Study Overview
Objective. To determine the effect of a single prostate-specific antigen (PSA) screening and standardized diagnostic pathway on prostate cancer–specific mortality when compared with no screening.
Design. Cluster randomized controlled trial.
Setting and participants. The study was conducted at 573 primary care clinics in the United Kingdom. 419,582 men, 50 to 69 years of age, were recruited between 2001 and 2009 and follow-up ended in 2016. Primary care clinics were randomized to intervention or control. Men in intervention group primary care clinics received an invitation to a single PSA test followed by standardized prostate biopsy in men with PSA levels of 3 ng/mL or greater. A trial that compared radical prostatectomy, radiotherapy, and androgen deprivation therapy and active monitoring was embedded within the screening trial [1]. The control group practices provided standard treatment and PSA testing was provided only to men who requested it. The majority of primary practices were in urban areas (88%–90%) and with multiple partners within the practice (88%–89%). Cases of prostate cancer that were detected in the intervention or control groups during the course of the study were managed by the same clinicians.
Main outcome measures. Main study outcome measures were definite, probable, or intervention-related prostate cancer mortality at a median follow-up of 10 years. An independent cause of death evaluation committee that was blinded to group assignment determined the cause of death in each case. The secondary outcomes included all-cause mortality and prostate cancer stage and Gleason grade at cancer diagnosis. The analysis was an intention-to-screen analysis. Survival analysis using Kaplan-Meier plots were done to demonstrate cumulative incidence of outcomes discussed above. Mixed effects Poisson regression models were used to compare prostate cancer incidence and mortality in intervention vs. control practices accounting for clustering.
Main results. A total of 189,386 men were in the intervention group, 40% attended the PSA testing clinic, and 67,313 (36%) had a blood sample taken for PSA testing, resulting in 64,436 valid PSA test result. 6857 (11%) had elevated PSA levels, of which 85% had a prostate biopsy. In the control group, it was estimated that contamination (PSA testing in the control group) occurred at a rate of approximately 10%–15% over 10 years. After a median follow-up of 10 years, 549 men died of prostate cancer–related causes in the intervention group, at a rate of 0.3 per 1000 person-years, and 647 men died of prostate cancer–related causes in the control group, at a rate of 0.31 per 1000 person-years. The rate difference was 0.013 per 1000 person-years with a risk ratio (RR) of 0.96 (95% confidence interval [CI], 0.85–1.08), P = 0.50), which was not statistically significant. The number of men diagnosed with prostate cancer was higher in the intervention group than in the control group (4.3% vs. 3.6%, RR 1.19 (95% CI 1.14–1.25), P < 0.001). The incidence rate was 4.45 per 1000 person-years in the intervention group and 3.80 per 1000 person-years in the control group. The prostate cancer tumors in the intervention group were less likely to be high grade or advanced stage when compared to the control group. There were 25,459 deaths in the intervention group and 28,306 deaths in the control group. There was no significant difference in the rates of all-cause mortality between the two groups.
Conclusion. The study found that a single PSA screening among men aged 50–69 did not reduce prostate cancer mortality at 10 years follow-up, but led to the increase in the detection of low-risk prostate cancer cases. This result does not support the screening strategy of a single PSA testing for population-based screening for prostate cancer.
Commentary
The use of a PSA test for population-based screening for prostate cancer is controversial; the United States Preventive Services Task Force (USPSTF) recommended against the routine use of PSA test for screening for prostate cancer because the evidence of its benefit is weak and because of the potential risks of unintended consequences of PSA screening [2]. This study is the largest study to date on PSA screening and it found that a low-intensity screening approach—a single PSA test—was not effective in reducing prostate cancer deaths, but rather identified early-stage prostate cancer cases. This result contrasts with previous large scale studies that found that screening led to an increased rate of prostate cancer diagnosis and reduced prostate cancer mortality in one trial [3] and no effect on diagnosis or mortality in another [4].
The rationale for USPSTF recommendation has a lot to do with the unintended consequences of PSA screening; PSA is a rather nonspecific test and elevated levels can be caused by a number of different prostate pathologies. Screening can often lead to procedures and treatments that cause harm to individuals who may not have prostate cancer to begin with or have slow-growing cancer that would otherwise not impact their overall health status over time [5]. This is particularly relevant for older adults that may have other comorbid diseases that impact their health. The selection of a single PSA test as the screening strategy in this study is an attempt to reduce the potential burden of repeated testing and thereby reduce risk of unintended harms. The tradeoff is that it is less effective in identifying prostate cancer over time and may partly explain why this study’s result contrasts with prior studies.