We emphasize that this experience was in the pre-MRI and biomarker era and also reflected the learning curve of active surveillance. Today, such patients would have the benefit of an MRI, with a high likelihood of identifying large-volume potentially lethal cancer and also, potentially, of a molecular biomarker to predict risk [15].

Another experience with surveillance in intermediate risk is derived from the National Prostate Cancer Register of Sweden [16] compared outcomes of 4163 intermediate-risk patients who were managed with active surveillance (23%), radical prostatectomy (52%), and radiation therapy (25%). Among patients with intermediate-risk disease, the prostate cancer mortality was 5.2% in the active surveillance group, 3.4% in the radical prostatectomy group, and 3.8% in the radiation therapy group. These figures are similar to those reported in the Sunnybrook cohort.

Because of the very favorable experience with Gleason 6 cancer, and the significantly higher rate of progression with Gleason 7 disease , most groups have now converged to a middle ground, offering surveillance to most Gleason 6 cases regardless of cancer volume and being very selective about offering it to Gleason 7 patients.

As of the publication of this document, three genetic tissue based assays summarized below have been approved by the FDA for men with prostate cancer. None of these tests have yet been validated as providing substantial benefit in the active surveillance population. However, the “sweet spot” for molecular biomarkers is the otherwise favorable risk patient with small amount of pattern 4 (Grade Group 2) on biopsy who prefers a conservative approach if possible. A low score on a validated molecular assay provides a great deal of reassurance about the safety of nonintervention.

Evidence indicates that these genomic assays can predict indolent disease behavior despite the appearance of higher-grade cancer on biopsy. For example, a patient with Grade Group 2 (Gleason 3 + 4) PCa and a “low-risk” Oncotype DX® or Prolaris® test should have an mp-MRI to rule out any multifocal disease and can be advised to have conservative management. Future research goals will be to integrate and correlate information obtained through mp-MRI and results of genetic biomarkers.

Young age, in contrast, has not been demonstrated to be a risk factor for progression. Indeed, the likelihood of harboring higher-grade cancer at diagnosis is lower in young men with Gleason 6 cancer. In the Sakr autopsy series, 29% of men in their 30s harbored microfocal Gleason 6 cancer [23]. Finding small amounts of low-grade cancer in a young man in no way means that he is destined to progress to significant cancer. The caveat is that they have a longer period of time to develop biologic disease progression (to higher-grade cancer). The best estimate of the likelihood of grade progression (as distinct from disease reclassification due to more accurate or repeat sampling) is 1.2–2% per year [24].

A recent study evaluated the association of age with various active surveillance endpoints [25]. Patients less than 60 years old received more surveillance biopsies per time interval. Despite the more intensive assessment, younger age was associated with a lower risk of biopsy upgrade and progression. There were no differences with respect to treatment, adverse disease, or biochemical recurrence. Younger patients should be advised that intermediate-term outcomes are not worse but that longer-term follow-up is needed. Thus, young patients can in most cases be managed conservatively but require long-term follow-up.