Active surveillance (AS) is an increasingly recommended strategy for carefully selected men with a biopsy diagnosis of low grade, localized prostate cancer. It involves delaying primary intervention with careful follow-up monitoring with a goal of avoiding the morbidity of initial treatment while preserving a subsequent treatment outcome similar to that which would likely have resulted had a man been treated at initial diagnosis. This strategy was pioneered in the early 1990’s by three gurus of the disease: Dr. Ballentine Carter at Johns Hopkins, Dr. Leonard Klotz at Sunnybrook in Toronto, and Dr. Peter Carroll at UCSF. This Commentary presents the newest data regarding patient selection, monitoring during surveillance and outcome.
The protocols developed at the three institutions slightly differ in eligibility requirements. Tight restrictions, as developed at Johns Hopkins, yield the most favorable outcomes, but to achieve their results eligibility is limited. A more lenient protocol, as effected in Toronto, accepts a minimal amount of secondary Gleason pattern 4 (‘favorable’ intermediate-risk) and thus allows greater participation.
The Johns Hopkins AS Model: — How it works? (Reference: Tosoian et al., JCO. 2015)
Their initial study was based on 1298 men with biopsy diagnosed low-risk PC. It was subdivided in very low-risk (VLR) and low-risk (LR):
- VLR – Gleason score 6; normal feeling prostate; PSA density, <0.15; 1 or 2 biopsy cores positive for cancer with <50% cancer in any core.
- For LR – One nodule on the prostate was allowed; PSA <10 ng/mL and Gleason score 6.
PSA was tested every 6 months, a digital rectal exam was done annually and a ‘confirmation’ biopsy was done within 1 -2 years.
Curative intervention was recommended for progression on biopsy to a higher Gleason score or increasing cancer volume or increased number of positive biopsies on the confirmation study.
Reclassification occurred and treatment recommended at 5-, 10-, and 15-years in 35%. 50% and 56% of men.
Their findings: The cancer-specific survival and metastases-free survival at 5 and 10 years were the same in both groups: 99.9% and 99.4% respectively. The median treatment-free survival was 8.5 years.
The Klotz Study: (Klotz et.al., JC0. Jan 2015)
This study of 993 men had the more lenient eligibility and focused on men with Gleason score < 6 and PSA < 10 ng/mL. For men older than 70 yrs PSA < 15 ng/mL or Gleason score 3+4 were allowed.
A confirmatory biopsy was done within 12 months and every 3-4 years thereafter. Curative intervention was recommended if a nodule was found on follow-up DRE or progression was found on biopsy. A PSA doubling time less than <3 years served as an indicator for closer scrutiny.
Their findings: “The 5- and 10-year actuarial cancer-specific survival was 98% and 94%.” Reclassification occurred and treatment recommended at 5-, 10-, and 15-years in approximately 24.3%, 36% and 55% of men respectively.
Of interest, the ratio of non-prostate cancer deaths to prostate cancer deaths was 9.2 to 1, [with cardiac disease being the most common non-prostate cause of death].
Cancer-specific Survival — Definition:
This term refers to the percentage of men living at the time data tabulation was concluded. The figures for CSS for the Johns Hopkins and Klotz studies are exemplar. However, CSS includes men who have had primary intervention and may have had advancing disease and a variety of treatments, but are living with their cancer.
Importance of Confirmation Biopsies Within 1 – 2 Years After Initial Diagnosis:
In the Canary Prostate Active Surveillance Study (JCO. Liss et al., Oct 2020) the accuracy (as expressed as the negative predictive value) of a confirmation MRI guided fusion biopsy was studied in 361 men.
Study eligibility required a Gleason score 3+3 on a non-MRI guided initial diagnostic biopsy. At a confirmation mpMRI guided fusion biopsy at a median of 25 months, reclassification occurred in 28% to Gleason grade 2 (3+4) or higher.
The important finding, which confirmed what many other studies have reported, was that a ‘negative’ MRI (i.e., no ‘region of interest’) misses ~17% of significant cancers, i.e., Gleason grade 2 or higher. They recommend a standard 12 core biopsy to accompany the MRI targeted biopsies. The standard systematic biopsies added an additional 13% of upgrades not found on the MRI biopsy.
This observation addresses the frequent question as to whether a man on AS can be monitored exclusively with a series of mpMRIs. By combining biomarkers and MRI there is room for individualized decisions on this point and the biopsy interval may be extended beyond 3, 4 and 5 years. There is plenty of room for the art of medicine in this area.
“Canary PASS (Prostate Active Surveillance Study) Active Surveillance Risk Calculators”:
Based on the data collected in their study two risk calculators are offered online (Google: Calculator – Canary PASS).
“The Biopsy Calculator for Current Risk” estimates for “how likely a man is to have more aggressive cancer on his next surveillance biopsy.”
“Calculator for Future Progression on Active Surveillance” estimates for “how likely a man is to have more aggressive cancer found in a surveillance biopsy during the next four years.”
Optimizing Patient Selection:
The heterogeneity of prostate cancer frustrates the optimal selection of men because a cancer’s aggressive molecular potential can be hidden from the conventional visual pathologic assessment of a tissue specimen.
- Conventionally available metrics can signal concern for unexpected cancer aggressiveness and suggest caution as to AS eligibility. These metrics include older age, PSA density above 0.15 (PSA divided by prostate volume in grams); a rapid PSA doubling time prior to biopsy; number of positive biopsy cores exceeding 2 or 3; volume of cancer on MRI greater than 2.5 cm.
- Genomic analysis of biopsy tissue can reveal hidden risks. A mutated BRCA2 gene confers a 2.7X greater risk of grade reclassification to Gleason score > 3+4 on a confirmation biopsy at a median interval of 1 year. Mutation in BRCA1 confers a slightly lower risk. An ATM mutation conferred increased risk but considerably lower. (Carter et al., Eur Urol . 2019). FoundationOne, Myriad Genetics, Guardant360 and others offer BRACAnalysis CDx panels for assaying these genes using circulating tumor DNA found in blood
- Genomic Risk Assessment Panels: The Oncotype DX, Prolaris and Decipher gene panels are designed and validated to find the “molecular sleepers” that portend an early class upgrade among biopsy specimens that have been assigned Gleason score 3+3 or 3+4.
In Herlemann et al., (Prostate Cancer Prostatic Dis. 2020 Mar) the title indicates their conclusion: “Decipher identifies men with otherwise clinically favorable-intermediate risk disease who may not be good candidate for active surveillance.
These three tests all run about $5000 per assay. They probably should be used judiciously as ‘tie breakers’ when assessing the suitability of men for active surveillance with Gleason 3+3 who have concerning risk factors and men with Gleason 3+4 disease.
Assessing the Risk of Reclassification During AS:
Lonergan and colleagues at UCSF (J. Urol. Dec 2020) re-emphasized the importance in predicting reclassification in follow-up of a PSA density >0.15 ng/ml/cc and a high genomic score on Decipher, Prolaris or Oncotype Dx testing. Additionally significant were an increase in positive cores on a subsequent biopsy and a concerning PSA increase.
In personal correspondence Dr. Lonergan cited the statistical difficulties in presenting a straightforward PSA metric to assess risk of reclassification. Currently the best risk assessment can be determined by using the two Canary Risk Calculators.
Risk analysis with available biomarkers, genomic tests for adverse mutations in the BRCA family and genomic risk classification panels provide the tools to select optimal candidates for AS and identify those men better served by early intervention.