Originally published 7/5/2017
It’s been nearly 4 years since we posted the blog below, which was a “cautionary tale” about Active Surveillance (AS) and the risk of missing a treatment window if prostate cancer (PCa) progression was missed. If you read (or re-read) the original blog, you see a range of statistics and time frames for biochemical recurrence (possible PCa spread outside the gland). Anywhere from 2-5 years after starting on AS, the number of patients whose PSA began to rise was 7-25%, depending on the study. These numbers suggest three scary scenarios:
- Up to a quarter of patients on AS may not have initially been properly qualified, or
- They were inadequately monitored by PSA and repeat biopsy, so PCa spread was missed, or
- A combination of the two.
However, there’s good news! During the intervening years, the widespread integration of multiparametric MRI (mpMRI) and MRI-guided targeted biopsies has resulted in both better initial qualification of AS candidates, and significantly better ability to monitor for significant PCa by PSA + mpMRI. As a side benefit, such monitoring helps reduce the number of unnecessary repeat biopsies. Therefore, patients on AS are successfully staying on AS for longer duration, with fewer men experiencing biochemical recurrence/metastasis.
For such confidence, we can thank a cooperative study out of Italy and California; in fact, one of our most admired clinician-researchers, Dr. Peter Carroll, is a co-author. Their paper, “The Long-Term Risks of Metastases in Men on Active Surveillance for Early Stage Prostate Cancer,”[i] is encouraging. Their retrospective analysis of 1,450 cases of men on AS (average follow-up 6.5 years) found that the 7-year metastasis-free survival rate was 99%. They report that “Metastases developed in 15 men at a median of 62 months (IQR 29-104), of which 69% were confined to lymph nodes.”
Specifically, they found that the predictors of metastasis included biopsy-based (Gleason) Grade Group >2. PSA velocity (the speed with which PSA rises), and mpMRI PI-RADS 4-5. Thus, men with these clinical features may not be qualified for AS. In short, meticulous diagnosis that includes mpMRI, and faithful monitoring using PSA + mpMRI facilitate long, safe years on AS without missing a treatment window.
Active Surveillance (AS) has gained considerable ground as a means to hold off on aggressive treatment for prostate cancer (PCa). AS is like a balancing act aimed at maintaining current quality of life without missing a window for cure. For low-risk PCa patients who want to avoid the risks and complications of radical prostatectomy or radiation as long as possible, AS, with its schedule of tests, seems reasonable. The problem is, PCa is not a single disease that behaves exactly the same in each patient.
No universal AS criteria
Prescribing AS is complex since there are no universal standards regarding its three key elements:
- Patient selection – which criteria determine the best AS candidates?
- Intensity of AS monitoring – frequency of PSA testing, imaging, rebiopsy?
- Triggers for treatment – what change(s) in a patient’s clinical factors signal it’s time for treatment, and what will the treatment options be by then?
According to Tosoian et al. (2016)[ii], AS programs range from stringent (e.g. Johns Hopkins accepts only low-risk patients and mandates yearly rebiopsy) to more relaxed (e.g. Sunnybrook will include some intermediate-risk cases, rebiopsy mainly every 3-4 years). But here’s the tradeoff: Johns Hopkins data demonstrates “…higher rates of treatment within 10 years (50% versus 36% at Sunnybrook) but lower risk of prostate cancer death (0.1% versus 1.9%).”
In other words, Johns Hopkins closely observes each patient, with a hair-trigger move to the only choice – radical treatment – that might be overtreating insignificant PCa. Former AS patients now risk wearing incontinence pads for weeks or months, and likely 6-18 months of ED. Ironically, they go on to have the treatment they wanted to defer to begin with, but urologists are biased toward whole gland therapies. On the other hand, Johns Hopkins statistics show they rarely miss a window for cure.
Playing with a loaded gun
It was the concern about overtreatment that originally encouraged wider adoption of AS. Now, there is a different concern as newly available 5+ year data suggests that some urologists keep men on AS beyond the window for curative treatment. Without diagnostic certainty about which cell line is growing in a man’s body, there is always the possibility that he’s harboring a disease that does not generate a high PSA but which has the capability to progress rapidly, spread beyond the gland and become lethal. In this respect, AS is like playing with a gun that holds an unknown bullet.
Tosoian et al. assembled data from various published AS studies. Within 5 years of starting AS, the proportion of men who are upgraded by biopsy and receive whole gland treatment ranges from 24-50%. Of four studies that followed treated patients, biochemical recurrence (rising PSA after treatment) ranged from 8-25%; one particular study (Selvadurai et al., 2013) reported biochemical recurrence rates of 7% at 2 years and 15% at 5 years. Biochemical recurrence means tumor cells had already left the gland at the time of surgery/radiation and are now multiplying locally, regionally, or distantly.
Reasons for treatment failure after going off AS
Urology has long been the specialty that deals with prostate cancer detection, diagnosis, treatment, and follow up. No urologist knowingly or intentionally puts his patients in harm’s way, but the traditional diagnostic resources are simply inadequate to qualify patients for AS. This means that many doctors are prescribing this balancing act based on educated guesses, and unwittingly leaving some patients with buyer’s remorse. There is no simple reason for missing a treatment window, but here are some factors that explain the incidence of biochemical recurrence once an AS patient has had aggressive treatment:
- The prescribing and practice of AS varies widely across urologic communities (academic institutions and urology community practices). Some physicians may include patients with Gleason 3+4 disease, some may have insufficient monitoring tools such as randomized TRUS biopsies that miss progression, etc.
- Patient compliance may be inconsistent. Early on, patients may agree to annual biopsies but begin to skip them for a number of reasons, fear/anxiety being common.
- The original diagnosis was mistaken (biopsy missed significant disease).
- Lack of genomic information
Two new technology advances add confidence to prescribing AS:
- Multiparametric MRI (mpMRI) – Starting with a baseline mpMRI at the time of biopsy, scans at regular intervals give an ongoing portrait of a tumor’s activity, especially when interpreted by an experienced reader. “Multiparametric MRI (mpMRI) has emerged as a useful adjunct tool in the detection of prostate cancer, and several studies have shown that suspicious findings on MRI predict an increased risk of reclassification during AS.”[iii] In fact, studies of mpMRI as a routine surveillance tool show how it increases AS safety by detecting early tumor changes, helping avoid needless repeat biopsies, and allowing for accurate, in-bore MRI-guided targeted biopsies. MRI is safe and noninvasive, encouraging patient compliance with monitoring schedules.
- Genomic testing – This should be done at the time of the original biopsy to determine if a patient is harboring a dangerous cell line and/or genetic mutations such as inherited breast cancer genes. This raises the question as to whether AS is a responsible recommendation for the estimated 15% of PCa patients who carry a potentially lethal disease.
There is no reason why AS patients should not be more thoroughly qualified for AS. In fact, such thorough evaluation may reveal a high percentage of men who are candidates for a targeted therapy such as Focal Laser Ablation (FLA). This approach safely and effectively bridges the gap between no treatment vs. radical treatment. It has the advantages of AS with none of the doubts or fears, and is repeatable if necessary. Why worry about staying on AS too long? Focal therapy is a happier medium.
[i] Maggi M, Cowan JE, Fasulo V, Washington SL 3rd et al. The Long-Term Risks of Metastases in Men on Active Surveillance for Early Stage Prostate Cancer. J Urol. 2020 Dec;204(6):1222-1228.
[ii] Tosoian JJ, Carter HB, Lepor A, Loeb S. Active surveillance for prostate cancer: current evidence and contemporary state of practice. Nat Rev Urol. 2016 Apr;13(4):205-15. doi: 10.1038/nrurol.2016.45. Epub 2016 Mar 8.