Active Surveillance for Early-Stage Prostate Cancer: Defining the Triggers for Intervention
Authors: Jared M. Whitson, Peter R. Carroll
Journal: Journal of Clinical Oncology (2010)

After the initiation of prostate-specific antigen (PSA) –based screening practices in the 1990s, the proportion of patients with lowrisk disease (defined as low-grade, stage, and volume) at the time of diagnosis has nearly doubled to almost 50%. For patients who would have presented with higher-risk tumors without timely PSA testing, this is a welcome finding. However, many of the nearly 200,000 men who were diagnosed with prostate cancer (PCa) in 2009 may never have been diagnosed without PSA testing, nor would they have developed illness or died from undetected disease. Although two recently reported PSA screening studies showed disparate findings with regard to any impact on PCa specific mortality, both showed that the single biggest risk to screening is overdetection. Despite this latter fact, the vast majority of men with PCa are actively treated with surgery, radiation, androgen ablation, or all three. This holds true even for those cancers deemed ideal for surveillance. It is clear from this discrepancy in the natural history and aggressive treatment of low-risk PCa that patients and their physicians are not convinced of the favorable benefit to risk ratio proposed by supporters of active surveillance (AS). Consensus is needed on the appropriate patient inclusion criteria for AS, as well as monitoring strategies and indications for treatment for those on AS. In this issue of Journal of Clinical Oncology, Ross et al report the results of a retrospective cohort study which examined the association between PSA kinetics (PSA doubling time [PSADT] or PSA velocity [PSAV]) and surveillance biopsy results in men with low-risk PCa who have chosen AS as their initial management strategy. This is a timely article, given the recent inclusion in the National Comprehensive Cancer Network guidelines of AS as an initial management strategy in newly diagnosed patients with PCa; furthermore, PSADT shorter than 3 months is listed as a marker of disease progression. In this study, 290 of 618 men on AS met the inclusion and exclusion criteria defined by clinical stage T1c (non-palpable or visible), a PSA density less than 0.15 ng/mL/cm, Gleason 6, and 2 cores positive with no core more than 50% involved in at least a 12-core biopsy scheme. Ross et al were unable to identify a PSAV or PSADT threshold which could classify those with and without more adverse pathology detected on surveillance biopsy. The authors suggest that at present surveillance biopsy is a critical component in any AS strategy and that PSA kinetics are not sufficient to define disease progression, identification of higher grade disease on follow-up biopsy, and need for treatment. One of the primary strengths of this study is that PSA kinetics were not used to define disease progression. This prevents incorporation bias in the association between PSA kinetics and worsening disease. This form of bias occurs when the index test, usually among other factors, is used as evidence that the outcome has occurred. The authors’ study design also prevents verification bias in the association between PSA kinetics and adverse pathology at radical prostatectomy. This form of bias occurs when application of the gold standard, often an invasive procedure, is necessary for inclusion in the study and occurs preferentially in those with an abnormal index test. Both incorporation and verification bias have been present in many previous assessments of PSA. However, the results of this study are somewhat unexpected in light of the existing PCa literature. In men undergoing radical prostatectomy, higher PSAV is associated with both worse Gleason score and T stage. Furthermore, in patients undergoing either prostatectomy or radiation therapy, a PSAV higher than 2.0 ng/mL/yr in the year before diagnosis predicts PCa specific mortality. The authors’ institution has previously reported that a PSAV higher than 0.35 ng/mL/yr 10 to 15 years before the diagnosis of PCa is predictive of PCa-specific mortality. In that study, the median values of PSAV between patients without PCa and who died of PCa were roughly 0 and 0.2, with significant overlap. In this study, the median PSAV values for patients who did not progress and who progressed were 0.2 and 0.5, respectively, again with significant overlap. Therefore, one must wonder the role sample size could have played in the lack of significant findings in this study. Furthermore, the authors’ findings differ from other studies in men specifically in AS protocols. Three prior articles have shown a statistically significant association between PSA kinetics and biopsy progression. Only one prior article failed to show an association between PSADT and biopsy progression. In addition, one study from the authors’ institution has shown an association between PSA kinetics and treatment. Perhaps most importantly, an association between shorter PSADT and worse outcomes in men on AS who subsequently undergo treatment has been reported. One important caveat is that verification bias may have played a role in some of these studies because PSA kinetics may have been used as a prompt for biopsy or treatment. The authors have appropriately mentioned some of the limitations of this study, including generalizability to those with higher-risk disease being managed with AS, the potential for measurement error JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 28 NUMBER 17 JUNE 1