Who and when should we screen for prostate cancer? Interviews with key opinion leaders

Prostate cancer screening using prostate-specific antigen (PSA) is highly controversial. In this Q & A, Guest Editors for BMC Medicine's 'Spotlight on Prostate Cancer' article collection, Sigrid Carlsson and Andrew Vickers, invite some of the world's key opinion leaders to discuss who, and when, to screen for prostate cancer. In response to the points of view from the invited experts, the Guest Editors summarize the experts' views and give their own personal opinions on PSA screening

Impact of cause of death adjudication on the results of the European prostate cancer screening trial

Background:The European Randomised Study of Prostate Cancer Screening has shown a 21% relative reduction in prostate cancer mortality at 13 years. The causes of death can be misattributed, particularly in elderly men with multiple comorbidities, and therefore accurate assessment of the underlying cause of death is crucial for valid results. To address potential unreliability of end-point assessment, and its possible impact on mortality results, we analysed the study outcome adjudication data in six countries.Methods:Latent class statistical models were formulated to compare the accuracy of individual adjudicators, and to assess whether accuracy differed between the trial arms. We used the model to assess whether correcting for adjudication inaccuracies might modify the study results.Results:There was some heterogeneity in adjudication accuracy of causes of death, but no consistent differential accuracy by trial arm. Correcting the estimated screening effect for misclassification did not alter the estimated mortality effect of screening.Conclusions:Our findings were consistent with earlier reports on the European screening trial. Observer variation, while demonstrably present, is unlikely to have materially biased the main study results. A bias in assigning causes of death that might have explained the mortality reduction by screening can be effectively ruled out

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

What's new in screening in 2015?

Purpose of review The aim of this review was to highlight important articles in the field of prostate cancer screening published during 2015 and early 2016. Four major areas were identified for the purpose: screening strategies, post-United States Preventive Services Task Force (USPSTF) 2011-2012, screening trends/patterns, and shared decision making. Recent findings Several studies furthered the evidence that screening reduces the risk of metastasis and death from prostate cancer. Multiplex screening strategies are of proven benefit; genetics and MRI need further evaluation. Prostate-specific antigen (PSA) screening rates declined in men above age of 50 years, as did the overall prostate cancer incidence following the USPSTF 2011-2012 recommendation against PSA. The consequences of declining screening rates will become apparent in the next few years. More research is needed to identify the most optimal approach to engage in, and implement, an effective shared decisionmaking in clinical practice. Summary Data emerging in 2015 provided evidence on the question of how best to screen and brought more steps in the right direction of 'next-generation prostate cancer screening'. Screening is an ongoing process in all men regardless of whether or not they might benefit from early detection and treatment. After the USPSTF 2011-2012 recommendation, the rates of PSA testing are declining; however, this decline is observed in all men and not solely in those who will not benefit from the screening. The long-term effect of this recommendation might not be as anticipated. More studies are needed on how to implement the best available evidence on who, and when, to screen in clinical practice

Free PSA and Clinically Significant and Fatal Prostate Cancer in the PLCO Screening Trial

INTRODUCTION: We studied whether adding percent free prostate-specific antigen (%fPSA) to total PSA improves prediction of clinically significant prostate cancer (csPCa) and fatal PCa.METHODS: 6727 men within the intervention arm of the Prostate, Lung, Colorectal and Ovarian Trial had baseline %fPSA. Of this cohort, 475 had csPCa and 98 had fatal PCa. Cumulative incidence and Cox analyses were conducted to evaluate the association between %fPSA/PSA and csPCa/fatal PCa. Harrell's concordance-index (C-index) evaluated predictive ability. Kaplan-Meier analysis assessed survival.RESULTS: Median follow-up was 19.7 years, median baseline PSA was 1.19 ng/mL, median %fPSA was 18%. Cumulative incidence of fatal PCa for men with baseline PSA≥2 ng/mL and %fPSA ≤10 was 3.2% and 6.1% at 15 and 25 years, compared to 0.03% and 1.1% for men with %fPSA >25%. In younger men (55-64 yr) with baseline PSA 2-10 ng/mL, C-index improved from 0.56 to 0.60 for csPCa and from 0.53 to 0.64 for fatal PCa with addition of %fPSA. In older men (65-74 yr), C-index improved for csPCa from 0.60 to 0.66, while no improvement in fatal PCa. Adjusting for age, digital rectal exam, family history of PCa, and total PSA, %fPSA was associated with csPCa (HR 1.05, P < .001) per 1% decrease. %fPSA improved prediction of csPCa and fatal PCA for all race groups. CONCLUSION: In a large US screening trial, the addition of %fPSA to total PSA in men with baseline PSA ≥2 ng/mL improved prediction of csPCa and fatal PCa. Free PSA should be used to risk-stratify screening and decrease unnecessary prostate biopsies

Active surveillance for prostate cancer: A systematic review of clinicopathologic variables and biomarkers for risk stratification

Context Active surveillance (AS) is an important strategy to reduce prostate cancer overtreatment. However, the optimal criteria for eligibility and predictors of progression while on AS are debated. Objective To review primary data on markers, genetic factors, and risk stratification for patient selection and predictors of progression during AS. Evidence acquisition Electronic searches were conducted in PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 2014 for original articles on biomarkers and risk stratification for AS. Evidence synthesis Patient factors associated with AS outcomes in some studies include age, race, and family history. Multiple studies provide consistent evidence that a lower percentage of free prostate-specific antigen (PSA), a higher Prostate Health Index (PHI), a higher PSA density (PSAD), and greater biopsy core involvement at baseline predict a greater risk of progression. During follow-up, serial measurements of PHI and PSAD, as well as repeat biopsy results, predict later biopsy progression. While some studies have suggested a univariate relationship between urinary prostate cancer antigen 3 (PCA3) and transmembrane protease, serine 2-v-ets avian erythroblastosis virus E26 oncogene homolog gene fusion (TMPRSS2:ERG) with adverse biopsy features, these markers have not been consistently shown to independently predict AS outcomes. No conclusive data support the use of genetic tests in AS. Limitations of these studies include heterogeneous definitions of progression and limited follow-up. Conclusions There is a growing body of literature on patient characteristics, biopsy features, and biomarkers with potential utility in AS. More data are needed on practical applications such as combining these tests into multivariable clinical algorithms and long-term outcomes to further improve AS in the future. Patient summary Several PSA-based tests (free PSA, PHI, PSAD) and the extent of cancer on biopsy can help to stratify the risk of progression during active surveillance. Investigation of several other markers is under way