Prostate-Specific Antigen Screening and Active Surveillance for High-Risk Individuals

Bergengren et al¹ and Nelson et al² report on 2 important and controversial topics in prostate cancer: (1) prostate-specific antigen (PSA) screening and (2) active surveillance for high-risk individuals (ie, men of African ancestry). These 2 topics highlight the complexity of current practices in both the early detection of prostate cancer and the management of localized disease.

In their study, Bergengren and colleagues¹ demonstrate that the use of PSA testing and the resultant increase in diagnostic activity, from 1996 to 2016, corresponded with a 15% decrease in prostate cancer deaths—at the expense of both overdiagnosis and overtreatment—when compared with a simulated scenario in which the use of diagnostic activity was held constant at the rate of testing in 1996 (the early period of routine PSA screening). The study found that the actual number of low-risk and intermediate-risk cancers was 148% higher and that the rate of definitive treatment was more than 2-fold higher compared with the simulated scenario. The modeling strategy used in this study applies both diagnostic and treatment paradigms from nearly 3 decades ago in its simulation model. This strategy, unfortunately, overemphasized past practices and does not adequately account for the significant advances that have been made in the field to date. For instance, nearly 20% of men in the observed cohort had their cancer detected after the age of 80 years; consequently, this study models screening for older men who should not be offered routine PSA testing. The last decade has seen a dramatic increase in the use of active surveillance as a management strategy for men with low-risk prostate cancers at diagnosis.³ Diagnostic tools such as multiparametric prostate magnetic resonance imaging^4,5 and tissue-based molecular testing^6,7 are providing clinicians with additional tools to better discriminate men at risk for prostate cancer, and they are likely to decrease the use of unnecessary prostate biopsies and the overdetection of prostate cancer. Simulation-based studies have also demonstrated that strategies such as age restriction and biennial PSA testing may reduce the burden of overdetecting favorable-risk prostate cancers.⁸

Shoag et al⁹ demonstrated that the benefit from PSA screening continues to accrue even with follow-up extending to 25 years, based on modeling statistics calibrated to population-level incidence rates in the US and the observed screening benefit from a large screening trial. Recent population studies from the US have shown an increase in the rate of incident metastatic prostate cancer since the US Preventive Services Task Force recommendation against routine screening in 2012.¹⁰ A recent study shows that the observed increase in metastatic prostate cancer in the US since 2012 likely is associated withs some decrease in PSA testing in the population.¹¹ Bergengren and colleagues¹ highlight the importance of working toward a strategy of early detection and localized treatment that aims to avoid unnecessary diagnosis and treatment for men because the benefit of screening older men and treating favorable-risk disease is marginal. However, our path to this goal should rely on strategies that do not reduce overdetection at the expense of increasing the detection of incurable and advanced cancers.

Clinicians have struggled with the optimal strategy for monitoring high-risk populations of men with favorable-risk prostate cancer, such as men of African ancestry and men with strong family histories of prostate cancer. Early studies evaluating pathologic specimens from low-risk men treated with surgery suggested that active surveillance would yield unfavorable results for Black men, owing to their increased risk of disease upgrading at prostatectomy.¹² However, more recent studies have provided data that illustrate the safety of active surveillance for Black men.^13,14 Nelson and colleagues² evaluated the association of PSA velocity with grade reclassification among 5296 men identified from the Veterans Affairs Informatics and Computing Infrastructure (2001-2015) that met inclusion criteria for low-risk disease and at least 1 surveillance biopsy within 1 year of diagnosis. The study includes 1377 (26%) Black men over this time period and is impressive in the breadth of its data and length of longitudinal follow-up (mean [SD] follow-up of 7.9 [3.0] years).

The study, however, concludes that Black men should have a different cut point for PSA velocity (0.44 ng/mL/y) compared with White men (1.18 ng/mL/y), based on a multivariable model that assessed various clinical and demographic variables with upgrading at prostate biopsy or surgery. Historically, nearly 30% of men who met criteria for low-risk disease were reclassified to higher-grade disease at their first prostate biopsy after their initial diagnosis.¹⁵ Disease upgrading is a phenomenon that can be observed more frequently at surgery owing to the improved sampling of the entire prostate during pathologic review. A failure to understand the timing of upgrading events and the criteria for treatment may introduce bias and confounding in this analysis, which may make it difficult to interpret the results in routine clinical practice. It would also be important to understand whether these upgrading events occurred at the first biopsy after diagnosis, which would suggest that these men may have had their true disease burden misclassified at their initial biopsy. In this scenario, equitable care for Black men with low-risk disease may involve diagnostic multiparametric prostate magnetic resonance imaging to improve initial and surveillance biopsy results.

Last, race-based medical practices have the potential to create their own disparities. This scenario has been described, for instance, with estimated glomerular filtration rates, for which the adjustment for race impacted patient eligibility for potentially life-saving interventions, such as a timely transplant.¹⁶ Race is a social construct, and although this may inform biology, it also reflects the association of structural, social, and environmental factors with health. It is unclear from this study why we should take a differential approach to the management of favorable-risk prostate cancer based on race and PSA velocity alone. A Black man whose PSA increases from 5.0 to 5.44 ng/mL during the course of 1 year should not be considered unsuitable for continuation of active surveillance. Such a strategy may unduly increase this patient’s risk of overtreatment. It also highlights the importance of nuance in interpreting PSA parameters in active surveillance, which should also factor in absolute PSA values.

Published: May 17, 2021. doi:10.1001/jamanetworkopen.2021.9711

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Nyame YA et al. JAMA Network Open.

Corresponding Author: Michael P. Porter, MD, MS, Department of Surgery, Urology Section, Veterans Affairs Puget Sound Healthcare System, 1660 S Columbian Way, S-112-GU, Seattle, WA 98108 (mporter@uw.edu).

Conflict of Interest Disclosures: None reported.