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

Abstract

Importance: Prostate cancer screening remains controversial because potential mortality or quality-of-life benefits may be outweighed by harms from overdetection and overtreatment.

Objective: To evaluate the effect of a single prostate-specific antigen (PSA) screening intervention and standardized diagnostic pathway on prostate cancer-specific mortality.

Design, setting, and participants: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) included 419 582 men aged 50 to 69 years and was conducted at 573 primary care practices across the United Kingdom. Randomization and recruitment of the practices occurred between 2001 and 2009; patient follow-up ended on March 31, 2016.

Intervention: An invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice.

Main outcomes and measures: Primary outcome: prostate cancer-specific mortality at a median follow-up of 10 years. Prespecified secondary outcomes: diagnostic cancer stage and Gleason grade (range, 2-10; higher scores indicate a poorer prognosis) of prostate cancers identified, all-cause mortality, and an instrumental variable analysis estimating the causal effect of attending the PSA screening clinic.

Results: Among 415 357 randomized men (mean [SD] age, 59.0 [5.6] years), 189 386 in the intervention group and 219 439 in the control group were included in the analysis (n = 408 825; 98%). In the intervention group, 75 707 (40%) attended the PSA testing clinic and 67 313 (36%) underwent PSA testing. Of 64 436 with a valid PSA test result, 6857 (11%) had a PSA level between 3 ng/mL and 19.9 ng/mL, of whom 5850 (85%) had a prostate biopsy. After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) died of prostate cancer in the intervention group vs 647 (0.31 per 1000 person-years) in the control group (rate difference, -0.013 per 1000 person-years [95% CI, -0.047 to 0.022]; rate ratio [RR], 0.96 [95% CI, 0.85 to 1.08]; P = .50). The number diagnosed with prostate cancer was higher in the intervention group (n = 8054; 4.3%) than in the control group (n = 7853; 3.6%) (RR, 1.19 [95% CI, 1.14 to 1.25]; P < .001). More prostate cancer tumors with a Gleason grade of 6 or lower were identified in the intervention group (n = 3263/189 386 [1.7%]) than in the control group (n = 2440/219 439 [1.1%]) (difference per 1000 men, 6.11 [95% CI, 5.38 to 6.84]; P < .001). In the analysis of all-cause mortality, there were 25 459 deaths in the intervention group vs 28 306 deaths in the control group (RR, 0.99 [95% CI, 0.94 to 1.03]; P = .49). In the instrumental variable analysis for prostate cancer mortality, the adherence-adjusted causal RR was 0.93 (95% CI, 0.67 to 1.29; P = .66).

Conclusions and relevance: Among practices randomized to a single PSA screening intervention vs standard practice without screening, there was no significant difference in prostate cancer mortality after a median follow-up of 10 years but the detection of low-risk prostate cancer cases increased. Although longer-term follow-up is under way, the findings do not support single PSA testing for population-based screening.

Trial registration: ISRCTN Identifier: ISRCTN92187251.

Figure 1.. Recruitment and Retention of Practices and Patients in the Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP)

Adapted from Turner et al with updated data from the National Health Service (NHS) Digital Organization as of June 2017. IQR indicates interquartile range; PSA, prostate-specific antigen. ^aIndicates that the practice could not provide a list of men aged 50 to 69 years registered at the practice usually because it treated a subset of the UK population (eg, homeless, elderly care home). ^bThese practices took part in the feasibility study for the intervention and therefore were not eligible for inclusion in the main trial. ^cDue to emigration out of the United Kingdom or other reasons.

Figure 2.. Cumulative Incidence of Prostate Cancer Detection and Mortality in the Single Prostate-Specific Antigen Testing Intervention Group vs Standard Practice (Control)

Y-axis shown in blue indicates range from 0 to 8 events per 1000 men. For part A, the median follow-up was 10.03 years (interquartile range [IQR], 8.80 to 11.50) for the intervention group vs 9.92 years (IQR, 8.74 to 10.93) for the control group (crude rate difference, −0.01 per 1000 person-years; 95% CI, −0.05 to 0.02). For part B, the median follow-up was 9.85 years (IQR, 8.61 to 11.43) for the intervention group vs 9.82 years (IQR, 8.67 to 10.92) for the control group (crude rate difference, 0.65 per 1000 person-years; 95% CI, 0.52 to 0.78). ^aDefined as definite, probable, or intervention-related prostate cancer death as determined by an independent cause of death committee.