Active surveillance has been proven safe in men with low-risk prostate cancer.[1-3] More recently, it has been suggested that the inclusion criteria for active surveillance should be expanded to include men with Gleason score 3+4 histology. The National Comprehensive Cancer Network (NCCN) guidelines list active surveillance as an option for favorable intermediate-risk prostate cancer, which is defined as confined to the organ, with a clinical stage of T2, Gleason score 3+4, or a prostate-specific antigen (PSA) level of 10–20 ng/mL, as well as less than 50% of positive biopsy cores. Much of the rationale for this guideline is based on the revised International Society of Urological Pathology (ISUP) definition of Gleason pattern 4 disease from 2005, which has resulted in reclassification of cases formerly reported as Gleason score 3+3 to 3+4 and 4+3. However, we propose that active surveillance should not be routinely offered to all men with Gleason score 3+4 prostate cancer, since the drawbacks of active surveillance are potentially magnified in this population.
While Gleason pattern 4 has evolved over time, currently four architectural subtypes exist: ill-formed, fused, glomeruloid, and cribriform. Several groups have shown Gleason score 3+4 prostate cancer with cribriform architecture on biopsy to be associated with distant metastasis and pathologic upstaging on radical prostatectomy (RP).[7,8] While the outcomes of active surveillance for men with cribriform Gleason pattern 4 disease have not been adequately studied, available evidence suggests this to be a relative contraindication.
The percentage of men who will eventually undergo curative treatment after starting active surveillance ranges from 20% to 50%.[9,10] For men with low-risk disease, multiple reports have shown that delayed RP is not associated with adverse pathology on final RP specimen.[11-13] However, we previously retrospectively investigated 1,561 low- and intermediate-risk men from multiple Veterans Affairs centers and showed that a delay > 9 months to RP in men with intermediate-risk prostate cancer was associated with biochemical recurrence (BCR) and positive surgical margins (PSMs). The same findings were true in “lower-risk” subgroups of men with intermediate-risk prostate cancer, including those with low-volume Gleason score 3+4 disease. Similarly, Cooperberg et al retrospectively evaluated the CapSURE database for men with intermediate-risk disease as defined by Gleason score 3+4 or a UCSF Cancer of the Prostate Risk Assessment (CAPRA) score of 3–5 managed with active surveillance who ultimately underwent RP. They reported a 50% incidence of pT3 disease in the active surveillance arm compared with 23% in the entire cohort that underwent immediate RP, suggesting that active surveillance may be suboptimal for men with favorable intermediate-risk disease.
Standard-of-care 12-core transrectal ultrasound (TRUS)-guided prostate biopsies are prone to significant sampling error. As a result, about 30% of RP specimens are upgraded and/or upstaged from their biopsy Gleason grade or stage.[9,16,17] A recent retrospective series reported only 57.4% grade concordance on final RP specimen for TRUS-guided biopsy-proven Gleason score 3+4 disease and upgrading of 10.7%, 19.1%, and 6.4% to Gleason score 4+3, 4+4, and 9–10, respectively. Similarly, Epstein et al have previously reported a concordance of 49.7% for 3+4 disease and an upgrade of 25.8%. More recently, Yang et al retrospectively investigated 10,000 patients with Gleason score 3+4 favorable intermediate-risk disease and also found about 30.3% of upgrading and/or upstaging. In this series, 17% of the entire cohort were upstaged to ≥ pT3a disease. Risk of more aggressive disease in this cohort was associated with higher PSA levels, older age (> 67 years), higher percentage of positive biopsy cores, and cT2a stage. Taken together, these data suggest that as many as one-third of men offered active surveillance for favorable intermediate-risk prostate cancer diagnosed on TRUS-guided biopsy are already harboring higher-risk disease and would not be offered surveillance had the prostate been adequately sampled.
There are also high-risk populations for which the current inclusion of active surveillance must be utilized with caution. For example, African American men on average make up less than 10% of the active surveillance cohorts, but are 2.4 times more likely to die from prostate cancer than their Caucasian counterparts.[20-23] Sundi et al showed that African American men with very-low-risk prostate cancer who met criteria for active surveillance but underwent immediate RP had higher rates of upgrading and PSMs compared with other races. Iremashvili et al included the following in their inclusion criteria for active surveillance: Gleason score < 7, two or fewer positive biopsy cores, 20% or less tumor in any core, and clinical stage T1–T2a, with any change from these parameters above these limits considered progression. In their study, they showed that African American men were significantly more likely to have disease progression, with an adjusted hazard ratio of 3.87–4.12. We previously retrospectively analyzed a Duke University active surveillance cohort with inclusion criteria consisting of clinical stage < cT3, PSA level < 10 ng/mL, Gleason sum ≤ 6, and ≤ 33% positive biopsy cores. On the basis of both objective disease progression and patient-driven decisions, African American men progressed to treatment faster on active surveillance compared with other races. While many unanswered questions remain regarding potential race disparities in prostate cancer, there are insufficient data to support active surveillance for intermediate-risk prostate cancer in high-risk populations such as African American men.
It should be stated that the reported 10-year outcomes from the ProtecT trial did not show an improvement in survival with treatment compared with active monitoring; however, only 21% of the patients on active monitoring had Gleason 7 disease. Despite the primarily low-risk profile of the ProtecT cohort, there was a statistically significant increase in metastases and clinical progression in the active monitoring arm. In the Prostate Intervention vs Observation Trial (PIVOT), which randomized US veterans to either RP or observation for clinically localized prostate cancer, the overall conclusion was that RP did not improve survival. However, the intermediate-risk subgroup that underwent RP had statistically improved overall survival and prostate cancer–specific survival (hazard ratio, 0.53) that did not reach statistical significance. Taken together, although the active monitoring or observation used in PIVOT and ProtecT were not as intensive as modern active surveillance, and neither trial was powered to detect survival differences for Gleason score 3+4 prostate cancer, these level 1 data do not definitively prove the safety of active surveillance in this population.
We summarize the caveats to offering active surveillance in men with Gleason score 3+4 prostate cancer in the Table. However, how do we move forward? To confidently offer active surveillance in men with Gleason score 3+4 prostate cancer, we feel that confirmatory biomarkers are needed as a safety measure for inclusion. The most data currently exist for multiparametric MRI (mpMRI) and tissue-based genomic panels, which are increasingly utilized clinically for active surveillance. The high negative predictive value of mpMRI for high- and intermediate-risk prostate cancer could increase confidence in a recommendation for active surveillance, and also provides targets for a re-sampling confirmatory biopsy. Other tools that may be alternatives or complementary to mpMRI are the several commercially available tissue-based genomic panels validated to predict adverse RP histology and prostate cancer outcomes, such as metastasis-free survival. There are reports of changed and more confident decision making for newly diagnosed prostate cancer with these tests in both physicians and patients compared with groups in which these tests were not utilized.[30,31] Our current ongoing study, the ENACT trial, which randomizes men with newly diagnosed very-low-, low-, or favorable intermediate-risk prostate cancer to either standard counseling vs counseling with a tissue genomic panel, should help to determine the clinical utility of a tissue-based biomarker approach to active surveillance selection.
In conclusion, men with Gleason score 3+4=7 prostate cancer represent a heterogeneous group. There are inadequate data regarding the long-term outcomes of active surveillance in these men, especially in high-risk populations such as African American men. The use of imaging and tissue-based biomarkers hold promise in helping us to find the most favorable subset of men with intermediate-risk prostate cancer for which active surveillance may be the favored initial management strategy.
Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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