Zachary Klaassen: Hello and thank you for joining us for this UroToday discussion of the NCCN Clinical Practice Guidelines in Oncology, specifically looking at prostate cancer version 1.2022. And today we will be discussing active surveillance.
The active surveillance portion of the NCCN guidelines is quite robust as you can see here. There are six different sections looking at the introduction, the rationale, patient selection, confirmatory testing, discussing an NCCN active surveillance program, and then highlighting reclassification criteria.
In a previous UroToday discussion, we have discussed introduction, rationale, and patient selection. So today we will look at the final three points in this section.
So, looking at confirmatory testing for active surveillance.
Before starting an active surveillance program, the NCCN panel suggested a multiparametric MRI and/or a prostate biopsy should be considered to confirm a patient’s active surveillance candidacy. Previous studies have shown that men with PI-RADS 4 or 5 lesions have an increased risk of biopsy progression and they also note that in low and favorable intermediate-risk disease, molecular analysis may be helpful in determining a patient’s active surveillance candidacy.
Next, we will talk about the NCCN Active Surveillance program that they provide in the guidelines.
And there are several key components of this program that I’ve highlighted on this slide. The recommendation is for PSA no more often than every six months unless clinically indicated, a digital rectal exam no more often than every 12 months unless clinically indicated, a repeat prostate biopsy no more often than every 12 months unless clinically indicated and a repeat multiparametric MRI no more than every 12 months also unless clinically indicated. Importantly, they highlight that repeat molecular tumor analysis is discouraged during the active surveillance follow-up.
There is also a nice section on repeat prostate biopsies and timing of prostate biopsies and the recommendations are that within six months of diagnosis, a repeat biopsy is indicated if the initial biopsy was taken with less than 10 cores. Also important is a repeat biopsy to be considered if the prostate exam changes during follow-up, a multiparametric MRI suggests more aggressive disease, or the PSA increases. Repeat prostate biopsies can be used to assess for disease progression regardless of clinical findings but should be performed no more often than every 12 months. This is useful to determine whether a high Gleason grade does exist, which certainly may influence prognosis and the decision to continue active surveillance.
This study is a study from the British Journal of Urology International from 2019, looking at four-year outcomes from a multiparametric MRI-based active surveillance program. This study included 211 patients with Grade Group 1 prostate cancer who had initial and repeat MRIs as well as PSA monitoring. The highlight of this study is that a negative multiparametric MRI predicts a lower risk of Gleason upgrading by systemic biopsy, as you can see here on the right in this figure, with no lesions visible in MRI, being the green curve and showing less risk of progression. This was looked at also in a meta-analysis in the same year, of 43 studies showing that the sensitivity of multiparametric MRI is 0.81 and the negative predictive value is 0.78.
I will now pass it off to Chris who will take us through reclassification criteria for active surveillance.
Christopher Wallis: Thanks, Zach. Clearly, when patients go on surveillance, the whole rationale is to monitor them for the development of disease which warrants treatment and so we need to consider those criteria that we would use to initiate treatment.
And there are a variety of criteria that have been suggested. Unfortunately, reliable parameters of prostate cancer progression really are not available and await results of ongoing work. Unfortunately, while we had hoped that PSA kinetics and characteristics would be useful, PSA doubling time has not been considered reliable enough to be used in isolation to detect disease progression. Certainly, when repeat biopsy shows upgrading, this needs to warrant intervention.
We have a variety of rates of reclassification across a variety of active surveillance cohorts, and clearly, this also varies on the basis of the duration of follow-up. And so in the Toronto cohort with a median follow-up of seven years, reclassification criteria were met by just under one-quarter of men. At Hopkins over a follow-up of five years, over one-third of men met their reclassification criteria. And in the UCSF cohort, with a median follow-up of three and a half years, we had reclassification criteria met by 16% of included members. And so these characteristics are affected by both the initial inclusion criteria, the duration of follow up and also the reclassification criteria utilized. And so we will talk through some of these.
And this here highlights these cohorts. This table is taken from the guidelines themselves, and we can see that when we are looking for the reasons for treatment, we see upgrading relatively infrequently in the Toronto cohort and much more frequently in the UCSF cohort, PSA increases and personal choice.
When we consider the validity of reclassification criteria, we initially in the Toronto cohort had considered a PSA doubling time trigger and there were subsequent efforts to improve the characteristics of this criterion. And so using PSA thresholds or a variety of different techniques to calculate PSA doubling time or to operationalize PSA velocity differently, unfortunately, did not improve the accuracy of this as an intervention trigger. In the Hopkins cohort, neither PSA doubling time nor velocity were meaningfully associated with prostate biopsy reclassification, either by upgrading or increasing tumor volume and thus taken together, we can conclude that PSA kinetics cannot replace a routine follow up biopsy. And remember that these cohorts were accrued at the time that MRI was not a routine portion of active surveillance protocols.
Just to highlight some of the data out of key cohorts, this is Dr. Klotz’s report from 2010 in the Toronto cohort. At that time, 450 patients were included with a mean follow-up of just under seven years. Overall survival was 79%, a 10-year prostate cancer actuarial survival was exceeded of 97%. You can see that there was approximately a 30% reclassification rate with 135 of 145 patients eventually undergoing treatment. The majority of them received external beam radiotherapy but some received radical prostatectomy or ADT alone. And so you can see here, the PSA failure rates are following intervention graphed in this Kaplan-Meier curve to the right.
Subsequent longer follow-up of the same cohort published in 2015 shows a 10-year actuarial prostate cancer-specific survival of 98% and a 15-year of 94%. Of the nearly 1,000 patients followed in this cohort at that time, only 15 had died of prostate cancer. And then an additional 13 men had developed metastatic disease but were still alive. At 10 years, just over one-third of the cohort had received treatment and the remainder remained intervention-free.
When we look at the subset of approximately 600 men who had at least one on more repeat biopsies, just under one-third had upgraded, and 15% of those were upgraded to high-grade histology of Gleason 8 or higher. The majority of these patients proceeded to active treatment. And when we look at the development of metastatic disease, this happened in less than 10% of men who had upgraded to Gleason 7 and a much lower proportion, 2% of men who had Gleason 6 disease. We can see here that while PSA doubling time was not a good predictor of upgrading, among those who did upgrade, PSA doubling time and the percent or number of positive cores were predictors of the development of metastatic disease.
We can now contrast this with the Hopkins experience and this is the 2011 publication at which time just under 200 of the 770 patients underwent a delayed treatment at a median of two years following their initial diagnosis. the five-year biochemical progression-free survival was 96% for those who underwent radical prostatectomy following their delayed intervention and somewhat lower for those who underwent radiotherapy, again highlighted in the Kaplan-Meier curve to the right.
The updated Hopkins experience published in 2015 showed that approximately 8% of men who received definitive therapy after initial active surveillance experienced biochemical recurrence and this was independent of treatment modality, whether surgically or radiotherapy treated.
So when we summarize the available data on active surveillance, there are a number of large prospective cohort studies that have shown that active surveillance is both a safe and durable treatment approach for men with low and favorable intermediate-risk prostate cancer. Confirmatory testing on active surveillance protocol should include a multiparametric MRI or prostate biopsy to confirm active surveillance candidacy following initial diagnosis. The optimal repeat biopsy schedule is unknown but can be influenced by clinical features, including a physical exam and PSA characteristics. Ongoing work, however, continues to assess the ideal reclassification criteria, while today we use PSA doubling time, biopsy grade upgrading, and increases in tumor volume.
We hope that this discussion has proved useful to you and maybe alleviated some of the controversies associated with active surveillance and the recent changes in the NCCN guidelines regarding its recommendations.
And we hope you will join us for other summaries of the NCCN Clinical Practice Guidelines in Oncology focusing on other aspects of the care of patients with prostate cancer.