Position PaperActive Surveillance for Low-risk Prostate Cancer: The European Association of Urology Position in 2018
Introduction
Approximately 45% of men with screening-detected localized prostate cancer (PCa) are candidates for deferred treatment [1]. The Cluster Randomized Trial of PSA Testing for Prostate Cancer showed that a single PSA screening intervention increased the detection of low-risk PCa [2]. In this context, active surveillance (AS) represents a well-recognized option for the initial management of selected patients with low- and very low-risk PCa. This approach is increasingly used in this setting [3], [4], with the aims of reducing possible overtreatment and achieving curative treatment for those with progressive disease without losing the window of curability [5]. Patients remain under close surveillance, and treatment is prompted by predefined thresholds indicative of potentially life-threatening but still curable disease in men with adequate life expectancy. Current data supporting the role of AS are derived from ongoing prospective or retrospective cohorts. No formal randomized controlled trial is available comparing AS to standard treatment, although a randomized study of less intensive active monitoring showed no difference in overall survival (OS) at 10 yr when compared to active treatment mainly in men with low- and intermediate-risk PCa [6]. The largest published AS cohort coupled with the longest follow-up included 993 patients with low- or intermediate-risk PCa [7]. This prospective cohort enrolled men with clinical stage T1 or T2a and PSA ≤10 ng/ml, age ≤70 yr, and a Gleason score ≤6 or age >70 yr with a Gleason score of ≤3 + 4. Interestingly, men with intermediate-risk disease represented approximately 20% of the entire cohort of study. Moreover, neither multiparametric magnetic resonance imaging (mp-MRI; not available at the time of study initiation) nor extensive biopsy sampling were considered in the study. After a median follow-up of 6.4 yr, the 10- and 15-yr OS were 80% and 62%, respectively, and cancer-specific survival (CSS) rates were 98.1% and 94.3%, respectively. Radical treatment was received by 27% of this population, prompted by a PSA doubling time <3 yr (43.5%), a Gleason score progression on repeat biopsies (35%), and patient preference (6%). Thirty men (3%) developed metastases during follow-up: 2% of those initially classified as Gleason 6 as compared to 9.7% if initially Gleason 7 [8]. Several other protocols have investigated AS in organ-confined disease [9], including the PRIAS study which represents the largest prospectively enrolled cohort of men initially managed with AS [10]. Although a decline in adherence has been observed in real life [11], AS showed to be safe and able to reduce the extent of overtreatment in low-risk PCa, provided accurate patient selection. Given such favorable outcomes, several studies focused on how to expand indications and to increase adherence to AS protocols [12], [13]. This has contributed to an increasing number of studies and recommendations [14], [15], sometimes based on single institution expertise rather than on strong, large evidence. In particular, the role of imaging and biomarkers during AS is not yet standardized and different protocols have been implemented with these approaches at different stages of AS. Some studies used mp-MRI to confirm eligibility for AS [16], [17], others included imaging to expand inclusion criteria for AS and to reduce misclassification by using fusion biopsies [18], [19], or even to replace the key role of prostate biopsy during follow-up [20]. In addition to such recent implementations, there are still considerable variations among studies regarding patient selection, follow-up schedule, the use of confirmatory or repeat biopsy and what should trigger active treatment. Moreover, existing guidelines regarding AS for PCa vary widely [21]. These differences not only make comparison between these studies difficult but also contribute to highly heterogeneous protocols for AS, which is confusing to both physicians and patients. All these reasons have prompted the European Association of Urology (EAU) to produce a position paper on AS, as done previously for other topics [22], [23], [24].
Section snippets
Statement
Include all men with low-risk PCa for AS using a standardized prospective protocol. Men with longer life expectancy (ie, >20 yr) should be properly counseled about the lack of very long-term data of AS.
Scientific background
There are several long-term prospective AS cohorts that have been reported, with different inclusion criteria and different protocols [25], [26], [27], [28], [29]. These different selection criteria included men fit for curative treatment and a life expectancy of at least 10 yr with low/very
Statement
Report the number of cores submitted for pathological assessment and the number of positive cores per side. Report the linear percentage or length (in mm) of involvement by carcinoma in the single core with the greatest amount of tumor. Finally, consider central pathological review of biopsy specimens when commencing long-term conservative treatments.
Scientific background
Accurate histopathologic assessment at biopsy is crucial for the selection of men suitable for AS. According to a recent consensus meeting, the
Use and timing of MRI in active surveillance
mp-MRI can be used to detect clinically significant PCa in men on AS in order to improve patient selection and to optimize cancer diagnosis and timing for intervention. This can be done in three settings during AS:
- 1.
mp-MRI at the time of initial diagnosis.
- 2.
mp-MRI before confirmatory biopsy.
- 3.
mp-MRI during follow-up.
Statement
The follow-up strategy still relies mainly on clinical and biopsy assessment. It is based on serial digital rectal examination (at least once a year), PSA (at least once every 6 mo), and repeated biopsy (at a minimum interval of 3–5 yr). mp-MRI cannot be used as a stand-alone tool to trigger follow-up biopsies.
Scientific background
Follow-up schedules of the largest AS series are reported in Table 2. Based on two single-center studies [50], [52], not all patients with progression/reclassification at biopsy had
Statement
Despite the evidence that some men with Gleason 3 + 4 may have favorable final pathology and good outcomes on AS, it is clear that these men have an increased risk of clinical progression and the development of metastasis when monitored using an AS protocol. If men with limited Gleason 3 + 4 at biopsy decide to undergo AS, this should be done within a standardized protocol where patients are correctly informed about the lack of robust data and the increased risk of progression.
Scientific background
Although most
Statement
After appropriate risk stratification, patients should be counseled that outcomes of AS appear similar between younger and older patients, albeit that younger men need longer follow-up. Therefore, young age is not a preclusion from AS. However, young patient (<55 yr) with long life expectancy (ie, >20 yr) need to be counseled regarding the lack of robust data at very long-term follow-up, although they may also have more to gain from delaying radical therapy for many years.
Scientific background
Overtreatment of
Statement
Given the lack of prospective data on AS outcomes stratified according to race, patient race should not modify eligibility to and follow-up during AS.
Scientific background
Previous studies have reported higher rate of occult co-existent cancer in low-risk African-American patients as well as higher rates of biochemical recurrence after surgery [66], [67]. However, one large recent study of the SEARCH database including 40% African-American men with low-risk cancer showed no difference in pathological upstaging or
Statement
Biological markers, including PSA isoforms, urine PCA3, TMPRSS2-ERG, 4K score, or GPS appear promising to guide care of men with AS. However, they have not yet been prospectively robustly tested in the AS setting. Therefore, while waiting for further data and even though some men may benefit for assessment of these biomarkers, their use cannot be currently routinely recommended in AS.
[–2]proPSA and Prostate Health Index
[–2]proPSA and Prostate Health Index, measured at diagnosis or during AS, have discriminatory power for the
Statement
Patient distress should not necessarily trigger radical treatment. Men with favorable-risk PCa suitable for AS should be properly reassured about the safety of this approach. Therefore, psycho-oncological support in men on AS is encouraged to minimize patient distress and optimize adherence to AS.
Scientific background
Patient preference accounts for approximately 6% of reasons for discontinuing surveillance [7]. Moreover, patient preference is related to non-adherence, which in the end may lead to discontinuation.
Statement
The decision to deliver active treatment should be based on the deterioration (ie, disease progression) of the prior inclusion criteria (Table 1). A worsening in mp-MRI features such as increased volume of the index lesion, appearance of new lesions or increased PIRADS score at a given lesion do not represent “per se” trigger for intervention. Rather, these parameters should be used to optimize timing, targeting, and extent of biopsies. When the life expectancy decreases, the decision to remain
Conclusions
AS should be considered for all men with low-risk PCa, fit for curative treatment, and willing to adhere to AS protocols, including younger men who are provided accurate assessment to exclude misclassification of higher-grade disease. However, men with very long life expectancy should be counseled about the lack of very long-term data of AS. Consider central pathological review of the biopsy specimens in patients within AS programs, especially when recommendations for reporting criteria are not
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