Dataset Information

Multi-marker risk-based screening for prostate cancer.

ABSTRACT:

Objective

To determine prostate cancer screening performance using prostate specific antigen (PSA) along with other markers, expressing markers in age-specific multiples of the median (MoM), and age.

Methods

A prospective nested case-control study used stored serum from 571 men who died of, or with history of, prostate cancer (cases), and 2169 matched controls. Total, free and intact PSA, human kallikrein-related peptidase 2 (hK2), and microseminoprotein were measured and converted into MoM values. Screening marker distribution parameters were estimated in cases and controls. Monte Carlo simulation used these in a risk-based algorithm to estimate screening performance (detection rates [DRs] and false-positive rates [FPRs]).

Results

Almost all (99%) cases occurred aged ≥55. Marker values were similar in cases who did and did not die of prostate cancer. Combining age, total PSA and hK2 MoM values (other markers added little or no discrimination) yielded a 1.2% FPR (95% CI 0.2-4.8%) for a 90% DR (59-98%) in men who died of or with a prostate cancer diagnosis within 5 years of blood collection (risk cut-off 1 in 20), two-thirds less than the 4.5% FPR using total PSA alone measured in ng/ml for the same 90% DR (cut-off 3.1 ng/ml). Screening performance over 10 years yielded a 33% (22-46%) FPR for a 90% DR.

Conclusion

Screening performed up to every 5 years from age 55 using the multi-marker risk-based screening algorithm for future prostate cancer achieves a high DR and a much lower FPR than using PSA alone, resulting in reductions in overdiagnosis and overtreatment.

SUBMITTER: Wald NJ

PROVIDER: S-EPMC9087319 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Publications

Multi-marker risk-based screening for prostate cancer.

Wald Nicholas J NJ Bestwick Jonathan P JP Morris Joan K JK

Journal of medical screening 20220307 2

<h4>Objective</h4>To determine prostate cancer screening performance using prostate specific antigen (PSA) along with other markers, expressing markers in age-specific multiples of the median (MoM), and age.<h4>Methods</h4>A prospective nested case-control study used stored serum from 571 men who died of, or with history of, prostate cancer (cases), and 2169 matched controls. Total, free and intact PSA, human kallikrein-related peptidase 2 (hK2), and microseminoprotein were measured and converte ...[more]

PMID: 35255236

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Project description:BackgroundAlthough prostate-specific antigen (PSA) is widely used in prostate cancer (PCa) screening, nearly half of PCa cases are missed and less than one-third of cases are non-lethal. Adopting diagnostic criteria in population-based screening and ignoring PSA progression are presumed leading causes.MethodsA total of 31,942 participants with multi-round PSA tests from the PLCO trial were included. Time-dependent receiver-operating-characteristic curves and area under curves (tdAUCs) were performed to determine the screening reference level and the optimal subgroup-specific progression indicator. Effects of risk-stratified multi-round PSA screening were evaluated with multivariable Cox regression and measured with hazard ratio [HR (95%CIs)].ResultsAfter a median follow-up of 11.6 years, a total of 3484 PCa cases and 216 PCa deaths were documented. The tdAUC of 10-year incidence PCa with PSA was 0.816, and the cut-off value was 1.61 ng/ml. Compared to subgroup with stable negative PSA in both first-round (FR) and last-round (LR) tests [FR(-)/LR(-)], HRs (95%CI) of PCa incidence were 1.66 (1.20-2.29), 8.29 (7.25-9.48), and 14.52 (12.95-16.28) for subgroups with loss of positive PSA[FR(+)/LR(-)], gain of positive PSA[FR(-)/LR(+)], and stable positive PSA[FR(+)/LR(+)]; while HRs(95%CI) of PCa mortality were 1.47 (0.52-4.15), 5.71 (3.68-8.86), and 5.01 (3.41-7.37). After excluding regressive PSA [(namely FR(+)/LR(-)], absolute velocity was the shared optimal progression indicator for subgroups with FR(-)/LR(-), FR(-)/LR(+), and FR(+)/LR(+), with tdAUCs of 0.665, 0.681 and 0.741, and cut-off values of 0.07, 0.21, and 0.33 ng/ml/year. After reclassifying participants into groups with positive and negative progression based on subgroup-specific progression indicators, incidence HR (95%CI) were 2.41 (1.87-3.10), 2.91 (2.43-3.48), and 3.16 (2.88-3.46) for positive progression compared to negative progression within subgroups of FR(-)/LR(-), FR(-)/LR(+), and FR(+)/LR(+), while mortality HR (95%CI) were 2.22 (0.91-5.38), 2.37 (1.28-4.38), and 2.98 (1.94-4.59). To improve screening performances by excluding regressive PSA and low-risk positive progression in FR(-)/LR(-), optimized screening strategy not only significantly reduce 32.4% of missed PCa (54.0% [1881/3484] vs. 21.6% [754/3484], P < 0.001), but also detected additional 8.0% of high-grade PCa (Gleason score 7-10: 36.0% [665/1849] vs. 28.0% [206/736], P < 0.001) than traditional screening strategy.ConclusionsRisk-stratified multi-round PSA screening strategy integrating the screening reference level and the optimal subgroup-specific progression indicator of PSA could be recommended as a fundamental strategy to reduce missed diagnosis and improve the detection of high-grade PCa cases.

Project description:BackgroundShared decision making improves value-concordant decision-making around prostate cancer screening (PrCS). Yet, PrCS discussions remain complex, challenging and often emotional for physicians and average-risk men.ObjectiveIn July 2011, the Centers for Disease Control and Prevention convened a multidisciplinary expert panel to identify priorities for funding agencies and development groups to promote evidence-based, value-concordant decisions between men at average risk for prostate cancer and their physicians.DesignTwo-day multidisciplinary expert panel in Atlanta, Georgia, with structured discussions and formal consensus processes.ParticipantsSixteen panelists represented diverse specialties (primary care, medical oncology, urology), disciplines (sociology, communication, medical education, clinical epidemiology) and market sectors (patient advocacy groups, Federal funding agencies, guideline-development organizations).Main measuresPanelists used guiding interactional and evaluation models to identify and rate strategies that might improve PrCS discussions and decisions for physicians, patients and health systems/society. Efficacy was defined as the likelihood of each strategy to impact outcomes. Effort was defined as the relative amount of effort to develop, implement and sustain the strategy. Each strategy was rated (1-7 scale; 7 = maximum) using group process software (ThinkTank(TM)). For each group, intervention strategies were grouped as financial/regulatory, educational, communication or attitudinal levers. For each strategy, barriers were identified.Key resultsHighly ranked strategies to improve value-concordant shared decision-making (SDM) included: changing outpatient clinic visit reimbursement to reward SDM; development of evidence-based, technology-assisted, point-of-service tools for physicians and patients; reframing confusing prostate cancer screening messages; providing pre-visit decision support interventions; utilizing electronic health records to promote benchmarking/best practices; providing additional training for physicians around value-concordant decision-making; and using re-accreditation to promote training.ConclusionsConference outcomes present an expert consensus of strategies likely to improve value-concordant prostate cancer screening decisions. In addition, the methodology used to obtain agreement provides a model of successful collaboration around this and future controversial cancer screening issues, which may be of interest to funding agencies, educators and policy makers.

Project description:Take Home Message Results from this population-based screening cohort show that the calibration of risk prediction tools need to be assessed in the local setting before using in clinical practice. The Prostate Biopsy Collaborative Group Risk Calculator provided benefit in the online version. The Rotterdam Prostate Cancer Risk Calculator needed recalibration for similar benefit. Background External validation of risk calculators (RCs) is necessary to determine their clinical applicability beyond the setting in which these were developed. Objective To assess the performance of the Rotterdam Prostate Cancer RC (RPCRC) and the Prostate Biopsy Collaborative Group RC (PBCG-RC). Design, setting, and participants We used data from the prospective, population-based STHLM3 screening study, performed in 2012–2015. Participants with prostate-specific antigen ≥3 ng/ml who underwent systematic prostate biopsies were included. Outcome measurements and statistical analysis Probabilities for clinically significant prostate cancer (csPCa), defined as International Society of Urological Pathology grade ≥2, were calculated for each participant. External validity was assessed by calibration, discrimination, and clinical usefulness for both original and recalibrated models. Results and limitations Out of 5841 men, 1054 (18%) had csPCa. Distribution of risk predictions differed between RCs; median risks for csPCa using the RPCRC and PBCG-RC were 3.3% (interquartile range [IQR] 2.1–7.1%) and 20% (IQR 15–28%), respectively. The correlation between RC risk estimates on individual level was moderate (Spearman’s r = 0.55). Using the RPCRC’s recommended risk threshold of ≥4% for finding csPCa, 36% of participants would get concordant biopsy recommendations. At 10% risk cut-off, RCs agreed in 23% of cases. Both RCs showed good discrimination, with areas under the curves for the RPCRC of 0.74 (95% confidence interval [CI] 0.72–0.76) and the PBCG-RC of 0.70 (95% CI 0.68–0.72). Calibration was adequate using the PBCG-RC (calibration slope: 1.13 [95% CI 1.03–1.23]), but the RPCRC underestimated the risk of csPCa (calibration slope: 0.73 [0.68–0.79]). The PBCG-RC showed a net benefit in a decision curve analysis, whereas the RPCRC showed no net benefit at clinically relevant risk threshold levels. Recalibration improved clinical benefit, and differences between RCs decreased. Conclusions Assessment of calibration is essential to ensure the clinical value of risk prediction tools. The PBCG-RC provided clinical benefit in its current version online. On the contrary, the RPCRC cannot be recommended in this setting. Patient summary Predicting the probability of finding prostate cancer on biopsy differed between two assessed risk calculators. After recalibration, the agreement of the models improved, and both were shown to be clinically useful.

Dataset Information

Multi-marker risk-based screening for prostate cancer.

Objective

Methods

Results

Conclusion

Publications

Multi-marker risk-based screening for prostate cancer.

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