STHLM3-F/U Study Protocol: Long-Term Effects on Prostate Cancer Mortality after the Stockholm3 Prostate Cancer Screening Trial (STHLM3)

BackgroundProstate cancer (PCa) is the leading cause of cancer death among men in Sweden. Although PSA (prostate-specific antigen) testing to screen for prostate cancer is common, its use remains controversial. This debate is primarily fueled by its insufficient operating characteristics, resulting in many benign biopsies and overdiagnosis of indolent disease. The population-based diagnostic STHLM3 trial developed and validated the Stockholm3 test, demonstrating that the combined use of PSA and Stockholm3 can identify clinically significant PCa with higher specificity while retaining the same sensitivity as PSA alone. However, the long-term implications of screening with the combined use of PSA and Stockholm3 on mortality remain unknown. AimThis study aims to evaluate the effect of a one-time invitation for prostate cancer screening (using PSA and Stockholm3 test in combination) in men aged 50-69 living in Stockholm on prostate cancer mortality and all-cause mortality, as well as its effects on prostate cancer incidence, PSA testing, and biopsy rates. The research question investigated in this study (STHLM3-F/U) concerns one of the pre-specified secondary outcomes of the original population-based diagnostic STHLM3 study (ISRCTN84445406). Randomization and InterventionThe trial involves men aged 50 to 69 living in Stockholm at the moment of invitation and who did not have a prostate cancer diagnosis. Randomization occurred at the population level using registry-based information, eligible men were randomly assigned to receive an invitation for screening or to continue with standard care. Invited men who decided to participate in the STHLM3 trial took a PSA test, followed by the Stockholm3 test if PSA level was above 1 ng/mL. Systematic biopsy was recommended for those with PSA [≥] 3 ng/mL and/or a Stockholm3 score [≥] 10%. The non-invited group did not receive any invitations and relied on standard care. Outcomes and analysisPrimary outcome was prostate cancer mortality. Secondary outcomes included all-cause mortality, prostate cancer incidence, PSA testing, and biopsy rates. Data will be analyzed using registry information, with primary analysis using follow-up data until 2023-12-31. Time to prostate cancer mortality will be analyzed using the Aalen-Johansen estimator. Cumulative risks at the end of the follow-up will be compared between the invited and non-invited groups by means of a Risk Ratio at an alpha level of 3.5%. Both intention-to-screen and compliance-adjusted analyses will be performed. DiscussionThis study aims to address the knowledge gap regarding the long-term effect of screening with PSA and Stockholm3 tests in combination and provide insights into its potential effects on preventing mortality. Understanding whether a systematic organized screening intervention, using a combination of PSA and Stockholm3 has any effect on mortality can help inform decisions on prostate cancer screening policies. Ethics and disseminationApproval for ethical conduct has been obtained from the Stockholm regional ethics committee. Results will be shared through peer-reviewed publications.