Ilic D, Neuberger MM, Djulbegovic M, Dahm P
Screening for prostate cancer.
Cochrane Database Syst Rev. 2013; 1:CD004720 [PubMed]

BACKGROUND: Any form of screening aims to reduce disease-specific and overall mortality, and to improve a person's future quality of life. Screening for prostate cancer has generated considerable debate within the medical and broader community, as demonstrated by the varying recommendations made by medical organizations and governed by national policies. To better inform individual patient decision-making and health policy decisions, we need to consider the entire body of data from randomised controlled trials (RCTs) on prostate cancer screening summarised in a systematic review. In 2006, our Cochrane review identified insufficient evidence to either support or refute the use of routine mass, selective, or opportunistic screening for prostate cancer. An update of the review in 2010 included three additional trials. Meta-analysis of the five studies included in the 2010 review concluded that screening did not significantly reduce prostate cancer-specific mortality. In the past two years, several updates to studies included in the 2010 review have been published thereby providing the rationale for this update of the 2010 systematic review.
OBJECTIVES: To determine whether screening for prostate cancer reduces prostate cancer-specific mortality or all-cause mortality and to assess its impact on quality of life and adverse events.
SEARCH METHODS: An updated search of electronic databases (PROSTATE register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CANCERLIT, and the NHS EED) was performed, in addition to handsearching of specific journals and bibliographies, in an effort to identify both published and unpublished trials.
SELECTION CRITERIA: All RCTs of screening versus no screening for prostate cancer were eligible for inclusion in this review.
DATA COLLECTION AND ANALYSIS: The original search (2006) identified 99 potentially relevant articles that were selected for full-text review. From these citations, two RCTs were identified as meeting the inclusion criteria. The search for the 2010 version of the review identified a further 106 potentially relevant articles, from which three new RCTs were included in the review. A total of 31 articles were retrieved for full-text examination based on the updated search in 2012. Updated data on three studies were included in this review. Data from the trials were independently extracted by two authors.
MAIN RESULTS: Five RCTs with a total of 341,342 participants were included in this review. All involved prostate-specific antigen (PSA) testing, with or without digital rectal examination (DRE), though the interval and threshold for further evaluation varied across trials. The age of participants ranged from 45 to 80 years and duration of follow-up from 7 to 20 years. Our meta-analysis of the five included studies indicated no statistically significant difference in prostate cancer-specific mortality between men randomised to the screening and control groups (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.86 to 1.17). The methodological quality of three of the studies was assessed as posing a high risk of bias. The European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial were assessed as posing a low risk of bias, but provided contradicting results. The ERSPC study reported a significant reduction in prostate cancer-specific mortality (RR 0.84, 95% CI 0.73 to 0.95), whilst the PLCO study concluded no significant benefit (RR 1.15, 95% CI 0.86 to 1.54). The ERSPC was the only study of the five included in this review that reported a significant reduction in prostate cancer-specific mortality, in a pre-specified subgroup of men aged 55 to 69 years of age. Sensitivity analysis for overall risk of bias indicated no significant difference in prostate cancer-specific mortality when referring to the meta analysis of only the ERSPC and PLCO trial data (RR 0.96, 95% CI 0.70 to 1.30). Subgroup analyses indicated that prostate cancer-specific mortality was not affected by the age at which participants were screened. Meta-analysis of four studies investigating all-cause mortality did not determine any significant differences between men randomised to screening or control (RR 1.00, 95% CI 0.96 to 1.03). A diagnosis of prostate cancer was significantly greater in men randomised to screening compared to those randomised to control (RR 1.30, 95% CI 1.02 to 1.65). Localised prostate cancer was more commonly diagnosed in men randomised to screening (RR 1.79, 95% CI 1.19 to 2.70), whilst the proportion of men diagnosed with advanced prostate cancer was significantly lower in the screening group compared to the men serving as controls (RR 0.80, 95% CI 0.73 to 0.87). Screening resulted in a range of harms that can be considered minor to major in severity and duration. Common minor harms from screening include bleeding, bruising and short-term anxiety. Common major harms include overdiagnosis and overtreatment, including infection, blood loss requiring transfusion, pneumonia, erectile dysfunction, and incontinence. Harms of screening included false-positive results for the PSA test and overdiagnosis (up to 50% in the ERSPC study). Adverse events associated with transrectal ultrasound (TRUS)-guided biopsies included infection, bleeding and pain. No deaths were attributed to any biopsy procedure. None of the studies provided detailed assessment of the effect of screening on quality of life or provided a comprehensive assessment of resource utilization associated with screening (although preliminary analyses were reported).
AUTHORS' CONCLUSIONS: Prostate cancer screening did not significantly decrease prostate cancer-specific mortality in a combined meta-analysis of five RCTs. Only one study (ERSPC) reported a 21% significant reduction of prostate cancer-specific mortality in a pre-specified subgroup of men aged 55 to 69 years. Pooled data currently demonstrates no significant reduction in prostate cancer-specific and overall mortality. Harms associated with PSA-based screening and subsequent diagnostic evaluations are frequent, and moderate in severity. Overdiagnosis and overtreatment are common and are associated with treatment-related harms. Men should be informed of this and the demonstrated adverse effects when they are deciding whether or not to undertake screening for prostate cancer. Any reduction in prostate cancer-specific mortality may take up to 10 years to accrue; therefore, men who have a life expectancy less than 10 to 15 years should be informed that screening for prostate cancer is unlikely to be beneficial. No studies examined the independent role of screening by DRE.

Pignone MP, Howard K, Brenner AT, et al.
Comparing 3 techniques for eliciting patient values for decision making about prostate-specific antigen screening: a randomized controlled trial.
JAMA Intern Med. 2013; 173(5):362-8 [PubMed]

IMPORTANCE: To make good decisions about prostate-specific antigen (PSA) screening, men must consider how they value the different potential outcomes.
OBJECTIVE: To determine the effects of different methods of helping men consider such values.
DESIGN AND SETTING: Randomized trial from October 12 to 27, 2011, in the general community.
PARTICIPANTS: A total of 911 men aged 50 to 70 years from the United States and Australia who had average risk. Participants were drawn from online panels from a survey research firm in each country and were randomized by the survey firm to 1 of 3 values clarification methods: a balance sheet (n = 302), a rating and ranking task (n = 307), or a discrete choice experiment (n = 302).
INTERVENTION: Participants underwent a values clarification task and then chose the most important attribute.
MAIN OUTCOME MEASURES: The main outcome was the difference among groups in the most important attribute. Secondary outcomes were differences in unlabeled test preference and intent to undergo screening with PSA.
RESULTS: The mean age was 59.8 years; most participants were white and more than one-third had graduated from college. More than 40% reported a PSA test within 12 months. The participants who received the rating and ranking task were more likely to report reducing the chance of death from prostate cancer as being most important (54.4%) compared with those who received the balance sheet (35.1%) or the discrete choice experiment (32.5%) (P < .001). Those receiving the balance sheet were more likely (43.7%) to prefer the unlabeled PSA-like option (as opposed to the "no screening"-like option) compared with those who received rating and ranking (34.2%) or the discrete choice experiment (20.2%). However, the proportion who intended to undergo PSA testing was high and did not differ between groups (balance sheet, 77.1%; rating and ranking, 76.8%; and discrete choice experiment, 73.5%; P = .73).
CONCLUSIONS AND RELEVANCE: Different values clarification methods produce different patterns of attribute importance and different preferences for screening when presented with an unlabeled choice. Further studies with more distal outcome measures are needed to determine the best method of values clarification, if any, for decisions such as whether to undergo screening with PSA.

Gulati R, Gore JL, Etzioni R
Comparative effectiveness of alternative prostate-specific antigen--based prostate cancer screening strategies: model estimates of potential benefits and harms.
Ann Intern Med. 2013; 158(3):145-53 [PubMed]

BACKGROUND: The U.S. Preventive Services Task Force recently concluded that the harms of existing prostate-specific antigen (PSA) screening strategies outweigh the benefits.
OBJECTIVE: To evaluate comparative effectiveness of alternative PSA screening strategies.
DESIGN: Microsimulation model of prostate cancer incidence and mortality quantifying harms and lives saved for alternative PSA screening strategies.
DATA SOURCES: National and trial data on PSA growth, screening and biopsy patterns, incidence, treatment distributions, treatment efficacy, and mortality.
TARGET POPULATION: A contemporary cohort of U.S. men.
TIME HORIZON: Lifetime.
PERSPECTIVE: Societal.
INTERVENTION: 35 screening strategies that vary by start and stop ages, screening intervals, and thresholds for biopsy referral.
OUTCOME MEASURES: PSA tests, false-positive test results, cancer detected, overdiagnoses, prostate cancer deaths, lives saved, and months of life saved.
RESULTS OF BASE-CASE ANALYSIS: Without screening, the risk for prostate cancer death is 2.86%. A reference strategy that screens men aged 50 to 74 years annually with a PSA threshold for biopsy referral of 4 µg/L reduces the risk for prostate cancer death to 2.15%, with risk for overdiagnosis of 3.3%. A strategy that uses higher PSA thresholds for biopsy referral in older men achieves a similar risk for prostate cancer death (2.23%) but reduces the risk for overdiagnosis to 2.3%. A strategy that screens biennially with longer screening intervals for men with low PSA levels achieves similar risks for prostate cancer death (2.27%) and overdiagnosis (2.4%), but reduces total tests by 59% and false-positive results by 50%.
RESULTS OF SENSITIVITY ANALYSIS: Varying incidence inputs or reducing the survival improvement due to screening did not change conclusions.
LIMITATION: The model is a simplification of the natural history of prostate cancer, and improvement in survival due to screening is uncertain.
CONCLUSION: Compared with standard screening, PSA screening strategies that use higher thresholds for biopsy referral for older men and that screen men with low PSA levels less frequently can reduce harms while preserving lives.
PRIMARY FUNDING SOURCE: National Cancer Institute and Centers for Disease Control and Prevention.

Gardiner RF, Yaxley J, Baade PD
Integrating disparate snippets of information in an approach to PSA testing in Australia and New Zealand.
BJU Int. 2012; 110 Suppl 4:35-7 [PubMed]

• An invited response to 'Stricker PD, Frydenberg M, Kneebone A, Chopra S. Informed prostate cancer risk-adjusted testing: a new paradigm'.

Stricker PD, Frydenberg M, Kneebone A, Chopra S
Informed prostate cancer risk-adjusted testing: a new paradigm.
BJU Int. 2012; 110 Suppl 4:30-4 [PubMed]

• Currently there is significant confusion and polarisation about prostate cancer screening for both patients and physicians alike. • We propose a risk-adjusted testing programme, which would lead to fewer patients who need to be tested and treated to save a life and also eliminate inappropriate prostate-specific antigen testing in the elderly and patients with severe co-morbidities where there is no clear benefit.

Zhu X, van Leeuwen PJ, Holmberg E, et al.
Efficacy versus effectiveness study design within the European screening trial for prostate cancer: consequences for cancer incidence, overall mortality and cancer-specific mortality.
J Med Screen. 2012; 19(3):133-40 [PubMed]

OBJECTIVE: To assess the impact of different study designs on outcome data within the European Randomized Study of Screening for Prostate Cancer (ERSPC).
METHODS: Observed data from the Gothenburg centre (effectiveness trial with upfront randomization before informed consent) and the Rotterdam centre (efficacy trial with randomization after informed consent) were compared with expected data, which were retrieved from national cancer registries and life tables. Endpoints were 11-year cumulative prostate cancer (PC) incidence, overall mortality and PC-specific mortality.
RESULTS: In Gothenburg, the 11-year PC incidence was higher than predicted (5.8%) in both the intervention (12.4%) and control arms (7.3%). The observed overall mortality was higher than predicted (15.9%) in both the intervention (17.8%) and control arms (18.5%). The observed PC-specific mortality in the intervention arm was 0.56% versus 0.83% in the control arm, while the expected mortality was 0.83%. In Rotterdam, the observed PC incidence in the intervention arm (10.4%) was higher than expected (4.4%). The incidence in the control arm was 4.6%. The observed overall mortality was lower than expected: 13.6% in the intervention arm and 14.0% in the control arm versus an expected mortality of 16.1%. The observed PC-specific mortality was lower than expected (0.65%) in both the intervention (0.27%) and control arms (0.41%).
CONCLUSIONS: Our results suggest that an efficacy trial with informed consent prior to randomization may have introduced a 'healthy screenee bias'. Therefore, an effectiveness trial with consent after randomization may more accurately estimate the PC-specific mortality reduction if population-based screening is introduced.

Schröder FH
Landmarks in prostate cancer screening.
BJU Int. 2012; 110 Suppl 1:3-7 [PubMed]

• Prostate-specific antigen (PSA) has been widely applied to diagnosis and follow-up of prostate cancer, which led to research on its potential role in the early detection of the disease and its use in screening. • The value of PSA screening in reducing disease mortality is controversial and several studies have been conducted to determine the actual benefits. One of the early studies, the Tyrol Screening Study conducted in 1993, showed that during 2004 to 2008 there was a significant reduction in prostate cancer mortality in men aged >60 years compared with the mortality rate during 1989 to 1993. • Two studies that showed no benefit of screening in terms of prostate cancer death were conducted in Sweden in 1987 and 1988. • The Prostate, Lung, Colorectal, and Ovarian Screening Study conducted in the USA during 1993 to 2001 and involving 76,693 men showed no benefit of screening at 10 years but the trial can be criticised due to excessive contamination of the unscreened group. • In contrast, the European Randomized Study of Screening for Prostate Cancer (ERSPC), the largest randomised study with 162,388 participants study, showed that at a median follow-up of 9 years a prostate cancer mortality reduction of 20% resulted (P= 0.04). In an analysis limited to four ERSPC centres with a follow-up of 12.0 years, screening resulted in an overall reduction of metastatic disease of 31%. • The arguments against PSA screening include the risks associated with screening tests themselves, e.g. biopsy-related haematuria, urosepsis, and over diagnosis and overtreatment of prostate cancer. The overall evidence points in favour of PSA screening and steps can be taken to avoid overtreatment by offering patients active surveillance.

PSA-based screening for prostate cancer. Too many adverse effects.
Prescrire Int. 2012; 21(130):215-7 [PubMed]

Has the evaluation of PSA screening for prostate cancer progressed since 2009? We examined the recent literature on the value of this test, using the standard Prescrire methodology. Five randomised trials have yielded conflicting results. One trial was too flawed to be conclusive. In two trials, the Erspc and Gothenburg studies, PSA-based screening appeared to prevent about 1 death from prostate cancer per 300 to 1400 men screened. However, two other trials, including the PLCO study that enrolled 77 000 men, showed no statistically significant benefit from screening. Two meta-analyses showed that PSA screening did not reduce mortality from prostate cancer among 340 000 and 390 000 men followed for 9 to 15 years. About 70% of men with PSA levels above 4 ng/l do not have prostate cancer. These false-positive results unnecessarily expose patients to the adverse effects of prostate biopsy, which include haematuria, pain, infections and septicaemia. Between 30% and 80% of cancers diagnosed by screening would never have compromised patients' health if they had remained undetected. This over-diagnosis unnecessarily exposes patients to the adverse effects of treatment, which include urinary incontinence, erectile dysfunction, and psychological effects. In early 2012, the clinical utility of PSA-based screening for prostate cancer has not been demonstrated. Patients should be informed of the natural history of localised prostate cancer and the adverse effects of screening.

Wallner L, Frencher S, Hsu JW, et al.
Prostate cancer screening trends in a large, integrated health care system.
Perm J. 2012; 16(3):4-9 [PubMed] Free Access to Full Article

BACKGROUND: As the debate over the effectiveness of prostate-specific antigen (PSA) screening for prostate cancer continues, it is increasingly important to understand how PSA screening occurs in general-practice settings.
METHODS: We conducted a retrospective cohort study within Kaiser Permanente Southern California, a large integrated health care system. Men aged 35 years and older at baseline, in 1998, were eligible. The proportion of men who underwent PSA screening was estimated and compared across groups defined by patient and physician characteristics. We also evaluated trends in screening across time and serum PSA levels for all subgroups.
RESULTS: Of 2,061,047 men, 572,306 (28%) underwent PSA screening from 1998 through 2007. Patterns of PSA screening varied modestly by age, race, and physician. The lowest frequencies of screening occurred among men younger than age 45 years (19%) and men ages 85 years and older (13%). PSA screening was most common among white men (33.5%) and in men seen by physicians of the same race/ethnicity (32%), compared with men with physicians of disparate race/ethnicity (26%, p < 0.001). PSA screening increased over time for all racial/ethnic groups and among men age 75 years and older but decreased over time for men younger than age 75 years old.
CONCLUSIONS: Nearly 1 in 4 eligible men underwent PSA screening from 1998 through 2007, and screening varied only modestly by patient and physician characteristics. Estimates of the frequency of PSA screening in general-practice settings can inform the debate and provide useful insight as to how changes in cancer screening guidelines would alter practice patterns in an increasingly integrated health care environment.

Cózar JM, Miñana B, Gómez-Veiga F, et al.
Prostate cancer incidence and newly diagnosed patient profile in Spain in 2010.
BJU Int. 2012; 110(11 Pt B):E701-6 [PubMed]

UNLABELLED: What's known on the subject? and What does the study add? Prostate cancer (PCa) accounts for 12% of newly diagnosed cases of cancer in Europe. It is one of the most frequently diagnosed tumours in the developed world. Since the introduction of prostate specific antigen as a test for early detection of PCa, the rate of diagnosis has increased significantly and specific mortality has reduced in most western countries. Most of the data on the incidence of PCa are obtained from population-based cancer registries which frequently do not cover the whole population. This first national hospital-based PCa registry aims not only to estimate the incidence of the disease but to ascertain the clinical profile of newly diagnosed PCa patients, a useful tool for evaluating the impact of the disease and its socio-health management.
OBJECTIVES: • To estimate the 2010 incidence of prostate cancer (PCa) in Spain. • To describe the clinical profile of newly diagnosed cases using a nationwide hospital-based registry.
PATIENTS AND METHODS: • This was a national epidemiological observational study in 25 public hospitals with a specific reference population according to the National Health System. • Sociodemographic and clinical variables of all newly diagnosed, histopathologically confirmed PCa cases were collected in 2010, in the area of influence of each centre. Cases diagnosed in private practice were not collected (estimated nearly 10% in Spain). • Data monitoring was external to guarantee quality and homogeneity. • The age-standardized PCa incidence was determined based on the age distribution of the European standard population.
RESULTS: • In all, 4087 new cases of PCa were diagnosed for a reference population of 4933940 men (21.8% of the Spanish male population). • The estimated age-standardized PCa incidence was 70.75 cases per 100000 men. • Mean age at diagnosis was 69 years; 11.6% of patients presented with tumour-related symptoms and 39.5% with LUTS. Median PSA was 8 ng/mL. Gleason score was ≤ 6 in 56.5%, 7 in 26.7% and >7 in 16.8% of patients. At diagnosis, 89.8% had localized, 6.4% locally advanced and 3.8% metastatic disease.
CONCLUSIONS: • This study on PCa incidence in Spain, a western country with intensive opportunistic PSA screening, shows that PCa is a high incidence tumour, diagnosed close to 70 years, usually asymptomatic. • Almost 40% of cases have low risk disease with a risk of over-diagnosis and over-treatment. • Around 55% of patients with intermediate or high risk disease are candidates for active therapy which may result in a reduction of cancer-specific mortality.

Kotwal AA, Schumm P, Mohile SG, Dale W
The influence of stress, depression, and anxiety on PSA screening rates in a nationally representative sample.
Med Care. 2012; 50(12):1037-44 [PubMed] Article available free on PMC after 01/12/2013

BACKGROUND: Prostate-specific antigen (PSA) testing for prostate cancer is controversial, with concerning rates of both overscreening and underscreening. The reasons for the observed rates of screening are unknown, and few studies have examined the relationship of psychological health to PSA screening rates. Understanding this relationship can help guide interventions to improve informed decision-making for screening.
METHODS: A nationally representative sample of men 57-85 years old without prostate cancer (N = 1169) from the National Social life, Health and Aging Project was analyzed. The independent relationship of validated psychological health scales measuring stress, anxiety, and depression to PSA testing rates was assessed using multivariable logistic regression analyses.
RESULTS: PSA screening rates were significantly lower for men with higher perceived stress [odds ratio (OR) = 0.76, P = 0.006], but not for higher depressive symptoms (OR = 0.89, P = 0.22) when accounting for stress. Anxiety influences PSA screening through an interaction with number of doctor visits (P = 0.02). Among the men who visited the doctor once those with higher anxiety were less likely to be screened (OR = 0.65, P = 0.04). Conversely, those who visited the doctor 10+ times with higher anxiety were more likely to be screened (OR = 1.71, P = 0.04).
CONCLUSIONS: Perceived stress significantly lowers PSA screening likelihood, and it seems to partly mediate the negative relationship of depression with screening likelihood. Anxiety affects PSA screening rates differently for men with different numbers of doctor visits. Interventions to influence PSA screening rates should recognize the role of the patients' psychological state to improve their likelihood of making informed decisions and improve screening appropriateness.

Faria EF, Carvalhal GF, dos Reis RB, et al.
Use of low free to total PSA ratio in prostate cancer screening: detection rates, clinical and pathological findings in Brazilian men with serum PSA levels <4.0 ng/mL.
BJU Int. 2012; 110(11 Pt B):E653-7 [PubMed]

UNLABELLED: What's known on the subject? and What does the study add? In spite of its low specificity, PSA is the most widely used screening test for prostate cancer (PCa), and is considered the main cause of the stage migration recently observed. The ratio of free to total PSA (%fPSA) has been shown to increase PSA accuracy in cancer detection; however, few screening studies have systematically evaluated its role in cancer detection rates in men with PSA levels <4.0 ng/mL and normal DRE. The present study supports a possible role of %fPSA as an adjunct to screening in men with total PSA 2.5-4.0 ng/mL and normal DRE, with a marked increase in cancer detection rates in a large Brazilian PCa screening study. We believe that %fPSA maybe a useful refinement to biopsy indications in men with low PSA levels.
OBJECTIVE: • To evaluate the role of the free to total prostate-specific antigen ratio (%fPSA) in identifying prostate cancer (PCa) in men with a prostate-specific antigen (PSA) level of 2.5-3.9 ng/mL and a normal digital rectal examination (DRE).
PATIENTS AND METHODS: • A prospective PCa screening study was conducted, which included 17571 men aged ≥ 45 years, across six Brazilian states, where men were recalled for further evaluation in the case of either a suspicious DRE and/or PSA ≥ 4.0 ng/mL, or PSA 2.5-3.9 ng/mL and %fPSA ≤ 15. • We evaluated the impact of a %fPSA ≤ 15 on cancer detection rates and the clinical and pathological stage of tumours in men with a normal DRE and PSA 2.5-3.9 ng/mL.
RESULTS: • When suspicious DRE and/or PSA ≥ 4.0 ng/mL were considered as criteria to prompt further evaluation, the cancer detection rate was 3.1%. When %fPSA ≤ 15 in men with total PSA levels of 2.5-3.9 ng/mL were considered as criteria, the PCa detection rate increased to 3.7%. Considering %fPSA ≤ 15 in men with PSA 2.5-3.9 ng/mL and normal DRE, the positive predictive value of biopsy was 31.1%. • Clinical stage was more favourable among men with PSA 2.5-3.9 ng/mL, normal DRE, and %fPSA ≤ 15 compared with men with normal DRE and PSA ≥ 4.0 ng/mL (P= 0.02). • Among those who underwent radical prostatectomy, pathological stage and the proportion of insignificant tumours were similar between men with PSA 2.5-3.9 ng/mL, normal DRE findings and %fPSA ≤ 15, and men with PSA ≥ 4.0 ng/mL.
CONCLUSIONS: • The use of %fPSA ≤ 15 as a biopsy indication in men with normal DRE and PSA 2.5-4.0 ng/mL in a PCa screening programme, increased cancer detection rates. Tumours in this subset of patients had similar pathological characteristics. • Using %fPSA ≤ 15 to indicate biopsy in men with PSA 2.5-3.9 ng/mL is a useful adjunct to PCa screening.

Moyer VA,
Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement.
Ann Intern Med. 2012; 157(2):120-34 [PubMed]

DESCRIPTION: Update of the 2008 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for prostate cancer.
METHODS: The USPSTF reviewed new evidence on the benefits and harms of prostate-specific antigen (PSA)-based screening for prostate cancer, as well as the benefits and harms of treatment of localized prostate cancer.
RECOMMENDATION: The USPSTF recommends against PSA-based screening for prostate cancer (grade D recommendation).This recommendation applies to men in the general U.S. population, regardless of age. This recommendation does not include the use of the PSA test for surveillance after diagnosis or treatment of prostate cancer; the use of the PSA test for this indication is outside the scope of the USPSTF.

Schröder FH, Hugosson J, Carlsson S, et al.
Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC).
Eur Urol. 2012; 62(5):745-52 [PubMed]

BACKGROUND: Metastatic disease is a major morbidity of prostate cancer (PCa). Its prevention is an important goal.
OBJECTIVE: To assess the effect of screening for PCa on the incidence of metastatic disease in a randomized trial.
DESIGN, SETTING, AND PARTICIPANTS: Data were available for 76,813 men aged 55-69 yr coming from four centers of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The presence of metastatic disease was evaluated by imaging or by prostate-specific antigen (PSA) values >100 ng/ml at diagnosis and during follow-up.
INTERVENTION: Regular screening based on serum PSA measurements was offered to 36270 men randomized to the screening arm, while no screening was provided to the 40543 men in the control arm. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The Nelson-Aalen technique and Poisson regression were used to calculate cumulative incidence and rate ratios of M+ disease.
RESULTS AND LIMITATIONS: After a median follow-up of 12 yr, 666 men with M+ PCa were detected, 256 in the screening arm and 410 in the control arm, resulting in cumulative incidence of 0.67% and 0.86% per 1000 men, respectively (p<0.001). This finding translated into a relative reduction of 30% (hazard ratio [HR]: 0.70; 95% confidence interval [CI], 0.60-0.82; p=0.001) in the intention-to-screen analysis and a 42% (p=0.0001) reduction for men who were actually screened. An absolute risk reduction of metastatic disease of 3.1 per 1000 men randomized (0.31%) was found. A large discrepancy was seen when comparing the rates of M+ detected at diagnosis and all M+ cases that emerged during the total follow-up period, a 50% reduction (HR: 0.50; 95% CI, 0.41-0.62) versus the 30% reduction. The main limitation is incomplete explanation of the lack of an effect of screening during follow-up.
CONCLUSIONS: PSA screening significantly reduces the risk of developing metastatic PCa. However, despite earlier diagnosis with screening, certain men still progress and develop metastases. The ERSPC trial is registered under number ISRCTN49127736.

Linder SK, Swank PR, Vernon SW, et al.
Is a prostate cancer screening anxiety measure invariant across two different samples of age-appropriate men?
BMC Med Inform Decis Mak. 2012; 12:52 [PubMed] Article available free on PMC after 01/12/2013

BACKGROUND: In order to explore the influence of anxiety on decision-making processes, valid anxiety measures are needed. We evaluated a prostate cancer screening (PCS) anxiety scale that measures anxiety related to the prostate-specific antigen (PSA) test, the digital rectal examination (DRE), and the decision to undergo PCS (PCS-D) using two samples in different settings.
METHODS: We assessed four psychometric properties of the scale using baseline data from a randomized, controlled decision aid trial (n = 301, private clinic; n = 149, public).
RESULTS: The 3-factor measure had adequate internal consistency reliability, construct validity, and discriminant validity. Confirmatory factor analyses indicated that the 3-factor model did not have adequate fit. When subscales were considered separately, only the 6-item PCS-D anxiety measure had adequate fit and was invariant across clinics.
CONCLUSIONS: Our results support the use of a 6-item PCS-D anxiety measure with age-appropriate men in public and private settings. The development of unique anxiety items relating to the PSA test and DRE is still needed.

Liang Y, Ketchum NS, Louden C, et al.
The use of the finasteride-adjusted Prostate Cancer Prevention Trial Prostate Cancer Risk Calculator in a Mexican referral population: a validation study.
Urol Int. 2012; 89(1):9-16 [PubMed]

OBJECTIVES: To perform the first validation study of the finasteride-adjusted Prostate Cancer Prevention Trial Prostate Cancer Risk Calculator (finPCPTRC) in a contemporary referral population in Mexico.
METHODS: 837 patients referred to the Instituto Nacional de Cancerología, Mexico City, Mexico, between 2005 and 2009 were used to validate the finPCPTRC by examining various measures of discrimination and calibration. Net benefit curve analysis was used to gain insight into the use of the finPCPTRC for clinical decisions.
RESULTS: Prostate cancer (PCa) incidence (72.8%) was high in this Mexican referral cohort and 45.7% of men who were diagnosed with PCa had high-grade lesions (HGPCa, Gleason score >6). 1.3% of the patients were taking finasteride. The finPCPTRC was a superior diagnostic tool compared to prostate-specific antigen alone when discriminating patients with PCa from those without PCa (AUC = 0.784 vs. AUC = 0.687, p < 0.001) and when discriminating patients with HGPCa from those without HGPCa (AUC = 0.768 vs. AUC = 0.739, p < 0.001). The finPCPTRC underestimated the risk of PCa but overestimated the risk of HGPCa (both p < 0.001). Compared with other strategies to opt for biopsy, the net benefit would be larger with utilization of the finPCPTRC for patients accepting higher risks of HGPCa.
CONCLUSIONS: Rates of biopsy-detectable PCa and HGPCa were high and 1.3% of this referral cohort in Mexico was taking finasteride. The risks of PCa or HGPCa calculated by the finPCPTRC were not well calibrated for this referral Mexican population and new clinical diagnostic tools are needed.

Heidelbaugh JJ, Tortorello M
The adult well male examination.
Am Fam Physician. 2012; 85(10):964-71 [PubMed]

The adult well male examination should incorporate evidence-based guidance toward the promotion of optimal health and well-being, including screening tests shown to improve health outcomes. Nearly one-third of men report not having a primary care physician. The medical history should include substance use; risk factors for sexually transmitted infections; diet and exercise habits; and symptoms of depression. Physical examination should include blood pressure and body mass index screening. Men with sustained blood pressures greater than 135/80 mm Hg should be screened for diabetes mellitus. Lipid screening is warranted in all men 35 years and older, and in men 20 to 34 years of age who have cardiovascular risk factors. Ultrasound screening for abdominal aortic aneurysm should occur between 65 and 75 years of age in men who have ever smoked. There is insufficient evidence to recommend screening men for osteoporosis or skin cancer. The U.S. Preventive Services Task Force has provisionally recommended against prostate-specific antigen-based screening for prostate cancer because the harms of testing and overtreatment outweigh potential benefits. Screening for colorectal cancer should begin at 50 years of age in men of average risk and continue until at least 75 years of age. Screening should be performed by high-sensitivity fecal occult blood testing every year, flexible sigmoidoscopy every five years combined with [corrected] fecal occult blood testing every three years. [corrected]. The U.S. Preventive Services Task Force recommends against screening for testicular cancer and chronic obstructive pulmonary disease. Immunizations should be recommended according to guidelines from the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention.

Yu EY, Miller K, Nelson J, et al.
Detection of previously unidentified metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic, castration resistant prostate cancer.
J Urol. 2012; 188(1):103-9 [PubMed] Article available free on PMC after 01/07/2013

PURPOSE: Understanding the extent of disease in asymptomatic patients with castration resistant prostate cancer is important when making treatment decisions and designing clinical trials. The ENTHUSE M0 (ENdoTHelin A USE) trial (NCT00626548) was a large phase III study comparing the endothelin A receptor antagonist zibotentan with placebo in patients with nonmetastatic, castration resistant prostate cancer. The study was stopped prematurely after early efficacy review indicated that it was unlikely to meet its co-primary objectives of improved overall and progression-free survival vs placebo. Screening failed in an unexpectedly high number of patients. We investigated this screening failure rate to promote better classification of patients thought to have nonmetastatic castration resistant prostate cancer and inform the design of future clinical trials in this setting.
MATERIALS AND METHODS: The number of patients enrolled in and subsequently excluded from study was analyzed by geographic region and by the specialty of the investigating clinician (oncology or urology) who enrolled the study patients.
RESULTS: Of 2,577 patients enrolled in a total of 350 hospital based centers in 39 countries screening failed in 1,155 (45%). The most common reason for screening failure was the detection of metastatic disease in 32% of all screened patients and in 71% of those in whom screening failed. The leading reasons for failed screening did not differ between investigator specialties overall or by geographic region.
CONCLUSIONS: The high frequency of asymptomatic metastasis in men thought to have nonmetastatic, castration resistant prostate cancer highlights the importance of periodic staging assessments for the condition. Optimal treatment modalities may differ for metastatic and nonmetastatic disease.

Margel D, Fleshner N
The role of 5-alpha-reductase inhibitors in active surveillance.
Curr Opin Urol. 2012; 22(3):243-6 [PubMed]

PURPOSE OF REVIEW: Active surveillance is now considered one of the preferred treatments for men with favorable risk prostate cancer (PCa). Unfortunately, 30-50% of men choosing active surveillance will progress and require therapy. In this context, we will present recent data on the efficacy of 5-alpha-reductase inhibitors (5-ARIs) in secondary prevention among men with low-risk PCa choosing active surveillance.
RECENT FINDINGS: Two recent studies including a multicenter randomized controlled study demonstrate that 5-ARI may reduce the rate of clinical progression in low-risk PCa.
SUMMARY: 5-ARIs may play an important role in secondary prevention in low-risk PCa. These results should be interpreted with caution in view of the recent US Food and Drug Administration recommendation against PCa chemoprevention labeling for 5-ARIs.

Klotz L
Cancer overdiagnosis and overtreatment.
Curr Opin Urol. 2012; 22(3):203-9 [PubMed]

PURPOSE OF REVIEW: Overdiagnosis has become a major problem in medicine in general and cancer in particular. This is a summary of this problem.
RECENT FINDINGS: Because of earlier detection, the nature of cancer has changed, from a disease usually diagnosed at a late and incurable stage to a heterogeneous condition that varies from clinically insignificant to rapidly aggressive. Screening programs for cancer have resulted in a dramatic increase in the diagnosis of clinically insignificant disease, balanced by improved survival and mortality because of significant cancers being diagnosed at a more curable stage. Overdiagnosis requires the presence of microfocal disease and a screening test to identify this. This exists for breast, prostate, and thyroid cancers, and to a lesser degree for renal and lung cancer. The problem of cancer overdiagnosis and overtreatment is complex, with numerous causes and many trade-offs. It is particularly important in prostate cancer, but is a major issue in many other cancer sites. Screening for prostate cancer appears, based on the best data from randomized trials, to significantly reduce cancer mortality.
SUMMARY: Reducing overtreatment in patients diagnosed with indolent disease is critical to the success of screening.

Klotz L
Active surveillance: the Canadian experience.
Curr Opin Urol. 2012; 22(3):222-30 [PubMed]

PURPOSE OF REVIEW: Active surveillance has evolved to become a standard of care for favorable-risk prostate cancer. This article is a summary of the rationale, method, and results of active surveillance beginning in 1995 with the first prospective trial of this approach.
RECENT FINDINGS: This was a prospective, single arm cohort study. Patients were managed with an initial expectant approach. Definitive intervention was offered to those patients with a prostate specific antigen (PSA) doubling time of less than 3 years, Gleason score progression (to 4 + 3 or greater), or unequivocal clinical progression. Since November 1995, 450 patients have been managed with active surveillance. Median follow-up is 6.8 years (range 1-16 years). Overall survival is 78.6%. Ten-year prostate cancer actuarial survival is 97.2%. Five of 450 patients (1.1%) have died of prostate cancer. Thirty percent of patients have been reclassified as higher risk and offered definitive therapy. The commonest indication for treatment was a PSA doubling time less than 3 years (48%) or Gleason upgrading (26%). Of 117 patients treated radically, the PSA failure rate was 50%. This represents 13% of the total cohort. Most PSA failures occurred early; at 2 years, 44% of the treated patients had PSA failure. The hazard ratio for nonprostate cancer to prostate cancer mortality was 18.6 at 10 years.
SUMMARY: We observed a very low rate of prostate cancer mortality in an intermediate time frame. Among the one-third of patients who were reclassified as higher risk and retreated, PSA failure was relatively common. However, other cause mortality accounted for almost all of the deaths. Further studies are warranted to improve the identification of patients who harbor more aggressive disease in spite of favorable clinical parameters at diagnosis.

Bangma CH, Bul M, Roobol M
The Prostate cancer Research International: Active Surveillance study.
Curr Opin Urol. 2012; 22(3):216-21 [PubMed]

PURPOSE OF REVIEW: To inform readers on the ongoing activities of the Prostate cancer Research International: Active Surveillance (PRIAS) study in the light of current findings and research problems on active surveillance worldwide.
RECENT FINDINGS: Recent data from the PRIAS study combined with PubMed-based literature from the last 3 years.
SUMMARY: The PRIAS study is a rapidly growing registry for active surveillance of low-risk prostate cancer. The study is conducted worldwide, facilitated by an electronic Web-based decision tool with password-restricted access for physicians. Inclusion and monitoring is performed according to protocol. Over 2000 men have been included from over 100 participating centres in 17 countries in four continents. The study was initiated in December 2006. Risk reclassification on repeat biopsy during follow-up has occurred in 27% of biopsied men, although a switch towards active therapy has been performed in 22% of the total cohort.

Dogan B, Serefoglu EC, Atmaca AF, et al.
Is sampling transitional zone in patients who had prior negative prostate biopsy necessary?
Int Urol Nephrol. 2012; 44(4):1071-5 [PubMed]

OBJECTIVE: To assess the necessity of transitional zone sampling of the prostate during repeat prostate biopsy procedures.
METHODS: Patients treated for lower urinary tract symptoms with transurethral resection of the prostate (TURP) from April 2004 to July 2009 whom had at least 1 negative prostate biopsy prior to this treatment were chosen as the study group. A histopathological analysis of surgical specimens was employed to determine cancer detection rates.
RESULTS: A total of 72 patients with the mean age of 66.1, mean prostate-specific antigen (PSA) of 10.4 ng/mL and mean prostate volume of 63.2 cc were included. Of the patients, 50 had 1 biopsy set, 17 had 2 sets, 4 had 3 sets and 1 patient had 4 sets of consecutive biopsies. All biopsy results were negative for prostate cancer. After the analysis of surgical specimens obtained during TURP, cancer was detected in 3 patients (4.2%). Transitional zone sampling during prostate biopsies did not significantly improve the cancer detection rate. Transitional zone sampling was performed in 29 biopsies taken from 20 patients, one of whom (5%) had prostate cancer. The remaining 71 biopsies were taken from 52 patients without transitional zone sampling, and cancer was detected in 2 (3.8%) of them.
CONCLUSIONS: Since no significant difference was observed between patient groups (those with and those without transitional zone biopsies) in the detection of prostate cancer in the transitional zone, strategies for increasing the number of cores taken from transitional zone during repeat biopsies should be reconsidered.

Kim S, Dall'Era MA, Evans CP
Economic analysis of active surveillance for localized prostate cancer.
Curr Opin Urol. 2012; 22(3):247-53 [PubMed]

PURPOSE OF REVIEW: Active surveillance is gaining wider acceptance in the urologic community as an effective treatment option for patients with low-risk prostate cancer. The purpose of this review is to analyze the economics of active surveillance in comparison with other therapies.
RECENT FINDINGS: Evaluating the economics of active surveillance in patients with low-risk prostate cancer is constrained by a prolonged natural history of disease. Recent cost model studies using hypothetical patients with low-risk prostate cancer showed that the estimated direct cost of active surveillance over long term was the lowest compared with direct costs of immediate treatment with radical prostatectomy, external beam radiation therapy, primary androgen deprivation therapy or brachytherapy. Active surveillance is associated with more quality-adjusted life years than immediate therapies with similar or lower lifetime costs. Physician reimbursement for active surveillance exceeded that from upfront radical prostatectomy after 3-5 years of follow-up and may be an important driving factor for physicians to practice active surveillance.
SUMMARY: Active surveillance appears to reduce prostate cancer healthcare expenditure by reducing the number of costly therapies. Results from clinical trials will allow the measurement of the true economic value of active surveillance in the future.

Ouzzane A, Puech P, Villers A
MRI and surveillance.
Curr Opin Urol. 2012; 22(3):231-6 [PubMed]

PURPOSE OF REVIEW: In this review, we summarize the recent advances in modern imaging, particularly multiparametric (mp) MRI and its role in the selection and monitoring of patients on active surveillance.
RECENT FINDINGS: Current diagnostic pathway has some limitations in selecting patients with insignificant prostate cancer for active surveillance. Hence, percentage of men under active surveillance for insignificant prostate cancer and reclassified as significant cancer at 2 years is 20-30%. It is mainly because of anterior cancer underdiagnosis by systematic posterior biopsies. mp-MRI is accurate for significant cancer detection and staging, including anterior cancers, which represent 20% of cancers in an unselected population of men with suspicious prostate-specific antigen elevation. One way to reduce the risk of underestimation is to target the needle on significant cancer identified at prebiopsy anatomical and functional imaging, so that detection and personalized risk stratification can be improved. MRI reveals greater volume of cancers and higher grade than systematic 12-core biopsies. MRI 95% negative predictive value has the potential to avoid biopsy series for monitoring patients under active surveillance.
SUMMARY: Upon confirmation of these results, MRI may be used to better select patients for active surveillance inclusion. Incorporation of mp-MRI into active surveillance selection criterias for patients with low-risk prostate cancer can reduce the number of patients reclassified at subsequent biopsies because of better initial prognosis evaluation. In addition to additional cost, MRI requires a highly skilled team to obtain information adequate to drive clinical decisions.

Lees K, Durve M, Parker C
Active surveillance in prostate cancer: patient selection and triggers for intervention.
Curr Opin Urol. 2012; 22(3):210-5 [PubMed]

PURPOSE OF REVIEW: The long-term safety and effectiveness of active surveillance depends on our ability to select appropriate patients and trigger delayed treatment in those who need it, whereas avoiding intervention in those who do not. In this review, we will consider how recent advances have influenced patient selection for active surveillance and review the range of different intervention triggers that have been proposed.
RECENT FINDINGS: Several large surveillance cohort studies have been reported recently showing excellent medium-term outcomes in well selected patients, with approximately a third of patients going on to have deferred treatment. Debate continues on the most appropriate eligibility criteria for active surveillance and what triggers for intervention should be used. There is growing interest in the role of transperineal template biopsies and multiparametric MRI, both for patient selection and in identifying triggers for intervention.
SUMMARY: Active surveillance is a well tolerated treatment option in well selected groups of patients. There is no 'one size fits all' set of criteria for patient selection or triggers for intervention but decisions can be guided by information from histology, prostate-specific antigen kinetics and imaging.

Rolison JJ, Hanoch Y, Miron-Shatz T
Smokers: at risk for prostate cancer but unlikely to screen.
Addict Behav. 2012; 37(6):736-8 [PubMed]

Prostate cancer is the most commonly diagnosed cancer in men. Evidence suggests that smokers may be at increased risk of prostate cancer compared to non-smokers. In the present study we ask whether adult men who smoke are also less likely to undergo screening for prostate cancer. Adult men aged 46 and above completed a single questionnaire including demographic items and items concerning their smoking status and previous testing for prostate cancer. The questionnaire also included an 11 item numeracy scale. Compared to smokers, non-smokers and ex-smokers were around two times more likely to have undergone screening for prostate cancer, and had been tested more frequently. Smokers are not only more likely to develop prostate cancer, they are, paradoxically, less likely to undergo screening for prostate cancer. Health care professionals need to be cognizant of individual differences in screening behavior and that smokers have a reduced likelihood of choosing to screen.

van den Bergh RC, Korfage IJ, Bangma CH
Psychological aspects of active surveillance.
Curr Opin Urol. 2012; 22(3):237-42 [PubMed]

PURPOSE OF REVIEW: Active surveillance is emerging as a serious alternative to radical therapy for low-risk prostate cancer. In a situation in which the difference in effects on disease morbidity and mortality of different treatment options for these malignancies is likely to be small, the quality of life and psychological aspects may be decisive in treatment choice.
RECENT FINDINGS: The following three are the main issues being covered in the literature on psychological aspects of active surveillance. First, the process of consultation with the physician and treatment choice in men diagnosed with low-risk prostate cancer. Second, the effect of active surveillance on physical domains and resulting anxiety and distress, and on quality of life in general. And third, the possible supportive and educational interventions for patients on active surveillance. Observations are scarce and derived from nonrandomized studies with a limited follow-up after diagnosis.
SUMMARY: At the moment of treatment choice, fear of disease progression is the main reason to reject active surveillance. Active surveillance may spare physical domains and does not cause much anxiety or distress on short term in men who choose this strategy. Once men opt for active surveillance, only a minority of them switch to radical treatment due to psychological reasons. Supportive and educational interventions should be considered.

Tasian GE, Cooperberg MR, Potter MB, et al.
PSA screening: determinants of primary-care physician practice patterns.
Prostate Cancer Prostatic Dis. 2012; 15(2):189-94 [PubMed]

BACKGROUND: The effect of practice guidelines and the European Randomised Screening for Prostate Cancer (ERSPC) and Prostate, Lung, Colorectal and Ovarian (PLCO) trials on PSA screening practices of primary-care physicians (PCPs) is unknown.
METHODS: We conducted a national cross-sectional on-line survey of a random sample of 3010 PCPs from July to August 2010. Participants were queried about their knowledge of prostate cancer, PSA screening guidelines, the ERSPC and PLCO trials, and about their PSA screening practices. Factors associated with PSA screening were identified using multivariable linear regression.
RESULTS: A total of 152 (5%) participants opened and 89 completed the on-line survey, yielding a response rate of 58% for those that viewed the invitation. Eighty percent of respondents correctly identified prostate cancer risk factors. In all, 51% and 64% reported that they discuss and order PSA screening for men aged 50-75 years, respectively. Fifty-four percent were most influenced by the US Preventative Services Task Force (USPSTF) guidelines. Also, 21% and 28% of respondents stated that their PSA screening practices were influenced by the ERSPC and PLCO trials, respectively. Medical specialty was the only variable associated with propensity to screen, with family medicine physicians more likely to use PSA screening than internists (β=0.21, P=0.02).
CONCLUSIONS: Half of the physicians surveyed did not routinely discuss PSA screening with eligible patients. The impact of the ERSPC and PLCO trials on PSA screening practices was low among US PCPs. USPSTF recommendations for PSA screening continue to be the strongest influence on PCPs' propensity to use PSA screening.

Shah S, Jha B, Khanal MP
Effects of aging and ethnicity on serum free prostate specific antigen.
Asian Pac J Cancer Prev. 2011; 12(10):2509-12 [PubMed]

Understanding the relationship between ethnicity and free prostate specific antigen (fPSA) could identify the population that should be targeted for intervention and prevention program regarding prostate disease. In this study, we therefore examine the effects of aging and ethnicity on fPSA, measured in serum by chemiluminescent assay (CLIA) method of 351 men visiting Tribhuvan University Teaching Hospital (TUTH) for fPSA test from December to March. Medicinal records abstracts were used to obtain information regarding the ethnicity and age of the cases. Those cases whose age and surname could not be obtained were excluded in our study. The subjects were stratified in four ethnic groups viz; Indo-Nepalese, Tibeto-Nepalese, Indigenous and Other based on the origin. The relationship between age and fPSA level was analysed using bivariate coorelation. The age and the fPSA level of the cases were expressed in Mean ± SEM. The association among different age-group and ethnicity with fPSA were analysed using one way ANOVA. The mean fPSA and mean age of the subjects were 1.74 ± 0.22 and 66.84 ± 0.64 respectively. fPSA level was fairly correlated with the age (r=0.146, p=<0.01). The mean fPSA level (ng/ml) among the four age category (<45, 45-60, 60-75 and >75) were 0.49 ± 0.13, 0.69 ± 0.10, 1.94 ± 0.04 and 2.33 ± 0.43 respectively. The difference in mean fPSA level among four different age-groups was statistically significant (p=0.031). Analysis showed no correlation between the fPSA level and the ethnicity. These data suggest that the fPSA level is associated with the age.