lower 15-year metastasis-free survival than those who have a Gleason score of six.

So the NCCN guideline panel recommends that a subset of men with intermediate-risk prostate cancer may be considered for Active Surveillance. However, the criteria to decide this needs ongoing refinement and our follow-up protocols should likely be stricter, although again, these require further characterization. Active Surveillance in the context of favorable intermediate-risk prostate cancer should be approached with caution according to the panel and include informed decision making and close monitoring for progression.

The question of race in Active Surveillance is somewhat controversial. A number of studies have shown that African American men with very low-risk disease may harbor higher grade disease that was not detected on their initial diagnostic biopsies and as a result, they have a higher risk of pathologic upgrading. However, within the context of the search database, where there is equal access to care, no differences in rates of pathologic upgrading, upstaging, or biochemical recurrence were seen between African American men and Caucasian men.

Overall, we need to consider the alternative risks of therapy, as well as the risk of cancer progression, and African American men have an increased risk in all-cause mortality after treatment in part driven by cardiovascular complications of ADT that may be administered as part of their treatment course. So taking the entirety of the picture into consideration when we examine the effective race, we need to consider both underlining biological differences that may relate to potential differences in tumor location and diagnoses as well as differences in gene expression patterns, but also consider strongly the effects of access to care for particular African American men who may have barriers.

So summarizing this, which is going to be the first of two talks looking at non-interventional approaches to the treatment of prostate cancer. Observation is a viable means for monitoring patients with prostate cancer with poor life expectancy.  In contrast, Active Surveillance is a non-interventional approach, which is not restricted to those with poor life expectancy but rather seeks to defer the potential risks of treatment among men with evidence of low oncologic risk.

The uptake has improved over the past 10 or 15 years and low-risk men who have been appropriately counseled and followed may avoid the side effects of overtreatment by the use of Active Surveillance without any detriment to their survival. For men with favorable intermediate-risk prostate cancer and particularly in African American men, treatment counseling regarding Active Surveillance needs to consider the increased risk of progression to active therapy and potentially worse downstream prostate cancer outcomes according to the guideline panel.

We'd like to thank you for taking the time to join us for this discussion of the NCCN and clinical practice guidelines in oncology with a focus on Active Surveillance and Observation of prostate cancer and we hope you join us for further discussions of the guidelines.