US Trial shows no early mortality benefit from annual prostate cancer screening

PROSTATE SPECIFIC ANTIGEN BASED PROSTATE CANCER SCREENING: ACCUMULATING EVIDENCE OF EFFICACY BUT PERSISTENT UNCERTAINTY

Background: Vasectomy has been implicated as a risk factor for prostate cancer in multiple epidemiologic studies over the past 25 years. Whether this relationship is causal remains unclear. This study examines the association between vasectomy and prostate cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, which randomized men to usual care or annual prostate cancer screening.Methods: We performed a retrospective analysis of 13-year screening and outcomes data from the PLCO trial. Multivariable Cox proportional hazards regression stratified by study arm and age at vasectomy was performed.Results: There was an increased risk of prostate cancer in men who had undergone a vasectomy and were randomized to the usual care arm of the study (adjusted HR, 1.11; 95% confidence interval, 1.03-1.20; P = 0.008). There was no association between vasectomy and diagnosis of prostate cancer in men randomized to the prostate cancer screening arm. Only men undergoing vasectomy at an older age in the usual care arm of the study, but not the prostate cancer screening arm, were at increased risk of being diagnosed with prostate cancer.Conclusions: Vasectomy was not associated with prostate cancer risk among men who were screened for prostate cancer as part of a clinical trial, but was associated with prostate cancer detection in men receiving usual care.Impact: The positive association between vasectomy and prostate cancer is likely related to increased detection of prostate cancer based on patterns of care rather than a biological effect of vasectomy on prostate cancer development. Cancer Epidemiol Biomarkers Prev; 26(11); 1653-9. ©2017 AACR.

<div>Abstract<p><b>Background:</b> Vasectomy has been implicated as a risk factor for prostate cancer in multiple epidemiologic studies over the past 25 years. Whether this relationship is causal remains unclear. This study examines the association between vasectomy and prostate cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, which randomized men to usual care or annual prostate cancer screening.</p><p><b>Methods:</b> We performed a retrospective analysis of 13-year screening and outcomes data from the PLCO trial. Multivariable Cox proportional hazards regression stratified by study arm and age at vasectomy was performed.</p><p><b>Results:</b> There was an increased risk of prostate cancer in men who had undergone a vasectomy and were randomized to the usual care arm of the study (adjusted HR, 1.11; 95% confidence interval, 1.03–1.20; <i>P</i> = 0.008). There was no association between vasectomy and diagnosis of prostate cancer in men randomized to the prostate cancer screening arm. Only men undergoing vasectomy at an older age in the usual care arm of the study, but not the prostate cancer screening arm, were at increased risk of being diagnosed with prostate cancer.</p><p><b>Conclusions:</b> Vasectomy was not associated with prostate cancer risk among men who were screened for prostate cancer as part of a clinical trial, but was associated with prostate cancer detection in men receiving usual care.</p><p><b>Impact:</b> The positive association between vasectomy and prostate cancer is likely related to increased detection of prostate cancer based on patterns of care rather than a biological effect of vasectomy on prostate cancer development. <i>Cancer Epidemiol Biomarkers Prev; 26(11); 1653–9. ©2017 AACR</i>.</p></div>

<div>Abstract<p><b>Background:</b> Vasectomy has been implicated as a risk factor for prostate cancer in multiple epidemiologic studies over the past 25 years. Whether this relationship is causal remains unclear. This study examines the association between vasectomy and prostate cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, which randomized men to usual care or annual prostate cancer screening.</p><p><b>Methods:</b> We performed a retrospective analysis of 13-year screening and outcomes data from the PLCO trial. Multivariable Cox proportional hazards regression stratified by study arm and age at vasectomy was performed.</p><p><b>Results:</b> There was an increased risk of prostate cancer in men who had undergone a vasectomy and were randomized to the usual care arm of the study (adjusted HR, 1.11; 95% confidence interval, 1.03–1.20; <i>P</i> = 0.008). There was no association between vasectomy and diagnosis of prostate cancer in men randomized to the prostate cancer screening arm. Only men undergoing vasectomy at an older age in the usual care arm of the study, but not the prostate cancer screening arm, were at increased risk of being diagnosed with prostate cancer.</p><p><b>Conclusions:</b> Vasectomy was not associated with prostate cancer risk among men who were screened for prostate cancer as part of a clinical trial, but was associated with prostate cancer detection in men receiving usual care.</p><p><b>Impact:</b> The positive association between vasectomy and prostate cancer is likely related to increased detection of prostate cancer based on patterns of care rather than a biological effect of vasectomy on prostate cancer development. <i>Cancer Epidemiol Biomarkers Prev; 26(11); 1653–9. ©2017 AACR</i>.</p></div>

The benefit of screening for prostate cancer using prostate-specific antigen (PSA) testing and digital rectal examination (DRE) is uncertain and is under evaluation in a randomized prospective trial, the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Although the final results are several years away, the initial round of screening is complete. We describe the population enrolled in the PLCO trial, their baseline PSA and DRE screening results, and diagnostic follow-up results during the first year of follow-up. A total of 38,350 men were randomly assigned to the screening arm of the PLCO trial from November 1993 through June 2001. Men were advised to seek diagnostic follow-up from their primary care provider if their DRE was suspicious for cancer and/or if their serum PSA level was higher than 4 ng/mL. PLCO trial staff obtained records related to diagnostic follow-up. Compliance with both screening tests was high (more than 89%). At screening, 7.5% of men had a positive DRE (i.e., suspicious for cancer) and 7.9% had a PSA level higher than 4 ng/mL. Of the men with positive screening tests, 74.2% underwent additional diagnostic testing, and 31.5% underwent a prostatic biopsy within 1 year. Overall, 1.4% of the men in the screening arm were diagnosed with prostate cancer, the majority of whom had clinically localized cancer. These compliance, biopsy, and cancer detection rates appear to be representative of contemporary practice patterns. The PLCO trial is evaluating PSA- and DRE-based screening for prostate cancer in a clinically valid manner. Whether such screening will result in a reduction of prostate cancer mortality cannot be answered until the randomized comparison is completed.

The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) recently reported a reduction in the average overall mortality among ovarian cancer patients screened with an annual sequential, multimodal strategy that tracked biomarker CA125 over time, where increasing serum CA125 levels prompted ultrasound. However, multiple cases were documented wherein serum CA125 levels were rising, but ultrasound screens were normal, thus delaying surgical intervention. A significant factor which could contribute to false negatives is that many aggressive ovarian cancers are believed to arise from epithelial cells on the fimbriae of the fallopian tubes, which are not readily imaged. Moreover, because only a fraction of metastatic tumors may reach a sonographically-detectable size before they metastasize, annual screening with ultrasound may fail to detect a large fraction of early-stage ovarian cancers. The ability to detect ovarian carcinomas before they metastasize is critical and future efforts towards improving screening should focus on identifying unique features specific to aggressive, early-stage tumors, as well as improving imaging sensitivity to allow for detection of tubal lesions. Implementation of a three-stage multimodal screening strategy in which a third modality is employed in cases where the first-line blood-based assay is positive and the second-line ultrasound exam is negative may also prove fruitful in detecting early-stage cases missed by ultrasound.

Other and All-Cause Mortality among Men Diagnosed with Prostate Cancer in the PLCO Trial

Relationship Among Initial Serum Prostate Specific Antigen, Prostate Specific Antigen Progression and Prostate Cancer Detection at Repeat Screening Visits

To describe the results of the first four rounds (T0-T3) of prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial (designed to determine the value of screening in the four cancers), that for prostate cancer is evaluating whether annual screening with prostate-specific antigen (PSA) and a digital rectal examination (DRE) reduces prostate cancer-specific mortality. In all, 38 349 men aged 55-74 years were randomized to undergo annual screening with PSA (abnormal >4.0 ng/mL) and a DRE. The follow-up of abnormal screening results was at the discretion of subjects' physicians. PLCO staff obtained records related to diagnostic follow-up of positive screen results. Compliance with screening decreased slightly from 89% at baseline to 85% at T3. Both PSA positivity rates (range 7.7-8.8% at T0-T3) and DRE positivity rates (range 6.8-7.6% at T0-T3) were relatively constant over time. The positive predictive value (PPV) of a PSA level of >4.0 ng/mL decreased from 17.9% at T0 to 10.4-12.3% at T1-T3; the PPV for DRE (in the absence of a positive PSA test) was constant over time (2.9-3.6%). Cancer was diagnosed in 1902 men (4.9%). Screen-detected cancers at T0 (549) were more likely to be clinical stage III/IV (5.8%) and to have a Gleason score of 7-10 (34%) than screen-detected cancers at T1-T3 (1.5-4.2% stage III/IV and 24-27% Gleason score 7-10 among 1054 cases). The present findings on serial prostate screening are similar to those reported from other multi-round screening studies. Determining the effect of PSA screening on prostate cancer mortality awaits further follow-up.

To investigate the ability of the prostate genetic score (PGS-33), a germ-line biomarker of prostate cancer (PCa) risk, to categorize men participating in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We obtained the genetic data from the Cancer Genetic Markers of Susceptibility (CGEMS), a nested case control study examining germ-line DNA in the screened arm of the PLCO trial. A PGS-33 was calculated based on their genotype at 33 PCa associated single nucleotide polymorphisms (SNPs). The primary outcome was the diagnosis of PCa and primary predictor was PGS-33. We identified 2,244 subjects (no cancer, N = 1017) and cases (N = 1227). The PGS-33 (P<0.001), prostate specific antigen (PSA; P < 0.001), family history of PCa (< 0.001), abnormal digital rectal exam (DRE, P < 0.001), and history of ever smoking (P = 0.037) were associated with a PCa diagnosis. In multivariable analysis, the log (PGS-33) was associated with PCa diagnosis with an odds ratio of 1.68 (95% CI 1.36-2.08, P < 0.001), log (PSA) (OR 8.2; 95% CI 6.75-10.04, P < 0.001), and family history of PCa (OR 2.01; 95% CI 1.26-3.20, P = 0.003). PGS-33 quartiles noted an increasing rate of PCa detection in addition to PSA: 43.2% (Q1), 47.8% (Q2), 58.8% (Q3), and 69.4 (Q4) (P < 0.001) and improvement in PSA performance (P < 0.001). Germ-line DNA in the form of the PGS-33 is able to risk stratify men regarding their risk of PCa. The PGS-33 may have implications regarding who may benefit most from PCa screening and possibly add to PSA performance.

The ERSPC (European Randomized Study of Screening for Prostate Cancer) found that screening reduced prostate cancer mortality, but the PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) found no reduction. To evaluate whether effects of screening on prostate cancer mortality relative to no screening differed between the ERSPC and PLCO. Cox regression of prostate cancer death in each trial group, adjusted for age and trial. Extended analyses accounted for increased incidence due to screening and diagnostic work-up in each group via mean lead times (MLTs), which were estimated empirically and using analytic or microsimulation models. Randomized controlled trials in Europe and the United States. Men aged 55 to 69 (ERSPC) or 55 to 74 (PLCO) years at randomization. Prostate cancer screening. Prostate cancer incidence and survival from randomization; prostate cancer incidence in the United States before screening began. Estimated MLTs were similar in the ERSPC and PLCO intervention groups but were longer in the PLCO control group than the ERSPC control group. Extended analyses found no evidence that effects of screening differed between trials (P= 0.37 to 0.47 [range across MLT estimation approaches]) but strong evidence that benefit increased with MLT (P= 0.0027 to 0.0032). Screening was estimated to confer a 7% to 9% reduction in the risk for prostate cancer death per year of MLT. This translated into estimates of 25% to 31% and 27% to 32% lower risk for prostate cancer death with screening as performed in the ERSPC and PLCO intervention groups, respectively, compared with no screening. The MLT is a simple metric of screening and diagnostic work-up. After differences in implementation and settings are accounted for, the ERSPC and PLCO provide compatible evidence that screening reduces prostate cancer mortality. National Cancer Institute.

Mass Screening for Prostate Cancer in Korea: A Population Based Study

-2]Proenzyme Prostate Specific Antigen is More Accurate Than Total and Free Prostate Specific Antigen in Differentiating Prostate Cancer From Benign Disease in a Prospective Prostate Cancer Screening Study

At present, increased early detection of prostate cancer appears to be the most feasible way to reduce cancer-related mortality. As a result significant efforts have been made to identify more men with curable cancer. This article reviews the role of serum prostate-specific antigen in an early detection or screening strategy and describes efforts to enhance the specificity of prostate-specific antigen testing.

Since 2012, US guidelines have recommended against prostate-specific antigen (PSA) screening for prostate cancer. However, evidence of screening benefit from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening trial and the European Randomized Study of Screening for Prostate Cancer has been inconsistent, due partly to differences in noncompliance and contamination. Using system dynamics modeling, we replicated the PLCO trial and extrapolated follow-up to 20 years. We then simulated 3 scenarios correcting for contamination in the PLCO control arm using Surveillance, Epidemiology, and End Results (SEER) incidence and survival data collected prior to the PSA screening era (scenario 1), SEER data collected during the PLCO trial period (1993-2001) (scenario 2), and data from the European trial's control arm (1991-2005) (scenario 3). In all scenarios, noncompliance was corrected using incidence and survival rates for men with screen-detected cancer in the PLCO screening arm. Scenarios 1 and 3 showed a benefit of PSA screening, with relative risks of 0.62 (95% confidence interval: 0.53, 0.72) and 0.70 (95% confidence interval: 0.59, 0.83) for cancer-specific mortality after 20 years, respectively. In scenario 2, however, there was no benefit of screening. This simulation showed that after correcting for noncompliance and contamination, there is potential benefit of PSA screening in reducing prostate cancer mortality. It also demonstrates the utility of system dynamics modeling for synthesizing epidemiologic evidence to inform public policy.