• Department of Public Health, Erasmus Medical Center, Rotterdam, the Netherlands.
• Division of Public Health Sciences, Fred Hutchinson Cancer Research Institute, Seattle, Washington.
• Wolfson Institute, Queen Mary University of London, London, United Kingdom.
• Department of Urology, Sahlgrenska University Hospital, Goteborg, Sweden.
• Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland.
• Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medicine, Baltimore, Maryland.
• School of Health Sciences, University of Tampere, Tampere, Finland.
• Division of Urologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
• Department of Urology, Erasmus Medical Center, Rotterdam, the Netherlands.
• Urologic Oncology, University of Colorado, Denver, Colorado.

BACKGROUND: The European Randomized Study of Screening for Prostate Cancer (ERSPC) demonstrated that prostate-specific antigen (PSA) screening significantly reduced prostate cancer mortality (rate ratio, 0.79; 95% confidence interval, 0.69-0.91). The US Prostate, Lung, Colorectal, and Ovarian (PLCO) trial indicated no such reduction but had a wide 95% CI (rate ratio for prostate cancer mortality, 1.09; 95% CI, 0.87-1.36). Standard meta-analyses are unable to account for key differences between the trials that can impact the estimated effects of screening and the trials' point estimates.

METHODS: The authors calibrated 2 microsimulation models to individual-level incidence and mortality data from 238,936 men participating in the ERSPC and PLCO trials. A cure parameter for the underlying efficacy of screening was estimated by the models separately for each trial. The authors changed step-by-step major known differences in trial settings, including enrollment and attendance patterns, screening intervals, PSA thresholds, biopsy receipt, control arm contamination, and primary treatment, to reflect a more ideal protocol situation and differences between the trials.

RESULTS: Using the cure parameter estimated for the ERSPC, the models projected 19% to 21% and 6% to 8%, respectively, prostate cancer mortality reductions in the ERSPC and PLCO settings. Using this cure parameter, the models projected a reduction of 37% to 43% under annual screening with 100% attendance and biopsy compliance and no contamination. The cure parameter estimated for the PLCO trial was 0.

CONCLUSIONS: The observed cancer mortality reduction in screening trials appears to be highly sensitive to trial protocol and practice settings. Accounting for these differences, the efficacy of PSA screening in the PLCO setting is not necessarily inconsistent with ERSPC results. Cancer 2018;124:1197-206. © 2017 American Cancer Society.