cochrane systematic review prostate cancer screening

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Screening for prostate cancer

Prostate cancer is one of the most prevalent forms of cancer in men worldwide. Screening for prostate cancer implies that diagnostic tests be performed in the absence of any symptoms or indications of disease. These tests include the digital rectal examination (DRE), the prostate-specific antigen (PSA) blood test and transrectal ultrasound (TRUS) guided biopsy. Screening aims to identify cancers at an early and treatable stage, therefore increasing the chances of successful treatment while also improving a patient's future quality of life. This review identified five relevant studies, comprised of 341,342 participants in total. Two of the studies were assessed to be of low risk of bias, whilst the remaining three had more substantive methodological weaknesses. Meta-analysis of all five included studies demonstrated no statistically significant reduction in prostate cancer-specific mortality (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.86 to 1.17). Meta-analysis of the two low risk of bias studies indicated no significant reduction in prostate cancer-specific mortality (RR 0.96, 95% CI 0.70 to 1.30). Only one study included in this review (ERSPC) reported a significant 21% relative reduction (95% CI 31% to 8%) in prostate cancer-specific mortality in a pre-specified subgroup of men. These results were primarily driven by two countries within the ERSPC study that had very high prostate cancer mortality rates and unusually large reduction estimates. Among men aged 55 to 69 years in the ERSPC study, the study authors reported that 1055 men would need to be screened to prevent one additional death from prostate cancer during a median follow-up duration of 11 years. Harms included overdiagnosis and harms associated with overtreatment, including false-positive results for the PSA test, infection, bleeding, and pain associated with subsequent biopsy.

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.

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.

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.

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.

All RCTs of screening versus no screening for prostate cancer were eligible for inclusion in this review.

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.

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).

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[COCHRANE SYSTEMATIC REVIEWS ON PROSTATE CANCER]

PMID: 29087141

Prostate cancer is a common malignant tumor of the elderly, which accounts for a significant proportion of total morbidity but very low of mortality. In Croatia, it is the second most common cancer in men. Currently, there are many doubts concerning screening, early detection and treatment of prostate cancer. Therefore, this article brings results of Cochrane systematic reviews (SRs) on the topic of prostate cancer published in the last eight years. In June 2016, Cochrane database of systematic reviews was searched using the following keywords: Systematic Reviews, and Prostate Cancer (Malignancy, Neoplasm). Inclusion criterion was publication date of the Cochrane SR or its update in the last eight years. The abstracts were initially screened and those that matched the topic were included in further analysis. Then full texts of all SRs involved were obtained. SRs were classified into four topics: prevention, screening, treatment and psychosocial aspects. Our search retrieved a total of 19 Cochrane SRs on the topic of prostate cancer. Excluded were four articles that did not match the specific topic, and the remaining 15 full texts were obtained. One of these was on screening, two on prevention, the majority, i.e. eleven were on treatment, and one on the psychosocial aspects related to prostate cancer. Based on the results of the Cochrane SRs on prostate cancer, instead of mass/population screening, the individualized/opportunistic screening approach should be applied in men aged 55-69, always providing full information to the patient and taking into account the potential benefits and harms of this procedure.

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Prostate cancer screening with prostate-specific antigen (PSA) test: a systematic review and meta-analysis

Objective To investigate the efficacy and safety of prostate-specific antigen (PSA) testing to screen for prostate cancer.

Design Systematic review and meta-analysis.

Data sources Electronic search of Cochrane Central Register of Controlled Trials, Web of Science, Embase, Scopus, OpenGrey, LILACS, and Medline, and search of scientific meeting abstracts and trial registers to April 2018.

Eligibility criteria for selecting studies Randomised controlled trials comparing PSA screening with usual care in men without a diagnosis of prostate cancer.

Data extraction At least two reviewers screened studies, extracted data, and assessed the quality of eligible studies. A parallel guideline committee (BMJ Rapid Recommendation) provided input on the design and interpretation of the systematic review, including selection of outcomes important to patients. We used a random effects model to obtain pooled incidence rate ratios (IRR) and, when feasible, conducted subgroup analyses (defined a priori) based on age, frequency of screening, family history, ethnicity, and socioeconomic level, as well as a sensitivity analysis based on the risk of bias. The quality of the evidence was assessed with the GRADE approach.

Results Five randomised controlled trials, enrolling 721 718 men, were included. Studies varied with respect to screening frequency and intervals, PSA thresholds for biopsy, and risk of bias. When considering the whole body of evidence, screening probably has no effect on all-cause mortality (IRR 0.99, 95% CI 0.98 to 1.01; moderate certainty) and may have no effect on prostate-specific mortality (IRR 0.96, 0.85 to 1.08; low certainty). Sensitivity analysis of studies at lower risk of bias (n=1) also demonstrates that screening seems to have no effect on all-cause mortality (IRR 1.0, 0.98 to 1.02; moderate certainty) but may have a small effect on prostate-specific mortality (IRR 0.79, 0.69 to 0.91; moderate certainty). This corresponds to one less death from prostate cancer per 1000 men screened over 10 years. Direct comparative data on biopsy and treatment related complications from the included trials were limited. Using modelling, we estimated that for every 1000 men screened, approximately 1, 3, and 25 more men would be hospitalised for sepsis, require pads for urinary incontinence, and report erectile dysfunction, respectively.

Conclusions At best, screening for prostate cancer leads to a small reduction in disease-specific mortality over 10 years but has does not affect overall mortality. Clinicians and patients considering PSA based screening need to weigh these benefits against the potential short and long term harms of screening, including complications from biopsies and subsequent treatment, as well as the risk of overdiagnosis and overtreatment.

Systematic review registration PROSPERO registration number CRD42016042347.

Introduction

Prostate cancer is the second most common cancer and the fifth leading cause of cancer-associated mortality among men worldwide. 1 Screening for prostate cancer with serum prostate-specific antigen (PSA) aims to detect prostate cancer at an early, intervenable stage amenable to curative treatment and reduction in overall and disease-specific mortality. 2 3 However, the evidence has so far not demonstrated that screening for prostate cancer saves lives. 4 5 Instead, screening may be associated with increased harms such as overdiagnosis and complications of treatment for indolent disease. 2 3 4 5 Nevertheless, screening for prostate cancer remains highly controversial because of limitations in randomised trials including contamination and under-representation of black men. Difficulty of shared, informed decision-making between patients and primary care providers about PSA screening may also contribute to practice variations. 6 7 Recently, the US Preventive Services Task Force (USPSTF) updated their recommendation statement, changing it from a grade D (recommendation against PSA based screening for prostate cancer) to a grade C recommendation (advocating for an individualised approach to screening). 3 8 9

Our prior systematic review and meta-analysis that evaluated the effectiveness of prostate cancer screening included five studies that enrolled 341 342 patients. 5 In this 2013 Cochrane review we demonstrated that PSA screening led to an increase in prostate cancer diagnoses but did not reduce overall nor disease-specific mortality. Since the publication of this review, several of the included studies have reported outcomes at extended follow-up. In addition, a new, large trial has been published. 10 Therefore, the effectiveness of prostate cancer screening based on the current best evidence is uncertain. In contrast to the recently published USPSTF evidence report, we included and analysed all relevant screening trials using data from the longest available follow-up. 9

This systematic review is part of the BMJ Rapid Recommendations project, a collaborative effort from the MAGIC research and innovation programme ( www.magicproject.org ) and The BMJ . The aim of the project is to respond to new potentially practice changing evidence and provide a trustworthy practice guideline in a timely manner. 11 In our case, the stimulus was the recent Cluster Randomised Trial of PSA Testing for Prostate Cancer (CAP), 10 which randomised over 419 357 men at 573 primary care practices in the United Kingdom to PSA screening versus usual management. 10 In light of this new evidence, we conducted an update of prior systematic reviews by our group to address the potential benefits and harms of PSA based screening. 4 5 This systematic review informed the parallel guideline published in a multi-layered electronic format on bmj.com and MAGICapp (see box 1 ).

Linked articles in this BMJ Rapid Recommendation cluster

Tikkinen KAO, Dahm P, Lytvyn L, et al. Prostate cancer screening with prostate-specific antigen (PSA) test: a clinical practice guideline. BMJ 2018:362:k3581. doi: 10.1136/bmj.k3581

Summary of the results from the Rapid Recommendation process

Ilic D, Djulbegovic M, Jung JH, et al. Prostate cancer screening with prostate-specific antigen (PSA) test: a systematic review and meta-analysis. BMJ 2018:362:k3519. doi: 10.1136/bmj.k3519

Systematic review and meta-analysis of all available randomised trials that assessed PSA based screening for prostate cancer

Vernooij RWM, Lytvyn L, Pardo-Hernandez H, et al. Values and preferences of men for undergoing prostate-specific antigen screening for prostate cancer: a systematic review. BMJ Open 2018;0:e025470. doi: 10.1136/bmjopen-2018-025470

Systematic review of the values and preference of men considering PSA screening

MAGICapp ( https://app.magicapp.org/public/guideline/n32gkL )

Expanded version of the results with multilayered recommendations, evidence summaries, and decision aids for use on all devices

Protocol registration

The protocol for this systematic review was registered with PROSPERO (CRD42016042347). 14

BMJ Rapid Recommendation and patient involvement

In accordance with the BMJ Rapid Recommendations process, 11 a guideline panel provided critical input and guidance during the review process, which included identifying populations, subgroups, and outcomes of interest. The panel consisted of general practitioners, urologists, methodologists, and men eligible for screening. These eligible men received personal training and support to optimise contributions throughout the guideline development process. They were full members of the guideline panel and contributed to the selection and prioritisation of outcomes. They also contributed to the assessment of values and preferences and provided critical feedback to the systematic review protocol and BMJ Rapid Recommendations manuscript. 12 13

Search strategy

A trained medical librarian performed electronic searches of the Cochrane Central Register of Controlled Trials (via Wiley), Web of Science, Embase, Scopus, OpenGrey, LILACS, Medline (via Ovid) and PubMed (via National Library of Medicine) databases from their inception through to April 2018 (see appendix 1). Additionally, we scanned the reference lists of published narrative and systematic reviews to identify any potential studies not retrieved by our electronic search. In an effort to find unpublished studies, we also hand searched abstracts from the annual meetings of American Urological Association, American Society of Clinical Oncology, and European Urological Association from 2013 (the latest search date of our most recent systematic review 5 ) through to April 2018. To identify ongoing trials, we used the International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov search portals.

The randomised controlled trials reported limited data on the harms of screening compared with no screening. We therefore searched for follow-up evidence from the intervention arms of included trials and follow-up publications. We used the Finnish arm of the European Randomised Study of Screening for Prostate Cancer (ERSPC) for quality of life data 15 and false positive rates. 16 We estimated false negative rates among men with a low PSA concentration from a follow-up cohort study of the Prostate Cancer Prevention Trial. 17 We extracted complication rates from prostate cancer treatment modalities from the Prostate Testing for Cancer and Treatment (ProtecT) trial, which enrolled patients from the CAP trial who were diagnosed with prostate cancer and randomised to active monitoring, radical prostatectomy, or radical radiotherapy with hormones. 18 Similarly, we obtained complication rates from biopsies from the Prostate Biopsy Effects cohort study nested within the ProtecT trial. 19 By modelling the likelihood of elevated PSA levels, biopsies, cancer diagnoses, and treatment modalities (from the National Institute of Health Surveillance, Epidemiology, and End Results Program), 20 we estimated the absolute number of biopsy and treatment related complications among men who underwent screening compared with those who did not.

Study selection

After removing duplicates, we imported all citations into Covidence ( www.covidence.org ). Two study team members independently reviewed each citation and abstract according to a priori selection criteria. For studies that advanced beyond this stage, two study team members then performed independent full-text reviews. To determine eligibility, studies in non-English language were translated. References reporting on the same trial were mapped to unique study identifiers.

We considered all randomised controlled trials in any language comparing PSA based screening with usual care in men without a diagnosis of prostate cancer. Outcomes of interest were all-cause mortality, disease-specific mortality, prostate cancer incidence and stage (categorised as localised and advanced cancer), quality of life, false positive and false negative results, and harms related to screening.

Data extraction and risk of bias assessment

For each study selected for inclusion, two team members independently extracted data using a previously tested standardised form. Data collected were ( a ) general study information (authors, study year, publication type, country of origin, enrolment period, inclusion and exclusion criteria, and funding source); ( b ) study population details (ethnicity, sample size, age, and duration of follow-up); ( c ) details of the intervention and comparator (PSA, digital rectal examination, frequency of screening, and definition of control treatment or usual care); and ( d ) outcomes of interest as listed above. Inconsistencies in extracted data were resolved between the two team members through discussion, with a third team member serving as arbitrator. For the ERSPC study, we focused on the “core” group, which best corresponded to the target population of the accompanying Rapid Recommendation. The ERSPC study recruited men aged 50-74 years, but focused its data analysis on men in the core age group of 55-69 years.

To assess the risk of bias of the selected studies, we used Cochrane’s risk of bias tool on an outcome-specific basis. 21 Two team members independently evaluated each randomised controlled trial across several domains by relying on the information presented in the study report, available protocols, or secondary publications. No assumptions were made. These domains included sequence generation and concealment of allocation (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessors (detection bias), and completeness of follow-up (attrition bias). In addition, we assessed rates of adherence to the screening intervention and rates of contamination of the usual care arm. For each domain, two individual team members judged whether the risk of bias was low, high, or unclear. Any disagreements were reconciled by a third team member.

We rated the confidence in the estimates of effect for each outcome according to the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach, taking into account study limitations (risk of bias), inconsistency, imprecision, indirectness, and publication bias. 22 For each comparison, two team members independently rated the certainty of the effect estimates (that is, quality of evidence) for each outcome as high, moderate, low, or very low. We resolved discrepancies by consensus and, if needed, by arbitration by a third team member. The GRADE Summary of Findings table was generated using the MAGICapp platform ( www.magicapp.org ). The trials varied in their duration of follow-up from 10 to 20 years, and we pooled relative estimates of effect at the longest available follow-up time. To generate absolute effect size estimates, we consistently used the baseline risk from the CAP trial as it provided the most contemporary and therefore applicable control event rate in the absence of screening. 10 We calculated absolute effect size estimates at 10 years, which we determined to be an appropriate time horizon to base individuals’ and panel members’ deliberations on. We also explored how the absolute effect estimates varied according to baseline risks at different time horizons using data from the ERSPC trial.

Data synthesis and primary analysis

When person-years data were available, we used incidence rate ratios with 95% confidence intervals to express dichotomous outcomes; alternatively, we used risk ratios. When needed, we approximated risk ratio to incidence rate ratio if the event rate was low (<10%) and the sample size was large; in the case that the event rate was a little over 10% (~12% prostate cancer incidence in Stockholm study 23 ), we conducted a sensitivity analysis excluding this study. To account for different variances of the treatment effect due to clustering in the CAP trial, 10 we used the adjusted incidence rate ratio from the generalised regression approach for the outcome measure.

We conducted meta-analyses and pooled the effect estimates using DerSimonian and Laird’s inverse of variance random effects model and presented the results in forest plots. 24 Following GRADE guidance, statistical heterogeneity was determined using the Q statistic and I 2 which was interpreted as follows; ( a ) 0-40% may not be important, ( b ) 30-60% may indicate moderate heterogeneity, ( c ) 50-90% indicates substantial heterogeneity, and ( d ) 75-100% indicates considerable heterogeneity. 25 Decisions about downgrading for inconsistency were based on clinical relevance according to the clinical practice guideline that this systematic review supports. 26 27 Regardless of the observed statistical heterogeneity, and when the evidence was available, we conducted the following pre-specified subgroup analyses: age (50-54, 55-59, 60-64, 65-69, and ≥70 years), frequency of screening (periodic v one-time), family history (present v absent), ethnicity (African descent v not), and socioeconomic level (higher v lower) using lower levels of education (primary education only) as a proxy of lower socioeconomic status. 28 For subgroup analyses, we used the random effects meta-regression approach to test for interaction. We also conducted a sensitivity analysis limited to studies assessed as having a lower risk of bias. We planned to use funnel plots to examine the extent of publication bias for outcomes if there were 10 or more studies included, which was not the case. 14 Data were analysed using SAS (version 9.4, Cary, NC, US) and STATA software (Version 14.2, Texas, US). For all aspects of the review, we followed the guidelines of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist. 29

Description of included studies

Our electronic search identified 10 982 references. Of these, 5385 were excluded as duplicates, leaving 5597 for screening. We excluded 5488 during the initial screening phase based on the title and abstract. For the remaining 109 studies, we undertook full-text screening and eliminated 77 studies for reasons including ( a ) interventions or comparators were not aligned with screening versus no screening (n=28), ( b ) not randomised controlled trials (n=21), ( c ) duplicate studies (n=12), ( d ) secondary analyses of previously reported data (n=10), ( e ) study participants did not meet eligibility criteria (n=4), and ( f ) outcomes were not aligned with primary or secondary outcomes of interest (n=2). We excluded the Norköpping trial based on methodological grounds as it was quasi-randomised. 30 This left 32 references which mapped to five unique studies that ultimately met our inclusion criteria and were included in the meta-analysis. Figure 1 details the study selection process.

Flow diagram of study selection for systematic review

These five randomised controlled trials enrolled a total of 721 718 participants. The CAP study was conducted in the United Kingdom, recruiting 573 primary care practices. 10 The remaining four trials included the ERSPC study, 31 the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening trial conducted in the US, 32 and trials conducted in Canada (Quebec) 33 and Sweden (Stockholm). 23 The ERSPC study was a multicentre study across eight European countries. 31

Among the included studies, the age of men enrolled ranged from 40 to 80 years. Screening methods included PSA alone and PSA combined with digital rectal examination. PSA thresholds to indicate further investigation via biopsy differed across studies, as did the screening interval (varying from one-time, every two years or more, to annual screening). Table 1 and appendix 2 provide additional details of the included studies.

Characteristics of studies included in the systematic review

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All included studies were assessed as being potentially susceptible to performance bias because of the nature of the intervention. The CAP study had flawed allocation concealment (general practices consented after randomisation and group assignment) and adherence (only 40% of those randomised to screening adhered to it). 10 The PLCO study had poor allocation concealment and major contamination. 32 The two other smaller studies had further issues across several domains. 23 33 Figure 2 summarises the risk of bias assessment for each study. The summary of findings for the entire body of evidence is detailed in table 2 . Of the five included studies, only the ERSPC study was found to have a lower risk of bias than the rest of the evidence from other trials. 31 We therefore present a sensitivity analysis based on selected evidence from ERSPC in table 3 .

Risk of bias summary for each clinical trial included in the systematic review (the review team’s judgments about each risk of bias domain)

Summary of findings from pooled analysis of all eligible trials (n=5)

Summary of findings from lower risk of bias data (sensitivity analysis based on ERSPC trial)

Main analysis including all eligible trials

Effect of psa screening on all-cause mortality.

Based on four randomised controlled trials reporting this outcome, screening probably has no effect on all-cause mortality (incidence rate ratio (IRR) 0.99 (95% CI 0.98 to 1.01), I 2 =0%, moderate quality evidence; fig 3 , table 2 ). 10 23 31 32 This corresponds to one less death from any cause (95% CI 3 fewer to 1 more) per 1000 participants screened. We downgraded the quality of evidence for risk of bias.

Forest plot showing the incidence rate ratio (IRR) for all-cause mortality for PSA screening v control groups. Horizontal bars denote 95% CIs. Studies are represented as squares centred on the point estimate of the result of each study. The area of the square represents the weight given to the study in the meta-analysis. The pooled IRR was calculated by DerSimonian–Laird random effects model. The diamond represents the overall estimated effect and its 95% CI

Effect of PSA screening on prostate-specific mortality

PSA screening may have little or no effect on prostate cancer-specific mortality based on five trials reporting this outcome (IRR 0.96 (0.85 to 1.08), I 2 =58%, low quality evidence; fig 4 , table 2 ). 10 23 31 32 33 This corresponds to zero fewer deaths from prostate cancer (95% CI 0 fewer to 0 more) per 1000 participants screened. We downgraded the quality of evidence for risk of bias as well as clinically important inconsistency.

Forest plot showing the incidence rate ratio (IRR) for prostate-specific mortality for PSA screening v control groups. Horizontal bars denote 95% CIs. Studies are represented as squares centred on the point estimate of the result of each study. The area of the square represents the weight given to the study in the meta-analysis. The pooled IRR was calculated by DerSimonian–Laird random effects model. The diamond represents the overall estimated effect and its 95% CI

Effect of PSA screening on incidence of prostate cancer

Based on data from four trials, screening may increase the detection of prostate cancer of any stage (IRR 1.23 (1.03 to 1.48), I 2 =99%, low quality evidence; fig 5 , table 2 ). 10 23 31 32 This corresponds to seven more diagnoses of prostate cancer (95% CI 1 more to 15 more) per 1000 men screened. We downgraded the quality of evidence for risk of bias as well as clinically important inconsistency.

Forest plot showing the incidence rate ratio (IRR) for the incidence of prostate cancer for PSA screening v control groups. Horizontal bars denote 95% CIs. Studies are represented as squares centred on the point estimate of the result of each study. The area of the square represents the weight given to the study in the meta-analysis. The pooled IRR was calculated by DerSimonian–Laird random effects model. The diamond represents the overall estimated effect and its 95% CI

PSA screening may increase the detection of localised (stage I and II) prostate cancer based on evidence from three randomised controlled trials (risk ratio (RR) 1.39 (1.09 to 1.79), I 2 =99%, low quality evidence; fig 6 , table 2 ). 10 31 32 This corresponds to seven more localised prostate cancers diagnosed (95% CI 2 more to 15 more) per 1000 participants screened. We downgraded the quality of evidence due to risk of bias and clinically important inconsistency. Based on the same body of evidence, PSA screening may modestly decrease the incidence of advanced prostate cancer (stage III and IV) (RR 0.85 (0.72 to 0.99), I 2 =87%, low quality evidence; fig 7 , table 2 ). This corresponds to two fewer men diagnosed with advanced prostate cancer (95% CI 4 fewer to 0 fewer) per 1000 men screened. We downgraded the quality of evidence for risk of bias and clinically important inconsistency.

Forest plot showing relative risk (RR) for the incidence of localised (stages I and II) prostate cancer for PSA screening v control groups. Horizontal bars denote 95% CIs. Studies are represented as squares centred on the point estimate of the result of each study. The area of the square represents the weight given to the study in the meta-analysis. The pooled RR was calculated by DerSimonian–Laird random effects model. The diamond represents the overall estimated effect and its 95% CI

Forest plot showing relative risk (RR) for the incidence of advanced (stages III and IV) prostate cancer for PSA screening v control groups. Horizontal bars denote 95% CIs. Studies are represented as squares centred on the point estimate of the result of each study. The area of the square represents the weight given to the study in the meta-analysis. The pooled RR was calculated by DerSimonian–Laird random effects model. The diamond represents the overall estimated effect and its 95% CI

Subgroup analysis

We found no evidence of a subgroup effect according to age or screening frequency (appendix 3), but we did find a subgroup effect according to risk of bias (lower versus higher risk of bias).

Other outcomes

Only a single trial, the Finnish arm of the ERSPC trial 15 provided data on quality of life when comparing PSA screening with no screening. 15 31 This was based on a random sample of participants (n=1088) from both trial arms excluding men with a subsequent diagnosis of prostate cancer. Using the SF-6D instrument and a scale from 0 to 1.0 (with higher values indicating better quality of life), there was no difference between the two arms (mean difference 0.01 (95% CI 0.01 lower to 0.02 higher), low quality evidence; table 2 ). We downgraded the quality of evidence for risk of bias and indirectness.

Only the PLCO and CAP studies reported complications following biopsy. 10 32 The PLCO study reported 75 complications from biopsies, including 29 infectious and 48 non-infectious adverse events. The CAP study reported three biopsy related complications (1 attributed to biopsy, 2 post-biopsy). Based on the Prostate Biopsy Effects cohort study, rates of biopsy-related complications ranged from 93% (haematospermia) to 1.4% (hospital readmissions, most commonly for sepsis) 19 : this corresponds to 94 men and one more man, respectively, per 1000 men screened. Graded by severity, 64.6% (95% CI 61.6% to 67.8%) experienced minor complications, 31.8% (28.8% to 35.1%) had moderate complications, and 1.4% (0.8% to 2.4%) had major complications. There were no biopsy related deaths. At six years after active monitoring, radical surgery, and local radiation, rates of urinary incontinence were 8%, 17%, and 4%, respectively, and rates of erectile dysfunction were 70%, 83%, and 73%, respectively ( table 2 ). 18 Comparing screened and unscreened men, we estimated there would be three more men per 1000 screened presenting with urinary incontinence and 25 more men per 1000 screened with erectile dysfunction (appendix 4).

Approximately two thirds of men with an elevated PSA level can expect a false positive test result, meaning they will not be diagnosed with prostate cancer. 16 Approximately 15% of men with a PSA level <4 ng/mL will harbour prostate cancer of any grade consistent with a false negative result. Clinically meaningful disease with a Gleason score ≥7 can be expected in 2.3% of men with a PSA level <4 ng/mL ( table 2 ). 17

Sensitivity analysis based on low risk of bias studies

As planned, we performed an additional analysis using studies that were judged to be at lower risk of bias; this left only the ERSPC study. 31

Based on the ERSPC trial, PSA screening probably has no effect on all-cause mortality (IRR 1.0 (0.98 to 1.02), moderate quality evidence; table 3 ). This corresponds to zero fewer deaths of any cause (95% CI 3 fewer to 3 more) per 1000 participants screened. We downgraded the quality of evidence for risk of bias.

PSA screening probably has a small effect on prostate cancer-specific mortality (IRR 0.79 (0.69 to 0.91), moderate quality evidence; table 3 ). This corresponds to one fewer death from prostate cancer (95 CI 1 fewer to 0 fewer) per 1000 participants screened. We downgraded the quality of evidence for risk of bias. When using the ERSPC control event rate at 13 years 31 or that of the Göteborg arm of the ERSPC trial 34 at 18 years, this translates to one fewer (95% CI 1 fewer to 2 fewer) or three fewer (95% CI 1 fewer to 4 fewer) deaths from prostate cancer, respectively, per 1000 men screened.

Screening probably increases the detection of prostate cancer of any stage (IRR 1.57 (1.51 to 1.62), moderate quality evidence; table 3 ). This corresponds to 18 more diagnoses of prostate cancer (95% CI 16 more to 20 more) per 1000 men screened. We downgraded the quality of evidence for risk of bias. Results of this analysis changed little when the Stockholm trial was excluded in a sensitivity analysis. 23 Screening probably also increases the incidence of localised (stage I and II) prostate cancer (RR 1.75 (1.68 to 1.82)), corresponding to 14 more per 1000 (95% CI 13 more to 16 more), and probably decreases the incidence of advanced (stages III and IV) prostate cancer (RR 0.75 (0.69 to 0.82)), corresponding to three fewer per 1000 men screened (95% CI 4 fewer to 2 fewer).

Since all available data for these outcomes were from the ERSPC trial the results of the sensitivity analysis were the same as that of the main analysis.

Statement of principal findings

Based on moderate and low quality evidence, PSA screening seems to increase the detection of prostate cancer of any stage, increases the detection of stage I and II prostate cancer, and slightly decreases the detection of stage III and IV prostate cancer. At the same time, it probably modestly reduces prostate cancer specific mortality but has no effect on overall mortality. While findings from the ERSPC trial reflects a 21% relative risk reduction of prostate cancer-specific mortality (95% CI 9.0% to 31.0%), this corresponds to only one less death from prostate cancer (95% CI 1 fewer to 0 fewer) per 1000 men screened. Meanwhile, PSA screening is associated with considerable biopsy-related and cancer treatment-related complications. We estimated that, for every 1000 men screened, approximately one, three, and 25 more men will be hospitalised for sepsis, require pads for urinary incontinence, and report erectile dysfunction, respectively.

Strengths and weaknesses of the study

We conducted this review based on an a priori protocol that defined a rigorous methodological approach based on the Cochrane Handbook and GRADE approach. Patient-centric outcomes and secondary analyses were informed by input from stakeholder representatives from the Rapid Recommendations guideline panel as well as a systematic review of the values and preferences of affected individuals. 12 13 Our approach included a comprehensive search of multiple databases as well as other sources for relevant publications irrespective of language or publication status. While it is possible that we may have missed some secondary reports of the included trials, it seems unlikely that additional trials were missed.

The major limitation of this review stems from the included trials themselves. All trials had methodological limitations that lowered the confidence of their effect size estimates, as summarised in tables 2 and 3 . Except for overall mortality, we found evidence of considerable inconsistency for each pooled analysis, prompting us to further downgrade the quality of the evidence. The key issue was considerable clinical and methodological heterogeneity across trials and within the arms of the ERSPC trial itself. The limited number of available trials precluded many planned secondary analyses of observed inconsistencies. Potential sources of heterogeneity include different screening intensity (one-time screen in CAP versus multiple rounds in other trials), different screening intervals (annual in PLCO versus every 2-4 years in different arms of the ERSPC trial, for example), different PSA biopsy thresholds (ranging from 2.5 to 4 ng/mL), as well as various degrees of adherence and control group contamination. In contrast to other systematic review authors, 35 36 we chose not to adjust for these inconsistencies as this would introduce additional uncertainty. Second, the reported harms evidence was not based on a comprehensive evaluation of the published literature, but instead used any available follow-up evidence from the intervention arms of the included trials and respective follow-up publications. This data was used to estimate the absolute number of biopsy and treatment related complications among men who underwent screening versus those who did not (see also infographic in linked Rapid Recommendation article 12 and appendix 4).

Strengths and weaknesses in relation to other studies

We provide the most up to date report on the best available evidence on screening for prostate cancer. While our group 4 5 and others 37 have previously published similar reviews, these did not include the most recent updates of existing screening trials nor the recently published CAP trial.

The most relevant study for comparison is the systematic review and evidence report referenced by the recently published United States Public Services Task Force (USPSTF) recommendations on prostate cancer screening, which differs from our review in several important ways. 9 38 First, the CAP trial—the largest and most recent trial of PSA screening to date—is missing from their evidence report. While the USPSTF guideline developers gave it formal consideration, the CAP trial was published after the USPSTF’s literature search cut-off date of 1 February 2018. Second, the authors excluded three older, “poor quality” trials based on methodological grounds. Reasons included low adherence to the screening intervention, uncertain levels of contamination in the control arm, and lack of blinding of outcome assessors. While we appreciate these methodological issues, their severity did not prompt us to disregard two of the three studies entirely as the USPSTF Task Force did. We excluded the Norköpping trial on a number of methodological limitations, including quasi-randomisation. 30 Third, in contrast to the task force’s evidence report, we meta-analysed the entire body of evidence. This approach allowed us to evaluate for inconsistency between individual trials by conducting subgroup analyses (based on age and screening intervals) and a sensitivity analysis for risk of bias. Fourth, another major distinction lies in how we handled the control event rates. For the presentation of absolute effects in our summary of findings, we chose to draw this event rate from the CAP trial because it provides the most contemporary and broadly applicable estimation of what would occur in the absence of screening. These numbers were ascertained at a 10-year time horizon (while the effect estimates were pooled at the longest follow-up available in the included trials). This contributes to the lower absolute effect size estimates that we report compared with those reported by the USPSTF, but were deemed the most appropriate to inform the accompanying Rapid Recommendation panel deliberations. 12

Implications for clinicians and policy makers

This systematic review provides important information for an individual man’s decision making about prostate cancer screening. It supported the development of an evidence based clinical practice guideline, as reflected in the accompanying Rapid Recommendation article. 12 Our analysis indicates that PSA screening yields, at best, only a small benefit in prostate cancer specific mortality but does not reduce overall mortality. This small benefit should be weighed against the potential short term complications (biopsy related, false positive and false negative findings) and long term downstream effects (treatment related side effects, in particular related to urinary and sexual function). The latest results of the PIVOT and ProtecT trials should help guideline developers identify the subset of patients with clinically localised prostate cancer who will likely benefit from local, curative treatment while avoiding overtreatment. 39 40 Although active surveillance is increasingly accepted to treat low risk prostate cancer, it is burdensome to patients due to the need for frequent follow-up visits, PSA testing, digital rectal examinations, prostate biopsies, and, recently, magnetic resonance imaging (MRI). The value of MRI in determining which prostate cancers appear clinically relevant versus indolent seems promising but remains uncertain in the context of PSA screening. 41 42 43

What is already known on the subject

Prostate-specific antigen (PSA) screening leads to increased prostate cancer diagnoses. Although it is recommended by some clinical practice guidelines, PSA screening remains controversial

It is unclear whether screening improves overall and disease-specific mortality, the most critical outcomes for patients, or whether the overall benefits of screening outweigh the potential harms and costs of overdetection and overtreatment

The recent publication of a large cluster-randomised controlled trial provides new evidence

What this study adds

At best, screening for prostate cancer may result in a small absolute benefit in disease-specific mortality over 10 years but does not improve overall mortality

These benefits need to be weighed against the potential short and long term harms of PSA screening, including complications from biopsies and subsequent treatment and the risk of overdiagnosis and overtreatment

Practice, doi: 10.1136/bmj.k3581

Contributors: DI, MD, and PD were involved in the conception and design of the review. DI, MD, AC, and PD developed the search strategy and performed study selection. DI, MD, JHJ, ECH, and PD extracted data from included studies. QZ, TA, and PD were involved in the data analysis. DI, MD, JHJ, ECH, QZ, TA, and PD were involved in the interpretation and discussion of results. All authors drafted the manuscript, contributed to the drafting of the review, and revised it critically for important intellectual content. All authors approved the final version of the article. All authors had access to all of the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. PD is guarantor.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Competing interests All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Ethical approval: Not required.

Data sharing: No additional data available.

Transparency: DI and PD affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; no important aspects of the study have been omitted.

Patient involvement: As further described in the Methods section, three patient representatives helped inform the questions, outcomes and thresholds of clinical importance for this systematic review.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

Systematic review and meta-analysis of the diagnostic accuracy of prostate-specific antigen (PSA) for the detection of prostate cancer in symptomatic patients

BMC Medicine volume 20 , Article number: 54 ( 2022 ) Cite this article

Prostate-specific antigen (PSA) is a commonly used test to detect prostate cancer. Attention has mostly focused on the use of PSA in screening asymptomatic patients, but the diagnostic accuracy of PSA for prostate cancer in patients with symptoms is less well understood.

A systematic database search was conducted of Medline, EMBASE, Web of Science, and the Cochrane library. Studies reporting the diagnostic accuracy of PSA for prostate cancer in patients with symptoms were included. Two investigators independently assessed the titles and abstracts of all database search hits and full texts of potentially relevant studies against the inclusion criteria, and data extracted into a proforma. Study quality was assessed using the QUADAS-2 tool by two investigators independently. Summary estimates of diagnostic accuracy were calculated with meta-analysis using bivariate mixed effects regression.

Five hundred sixty-three search hits were assessed by title and abstract after de-duplication, with 75 full text papers reviewed. Nineteen studies met the inclusion criteria, 18 of which were conducted in secondary care settings with one from a screening study cohort. All studies used histology obtained by transrectal ultrasound-guided biopsy (TRUS) as a reference test; usually only for patients with elevated PSA or abnormal prostate examination. Pooled data from 14,489 patients found estimated sensitivity of PSA for prostate cancer was 0.93 (95% CI 0.88, 0.96) and specificity was 0.20 (95% CI 0.12, 0.33). The area under the hierarchical summary receiver operator characteristic curve was 0.72 (95% CI 0.68, 0.76). All studies were assessed as having a high risk of bias in at least one QUADAS-2 domain.

Conclusions

Currently available evidence suggests PSA is highly sensitive but poorly specific for prostate cancer detection in symptomatic patients. However, significant limitations in study design and reference test reduces the certainty of this estimate. There is very limited evidence for the performance of PSA in primary care, the healthcare setting where most PSA testing is performed.

Peer Review reports

Prostate-specific antigen (PSA) is a commonly used test for the detection of prostate cancer, identifying patients that may require a diagnostic test [ 1 ]. PSA testing is usually performed for one of two reasons: assessing a patient presenting to their general practitioner (GP) or primary care physician with lower urinary tract symptoms (LUTS) [ 2 ] or screening for a patient who is asymptomatic but concerned about their risk of prostate cancer [ 3 , 4 ]. Patients with an elevated PSA are usually referred to a urologist for diagnostic testing, which may include magnetic resonance imaging (MRI) of the prostate and/or a prostate biopsy [ 5 ]. Very large randomised controlled trials of PSA-based prostate cancer screening have been performed; these are summarised in a recent systematic review in 2018 that showed a small potential reduction in prostate cancer specific mortality with no change in all-cause mortality and an increased risk of complications from biopsy, overdiagnosis of clinically insignificant prostate cancer, and overtreatment [ 6 , 7 , 8 ]. However, uncertainty remains about the diagnostic accuracy of PSA for prostate cancer in patients with LUTS [ 9 ].

The most recent systematic review of the diagnostic accuracy of PSA was published by Harvey et al. in 2009 [ 10 ]. A range of estimates for the accuracy of PSA was found amongst the ten included studies. That review presented limited information on their methods; crucially, it was unclear whether the included studies were assessing PSA in symptomatic or asymptomatic patients nor was it clear whether any were relevant to primary care populations. Just et al. published a brief review of the literature in 2018, highlighting that the paucity of research in this area applicable to primary care, where a significant proportion of PSA testing is performed, still remains [ 9 ].

This systematic review aimed to determine the diagnostic accuracy of PSA for the detection of prostate cancer in patients, focusing on studies where the included patients (or a subset of included patients) had at least one symptom that could relate to an undiagnosed prostate cancer. Given the findings by Just et al., this review considered studies from primary and secondary care settings.

Types of studies

We included cross-sectional and cohort studies that reported paired data on the diagnostic accuracy of PSA for the detection of prostate cancer in symptomatic men, verified with the use of a reference test (prostate biopsy). We excluded studies if it was not possible to extract data for a complete two-by-two table for the target condition or if the patient cohort was only asymptomatic patients (i.e. a screening cohort). We did not restrict studies by publication date, country, or clinical setting.

Participants

The study population of interest was any patient with symptoms of a possible prostate cancer, with no history of the disease. We defined symptoms of prostate cancer as at least one of LUTS (nocturia, hesitancy, poor stream, incomplete voiding, double voiding, terminal dribbling, urgency, incontinence, frequency), haematuria, erectile dysfunction, or lower back pain. Symptoms may have been identified by a standardised tool, such as the International Prostate Symptom Score (IPSS), clinical coding, or through patient self-report. We did not exclude studies based on age of participants or study setting. Where studies included groups of both asymptomatic and symptomatic men, we included men in the symptomatic group.

The index test was prostate-specific antigen (PSA) in a peripheral blood sample, measured in nanograms per millilitre (ng/mL). We did not set an a priori PSA threshold for prostate cancer detection but instead extracted data based on the PSA thresholds used in each study.

Target condition

The target condition was prostate cancer, regardless of Gleason grade or clinicopathological stage.

Reference test

The reference test was a biopsy of the prostate with histological examination. We did not set an inclusion criteria on the basis of prostate biopsy approach used in studies, but this was recorded as part of the data extraction.

Electronic searches

Medline Ovid, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases were utilised to identify relevant studies. Key search terms, informed by the Scottish Intercollegiate Guidelines Network (SIGN) search strategies and pre-existing systematic reviews in the field of prostate cancer, were combined with MeSH terms for each database search. Hand-searching of reference lists from included studies and snowballing techniques were performed to locate any other possibly relevant studies. Please see Additional file 1 for the search strategy used in this review.

Data collection and analysis

Selection of studies.

Search hits from each database were downloaded and combined into a review database managed in Mendeley Desktop. Each search hit was screened against the inclusion/exclusion criteria by SM and a 2nd investigator (LP, SC, or EG) independently, based on title and abstract. Full text articles were reviewed if a reviewer was unclear on the basis of title and abstract. Any discrepancies of study inclusion were adjudicated by a third reviewer (WH or AS).

Data extraction

A pre-prepared proforma for data extraction was used to collate relevant data from each included study, including two by two tables for the index and reference tests. SM extracted the data from all included studies. A second investigator extracted data from a random sample of 10% of included studies for verification of accuracy of data extraction. Any discrepancies were adjudicated by a third reviewer (WH or AS).

Quality assessment

Risk of bias and applicability of all included studies was assessed by SM using the QUADAS-2 [ 11 ] tool, with a second investigator independently assessing 10% of included studies and discussed any discrepancies with SM.

Meta-analysis

Raw data extracted from included papers on PSA result and prostate cancer diagnoses were extracted and combined into 2 × 2 tables to assess diagnostic accuracy. Measures of pooled diagnostic accuracy were intended to be determined for the following outcomes using bivariate mixed effects regression [ 12 ]:

Any prostate cancer diagnosis

Clinically significant prostate cancer diagnosis (Gleason Grade Group ≥ 2)

The majority of included studies used a fixed PSA threshold of 4 ng/mL, and this was also used as the threshold for meta-analysis. No included studies reported sufficient information to Meta-analyse age-adjusted thresholds.

Heterogeneity

Heterogeneity was assessed for visually, using Forest plots of sensitivity and specificity.

All analyses were performed using Stata Version 16 (StataCorp, http://www.stata.com )

Protocol publication

The protocol for this systematic review and meta-analysis was registered with PROSPERO (CRD42021257783).

PRISMA reporting guidelines

This systematic review was conducted following the PRISMA reporting guidelines for systematic reviews and meta-analyses [ 13 ]. A completed PRISMA checklist can be found in Additional file 2 .

Database searching identified 631 potentially relevant studies, and a further 42 studies were identified through reference list checking and snowballing techniques from initial search hits and key papers. Following de-duplication, 563 search hits were assessed by two reviewers independently, and 75 papers selected for full text assessment. Nineteen papers were ultimately included. Details of full-text exclusions can be found in Fig. 1 .

PRISMA 2020 flow diagram

Risk of bias assessment using the QUADAS-2 tool demonstrated a number of potential areas of bias in the included studies (see Table 1 and Fig. 2 ). None of the studies were assessed as having a low risk of bias with regards to the reference standard test, which was almost always a transrectal ultrasound-guided (TRUS) biopsy. TRUS biopsy suffers from a significant risk of false negative or misclassification of prostate cancer diagnosis owing to the random nature of sampling of the prostate [ 14 ]. The reference standard was performed with knowledge of the index test (PSA) in 16 of 19 studies. Patient populations were drawn from hospital urology clinics in all but one study, affecting applicability to other clinical settings. Limited information with regards to patient selection was available in eight studies, and the majority had a low risk of bias with regards to the conduct of the index test.

Summary of QUADAS-2 risk of bias assessments

Table 2 summarises the features of the included studies. There was a wide range of countries and study sizes. One study focused on a symptomatic cohort within a population screening study, and the remainder were set in hospital urology clinics. No study was performed in a primary care population. Five studies gathered stage and grade data. All but one study used TRUS biopsy as a reference test, with three studies also gathering diagnostic data from transurethral resection of the prostate (TURP) or other urological surgical procedures involving the prostate.

Table 3 shows the measures of diagnostic accuracy calculated using reported data in 14 included studies featuring 14,489 patients that considered a PSA level of greater than or equal to 4 ng/mL as abnormal. The remaining five studies focused on populations in a specific part of the PSA range; either a low or raised PSA level. Meta-analysis showed an estimated combined sensitivity of a PSA greater than or equal to 4 ng/mL for any prostate cancer of 0.93 (95% CI 0.88, 0.96) and a combined specificity of 0.20 (95% CI 0.12, 0.33) (see Fig. 3 ). There was significant heterogeneity between included studies (sensitivity I 2 98.97, specificity I 2 99.61). Hierarchical summary receiver operator curve (HSROC) analysis showed an AUC of 0.72 (95% CI 0.68, 0.76) (see Fig. 4 ). A Fagan plot can be found in Additional File 3 .

Forest plot of included studies using PSA cut-off of 4 ng/mL

Hierarchical summary receiver operator curve (HSROC) of included studies using PSA cut-off of 4 ng/mL

Three studies included in the meta-analysis collected stage and grade data for prostate cancer cases; however, none of these studies reported data for clinically significant prostate cancer diagnoses at a PSA cut-off of ≥ 4 ng/mL. Chang et al. [ 18 ] did not report the accuracy of PSA but showed a statistically significant difference in free to total PSA ratio for a Gleason Score of seven or more compared to Gleason Score of six or lower (11.69 ± 0.98 vs 16.47 ± 2.25, p = 0.029). Richie et al. [ 29 ] did not report the Gleason Score data collected but found higher PSA levels and increasing age were associated with a higher risk of metastatic prostate cancer. Shahab et al. [ 31 ] identified a PSA cut-off of 6.95 ng/mL for differentiating moderate versus high Gleason Score (which was not defined).

Summary of findings

Published studies assessing the diagnostic accuracy of PSA in symptomatic patients reported high sensitivity and low specificity for the detection of prostate cancer. Eighteen of the included studies were undertaken in hospital urology outpatient populations, with one study focused on a symptomatic cohort within a population screening study. Importantly, there were no studies assessing the performance of PSA in a primary care population. Insufficient data was available to assess the diagnostic accuracy of PSA for clinically significant prostate cancer. Furthermore, all included studies had a high risk of bias in at least one QUADAS domain.

Comparison to existing literature

Harvey et al. [ 10 ] published a systematic review of the diagnostic accuracy of PSA for prostate cancer in European populations, focused on studies published between 1998 and 2008. Individual study level data from 10 included papers was reported, though without estimating a combined level of accuracy. They considered the accuracy of PSA for all prostate cancer types overall and showed a range of accuracy estimates similar to this study. Over half of the studies included in this review were published since the review by Harvey et al. A review of clinical features of prostate cancer in primary care by Young and colleagues [ 34 ] in 2015 identified one study from 1989 of 287 patients referred from primary care with bladder outlet obstruction, of whom 211 had a PSA test. High levels of sensitivity (89.5%) and specificity (90%) were reported, but Young and colleagues considered the true level of accuracy was likely to be lower given few patients with a normal PSA level had the reference test for prostate cancer.

Strengths and weaknesses

This study benefited from a rigorous, focused, methodological approach in conducting the review. All clinical settings were eligible, ensuring we found as many relevant studies as possible. Most included studies employed PSA in a similar manner, using similar indications and diagnostic thresholds, allowing for cross-study comparisons.

The evidence for the association between lower urinary tract symptoms and prostate cancer, particularly clinically significant prostate cancer, is equivocal. A number of secondary care studies suggest that symptoms do not discriminate well between prostate cancer and benign prostatic hypertrophy [ 35 , 36 ]. This assumption is largely untested in primary care populations and contrasts with studies showing that the majority of patients diagnosed with prostate cancer present to their GP with LUTS prior to diagnosis [ 37 , 38 , 39 , 40 ]. This controversy also means that LUTS and other relevant symptoms may not be reported or be the focus of some potentially relevant studies of PSA for prostate cancer and may have limited the sensitivity of the search strategy employed. However, key papers were picked up by the database searches and the majority of PSA studies will likely be focused on screening in asymptomatic populations.

All included studies employed TRUS biopsy as a reference test, with some also including pathological data obtained from urological procedures on the prostate. TRUS biopsy is recognised as having poor sensitivity as a diagnostic test [ 41 ], owing to the inability to visualise lesions within the prostate resulting in a random sampling of the gland, and thus misclassification bias. Reporting of histological classification of prostate cancers was only included in three studies, and each presented this data differently. Insufficient data was available to determine a relationship between PSA and clinically significant prostate cancer, which is a crucial consideration for the optimal use of PSA for prostate cancer detection. Most included studies only performed the reference test on patients with a raised PSA or abnormal prostate examination, introducing partial verification bias. Therefore, the true sensitivity of PSA in symptomatic patients is unknown and likely to be lower than reported.

Implications for research and practice

PSA is a commonly used test to assess for the presence of prostate cancer, mostly in a primary care setting, and is recommended as part of the assessment of patients with LUTS in national guidelines [ 42 , 43 , 44 ]. The lack of primary care evidence for the use of PSA to detect prostate cancer is known and is not the only condition for which secondary care evidence has been applied to primary care guidance [ 45 ]. Even so, this is a major gap in knowledge, as spectrum bias means that secondary care data (or screening data) do not translate to primary care. High-quality studies in primary care populations are needed to fill this gap, and future studies should report not just on prostate cancer per se but on clinically significant cancer as well. The introduction of more accurate diagnostic tests for prostate cancer, including multiparametric magnetic resonance imaging [ 41 ], increases the need for better understanding of the role of PSA in the early detection of symptomatic prostate cancer. PSA performance could also be enhanced by incorporating additional relevant clinical data in multivariable risk models [ 46 ], although only one has been validated in primary care [ 47 ].

Primary care clinicians are generally aware of the limitations of PSA testing [ 48 ], and clinical guidelines encourage a balanced discussion with patients of the potential benefits and harms of relying on PSA to detect prostate cancer [ 3 , 49 ]. The findings of this review suggest this is a pragmatic approach in providing care to patients with LUTS. False-positive PSA results can also occur from non-cancer conditions affecting the prostate such as benign prostatic hypertrophy or prostatitis, further limiting the clinical utility of the test for prostate cancer detection. Alternative tests to PSA have been extensively researched [ 50 , 51 ], and some show promise of improving the level of confidence in detecting prostate cancer, though none has entered primary care practice as yet.

Published evidence from almost entirely secondary care based studies suggests that PSA has high sensitivity and low specificity for the diagnosis of prostate cancer in symptomatic patients. Published studies suffer from a number of biases, which probably overestimate the accuracy of PSA, and there were no included studies assessing the accuracy of PSA in a primary care population. The utility of PSA for the diagnosis of clinically significant prostate cancer in primary care remains unclear and needs urgent study. A major focus of such a study would be to identify patients with clinically significant cancer, warranting radical treatments, whilst avoiding exacerbating the issue of overdiagnosis of clinically insignificant prostate cancer.

Availability of data and materials

All data were extracted from published research articles. The study protocol is available on PROSPERO and database search strategy is attached as an additional file.

Abbreviations

Area under the curve

Benign prostatic hypertrophy

Confidence interval

General practitioner

Holmium laser enucleation of the prostate

Hierarchical summary receiver operator curve

International prostate symptom score

Lower urinary tract symptoms

Multiparametric magnetic resonance imaging

Magnetic resonance imaging

Nanograms per millilitre

Scottish intercollegiate guidelines network

Tumour-node-metastasis

Transrectal ultrasound-guided biopsy

Transurethral resection of the prostate

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Acknowledgements

The authors would like to acknowledge the funders of this research.

This research arises from the CanTest Collaborative, which is funded by Cancer Research UK [C8640/A23385], of which SM is a Clinical Research Fellow, AS is an Associate Director, and FMW and WH are co-Directors. SC and LP are funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

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Contributions

SWDM, WH, FMW, and AS conceived the study. SWDM drafted the protocol, and all authors read and approved the final protocol. SWDM performed the database searches. SWDM, EG, SC, and LP performed database search hit screening. SWDM extracted data from the included studies and assessed study quality, with LP checking extraction and quality assessment for a random sample of 10% of included studies. SWDM performed the meta-analysis. SWDM drafted the manuscript. All authors read and approved the final manuscript.

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Correspondence to Samuel W. D. Merriel .

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Supplementary Information

Additional file 1..

Database search strategy.

Additional file 2.

PRISMA 2020 Checklist.

Additional file 3.

Supplementary figure 1—Fagan plot of included studies using PSA cut-off of 4ng/mL.

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Merriel, S.W.D., Pocock, L., Gilbert, E. et al. Systematic review and meta-analysis of the diagnostic accuracy of prostate-specific antigen (PSA) for the detection of prostate cancer in symptomatic patients. BMC Med 20 , 54 (2022). https://doi.org/10.1186/s12916-021-02230-y

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Received : 30 September 2021

Accepted : 30 December 2021

Published : 07 February 2022

DOI : https://doi.org/10.1186/s12916-021-02230-y

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cochrane systematic review prostate cancer screening

Screening for prostate cancer: A Cochrane systematic review

Cancer Causes & Control volume 18 , pages 279–285 ( 2007 ) Cite this article

Metrics details

The objective of this systematic review was to determine whether screening for prostate cancer reduces prostate cancer mortality.

A systematic search for randomised controlled trials was conducted through electronic scientific databases and a specialist register of the Cochrane Prostatic Diseases and Urologic Cancers Group. Manual searching of specific journals was also conducted. Two authors independently reviewed studies that met the inclusion criteria. Studies were independently assessed for quality. Data from included studies was also extracted independently.

Two randomised controlled trials were included however, both trials had methodological weaknesses. Re-analysis of the reported data using intention-to-screen and meta-analysis indicated no statistically significant difference in prostate cancer mortality between men randomized for prostate cancer screening and controls (RR 1.01, 95% CI: 0.80–1.29).

Conclusions

Given that only two randomised controlled trials were included, and the high risk of bias of both trials, there is insufficient evidence to either support or refute the routine use of screening compared to no screening for reducing prostate cancer mortality. Currently, no robust evidence from randomised controlled trials is available regarding the impact of screening on quality of life, harms of screening, or its economic value. Results from two ongoing large scale multi-center randomised controlled trials, which will be available in the upcoming few years, will assist patients and health professionals in making an evidence-based decision regarding the effectiveness of screening for prostate cancer

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Acknowledgments

We wish to thank Kristine Egberts for her help with this review. We would also like to thank the referees and editors of the Prostatic Diseases and Urologic Cancers Group for their comments and valuable assistance.

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Monash Institute of Health Services Research, Monash Medical Centre, Monash University, Locked Bag 29, Clayton, VIC, 3168, Australia

Dragan Ilic, Denise O’Connor & Sally Green

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Correspondence to Dragan Ilic .

Additional information

This paper is based on a Cochrane review first published in The Cochrane Library 2006, Issue 3 (see www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and The Cochrane Library should be consulted for the most recent version of the review. The results of a Cochrane review can be interpreted differently, depending on people’s perspectives and circumstances. Please consider the conclusions presented carefully. They are the opinions of review authors, and are not necessarily shared by The Cochrane Collaboration

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Ilic, D., O’Connor, D., Green, S. et al. Screening for prostate cancer: A Cochrane systematic review. Cancer Causes Control 18 , 279–285 (2007). https://doi.org/10.1007/s10552-006-0087-6

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Received : 10 July 2006

Accepted : 17 October 2006

Published : 06 January 2007

Issue Date : April 2007

DOI : https://doi.org/10.1007/s10552-006-0087-6

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IMAGES

Levels of evidence, systematic review and guidelines
Prostate cancer screening with prostate-specific antigen (PSA) test: a systematic review and
Cochrane reviews compared with industry supported meta-analyses and other meta-analyses of the
Reporting of Cochrane Systematic Review protocols with network meta-analyses
Prostate biopsy: targeting cancer that matters
COCHRANE HANDBOOK FOR SYSTEMATIC REVIEWS OF INTERVENTIONS VERSION 5.0.2 PDF

VIDEO

The Nuances of Prostate Cancer Screening
Prostate Cancer Nursing and NCLEX Lecture
Updates in Prostate Cancer Biomarkers
John Shearron, Advanced Prostate Cancer Support Group Leader, Shares His Perspective
Using the SRDR Screening Tool
Module 1: Asking the right question

COMMENTS

Screening for prostate cancer
Pooled data currently demonstrates no significant reduction in prostate cancer-specific and overall mortality. Harms associated with PSA-based
Screening for prostate cancer: an updated Cochrane ...
A pre-planned analysis of a 'core' age group of men aged 55-69 years from the largest RCT (European Randomised Study of Screening for Prostate Cancer) reported
[COCHRANE SYSTEMATIC REVIEWS ON PROSTATE CANCER]
Based on the results of the Cochrane SRs on prostate cancer, instead of mass/population screening, the individualized/opportunistic screening approach should be
Prostate cancer screening with prostate-specific antigen (PSA) test
Design Systematic review and meta-analysis. Data sources Electronic search of Cochrane Central Register of Controlled Trials, Web of Science
Systematic review and meta-analysis of the diagnostic accuracy of
Prostate-specific antigen (PSA) is a commonly used test to detect prostate cancer. Attention has mostly focused on the use of PSA in screening
Screening for prostate cancer: an updated Cochrane systematic
Meta-analysis of the five included studies indicated no statistically significant difference in prostate cancer-specific mortality between men randomized to.
Screening for prostate cancer: A Cochrane systematic review
Screening for prostate cancer may reduce both morbidity and mortality, yet the best method of screening (if any) is unknown. Equally, screening
Screening for prostate cancer: an updated ...
Five RCTs with a total of 341 351 participants were included in this updated Cochrane systematic review. All involved PSA testing
Screening for prostate cancer: An updated ...
A Cochrane review on screening for prostate cancer included five studies and found that screening did not significantly decrease prostate cancer
Brasil
Further studies to fully assess the effectiveness of cancer screening tests and adverse outcomes are required. KEY WORDS: Diagnosis; Early detection of cancer;