At least 75,000 new patients with prostate cancer (PCa) per year in the United States are diagnosed with low risk disease (prostate specific antigen [PSA] <10 ng/ml, Grade Group [GG] 1, cT1c/T2a), and active surveillance (AS) is the preferred management strategy for these patients, recommended by nearly all major guidelines.^1–3 Large single and multi-institutional AS cohorts with extended followup, in addition to randomized clinical trials of immediate treatment vs observation, have supported surveillance in this clinical setting.^4–8 Notably, many of the AS cohorts included men across the spectrum of PCa risk, not only including men with so-called “very low risk” PCa but also a substantial proportion of men with low-risk and even favorable-intermediate risk disease. Although guidelines provide near consensus preference for AS over active treatment for low risk PCa, there is lack of consensus regarding optimal monitoring protocols, including how frequently to perform PSA measurements, prostate biopsies and digital rectal examinations, in addition to the need for imaging or biomarkers. Herein, we will address the issue of what to tell your patients who are starting on AS with regards to their schedule for evaluation.

Serial surveillance prostate biopsy is a well-established and integral part of current AS protocols, although biopsies are also associated with significant risks of acute infection, pain and costs. The frequency of biopsies is variable across reported AS series, ranging from annual biopsies to every 3–5 years. One notable study examined 4 AS cohorts in the U.S., evaluating the tradeoffs of biopsy frequency and differences in the patient populations with the finding that biennial biopsies are an acceptable alternative to annual biopsies.⁹ We typically recommend a confirmatory biopsy at the 6–12-month timeframe after diagnosis with subsequent biopsies being biennial, unless triggered by clearly rising PSA levels. We have shown that the rate of adverse reclassification is similar whether the confirmatory biopsy is performed at 6 or 12 months,¹⁰ and some men may be reassured with an earlier confirmatory biopsy at 6 months. If the patient has no evidence of grade progression over the first 5–6 years, and in particular if the patient has multiple negative prostate biopsies as shown by our team,¹¹ we begin to decrease the frequency of surveillance biopsy.

The frequency of PSA measurements has also not been well established, with most guidelines recommending PSA assessments no more frequent than every 6 months. Although early reports suggested that PSA levels are not clearly related to risk of upgrading,¹² more recent reports associate rising PSA levels with higher grade disease on subsequent biopsies.¹³ One study examined PSA measurements taken every 3 months compared to every 6 months, demonstrating no clear value to more frequent measurements.¹³ We routinely obtain PSA on an every-6-months schedule that corresponds with patient clinical appointments.

While multiparametric magnetic resonance imaging (mpMRI) has been shown to improve the detection of clinically significant disease in the initial diagnosis of PCa,^14,15 it remains unclear whether mpMRI has utility in AS or whether mpMRI can safely replace surveillance biopsies in men with low-risk disease managed with AS. The only randomized clinical trial of mpMRI in AS was a negative trial, showing that mpMRI did not lead to detection of more clinically significant cancers when compared to the standard of care transrectal ultrasound-guided biopsies.¹⁶ Our group evaluated 395 magnetic resonance imagings (MRIs) performed within 12 months prior to a surveillance biopsy,¹⁷ reporting an 83% negative predictive value and 31% positive predictive value for GG2 or greater disease. Several other cohort studies have addressed the performance of MRI for predicting biopsy upgrading during AS with conflicting results, but general consensus that a negative MRI does not ensure a lack of tumor upgrading in a patient on AS. Additionally, if an MRI is abnormal, both targeted and systematic biopsies should be performed. Lastly, while higher Prostate Imaging–Reporting and Data System™ scores are associated with a greater risk of a clinically significant cancer on surveillance biopsy, several other clinical factors are associated with upgrading. As such, we do not recommend the routine use of MRI in all patients on AS, but consider its use in men with higher volume disease, higher PSA density, or a rising PSA. Furthermore, similar to published guidelines, we inform our patients that MRI should not be used as a replacement for surveillance biopsies.¹⁸

Multiple biomarkers, primarily tissue-based panels, are commercially available and have been shown to be associated with clinically relevant end points, such as adverse pathology and prostate cancer-specific mortality. Importantly, the majority of these platforms were developed and validated in patients who had already undergone radical prostatectomy across the spectrum of prostate cancer, including men with much higher risk PCa, not in men currently undergoing AS. The results of investigations in men on AS are relatively limited and conflicting. We would endorse the recent joint AUA-American Society of Clinical Oncology guideline that these biomarkers are not recommended for routine use; however, their use may be considered in situations where the result is more likely to affect management, such as in high-volume GG1 or low-volume GG2.¹⁹

Future advancements in the practice of AS will likely incorporate risk tools and models. These instruments will use the entire wealth of clinical variables, such as patient age, serum PSA value, prostate volume (or PSA density), ratio of biopsy cores containing cancer to total biopsy cores, number of prior negative biopsies and time from most recent biopsy to calculate the risk of adverse reclassification (or progression) vs stable disease.^20,21 Emerging iterations of these tools may incorporate imaging and biomarkers if studies prove their incremental value over existing clinical models. We recently reported on a model that can predict reclassification-free survival and thus potentially can identify subsets of low-risk patients in whom we can decrease intensity of surveillance and even avoid serial prostate biopsies.²² These findings suggest that AS intensity can be modulated based on an individual’s risk parameters and that many men may be safely monitored with a substantially less intensive surveillance regimen. Importantly, these tools may also alleviate patient anxiety that is sometimes associated with AS^23,24 and reduce the treatment in the absence of clear progression that is seen during AS.²⁵ Until these tools/instruments are validated, we have still endorsed the aforementioned array of biennial serial prostate biopsies, PSA measurements every 6 months, and judicious use of MRI and biomarkers.