The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear.
Objective
To evaluate the effect of a single invitation for PSA screening on prostate cancer–specific mortality at a median 15-year follow-up compared with no invitation for screening.
Design, Setting, and Participants
This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021.
Intervention
Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation).
Main Outcomes and Measures
The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer–specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis.
Results
Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P < .001) and localized (T1/T2: 3.6% vs 3.1%; P < .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment.
Conclusions and Relevance
In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small.
Trial Registration
srctn.org Identifier: ISRCTN92187251
Prostate cancer screening remains a matter of debate in the medical community. Due to the uncertain impact on patients’ survival, the risk of overdiagnosis and overtreatment, universal prostate-specific antigen (PSA) screening is generally not recommended. The Cluster Randomised Trial of PSA Testing for Prostate Cancer (CAP), evaluated the effectiveness of a single invitation for PSA screening vs. no screening in reducing mortality. The trial included 415,357 men aged 50 to 69 years. In a previous report, a median 10-year follow-up CAP showed no difference compared to control in prostate cancer (rate ratio [RR] 0.96, 95% confidence interval [CI] 0.85-1.08) and all-cause mortality (RR 0.99, 95% CI 0.94-1.03).
The study "Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality: A Secondary Analysis of the CAP Randomized Clinical Trial" published in JAMA provided an update of the CAP trial. At the median follow-up of 15.4 years (interquartile range, 14.2-16.4), the results demonstrated a reduction in prostate cancer mortality (RR 0.92, 95% CI 0.85-0.99); in the screening group, 0.69% of men died due to prostate cancer compared to the 0.78% in the control group. There were no difference in overall mortality – screening arm: 23.2%, control arm: 23.3% (RR 0.97, 95% CI, 0.94-1.01, p=0.11). Notably, around a 15-year follow-up single PSA screening led to increased detection of low-grade and localised prostate cancer, with patients undergoing screening aged 65 to 69 years being twice at risk of overdiagnosis compared to men who underwent single PSA measurement aged 50 to 54 years. There was some evidence for a lower risk of advanced tumours in the intervention arms. Nevertheless, CAP results raise concerns about the overall efficacy of single-invitation PSA screening in the detection or prevention of advanced prostate cancer. Although PSA screening does lower the mortality rate from prostate cancer, the overall advantage is slight and must be considered alongside the risks of overdiagnosis and overtreatment.
The modest reduction in prostate cancer mortality from PSA screening is counterbalanced by risks such as overdiagnosis and overtreatment, which can cause significant treatment-related toxicities. There is a necessity for continued research to develop screening strategies that will accurately allow for improved detection of potentially lethal cancers, which is beyond the detection of clinically significant or high-grade prostate cancer. Insights from the large-scale CAP study reveal that a one-size-fits-all approach to prostate cancer screening is suboptimal and should not be the standard in 2024, given the increased availability of imaging, risk calculators, and multi-analyte markers leading towards a risk-based screening strategy.