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Rashid Sayyid: Hello everyone, and thank you for joining us today in this special UroToday recording where we'll be discussing some key updates to the 2024 NCCN Prostate Cancer Guidelines. In this recording, we'll highlight the changes with regards to the management of very low-risk prostate cancer in this slide deck. I'm Rashid Sayyid, a urologic oncology fellow at the University of Toronto, and I'm joined by Zach Klaassen, associate professor and program director at WellStar MCG Health in Augusta, Georgia.

Before we get into the changes over the last couple of years, let's define very low-risk prostate cancer. There's very strict criteria outlined very clearly by the NCCN, and very low-risk prostate cancer is defined as the disease that meets all of the following criteria. This includes clinical T1C disease, meaning disease that was detected following a biopsy for an elevated PSA. Grade group one, a PSA less than 10 nanograms per ml, less than three prostate biopsy fragments or cores being positive. Let's say a patient had 12 cores taken, for example, it is one or two, and less than or equal to 50% core involvement per core, so meaning the core involves 50% or less disease. A PSA density, importantly, which factors in not only the PSA but also the volume of the prostate, less than 0.15 nanograms per ML per gram.

These are the simplified current recommendations by the NCCN for the management of very low-risk prostate cancer. Really what determines the recommended initial management is the life expectancy. If a patient is diagnosed with very low-risk disease and has a life expectancy of 10 years or greater, currently the NCCN recommends simply active surveillance. As we'll see in later slides, other options include active management, which includes radical prostatectomy and radiotherapy. Conversely, if a patient has less than 10 years of life expectancy, it is currently recommended that they undergo or submit to observation.

We see here in the slide the changes that have been made, and this is quite a busy slide. We won't go over every part of it, but essentially it shows you the changes that the NCCN has adopted. Previously, we took into consideration life expectancy in terms of tertiles, so less than 10 years or 10 to 20 or greater than 20 years. Now we see it's more simplified, simply 10 or greater or less than 10. If we see here in the greater or equal to 20 years previously, in addition to active surveillance, we saw radiotherapy being an option, radical prostatectomy being an option. These are important changes that have been made by the NCCN. Now when we see this in a cleaned-up version, again, we go back and we see that there is a very simplified paradigm right now.

Where do these changes come from? What are some of the data that has encouraged this panel to adopt these changes? There's been over the last year, in early 2023, we saw the 15-year data from ProtecT. This was a phase three randomized trial of about 1600 patients, localized prostate cancer, that were randomized to either active surveillance radical prostatectomy or radiotherapy. We know this is an earlier study between '99 and 2009. In the 15-year follow-up published in 2023, it was noted that there was no difference in prostate cancer mortality between the three arms. The active surveillance arm is 3.1%, then if we look at radical prostatectomy 2.2% and then radiotherapy 2.9%, so not any meaningful differences both clinically or statistically. Although, they did note a higher frequency of distant or regional nodal metastasis in the active surveillance group, about double, 10% versus 5%, and the use of ADT was significantly higher, about 13% in the active surveillance group versus 7.5% in the radical prostatectomy or radiotherapy.

Importantly, we noted that these patients were actively treated with significantly worse outcomes. The radical prostatectomy patients, significantly worse sexual function and urinary incontinence, which is not surprising given the nature of the treatment. In the radiotherapy patients, there was worse bowel function. Clearly, treatment is not benign. That's something we need to account for when we counsel patients, particularly in light of the no difference in prostate cancer mortality. One question the astute reader/observer may note is, well, did this trial restrict inclusion to patients with very low-risk disease? Well, that was not the case. Historically, there's not many trials out there, if any, that have restricted inclusion criteria to those with very low-risk disease. We're limited to these trials that are enriched for low-risk disease patients in order to rationalize this data and apply it to the very low-risk score.

If we look at the ProtecT trial specifically, about two-thirds of patients had low-risk disease and there were some that were intermediate or higher risk, about a third. What's important is, probably the percentage of true low-risk disease is actually lower as many of these patients weren't properly staged with an MRI pre-op, or may have had the cores that are misty, disease with the highest Gleason score. This was reflected in high-risk pathologic features in radical prostatectomy specimens. This lower-risk score is actually a bit of a higher risk when applied to the contemporary management of these patients. But despite this, there were no differences in mortality despite these metastases rates.

The majority of deaths that were seen in the active surveillance patients were in those with Gleason scores 7 to 10. In the 2020 publication of the eight patients who died of prostate cancer, five of them had patients with higher Gleason scores that meet intermediate or high-risk disease. Overall, we saw that the patient-reported outcomes favored the active surveillance group. When we rationalize this data and we consider an even lower-risk cohort, such as the very low risk, particularly no difference in mortalities with superior patient-reported outcomes, the decision was made by the panel to remove radical treatment options for patients with very low-risk disease. What we see here is the culmination of this rationale, whereby these patients, simply greater or equal to 10, active surveillance, less than 10 years, observation.

What's very important from a practical standpoint for the urologist is, well, how do we estimate life expectancy? Do we eyeball these patients? Do we ask them to take a fitness test? There are many different tools available, but one of the important ones that is highlighted by the NCCN is the Adult Comorbidity Evaluation-27, or the ACE-27 tool. Now, we see here this is a pretty standardized questionnaire that can be filled out, and gives an overall comorbidity score as we see here in the bottom right corner, and that can be used to guide treatment decision-making for these patients and avoid overtreatment in this very low-risk cohort.

Now, when we talk about active surveillance and observation, there are really some differences, and this is very nicely clarified by the NCCN. When we talk about observation, the principle of that is monitoring the course of prostate cancer with the expectation to deliver palliative and not curative therapy. This is administered when patients develop symptoms or they have a change in their exam findings or they have a PSA that suggests that symptoms are imminent. Not just a PSA rise, but this is a very high elevation that may suggest an impending spinal cord compression fracture, impingement syndrome, etc. The goal of observation isn't to cure these patients, but to maintain quality of life by avoiding non-curative treatment.

It involves typically monitoring with a history and physical exam no more often than every 12 months, and it's typically applicable to elderly or frail men with comorbidities that will outcompete prostate cancer for the cause of death. We see here that this fits in very nicely with those patients with very low-risk disease and a life expectancy of less than 10 years. At this point, Zach will go over active surveillance and their key principles of active surveillance, as well as giving us a relevant overview of the major series here and how they apply to the NCCN recommendations for this very low-risk group.

Zach Klaassen: Thanks so much, Rashid, for that great introduction and highlighting the important changes in the 2024 NCCN guidelines. Active surveillance essentially, by definition, involves actively monitoring the course of the disease with the expectation to intervene with curative intent if the cancer progresses. Really, the whole premise behind active surveillance is to defer treatment and the potential side effects of these treatments. Now, confirmatory testing is an important component of active surveillance protocols because we want to identify early those patients that are at higher risk of grade reclassification or cancer progression. Really what this recommendation states is that patients should undergo a confirmatory biopsy within about one to two years of a diagnostic biopsy. It may not be necessary for patients who had a multiparametric MRI prior to diagnostic biopsy, although there is some contention regarding the utilization of MRI and avoiding or delaying biopsies.

The panel overall remains concerned about the problems of overtreatment secondary to the increased frequency of prostate cancer diagnosis with the widespread use of PSA screening. Really, this debate has been going on for decades now, and the debate about the need to diagnose and treat every man with prostate cancer is secondary to several points. A high prevalence of prostate cancer at the time of autopsy, thus patients that are dying with prostate cancer, not of prostate cancer. High positive biopsy rates in men with normal DREs and PSAs. The contrast between incidence and mortality rates of prostate cancer, and really the need to treat roughly 37 men with screen-detected prostate cancer to prevent one death.

One of the key and really famous trials is the Göteborg Study. This was initially published in 2010. There were 20,000 men from Sweden that were randomized one-to-one to either the screening group with a PSA test every two years or the control group with no screening. A median of 14 years of follow-up, 1,138 men in the screening group and 718 men in the control group were diagnosed with prostate cancer. Overall, the absolute cumulative risk reduction in prostate cancer death was 0.40%, based on a difference between the control group, 0.9%, versus 0.5% in the screen group. If we take this together, 293 men were needed to be invited for screening and 12 had to be diagnosed with prostate cancer to prevent one prostate cancer mortality.

Now, this Göteborg study has updated a follow-up in 2018. This is an 18-year follow-up, and this reduced the number needed to be diagnosed to prevent one prostate cancer death from 12 in the 2010 study to 10 in the 2018 study. Thus, early detection when applied properly should reduce prostate cancer mortality. However, as we've discussed already, reduction comes at an expense as overtreatment may occur in as many as 50% of men treated with PSA-detected prostate cancer.

There are several key principles to active surveillance programs. You can see them listed here. So, with regards to PSA and DRE, PSA no more than every six months and DRE no more than every 12 months. Repeat prostate biopsy should be no more often than every 12 months unless clinically indicated. Generally, most programs recommend a prostate biopsy roughly every two to five years. MRI has certainly been instituted into the majority of active surveillance protocols and should be considered roughly every 12 months. Some protocols recommend every two years. We do know with MRI ultrasound fusion biopsy, this does improve the detection of greater than or equal to Gleason grade group two cancers. As Rashid mentioned, patients should be transitioned to observation when life expectancy decreases to less than 10 years. Repeat molecular tumor analysis is not encouraged, and the intensity of surveillance may be tailored based on life expectancy and risk of reclassification. Because of the low-risk disease, staging workup from metastasis is not encouraged.

This is the 2024 NCCN guideline table looking at some of the famous and most commonly referred to active surveillance programs. We can see at the top this includes a Toronto cohort, Johns Hopkins University, California, San Francisco, Canary Pass, the Cooley Catalona dataset, and the PRIAS dataset. These datasets range from 321 patients all the way up to over 6,000 patients. The median age is roughly in the mid-60s. You can see various definitions for core involvement based on these series. The median follow-up is very long for the majority of these, ranging from 28 months to 120 months. Conversion to treatment also varies based on the timeline instituted. We can see for the series that looked at a 10-year conversion to treatment, this ranges from roughly 37% to 73%.

Systemic progression and lymph node involvement and/or metastasis varies by study, but you can see across the board quite low, the highest up to 3.1% in the Toronto series. Cancer-specific survival, excellent in all these series, ranging from 98 to 100%. Overall survival at 10 years ranging from 80 to 98%. When we look at the reasons for conversion to treatment, the most common reason is typically Gleason grade group change. This ranges from 9.5% all the way up to 49%. PSA increase has led to some change, although there's been a push towards not relying strictly on the PSA for movement to treatment. Certainly, personal choice, most commonly anxiety, roughly 5 to 8%.

Taken together based on a lot of the data that we just discussed in that table, there are some pearls for patient counseling, and these are important take-home points. Roughly one-half to two-thirds of patients eligible for active surveillance may safely avoid treatment for more than 10 years. As we discussed, the most common reasons for conversion, Gleason score change, roughly 10 to 50% is the most common, PSA increase 9 to 26%, tumor volume increase 7%, and personal choice 5 to 8%, typically related to anxiety from being on active surveillance. What's important is that the risk of systemic progression is very low, roughly 0 to 3%. This higher boundary of 3% is driven by primarily the data in the Toronto series where there were some intermediate-risk patients included in this cohort. Again, cancer-specific survival is excellent at 98 to 100%.

This study from Matt Cooperberg published in 2023 in JAMA Network Open looked at the role and the uptake of active surveillance in the United States. This is based on the AQUA Registry. Nearly 21,000 patients with low-risk prostate cancer, and the AQUA Registry includes data from almost 2,000 urology practitioners across 350 practices across 48 US states and territories. What we see here on the right in the figure is that active surveillance has increased from 26.5% in 2014 up to nearly 60% in 2021. Although not surprisingly, significant variability at both the urology practice and practitioner levels does exist.

Taken together, radical therapy is no longer recommended as an option for patients with very low-risk prostate cancer, irrespective of life expectancy. Secondly, active surveillance is the preferred regimen in those with life expectancy greater than or equal to 10 years, and observation is the preferred regimen in those with life expectancy less than 10 years. We thank you very much for your attention. We hope you enjoyed this UroToday Update of the 2024 NCCN guidelines focusing on active surveillance in very low-risk prostate cancer patients.