Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer Mortality: The CAP Randomized Clinical Trial

Importance: Prostate-cancer screening remains controversial because of concerns that potential mortality or quality of life benefits are outweighed by harms from over-detection and subsequent over-treatment.

Objective: To evaluate the effect of a low-intensity, single PSA screening intervention and standardized diagnostic pathway on prostate cancer specific mortality.

Design, Setting, Participants: Cluster-randomized clinical trial conducted in 573 general practices (the clusters) across the UK and including 419,582 men aged 50-69 who were randomized between 2001 and 2009. Follow-up was completed March 31, 2016.

Intervention: An invitation to a single PSA-test versus standard (unscreened) practice.

Main outcome and measures: Primary outcome: prostate cancer mortality at a median of 10-years’ follow-up, analyzed by intention-to-screen. Pre-specified secondary outcomes: diagnostic stage and grade of prostate cancers identified, all-cause mortality and instrumental variable analysis estimating the causal effect of attending PSA screening.

Results: Among 415,357 eligible men who were randomized (mean age, 59.0 years), 189,386 men in the intervention-group and 219,439 controls were included in the analysis (n=408,825, 98%). In the intervention-group, 75,707 (40%) attended PSA-testing and 6,857 (4%) had a PSA ≥3-<20ng/ml, of whom 5,850 (85%) had a prostate biopsy. After a median follow-up of 10-years, 549 (0.30 per 1000-person years) men had died from prostate cancer in the intervention group compared with 647 (0.31 per 1000-person years) in the control-group (rate difference -0.013 per 1000-person years, 95%CI -0.047, 0.02; rate-ratio [RR] 0.96, 95%CI 0.85,1.08; p=0.50). The number of prostate cancers diagnosed was higher in the intervention-group (n=8,054; 4.3%) than control-group (n=7,853; 3.6%) (RR 1.19, 95%CI 1.14,1.25; p<0.001). More Gleason grade ≤6 tumors were identified in the intervention than control groups (n=3,263/189,386 [1.7%] vs. n=2,440/219,439 [1.1%]; difference per 1000 = 6.11, 95% CI 5.38, 6.84; p<0.001). In the analysis of all-cause mortality, there were 25,459 deaths in the intervention group, and 28,306 deaths in the control group (RR 0.99, 95%CI 0.94,1.03; p=0.49). In instrumental variable analysis, the adherence-adjusted causal RR for prostate cancer mortality was 0.93 (95%CI 0.67,1.29; p=0.66).

Conclusion and relevance: Among practices randomized to a low-intensity PSA screening intervention compared with standard practice, there was no significant difference in prostate cancer mortality after a median 10-years follow up, but the detection of low-risk prostate cancers increased. Although longer-term follow-up is in progress, the current findings do not support single PSA-testing for population-based screening.

Current Controlled Trials number: ISRCTN92187251.