Active Surveillance: What is the Schedule You Tell Your Patient?
By: William J. Ellis, MD; Daniel W. Lin, MD | Posted on: 01 Dec 2021
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 AS23,24 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.
- Sanda MG, Cadeddu JA, Kirkby E et al: Clinically localized prostate cancer: AUA/ASTRO/SUO guideline. Part II: recommended approaches and details of specific care options. J Urol 2018; 199: 990.
- Sanda MG, Cadeddu JA, Kirkby E et al: Clinically localized prostate cancer: AUA/ASTRO/SUO guideline. Part I: risk stratification, shared decision making, and care options. J Urol 2018; 199: 683.
- Bekelman JE, Rumble RB and Freedland SJ: Clinically localized prostate cancer: ASCO clinical practice guideline endorsement of an AUA/ASTRO/SUO guideline summary. J Oncol Pract 2018; 14: 618.
- Klotz L, Vesprini D, Sethukavalan P et al: Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J Clin Oncol 2015; 33: 272.
- Tosoian JJ, Mamawala M, Epstein JI et al: Intermediate and longer-term outcomes from a prospective active-surveillance program for favorable-risk prostate cancer. J Clin Oncol 2015; 33: 3379.
- Masic S, Cowan JE, Washington SL et al: Effects of initial Gleason grade on outcomes during active surveillance for prostate cancer. Eur Urol Oncol 2018; 1: 386.
- Bill-Axelson A, Holmberg L, Garmo H et al: radical prostatectomy or watchful waiting in prostate cancer–29-year follow-up. N Engl J Med 2018; 379: 2319.
- Wilt TJ, Jones KM, Barry MJ et al: Follow-up of prostatectomy versus observation for early prostate cancer. N Engl J Med 2017; 377: 132.
- Inoue LYT, Lin DW, Newcomb LF et al: Comparative analysis of biopsy upgrading in four prostate cancer active surveillance cohorts. Ann Intern Med 2018; 168: 1.
- Macleod LC, Ellis WJ, Newcomb LF et al: Timing of adverse prostate cancer reclassification on first surveillance biopsy: results from the Canary Prostate Cancer Active Surveillance Study. J Urol 2017; 197: 1026.
- Kearns JT, Faino AV, Newcomb LF et al: Role of surveillance biopsy with no cancer as a prognostic marker for reclassification: results from the Canary Prostate Active Surveillance Study. Eur Urol 2018; 73: 706.
- Ross AE, Loeb S, Landis P et al: Prostate-specific antigen kinetics during follow-up are an unreliable trigger for intervention in a prostate cancer surveillance program. J Clin Oncol 2010; 28: 2810.
- Cooperberg MR, Brooks JD, Faino AV et al: Refined analysis of prostate-specific antigen kinetics to predict prostate cancer active surveillance outcomes. Eur Urol 2018; 74: 211.
- Ahmed HU, El-Shater Bosaily A, Brown LC et al: Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet 2017; 389: 815.
- Kasivisvanathan V, Rannikko AS, Borghi M et al: MRI-targeted or standard biopsy for prostate-cancer diagnosis. N Engl J Med 2018; 378: 1767.
- Klotz L, Loblaw A, Sugar L et al: Active Surveillance Magnetic Resonance Imaging Study (ASIST): results of a randomized multicenter prospective trial. Eur Urol 2019; 75: 300.
- Liss MA, Newcomb LF, Zheng Y et al: magnetic resonance imaging for the detection of high grade cancer in the Canary Prostate Active Surveillance Study. J Urol 2020; 204: 701.
- Chen RC, Rumble RB, Loblaw DA et al: Active surveillance for the management of localized prostate cancer (Cancer Care Ontario guideline): American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol 2016; 34: 2182.
- Eggener SE, Rumble RB, Armstrong AJ et al: Molecular biomarkers in localized prostate cancer: ASCO guideline. J Clin Oncol 2020; 38: 1474.
- Ankerst DP, Xia J, Thompson IM Jr et al: Precision medicine in active surveillance for prostate cancer: development of the Canary-Early Detection Research Network Active Surveillance Biopsy Risk Calculator. Eur Urol 2015; 68: 1083.
- Tomer A, Nieboer D, Roobol MJ et al: Personalised biopsy schedules based on risk of Gleason upgrading for patients with low-risk prostate cancer on active surveillance. BJU Int 2021; 127: 96.
- Cooperberg MR, Zheng Y, Faino AV et al: Tailoring intensity of active surveillance for low-risk prostate cancer based on individualized prediction of risk stability. JAMA Oncol 2020; 6: e203187.
- Marzouk K, Assel M, Ehdaie B et al: Long-term cancer specific anxiety in men undergoing active surveillance of prostate cancer: findings from a large prospective cohort. J Urol 2018; 200: 1250.
- Tan HJ, Marks LS, Hoyt MA et al: The relationship between intolerance of uncertainty and anxiety in men on active surveillance for prostate cancer. J Urol 2016; 195: 1724.
- Kirk PS, Zhu K, Zheng Y et al: Treatment in the absence of disease reclassification among men on active surveillance for prostate cancer. Cancer 2021; https://doi.org/10.1002/cncr.33911.