Active Surveillance: Detecting Disease Progression
For patients with early stage, low risk prostate cancer (PCa), active surveillance (AS) can be an alternative to immediate intervention. The value of buying time lies in two AS features:
1) preservation of urinary and sexual function means high quality of life, and 2) insignificant cancers diagnosed by biopsy may remain indolent during the patient’s lifetime, thus avoiding treatment permanently. All patients on AS must be monitored because of the hidden danger of potential increase in cancer aggressiveness, so there are two important considerations.
First, prostate cancer progression can occur as an increase in the aggression of the cells, the growth of the tumor mass, and a spread in its location (more foci within the gland as well as escape beyond the prostate capsule).
The second issue is how to monitor. A currently accepted program uses an annual TRUS biopsy to detect an upgrading of the cancer, for example, from a Gleason score 3+3 to a Gleason score 3+4. This finding would trigger an intervention decision, and in most cases, patients would elect treatment. However, enforcing patient compliance can be difficult, as many men consciously or unconsciously with to avoid repeat biopsies. The failure to identify cancer progression in timely fashion risks missing a window of opportunity for curative treatment.
Two newly published studies address each of these issues in different ways. The first explores the ability to predict which patients may be at increased risk for progression, and the second considers the merits of two difference methods of monitoring for its occurrence.
- An international research team (U.S., Canada, Europe, Japan) conducted a thorough review of published literature on prostate cancer biomarkers, genetic factors, and risk stratification for patient selection and predictors of progression during AS.[i] The authors found lack of universal agreement on how to identify those at greatest risk for cancer progression. Some studies used factors such as patient age, race and family history. There was evidence that a combination of greater baseline biopsy core size with PSA, higher PSA density, and higher Prostate Health Index (PHI) scores were predictive of cancer progression. The team also found that during AS, tracking PSA density and PHI scores, as well as repeat biopsy results, indicated greater risk of progression. Interestingly, there was no conclusive link between genetic test results and prediction of progression. The authors conclude that while various methods can be used to qualify patients for AS and stratify them into risk groups, more study is need to develop a practical way to combine factors with greater degrees on certitude.
- The second study compared two protocols for monitoring AS patients for cancer progression.[ii] The Johns Hopkins Hospital method uses repeat biopsies at 1-year intervals, whereas the Prostate Cancer Research International Active Surveillance (PRIAS) protocol combines PSA doubling time, or PSA velocity, with repeat biopsy at intervals of 1, 4 and 7 years, or as triggered by PSA doubling time. The authors reviewed the case records of 1125 Hopkins active surveillance patients, and retrospectively applied the PRIAS standards to explore if the patient outcomes would have been different under PRIAS. According to the case records, over an average of 2.1 years follow up, 38% of the Hopkins patients had reclassification of their disease based on biopsy. Of those, 62% were detected at the same biopsy intervals used by PRIAS criteria, while 16% were detected between scheduled PRIAS biopsies, resulting in a median delay in detection of 1.9 years. The authors report that 202 men had more than 5 years of follow up, and 11% of them were reclassified (by biopsy) after the PRIAS protocol would have detected progression, “resulting in a median delay of 4.7 years to reclassification.” The authors calculated that 12% of Hopkins patients whose progression would have been picked up by a biopsy triggered by PSA doubling time would “never have undergone reclassification on the [Hopkins] protocol” and would therefore have missed a treatment window.
Both of these research studies were conducted within the conventional urologic models of qualifying patients for AS, and monitoring them for disease progression. It is arguable that as the clinical world is increasingly integrating multiparametric MRI in prostate cancer detection and diagnosis, a much more efficient and effective technology for predicting and monitoring tumor activity. The gift of imaging is its ability to make visible that which is hidden, including the secret danger of cancer progression. This is not to rule out the value of PSA velocity or the combination of PSA and PSA density as ongoing alerts. The present and future increase in using mpMRI lies in its ability to verify a treatment window early enough for the patient to have the greatest range of options, including continuing on AS
[i] Loeb @, Bruinsma S, Nicholson J et a. Active Surveillance for Prostate Cancer: A Systematic Review of Clinicopathologic Variables and Biomarkers for Risk Stratification. Eur Urol. 2014 Oct 31. pii: S0302-2838(14)01018-5. doi: 10.1016/j.eururo.2014.10.010. [Epub ahead of print]
[ii] Kates M, Tosoian J, Trock B et al. Indications for intervention during active surveillance of prostate cancer: a comparison of the Johns Hopkins and Prostate Cancer Research International Active Surveillance (PRIAS) protocols. BJU Int. 2015 Feb;115(2):216-22.