The key to optimal outcomes in active surveillance is careful patient selection and monitoring of participants during AS.
MRI guided biopsy at initial diagnosis:
Lee et al., Korean J Radiol. 2021 Jul, argue that in men in whom there is a clinical suspicion of prostate cancer an “mpMRI with targeted biopsy is superior to conventional clinical parameters, such as PSA, PSA density, clinical staging and systematic biopsy [alone] for defining AS eligibility….” There is consensus that a targeted biopsy combined with systematic biopsy is the optimal technique to detect suspicious clinically significant lesions. Active surveillance is now considered the preferred management option for most men with low grade cancer, i.e., Gleason grade 3+3. Conventionally, Gleason grade >7 has been disqualifying.
The MRI PI-RAD grading scale spans from 1-5 with scores of 1 and 2 regarded as “highly unlikely” and “unlikely” (in some articles termed “negative”) to signify clinically significant cancer of Gleason grade >7; 3+4 or 4+3). However, even in men with MRI grade 1 and 2, random systematic biopsies find some cancers even when a worrisome MRI target lesion was a not evident. Hence a combination of the two is generally recommended.
MRI guided biopsy preceding confirmatory biopsy: (a confirmatory biopsy is recommended within one year after men have been followed on AS) .
The ASIST trial as reported by Klotz and colleagues (Eur Urol. 2020 Mar) reported superior outcomes when an mpMRI preceded the confirmatory biopsy. In their study 259 men with Gleason Grade 1 (3+3=6) were randomized about a year after the confirmatory biopsy to either a systematic template biopsy only or a systematic and MRI guided biopsy. At further 2-yr follow-up after the confirmatory biopsy AS the need for intervention occurred in 19% in the MRI + systematic biopsy group vs 35% of men receiving only a systematic biopsy.
Active Surveillance for Men with Favorable-Intermediate Risk Cancer (F-IR).
Current studies are focusing on identifying men with F-IR who may safely choose AS. The NCCN classification for F-IR specifies: Gleason Grade 1 or 2 (3+3 or 3+4); <50% biopsy cores positive; and only one of the NCCN intermediate-risk factors: PSA 10 – 20 ng/mL; more than a single prostate nodule (cT2b-cT2c); Grade Group 2 or 3.
The percentage of Gleason secondary pattern 4 is an important risk variable. The risk of adverse pathology and the associated poorer outcome of AS increase sharply with higher percentages of secondary Gleason pattern 4 indicating the likelihood of a shorter time on AS. Studies by Klotz considered men with <5% of pattern 4 suitable candidate for AS. Less than 5% pattern 4 has been found to carry a risk similar to Gleason Score 3+3. When Gleason pattern 4 exceeds 50% the Gleason Score switches to Gleason 4+3, a feature of unfavorable intermediate-risk cancer.
This issue was thoroughly studied by Perlis et al., J Urol. 2017 who reported that the risk of adverse pathology upon surgical intervention rose sharply when pattern 4 exceeded 10%. Their study determined that men with <10% GP4, PSA <8 and fewer than 15% positive cores on diagnostic biopsy shared similar risk as men with Gleason 3+3.
Mutations in BRCA 1, 2 and ATM, and cribriform or intraductal histology are associated with increased risk.
Can molecular profiling with the genomic classifier Decipher assist in untangling the heterogeneity of F-IR and guide optimal patient selection?
Link to PCa Commentary #163 below discusses Decipher in more detail [control+click link to follow or visit https://prostatecancerfree.org/prostate-cancer-news]
This was addressed by Cooperberg et al., Prostatic Cancer Prostatic Diseases 2020 in a study “aimed to validate Decipher to predict adverse pathology (AP) at radical prostatectomy (RP) in 220 men with….F-IR … and to better select candidates for active surveillance (AS).”
The Decipher assay is based on the RNA of 22 genes selected for their predictive strength for developing metastases. The assay is performed on the prostatectomy or biopsy specimen. It reports values in a spread of 0 – 1.0. Men with scores of <.45 and up to 0.6 have a low or intermediate risk of adverse pathology compared to values of >6, which predicts for poorer outcome.
- In the 220 men in the NCCN F-IR category, 79% had Decipher scores of <0.46 and 13% between 0.45 and 0.6.
- Their conclusion: “Therefore, incorporating Decipher into clinical decision-making, particularly for F-IR PCa, may be useful to safely expand the use of active surveillance.”
Monitoring Active Surveillance to Achieve Optimal Outcomes: The Use of mpMRI
Sequential monitoring, with intervention upon the identification of grade progression, is the key to achieving an AS outcome similar to that which would have occurred had treatment been performed at the time of original diagnosis.
A study reported by the Canary Group (Lin et al., J.Urol. April 2022) serves as a model of what a man with Gleason Grade 2 at diagnosis (essentially F-IR) can expect to experience if he chooses AS and remains eligible after a confirmatory biopsy. The 154 GG2 men had low tumor burden at ultrasound transrectal diagnostic biopsy (i.e., only Tic and T2a). The median PSA was 5.4 ng/mL and the median percent cores positive was 17%. [The extent of secondary pattern 4 was not cited, and only later in the study some men underwent mpMRIs.]
The protocol stipulated PSA testing every 3 months and biopsies at 6 – 12, 24 months and at 2-year intervals thereafter. Intervention was prompted by biopsy progression to GG > 3 (4+3) or finding disease beyond the prostate.
At median 5-year follow-up 58% of the GG2 men transitioned to treatment. “… we did not observe differences in recurrence after treatment or metastases in men diagnosed with GG2” versus 1574 men with GG1 cancer who were included in the protocol.
Monitoring During Active Surveillance: The role of mpMRI.
A mpMRI targeted fusion biopsy combined with a systematic template biopsy can establish suitable eligibility for active surveillance. These same biopsy techniques are increasingly used in monitoring the patient during the course of AS, although some studies find a systematic biopsy alone sufficient. The goal of sequential monitoring is finding evidence of pathological progression to GG 3 or more.
There is no consensus on a regimen of MRI monitoring. However, a “negative” (PI-RAD 1 or 2) or stable findings in sequential imaging studies carry an up to 93% negative predictive value and if combined with the urine test for PCA3 the NPV rises to 100%. Men with follow-up MRIs with PI-RAD scores 1 and 2 may be followed for 2-3 year before a follow-up surveillance systematic biopsy. (Above text based on Lee, ibid)
The findings in a study of 145 men by Thurtle et al., BJU Int. 2018 underscore the importance of periodic protocol stipulated biopsies during surveillance. Of the 23 men who experienced pathological progression, detection in 4 men was based on PSA increase, in 10 on MRI changes, but 6 were diagnosed only on the basis of protocol planned biopsies.
Based on careful selection, confirmatory biopsies, and mpMRI monitoring during AS men with favorable intermediate-risk prostate cancer can be suitable candidates for active surveillance.