Lifetime Benefits and Harms of Prostate-Specific Antigen–Based Risk-Stratified Screening for Prostate Cancer

Eveline A.M. Heijnsdijk, PhD; Roman Gulati, MS; Alex Tsodikov, PhD; Jane M. Lange, PhD; Angela B. Mariotto, PhD; Andrew J. Vickers, PhD; Sigrid V. Carlsson, MD, PhD, MPH; Ruth Etzioni, PhD


J Natl Cancer Inst. 2020;112(10):1013-1020. 

In This Article

Abstract and Introduction


Background: Studies conducted in Swedish populations have shown that men with lowest prostate-specific antigen (PSA) levels at ages 44–50 years and 60 years have very low risk of future distant metastasis or death from prostate cancer. This study investigates benefits and harms of screening strategies stratified by PSA levels.

Methods: PSA levels and diagnosis patterns from two microsimulation models of prostate cancer progression, detection, and mortality were compared against results of the Malmö Preventive Project, which stored serum and tracked subsequent prostate cancer diagnoses for 25 years. The models predicted the harms (tests and overdiagnoses) and benefits (lives saved and life-years gained) of PSA-stratified screening strategies compared with biennial screening from age 45 years to age 69 years.

Results: Compared with biennial screening for ages 45–69 years, lengthening screening intervals for men with PSA less than 1.0 ng/mL at age 45 years led to 46.8–47.0% fewer tests (range between models), 0.9–2.1% fewer overdiagnoses, and 3.1–3.8% fewer lives saved. Stopping screening when PSA was less than 1.0 ng/mL at age 60 years and older led to 12.8–16.0% fewer tests, 5.0–24.0% fewer overdiagnoses, and 5.0–13.1% fewer lives saved. Differences in model results can be partially explained by differences in assumptions about the link between PSA growth and the risk of disease progression.

Conclusion: Relative to a biennial screening strategy, PSA-stratified screening strategies investigated in this study substantially reduced the testing burden and modestly reduced overdiagnosis while preserving most lives saved. Further research is needed to clarify the link between PSA growth and disease progression.


It has long been understood that controlling the harm–benefit trade-off of prostate-specific antigen (PSA) screening is critical for its sustainability. Strategies for reducing harms while preserving benefits include screening less frequently, using higher thresholds for biopsy referral in older men, and tailoring screening algorithms by PSA level.[1–15]

The recommendation to stratify screening by PSA level is largely based on studies that stored ethylenediamine tetraacetic acid plasma in an unscreened cohort of Swedish men aged 44–60 years in the 1980s.[4,11,12,16,17] Prostate cancer cases diagnosed up to 25 years later had statistically significantly higher PSA levels at their baseline blood draw than those not diagnosed. There was also a strong association between baseline PSA and prostate cancer mortality: 44% of prostate cancer deaths occurred in men with PSA in the top 10% of the PSA distribution at ages 44–49 years.[12] In addition, only 0.2% of men with PSA below 1.0 ng/mL at age 60 years died from prostate cancer within 25 years.[11] Other studies, including screened and unscreened cohorts, have confirmed that baseline PSA predicts the risk of future prostate cancer diagnosis or prostate cancer death.[5–7,13,15,18] These studies have motivated proposals to tailor the screening intensity to a man's current PSA level. However, the implications of such stratified policies for clinically important outcomes, such as prostate cancer deaths or overdiagnosis, compared with current practices have not been evaluated. Despite this, some guidelines are already incorporating PSA-stratified screening. The European Association of Urology guideline states that targeting men at a higher risk of prostate cancer (older than age 50 years, or with PSA >1.0 ng/mL at age 40 years, or >2.0 ng/mL at age 60 years) might reduce the number of unnecessary biopsies.[19] The American Urological Association guideline suggests that baseline PSA may be used to guide alternative screening strategies that screen less frequently.[20]

Some studies have attempted to evaluate the relative harms and benefits of different PSA-based screening strategies. Multiple studies using data from the European Randomized Study of Screening for Prostate Cancer support using a screening interval of 8 years in men with initial PSA levels below 1.0 ng/mL.[8–10,14] A modeling study showed that switching from annual to biennial screening when PSA is less than 2.5 ng/mL did not affect the probabilities of detection and overdiagnosis.[2] Although it is believed that screening intervals longer than 2 years delay the diagnosis of aggressive cancers yet still detect most indolent cancers, there are few studies with quantitative predictions.

This study analyzes harm–benefit trade-offs associated with lengthening the screening interval when PSA is below 1.0 ng/mL at age 45 or 50 years or discontinuing screening when PSA is below 1.0 ng/mL at age 60 years. We focus specifically on how these policies are likely to affect clinically important outcomes like lives saved and overdiagnosis. Ultimately, we aim to determine how stratified screening might change the balance between harms and benefits of screening compared with using a single screening strategy for the entire population.