Prostate-specific antigen (PSA) remains as the most used biomarker in the detection of early prostate cancer (PCa). Clinical practice guidelines (CPGs) are produced to facilitate incorporation of evidence into clinical practice. This is particularly useful when PCa screening remains controversial and guidelines diverge among different medical institutions, although opportunistic screening is not recommended.
We performed a systematic review of guidelines about PCa screening using PSA. Guidelines published since 2008 were included in this study. The most updated version of these CPGs was used for the evaluation.
Twenty-two guidelines were selected for review. In 59% of these guidelines, recommendations were graded according to level of evidence (n = 13), but only 18% of the guidelines provided clear algorithms (n = 4). Each CPG was assessed using a checklist of laboratory issues, including pre-analytical, analytical, and post-analytical factors. We found that laboratory medicine specialists participate in 9% of the guidelines reviewed (n = 2) and laboratory issues were frequently omitted. We remarked that information concerning the consequences of World Health Organization (WHO) standard in PSA testing was considered by only two of 22 CPGs evaluated in this study.
We concluded that the quality of PCa early detection guidelines could be improved properly considering the laboratory issues in their development.
Prostate cancer (PCa) is the most prevalent cancer in males in Western countries. In Europe, an incidence of 450,000 new cases and a mortality of 107,000 cancer deaths per year have been estimated for 2018 . Prostate-specific antigen (PSA) remains as the most used biomarker in the detection of early PCa. However, since 2009, PSA usefulness in PCa screening has been widely argued following the opposite results obtained in the two largest randomized screening studies. The European Randomized Study of Screening for Prostate Cancer (ERSPC), enrolling 162,387 men between 50 and 74 years old from seven European countries, found a PCa-specific mortality reduction of 20% in the screened group after a median follow-up of 9 years . In evident contrast, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial, based on 76,693 men, found no differences in the PCa-specific mortality after 7 years of follow-up between the screened group and the control group . Furthermore, these opposite results were confirmed by both groups increasing the time of follow-up and differences were confirmed by the ERSPC trial .
In 2011 the United States Preventive Services Task Force (USPSTF) strongly advise against PSA screening based on a review of six well-done trials, underlying harms related to subsequent evaluation and treatments . Nevertheless, several studies showed the evidence that screening reduces the risk of metastasis both at diagnosis and during follow-up , . Furthermore, Gulati et al.  suggested that discontinuing PSA screening for all men may generate many avoidable cancer deaths in the next years. On the other hand, Stephan et al.  remarked on methodological limitations in the meta-analysis showing no evidence of a PCa-specific mortality reduction, suggesting the value of multivariable risk-prediction tools to select appropriate treatment or active surveillance. Additionally, in a recent review, Carlsson and Roobol  underlined data emerging in last years that suggest a new approach to PCa screening according to PSA-based risk stratification at an early age. Similarly, Eapen et al.  postulated in favor of a smarter screening approach, based on relatively infrequent PSA testing, consistent use of multivariable risk stratification, and selective treatment focused on patients with high grade PCa.
Clinical practice guidelines (CPGs) are produced to facilitate incorporation of evidence into clinical practice. This is particularly useful when PCa screening remains controversial and guidelines diverge among different medical institutions. Ideally CPGs from different organizations should be based on high quality methodology to achieve similar clinical recommendations. Unfortunately, despite of the enormous energies invested in its realization, the value of CPGs varies considerably. Clinicians should consider recommendations of varying evidence levels differently. A multidisciplinary approach, the description of the sources of information used, and recommendations graded according to level of evidence are necessary items to be considered in a high-quality CPG.
The evidence-based laboratory medicine commission of the Spanish Society of Laboratory Medicine (SEQC-ML) has observed that, despite the obvious involvement of the clinical laboratory in the PCa screening using PSA, some technical aspects have been unremarked among clinicians .
We critically review the characteristics of guidelines about PCa detection, focusing the attention on the laboratory issues considered. In addition, we propose a checklist including several laboratory issues related to PSA measurement that in our opinion should be considered during the development of clinical practice guidelines.
Materials and methods
Information sources, search strategy and study selection
A systematic search was undertaken using several electronic databases: Medline/PubMed, Web of Science and Scopus. A strategic search was done by one reviewer looking for combinations of the following search terms: as publication type (“Guideline”, “Practice Guideline”), as medical subject heading MeSH (“Guidelines as Topic”, “Prostatic Neoplasms”, “Prostate-Specific Antigen”, “Mass Screening”, “Early Detection of Cancer”, “Diagnosis”) and as free search terms (“guideline”, “prostate cancer”, “prostate specific antigen”, “screening”, “diagnosis”). Guidelines published since 2008 were included in this study. The most updated version of these CPGs was used for the evaluation. This scientific literature search was complemented with three international guideline websites: National Guidelines Clearinghouse , Guidelines International Network Web site  and National Institute for Health and Care Excellence (NICE) .
All the guidelines were considered eligible for inclusion if they met the following criteria: publication type guideline, published in the last 10 years, written in English language.
Data collection process
Two of the authors participated in the final process of guideline selection. The main information, overall recommendation and remarkable quality information of each guideline was extracted by two researcher and independently checked for accuracy by the other researchers. Disagreements between researchers were resolved by discussion.
Each CPG was assessed using a checklist of laboratory issues following the criteria described by Aakre et al. . These criteria were adapted for the PSA assay. Previous versions of the selected GPCs were also checked for this purpose.
The Appraisal of Guidelines Research and Evaluation II (AGREE II) instrument was used to assess the quality of guidelines. This tool has 23 items distributed in six domains: scope and purpose (1), stakeholder involvement (2), rigor of development (3), clarity of presentation (4), applicability (5) and editorial independence (6). Each guideline was rated by four independent appraisers trained using the online training tools recommended by the AGREE collaboration. We also followed the AGREE II instrument guideline to calculate all the scores.
The study selection process is summarized in Figure 1.
A summary of the most relevant characteristics of the 22 selected PCa guidelines are shown in Table 1 , , , , , , , , , , , , , , , , , , , , , , including information concerning, among others, overall recommendation, laboratory issues considered, the description of the sources of information used, and recommendations graded according to the level of evidence. Shared decision considering benefits and harms of PCa screening is a frequent criterion in the evaluated guidelines, while mass screening is not recommended in any guideline. Differences among guidelines go from the non-restricted criteria counseled by the Canadian Urological Association to the recommendation against screening counseled by the American College of Physicians or the Australian Government National Health and Medical Research Council. Furthermore, in the majority of CPGs, screening is explicitly not recommended for men higher than 70 years old or with a life expectancy <10 years.
|Guidelines||Institution, year||Focused on PCa early detection||Overall recommendation (Level of evidence and grade of recommendation)||Additional biomarkers recommended||Shared decision||Clinical algorithms||Laboratory issues were considered||Laboratory medicine specialists participating in the guideline||Description of the sources of information used||Recommendations graded according to level of evidence|
|National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of Tumor Markers in Testicular, Prostate, Colorectal, Breast, and Ovarian Cancers ||National Academy of Clinical Biochemistry, 2008||No||These guidelines do not endorse a general recommendation for mass screening.|
More studies are necessary to decide to recommend the implementation of PSA as screening test
(LE: III; GR: A)
|The use of %fPSA is recommended as an aid in the detection of PCa in men with PSA 4–10 μg/L and DRE negative||Yes||Not provided||Yes||Yes||Review of the literature on PSA screening||Yes|
|The Japanese Guideline for Prostate Cancer Screening ||Japanese Research Group for Development of Cancer Screening Guidelines, 2009||Yes||There was no conclusive evidence that PSA screening reduces PCa mortality|
Opportunistic screening: PSA and DRE were not recommended for population-based screening programs, but they could be conducted as individual-based screening
|Not recommended||Yes||Not provided||No||No||Systematic literature review||Yes|
|Updated Japanese Urological Association Guidelines on prostate-specific antigen-based screening for prostate cancer in 2010 ||The Committee for Establishment of the Guidelines on Screening for Prostate Cancer and Japanese Urological Association, 2010||Yes||PSA screening should be offered to all men at risk of developing PCa with fact sheets showing updated benefits and drawbacks of screening for PCa||Not recommended||Yes||Not provided||No||No||Systematic literature review||No|
|American Cancer Society Guideline for the Early Detection of Prostate Cancer ||American Cancer Society, 2010||Yes||A symptomatic men who have at least a 10-year life expectancy should have an opportunity to make an informed decision about screening for PCa||Not recommended||Yes||Not provided||No||No||Systematic literature review||No|
|Prostate cancer screening: Canadian Guidelines ||Canadian Urological Association, 2011||Yes||Prostate cancer screening should be offered to all men 50 years of age with at least a 10-year life expectancy|
Strong consideration should be given to discontinuing PSA screening for Canadian men over 75 years of age
|The PSA velocity, PSAD and PSA free to total ratio may improve PSA sensitivity and specificity||Yes||Not provided||Yes||No||Systematic literature review||Yes|
|Screening for Prostate Cancer with Prostate-Specific Antigen Testing ||American Society of Clinical Oncology, 2012||Yes||In men with a life expectancy <10 years, it is recommended that general screening for prostate cancer with total PSA be discouraged, because harms seem to outweigh potential benefits|
In men with a life expectancy >10 years, it is recommended that physicians discuss with their patients whether PSA testing for prostate cancer screening is appropriate for them
(Evidence based: strong)
|Not recommended||Yes||Not provided||No||No||Systematic literature review||Yes|
|Prostate Cancer Taskforce. Diagnosis and Management of Prostate Cancer in New Zealand Men ||Recommendations from the Prostate Cancer Taskforce. Wellington: Ministry of Health, 2012||No||Population screening for asymptomatic men with PSA testing is currently not recommended|
However, for men with a request for PCa screening, primary health care should provide high-quality, culturally appropriate information on prostate cancer and PSA testing to men aged 50–70 years
|PSA modifications (%fPSA, PSA velocity, PSA doubling time, PSAD, age adjusted reference ranges) should be restricted in their use to those men in whom the decision on whether or not to biopsy is difficult||Yes||Not provided||No||No||Systematic literature review||No|
|Screening for PCa: a guidance statement from the Clinical Guidelines Committee of the American College of Physicians ||American College of Physicians, 2013||Yes||The guideline recommends that clinicians inform men from 50 to 69 years old about the limited potential benefits and substantial harms of screening for PCa|
ACP recommends that clinicians base the decision to screen for PCa using PSA based on the risk for PCa, a discussion of the benefits and harms of screening, the patient’s general health and life expectancy, and patient preferences
|Not recommended||Yes||Not provided||No||No||Search on the National Guideline Clearinghouse for guidelines on screening for prostate cancer||No|
|The Melbourne Consensus Statement on the early detection of PCa ||Multidisciplinary group of the world’s leading experts, 2013||Yes||While routine population-based screening is not recommended, healthy, well-informed men aged 50–69 years should be fully counseled benefits and harms of screening|
Experts disagree about whether PCa screening causes more benefit or harm
|New tools, such as PHI and PCA3, can help to better risk stratify men, potentially reducing overdiagnosis and overtreatment of indolent PCa||Yes||Not provided||No||No||An appraisal of existing guideline statements and an overview of published data about the early detection of PCa||Yes|
|University of Michigan Health System. Cancer screening ||University of Michigan Health System, 2014||No||If PCa screening is considered, for men who have at least a 10-year life expectancy, an informed decision-making process should precede a decision to perform screening|
(LE: I; GR: A)
|PCA3, is currently being studied; it may be most useful for men with elevated PSA and a prior negative prostate biopsy||Yes||Not provided||No||No||Systematic literature review||Yes|
|Recommendations on screening for prostate cancer with the prostate-specific antigen test ||Canadian Task Force on Preventive Health Care, 2014||Yes||We recommend not screening for PCa with the PSA test|
(Strong recommendation against screening for men <55 or ≥70; weak recommendation for the rest)
Because of recent efforts to encourage screening for PCa, some men may be interested in PSA screening despite the current recommendations. The PSA test should not be used for screening without a detailed discussion with the patient about benefits and harms of screening
|Not recommended||Yes||Not provided||No||No||Systematic literature review||Yes|
|PSA Testing for Prostate Cancer in symptomatic Men. Information for Health practitioners ||Australian Government. National Health and Medical Research Council, 2014||Yes||The present evidence is inconsistent as to whether PSA testing affects the risk of dying from PCa||Not recommended||Yes||Not provided||No||No||Summary of the evidence||No|
|National Collaborating Centre for Cancer, PCa: diagnosis and treatment ||National Institute for Health and Care Excellence, 2014||No||Give men information, support and adequate time to make a decision. Include explanation of the risks and benefits of screening|
|%fPSA or cPSA have been employed to increase specificity, particularly in the PSA range 2–10 μg/L and might reduce the number of unnecessary biopsies|
A raised PCA3 level was associated with PCa in men with a negative first prostate biopsy
|Yes||Yes||No||No||Systematic literature review||Yes|
|Cancer of the prostate: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up ||European Society for Medical oncology, 2015||No||Population-based PSA screening for PCa reduces PCa mortality at the expense of over diagnosis and overtreatment and is not recommended|
(LE: I; GR: C)
The decision whether or not to have a prostate biopsy should be made in the light of DRE findings, ethnicity, age, co-morbidities, PSA values, %fPSA, history of previous biopsy and patient values
Testing for PCa in asymptomatic men should not be done in men >70 years old
(LE: I; GR: B)
|%fPSA is considered to decide prostate biopsy||Yes||Not provided||No||No||The relevant literature has been selected by the expert authors||Yes|
(LE: I; GR: C, for population-based PCa screening; B for testing in men >70 years old)
|Prostate Cancer. Clinical Practice Guideline ||Alberta Health Services, 2015||No||Serum PSA should be checked in fit men between the ages of 50 and 75 years, where clinically indicated|
Serum PSA screening increases the detection rate of early stage clinically significant PCa; early detection may improve overall survival
Fit men between the ages of 50 and 75 years with at least 10 years life expectancy should be made aware of the availability of PSA as a detection test for PCa; they should be aware of the potential benefits and risks of early detection so they can make an informed decision as to whether to have the test performed
|Not recommended||Yes||Not provided||No||No||Systematic literature review||No|
|Choosing Wisely® in Preventive Medicine ||American College of Preventive Medicine Prevention Practice Committee, 2016||No||Men should only consent to being screened for PCa after they clearly understand the associated benefits and risks||Not recommended||Yes||Not provided||No||No||Each task force member developed two to three recommendations based on their individual evidence searches||No|
|The Memorial Sloan Kettering Cancer Center Recommendations for Prostate Cancer Screening ||Memorial Sloan Kettering Cancer Center, 2016||Yes||The best evidence suggests that more restricted indication for prostate biopsy and a more focused approach to pursue screening in men at highest risk of lethal cancer would retain most of the mortality benefits of aggressive screening schema, while importantly reducing harms from overdetection and overtreatment||Commercially available reflex tests that have been shown to be associated with the risk of high-grade disease include blood tests such as the %fPSA, the PHI, the 4Kscore, and the urinary testing of PCA3||Yes||Yes||No||Yes||Systematic review of literature was discarded|
The evidence base was to focus on three well-known high-quality studies: ERSPC, PLCO and Malmö Project Study These studies were complemented by other data for a limited number of uncontroversial areas
|Guidelines for preventive activities in general practice. 9th edition ||Royal Australian College of General Practitioners, 2016||No||Screening of asymptomatic (low-risk) men for prostate cancer by PSA testing is not recommended|
If after an informed process a man still requests PCa screening, a PSA is acceptable
|Not recommended||Yes||No||No||No||The recommendations are based on current, evidence-based guidelines||No|
|EAU–ESTRO–SIOG Guidelines on Prostate Cancer ||European Association of Urology, European Society for Radiotherapy and Oncology and International Society of Geriatric Oncology, 2017||No||Mass screening of PCa is not indicated. However, early diagnosis on an individual basis is possible offering an individualised risk-adapted strategy for early detection to a well-informed man with a good performance status and a life expectancy of at least 10–15 years|
(LE: III; GR: B)
|The %fPSA stratifies the risk of PCa in men with 4–10 μg/L total PSA and a previous negative biopsy|
Novel assays for risk stratification including the PHI and the 4Kscore are intended to reduce the number of unnecessary biopsies in men with a PSA between 2 and 10 μg/L
|Yes||No||No||No||Systematic literature review||Yes|
(LE: III; GR: B)
|Early detection of Prostate Cancer: AUA Guideline ||American Urological Association, 2018||Yes||For men ages 55–69 years the panel recognizes that the decision to undergo PSA screening involves weighing benefits and harms associated with screening and treatment|
The Panel recommends against PSA screening in men under age 54 years at average risk or in in men age 70 years or more, or any man with less than a 10–15-year life expectancy
|PSA derivatives (PSAD, age specific reference ranges, PSA kinetics (velocity and doubling time), %fPSA, proPSA, and PCA3 should be considered secondary tests with potential utility for determining the need for a prostate biopsy–or repeat biopsy- after PSA screening||Yes||Yes||No||No||Systematic review and meta analysis||Yes|
(GR: B for men from 55 to 69 years old; C for the rest)
|Prostate Cancer early detection (version 2.2018) ||National Comprehensive Cancer Network, 2018||Yes||Men opting to participate in an early detection program after receiving the appropriate counseling on benefits and harms|
The guidelines for when to start and stop screening, at what intervals to conduct screening, and when to biopsy were recommended by most panel members, but a consensus was not reached
(LE: II, GR: A)
|%fPSA <10%, PHI >35 or 4Kscore (which provides an estimate of the probability of high-grade PCa) are potentially informative in patients who have never undergone biopsy or after a negative biopsy|
A PCA3 score >35 is potentially informative after a negative biopsy
|Yes||Yes||Yes||No||Systematic literature review||Yes|
(LE: II, GR: A)
|Screening for Prostate Cancer US Preventive Services Task Force Recommendation Statement ||US Preventive Services Task Force, 2018||Yes||For men aged 55–69 years, the decision to undergo periodic PSA-based screening for PCa should be an individual one. Before deciding whether to be screened, men should have an opportunity to discuss the potential benefits and harms of screening with their clinician and to incorporate their values and preferences in the decision|
The panel recommends against PSA-based screening for prostate cancer in men 70 years and older
|Not recommended||Yes||No||No||No||Systematic literature review||Yes|
(Gr: C for men aged 55–69 years; D for men older than 70 years)
cPSA, complexed PSA; DRE, digital rectal examination; ERSPC, European randomized study of screening for prostate cancer; %fPSA, percentage of free PSA to total PSA; PCA3, prostate cancer 3 gene; LE, level of evidence; PHI, prostate health index; PCa, prostate cancer; PLCO, prostate, lung, colorectal and ovarian cancer screening trial; GR, grade of recommendation; PSA, prostate specific antigen; PSAD, prostate specific antigen density.
Table 2 shows a list of laboratory issues that should be examined for PSA measurement. CPGs should report information about these laboratory requirements for high quality results. The list was adapted from Aakre et al.  but modified according to the specific criteria for PSA . The issues were classified following three categories: pre-analytical, analytical and post-analytical phases. Specifically, guidelines should report information about the standard reference material used in the measurement of PSA and how reference ranges were established.
|Pre-analytical phase||Analytical phase||Post-analytical phase|
|Sampling handling: sample type; stability of specimen on storage; maximum number of freezing/thawing cycles
Prostate manipulation: digital rectal examination; prostate massage; cystoscopy; transrectal ultrasound; prostate biopsy; bladder catheterization|
Sexual activity (ejaculation)
Interferences caused by medication (5-alfa-reductase inhibitors)
Genetic factors (polymorphisms in the KLK3 gene)
|Methodology: information about the assay used in the measurement of PSA; standard used in the calibration of the assay|
Quality issues: imprecision intra- and inter-assay; external quality assessment; accreditation of the laboratory
Analytical interferences caused by lipemia, hemolysis or bilirubin
Interference from heterophilic or human anti-mouse antibodies (HAMA)
|Assay specific reference range|
We found data concerning consequences of the adoption of the standard reference material from the World Health Organization (WHO) in PSA testing in only two of 22 CPGs evaluated in this study, the National Academy of Clinical Biochemistry (NACB) and the National Comprehensive Cancer Network (NCCN) guidelines. Also, the guideline of the Canadian Urological Association informs of 20%–25% differences in the concentration of PSA among laboratories.
Previous versions of the selected GPCs were also checked for this purpose. We found relevant data in previous versions of American Urological Association (AUA) guidelines, corresponding to 2009, and the European Association of Urology (EAU) guidelines, corresponding to 2013 and 2015, respectively.
Three of the six CPGs considering laboratory issues remark that assays using the WHO standard offer results 20%–25% lower than those using the initial Hybritech© standard. The other three guidelines only refer that results between different PSA assays are not interchangeable. A summary of these characteristics is shown in Table 3 , , , , . The references cited in these guidelines about PSA standardization are also indicated.
|Guidelines||Institution, year||Information about PSA standardization||References concerning PSA assay cited in the guideline|
|National Academy of Clinical|
Biochemistry Laboratory Medicine
Practice Guidelines for Use of Tumor
Markers in Testicular, Prostate, Colorectal, Breast, and Ovarian Cancers 
|National Academy of Clinical Biochemistry, 2008||Two reference standards currently are commonly used for PSA assays: those traceable to the WHO International Standards and those traceable to the Hybritech, Inc. standard|
The initial Hybritech PSA values are about 20% higher than the WHO First International Standard for PSA
Although several studies suggest that between-method comparability has improved since introduction of the International Standards, there are still differences in PSA assays that may lead to clinical misinterpretation if different PSA assays are used when evaluating a single patient
|Sturgeon and Ellis |
Rafferty et al. 
Roddam et al. 
Kort et al. 
Stephan et al. 
Best Practice Statement: 2009 Update 
|American Urological Association, 2009||Importantly, laboratory variability can range from 20% to 25% depending upon the type of standardization used. Assays using the 1999 WHO standard yield results 20%–25% lower than those using the Hybritech standard. It is necessary to use the same assay for longitudinal monitoring because PSA assays are not interchangeable and there is no acknowledged conversion factor between them. Consideration should be given to confirming an abnormal PSA before proceeding to biopsy||Etzioni et al. |
Slev et al. 
|Prostate cancer screening: Canadian Guidelines||Canadian Urological Association, 2011||The variation between laboratories is 20%–25%; therefore using the same laboratory may reduce variability||Etzioni et al. |
Slev et al. 
|EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013 ||European Association of Urology, 2013||A PSA cut-off of 3 or 3.1 μg/L should be considered for WHO–calibrated assays to achieve the same sensitivity and specificity profile found with a cut-off of 4 μg/L in traditionally calibrated assays||Stephan et al. |
|EAU Guidelines on Prostate Cancer ||European Association of Urology, 2015||There are no agreed standards defined for measuring PSA||Semjonow et al. |
|Prostate Cancer early detection (version 2.2018) ||National Comprehensive Cancer Network, 2018||PSA measures obtained using different commercial assays are not directly comparable or interchangeable, since the values are calibrated against different standards||Not provided|
PSA, prostate specific antigen; WHO, World Health Organization.
We used the AGREE II instrument to evaluate the quality of the guidelines (Table 4). The overall assessment score ranged from 39.5% to 97% and 13 (59%) of the 22 guidelines obtained an overall assessment score higher to 70%. The highest score was reached by the NICE, the Canadian Task Force on Preventive Health Care and the AUA guidelines.
|Institution (reference)||AGREE-II domains||Overall guideline assessment|
|1||2||3||4||5||6||Overall assessment||Rate the overall quality of this guideline (mean)||I would recommend this guideline for use:|
|National Institute for Health and Care Excellence ||100%||97%||96%||97%||94%||98%||97.00||7.00||4 Yes|
|Canadian Task Force on Preventive Health Care ||90%||81%||90%||99%||73%||98%||88.50||6.50||4 Yes|
|American Urological Association ||100%||78%||87%||99%||52%||100%||86.00||6.00||3 Yes; 1 Yes, with modifications|
|American Cancer Society ||94%||82%||80%||75%||78%||90%||83.17||6.00||4 Yes|
|US Preventive Services Task Force ||96%||69%||78%||94%||51%||96%||80.67||5.75||3 Yes; 1 Yes, with modifications|
|National Comprehensive Cancer Network ||97%||86%||82%||97%||35%||75%||78.67||5.75||4 Yes|
|European Association of Urology, European Society for Radiotherapy and Oncology and International Society of Geriatric Oncology ||90%||81%||55%||93%||30%||100%||74.83||5.25||2 Yes; 2 Yes, with modifications|
|American College of Physicians ||92%||72%||48%||90%||69%||75%||74.33||5.25||3 Yes; 1 Yes, with modifications|
|National Academy of Clinical Biochemistry ||81%||76%||60%||94%||30%||96%||72.83||6.00||4 Yes|
|Japanese Research Group for Development of Cancer Screening Guidelines ||79%||64%||69%||89%||38%||96%||72.50||4.75||3 Yes, with modifications; 1 No|
|University of Michigan Health System ||83%||71%||64%||86%||35%||96%||72.50||5.00||2 Yes; 2 Yes, with modifications|
|American Society of Clinical Oncology ||90%||50%||53%||88%||54%||88%||70.50||4.75||1 Yes; 3 Yes, with modifications|
|Sloan Kettering Cancer Center ||99%||74%||51%||83%||34%||81%||70.33||5.25||3 Yes; 1 Yes, with modifications|
|Royal Australian College of General Practitioners ||93%||65%||57%||82%||40%||65%||67.00||4.00||1 Yes; 3 Yes, with modifications|
|American College of Preventive Medicine Prevention Practice Committee ||92%||51%||48%||69%||59%||75%||65.67||4.75||2 Yes; 2 Yes, with modifications|
|Recommendations from the Prostate Cancer Taskforce. Wellington: Ministry of Health ||89%||88%||40%||96%||67%||13%||65.50||5.00||2 Yes; 2 Yes, with modifications|
|Alberta Health Services ||79%||57%||46%||65%||28%||90%||60.83||4.25||1 Yes; 2 Yes, with modifications; 1 No|
|Canadian Urological Association ||78%||46%||65%||88%||21%||67%||60.83||5.00||2 Yes; 2 Yes, with modifications|
|Multidisciplinary group of the world’s leading experts ||88%||67%||28%||94%||17%||52%||57.67||4.50||4 Yes, with modifications|
|European Society for Medical oncology ||57%||35%||46%||96%||29%||73%||56.00||4.25||1 Yes; 2 Yes, with modifications; 1 No|
|Australian Government. National Health and Medical Research Council ||93%||49%||15%||82%||33%||0%||45.33||3.50||2 Yes, with modifications; 2 No|
|The Committee for Establishment of the Guidelines on Screening for Prostate Cancer and Japanese Urological Association ||78%||39%||22%||63%||35%||0%||39.50||3.75||1 Yes, with modifications; 3 No|
|Total||88 (57–100)||67 (35–97)||58 (15–96)||87 (63–99)||46 (17–94)||74 (0–100)||70.01 (39.5–97)||5.1 (3.5–7.0)||46 Yes; 34 Yes, with modifications; 8 No|
The usefulness of PSA as a screening test for reducing PCa mortality has been an area of intense controversy. Nowadays, PCa guidelines recommend against routine PSA testing or emphasize that the decision to undergo early PSA testing should be a shared decision between the patient and his physician, considering potential benefits and harms. Nonetheless, discussion about the opportunity of screening remains. Actually, a balance between benefits and harms is the key point to decide to screen. So, active surveillance has been proposed to mitigate harms related with overtreatment in patients with indolent PCa. On the other hand, recently, several studies have noted a reduction in PSA screening rates following the USPSTF ,  recommendation against systematic PSA screening in general population , , . Fleshner et al.  have recently remarked that the withdrawal of PSA screening would prevent all cases of overdiagnosis, but would fail to prevent 100% of avoidable deaths, leading to a 13%–20% increase in PCa-related deaths. These data demonstrate that harms associated with no screening must be also considered and suggest that the process of reviewing evidences and updating recommendations must be continuous. This is reflected in the remarkable changes in the recommendations of the US Preventive Services Task Force along the last decade. In 2008, the panel indicated for men younger than 75 years old that current evidence was insufficient to assess the balance of benefits and harms of PCa screening . Later on, in 2012, the group recommended against PCa screening , but, more recently, in 2018, the panel recommends a shared decision considering benefits and harms for men aged from 55 to 69 years .
On the other hand, additional reflex tests in blood (Prostate Health Index, 4Kscore) or urine (PCA3) has been proposed by several guidelines , , , , , ,  to increase PSA specificity and potentially to decrease the overdiagnosis of indolent PCa. Furthermore, recent data have demonstrated that these biomarkers can also improve the cost-effectiveness of PCa screening , , showing that is more cost-effective the use and development of screening tests than the use of tests after a negative biopsy .
The quality of PCa CPGs is heterogeneous according to published data. Heterogeneity of results has been emphasized by Gupta et al.  using the AGREE II instrument to assess the quality of 13 CPGs selected from 1999 to 2014. The authors showed that the guidelines from the NICE and AUA had the best scores in most domains using this tool. We share the same conclusion, remarking the heterogeneity of quality in guidelines and having obtained a high overall score for NICE and AUA guidelines, as well. In contrast, Qaseem et al.  gave a low overall quality rate to the AUA guideline, remarking the high quality of the American Cancer Society (ACS) guideline. All these results show the need for improving CPGs methodology and quality.
In our study, we found that recommendations were graded according to the level of evidence only in 12 of 22 guidelines evaluated and clear algorithms were only provided for four CPGs. On the other hand, we reviewed the sources of information used in every guideline evaluated in this study. It is remarkable that only one of 22 guidelines was not based on a wide review of data (Table 1). This procedure was specifically discarded by Vickers et al. , focusing their attention on three well-known screening high quality studies (ERSPC, the Prostate Cancer Prevention Trial and the Malmö Project Study), and arguing that regarding to other questions (frequency of PSA testing, indications for biopsy) a systematic review of the literature would be uninformative.
Finally, we found that laboratory issues are frequently (86%) omitted in GPCs. In our opinion, the no inclusion of laboratory medicine specialists in the development process of the guidelines is the main reason for it. The laboratory medicine experts can provide the perspective of the clinical laboratory that sometimes goes unmarked among clinicians .
We found that laboratory medicine specialists participate in only two of the 22 CPGs reviewed in our study, one of them corresponding to the NACB guideline. This guideline widely considers factors in the pre-analytical, analytical and post-analytical phases, which can affect the clinical interpretation of PSA results. We suggest a list of laboratory issues for PSA assays (Table 2) that should be examined in the CPGs, following Aakre et al.  and the specific criteria for PSA reported by Schmeller .
The lack of harmonization of the assays is a major problem in the interpretation of PSA results. The establishment of the 1st International Standard for PSA (World Health Organization 96/670) in 2000 and its adoption as primary calibrator by most manufacturers of PSA assays decreases differences between assays, but concordance has not yet been achieved . Additionally, the reference cut-off of 4 μg/L used to select patients for biopsy was obtained using the traditional Hybritech© standard. Information concerning the influence of WHO standard in the PSA cut-off was directly or indirectly reported by six guidelines (Table 3). Furthermore, the NACB, the 2009 AUA and the 2013 EAU guidelines explain that the initial Hybritech© PSA values are about 20% higher than the assays using the WHO 96/670 standard. The information furnished by the Canadian Urological Association guidelines is less precise, only reporting a 20%–25% variation among laboratories. In consequence, it would be necessary to change the cut-off of 4 μg/L for a cut-off of 3.1 μg/L to obtain similar clinical results. However, published data show that this is not absolutely true. Initial results comparing Access© PSA test using WHO and Hybritech© standards showed that PSA serum levels were 20%–25% lower when WHO standard is adopted . Similar results have been observed for other assays using the reference material from WHO, but there are assays were the differences with the Hybritech© PSA assay are minimal despite the fact that the WHO standard is used. This point was remarked by Stephan et al.  showing that PSA serum levels measured with Elecsys© (using the WHO standard) were very similar to the Hybritech© PSA values. More recently, Foj et al.  compared different assays calibrated against the WHO standard in relation to the Hybritech© PSA values. The authors showed lower PSA results when Advia Centaur©, and Architect© were used, but results for Elecsys©, Lumipulse G 1200©, and Immulite 2000© were substantially similar to the Hybritech© PSA values.
Despite the availability of numerous CPGs considering PCa screening, consensus is currently lacking among them, although opportunistic screening is not recommended. Discrepant methodologies have been applied in the development of these CPGs, even in one case a systematic review of the literature has been explicitly rejected. Also, differences in the quality of the CPGs available have been reported by several authors. We focused our attention on the laboratory issues, because they are frequently omitted in the development of GPCs. The mechanical transfer of the established Hybritech© reference range of <4.0 μg/L to other assays could lead to clinical mistakes in the selection of patients for biopsy. Differences between assays in the measurement of PSA serum levels are not taken into account by the majority of these guidelines. Furthermore, we detected some errors in three of the CPGs about the consequences of the calibration of PSA assays against the WHO. In conclusion, in our opinion, the quality of PCa early detection guidelines could be adequately improved considering the laboratory issues in their development.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
1. Ferlay J, Colombet M, Soerjomataram I, Dyba T, Randi G, Bettio M, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer 2018;103:356–87.10.1016/j.ejca.2018.07.005Search in Google Scholar
2. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009;360:1320–8.10.1056/NEJMoa0810084Search in Google Scholar
3. Andriole GL, Crawford ED, Grubb RL, Buys SS, Chia D, Church TR, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009;360:1310–9.10.1056/NEJMoa0810696Search in Google Scholar
4. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Zappa M, Nelen V, et al. Screening and prostate cancer mortality: results of the European Randomized Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet 2014;384:2027–35.10.1016/S0140-6736(14)60525-0Search in Google Scholar
5. Chou R, Croswell JM, Dana T, Bougatsos C, Blazina I, Fu R, et al. Screening for prostate cancer: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2011;155:762–71.10.7326/0003-4819-155-11-201112060-00375Search in Google Scholar PubMed
6. Schroeder FH, Hugosson J, Carlsson S, Tammela T, Määttänen L, Auvinen A, 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;62:745–52.10.1016/j.eururo.2012.05.068Search in Google Scholar PubMed
7. Buzzoni C, Auvinen A, Roobol MJ, Carlsson S, Moss SM, Puliti D, et al. Metastatic prostate cancer incidence and prostate-specific antigen testing: new insights from the European Randomized Study of Screening for Prostate Cancer. Eur Urol 2015;68:885–90.10.1016/j.eururo.2015.02.042Search in Google Scholar PubMed PubMed Central
8. Gulati R, Tsodikov A, Etzioni R, Hunter-Merrill RA, Gore JL, Mariotto AB, et al. Expected population impacts of discontinued prostate-specific antigen screening. Cancer 2014;120:3519–26.10.1002/cncr.28932Search in Google Scholar PubMed PubMed Central
9. Stephan C, Rittenhouse H, Hu X, Cammann H, Jung K. Prostate-Specific Antigen (PSA) screening and new biomarkers for prostate cancer (PCa). EJIFCC 2014;25:55–78.Search in Google Scholar
11. Eapen RS, Herlemann A, Washington 3rd SL, Cooperberg MR. Impact of the United States Preventive Services Task Force ‘D’ recommendation on prostate cancer screening and staging. Curr Opin Urol 2017;27:205–9.10.1097/MOU.0000000000000383Search in Google Scholar PubMed
12. Giménez N, Filella X, Gavagnach M, Allué JA, Pedrazas D, Ferrer F, et al. [Prostate cancer screening using prostate-specific antigen: The views of general and laboratory physicians]. Semergen 2018;44:409–19.10.1016/j.semerg.2018.02.001Search in Google Scholar PubMed
13. National Guidelines Clearinghouse. Available at: https://www.guideline.gov/help-and-about/search-browse/search-tips. Accessed: 5 Oct 2018.Search in Google Scholar
16. Aakre KM, Langlois MR, Watine J, Barth JH, Baum H, Collinson P, et al. Critical review of laboratory investigations in clinical practice guidelines: proposals for the description of investigation. Clin Chem Lab Med 2013;51:1217–26.10.1515/cclm-2012-0574Search in Google Scholar PubMed
17. Sturgeon CM, Duffy MJ, Stenman UH, Lilja H, Brünner N, Chan DW, et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem 2008;54:e11–79.10.1373/clinchem.2008.105601Search in Google Scholar PubMed
19. Updated Japanese Urological Association Guidelines on prostate-specific antigen-based screening for prostate cancer in 2010. The Committee for Establishment of the Guidelines on Screening for Prostate Cancer and Japanese Urological Association. Int J Urol 2010;17:830–8.10.1111/j.1442-2042.2010.02613.xSearch in Google Scholar PubMed
20. Wolf AM, Wender RC, Etzioni RB, Thompson IM, D’Amico AV, Volk RJ, et al. American Cancer Society PCa Advisory Committee. CA Cancer J Clin 2010;60:70–98.10.3322/caac.20066Search in Google Scholar PubMed
21. Izawa JI, Klotz L, Siemens DR, Kassouf W, So A, Jordan J, et al. Prostate cancer screening: Canadian guidelines 2011. Can Urol Assoc J 2011;5:235–40.10.5489/cuaj.11134Search in Google Scholar PubMed PubMed Central
22. Basch E, Oliver TK, Vickers A, Thompson I, Kantoff P, Parnes H, et al. Screening for prostate cancer with prostate-specific antigen testing: American Society of Clinical Oncology Provisional Clinical Opinion. J Clin Oncol 2012;30:3020–5.10.1200/JCO.2012.43.3441Search in Google Scholar PubMed PubMed Central
23. Prostate Cancer Taskforce. Diagnosis and management of prostate cancer in New Zealand men: recommendations from the Prostate Cancer Taskforce. Wellington: Ministry of Health, 2012. Available at: http://www.prostate.org.nz/documents/diagnosis-management-prostate-cancer-nz-men_(3).pdf. Accessed: 9 Oct 2018.Search in Google Scholar
24. Qaseem A, Barry MJ, Denberg TD, Owens DK, Shekelle P. Screening for PCa: a guidance statement from the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med 2013;158:761–9.10.7326/0003-4819-158-10-201305210-00633Search in Google Scholar PubMed
25. Murphy DG, Ahlering T, Catalona WJ, Crowe H, Crowe J, Clarke N, et al. The Melbourne Consensus Statement on the early detection of PCa. BJU Int 2014;113:186–8.10.1111/bju.12556Search in Google Scholar PubMed
26. Cancer Screening. Guidelines for clinical care ambulatory. University of Michigan, 2014. Available at: https://www.med.umich.edu/1info/FHP/practiceguides/adult.cancer/cancergline.pdf. Accessed: 9 Oct 2018.Search in Google Scholar
27. Recommendations on screening for prostate cancer with the prostate-specific antigen test. Canadian task force on preventive health care. Can Med Assoc J 2014;186:1225–34.10.1503/cmaj.140703Search in Google Scholar PubMed PubMed Central
28. PSA Testing for Prostate Cancer in Asymptomatic Men Information for Health Practitioners. Australian Government. National Health and Medical Research Council, 2014. Available at: https://nhmrc.gov.au/sites/default/files/documents/reports/clinical%20guidelines/men4d-psa-testing-asymptomatic.pdf. Accessed: 9 Oct 2018.Search in Google Scholar
29. National Collaborating Centre for Cancer. Prostate cancer: diagnosis and treatment. London (UK): National Institute for Health and Care Excellence (NICE), 2014. Available at: https://www.nice.org.uk/guidance/cg175/evidence/full-guideline-191710765. Accessed: 9 Oct 2018.Search in Google Scholar
30. Parker C, Gillessen S, Heidenreich A, Horwich A, on behalf of the ESMO Guidelines Committee. Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015;26(Supplement 5):v69–77.10.1093/annonc/mdv222Search in Google Scholar PubMed
31. Alberta Health Services. Prostate Cancer. Clinical practice guideline Alberta, 2015.Search in Google Scholar
32. Livingston CJ, Freeman RJ, Mohammad A, Costales VC, Titus TM, Harvey BJ, et al. Choosing Wisely® in preventive medicine: the American College of Preventive Medicine’s Top 5 List of Recommendations. Am J Prev Med 2016;51:141–9.10.1016/j.amepre.2016.03.009Search in Google Scholar PubMed
33. Vickers AJ, Eastham JA, Scardino PT, Lilja H. The Memorial Sloan Kettering Cancer Center recommendations for PCa screening. Urology 2016;91:12–8.10.1016/j.urology.2015.12.054Search in Google Scholar PubMed PubMed Central
34. The Royal Australian College of General Practitioners. Guidelines for preventive activities in general practice. 9th edn. East Melbourne, Vic: RACGP, 2016. Available at: https://www.racgp.org.au/your-practice/guidelines/redbook/9-early-detection-of-cancers/91-prostate-cancer/. Accessed: 9 Oct 2018.Search in Google Scholar
35. Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch MG, De Santis M, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent. Eur Urol 2017;71:618–29.10.1016/j.eururo.2016.08.003Search in Google Scholar PubMed
36. Carter HB, Albertsen PC, Barry MJ, Etzioni R, Freedland SJ, Greeneet KL, et al. Early detection of prostate cancer. American Urological Association, 2018. Available at: https://www.auanet.org/guidelines/prostate-cancer-early-detection-guideline. Accessed: 19 March 2019.Search in Google Scholar
37. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer Early Detection. Version 2.2018, April 2018. Available at: https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/prostate_detection.pdf. Accessed: 9 Oct 2018.Search in Google Scholar
38. Grossman DC, Curry SJ, Owens DK, Bibbins-Domingo K, Caughey AB, Davidson KW, et al. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. J Am Med Assoc 2018;319:1901–13.10.1001/jama.2018.3710Search in Google Scholar PubMed
39. Schmeller N. Clinical value of PSA. Bremen: UNI-Med Verlag, 2005.Search in Google Scholar
40. Sturgeon CM, Ellis AR. Improving the comparability of immunoassays for prostate-specific antigen (PSA): progress and problems. Clin Chim Acta 2007;381:8–92.10.1016/j.cca.2007.02.015Search in Google Scholar PubMed
41. Rafferty B, Rigsby P, Rose M, Stamey T, Gaines DR. Reference reagents for prostate-specific antigen (PSA): establishment of the first international standards for free PSA and PSA (90:10). Clin Chem 2000;46:1310–7.10.1093/clinchem/46.9.1310Search in Google Scholar
42. Roddam AW, Rimmer J, Nickerson C, Ward AM. Prostate-specific antigen: bias and molarity of commercial assays for PSA in use in England. Ann Clin Biochem 2006;43:35–48.10.1258/000456306775141731Search in Google Scholar PubMed
43. Kort SA, Martens F, Vanpoucke H, van Duijnhoven HL, Blankenstein MA. Comparison of 6 automated assays for total and free prostate specific antigen with special reference to their reactivity toward the WHO 96/670 reference preparation. Clin Chem 2006;52:1568–74.10.1373/clinchem.2006.069039Search in Google Scholar PubMed
44. Stephan C, Klaas M, Muller C, Schnorr D, Loening SA, Jung K. Interchangeability of measurements of total and free prostate specific antigen in serum with 5 frequently used assay combinations: an update. Clin Chem 2006;52:59–64.10.1373/clinchem.2005.059170Search in Google Scholar
45. Greene KL, Albertsen PC, Babaian RJ, Carter HB, Gann PH, Han M, et al. Prostate specific antigen best practice statement: 2009 update. J Urol 2009;182:2232–41.10.1016/j.juro.2009.07.093Search in Google Scholar
46. Etzioni RD, Ankerst DP, Weiss NS, Inoue LY, Thompson IM. Is prostate-specific antigen velocity useful in early detection of prostate cancer? A critical appraisal of the evidence. J Natl Cancer Inst 2007;99:1510–5.10.1093/jnci/djm171Search in Google Scholar
47. Slev PR, La’ulu SL, Roberts WL. Intermethod differences in results for total PSA, free PSA, and percentage of free PSA. Am J Clin Pathol 2008;129:952–8.10.1309/JYBPMFNUF6EYY9TBSearch in Google Scholar
48. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol 2014;65:124–37.10.1016/j.eururo.2013.09.046Search in Google Scholar
49. Stephan C, Köpke T, Semjonow A, Lein M, Deger S, Schrader M, et al. Discordant total and free prostate-specific antigen (PSA) assays: does calibration with WHO reference materials diminish the problem? Clin Chem Lab Med 2009;47:1325–31.10.1515/CCLM.2009.285Search in Google Scholar
50. Mottet N, Bellmunt J, Briers E, van den Bergh RC, Bolla M, van Casteren NJ, et al. EAU Guidelines on prostate cancer. Available at: https://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf. Accessed: 10 Oct 2018.Search in Google Scholar
51. Semjonow A, Brandt B, Oberpenning F, Roth S, Hertle L. Discordance of assay methods creates pitfalls for the interpretation of prostate specific antigen values. Prostate Suppl 1996;7:3–16.10.1002/(SICI)1097-0045(1996)7+<3::AID-PROS1>3.0.CO;2-TSearch in Google Scholar
52. Moyer VA, U.S. Preventive Services Task Force. Screening for PCa: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012;157:120–34.10.7326/0003-4819-157-2-201207170-00459Search in Google Scholar
53. Aslani A, Minnillo BJ, Johnson B, Cherullo EE, Ponsky LE, Abouassaly R. The impact of recent screening recommendations on prostate cancer screening in a large health care system. J Urol 2014;191:1737–42.10.1016/j.juro.2013.12.010Search in Google Scholar
54. Cohn JA, Wang CE, Lakeman JC, Silverstein JC, Brendler CB, Novakovic KR, et al. Primary care physician PSA screening practices before and after the final U.S. Preventive Services Task Force recommendation. Urol Oncol 2014;32:41.e23–30.10.1016/j.urolonc.2013.04.013Search in Google Scholar
55. Ong MS, Mandl KD. Trends in Prostate-Specific Antigen screening and prostate cancer interventions 3 years after the U.S. Preventive Services Task Force recommendation. Ann Intern Med 2017;166:451–2.10.7326/L16-0422Search in Google Scholar PubMed
56. Fleshner K, Carlsson SV, Roobol MJ. The effect of the USPSTF PSA screening recommendation on prostate cancer incidence patterns in the USA. Nat Rev Urol 2017;14:26–37.10.1038/nrurol.2016.251Search in Google Scholar PubMed PubMed Central
57. Calonge N, Petitti DB, DeWitt TG, Dietrich AJ, Gregory KD, Harris R, et al. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2008;149:185–91.10.7326/0003-4819-149-3-200808050-00008Search in Google Scholar PubMed
58. Heijnsdijk EA, Denham D, de Koning HJ. The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index. Value Health 2016;19:153–7.10.1016/j.jval.2015.12.002Search in Google Scholar PubMed
59. Mathieu R, Castelli C, Fardoun T, Peyronnet B, Shariat SF, Bensalah K, et al. Cost analysis of prostate cancer detection including the prostate health index (PHI). World J Urol 2019;37:481–7.10.1007/s00345-018-2362-zSearch in Google Scholar PubMed
60. Palenius E, Bonnevier E. Evaluation of the cost-effectiveness of novel tests in the screening and diagnostic. Phases of prostate cancer compared to current practice. Lund University, 2017.Search in Google Scholar
61. Gupta M, McCauley J, Farkas A, Gudeloglu A, Neuberger MM, Ho YY, et al. Clinical practice guidelines on prostate cancer: a critical appraisal. J Urol 2015;193:1153–8.10.1016/j.juro.2014.10.105Search in Google Scholar PubMed
63. Foj L, Filella X, Alcover J, Augé JM, Escudero JM, Molina R. Variability of assay methods for total and free PSA after WHO standardization. Tumor Biol 2014;35:1867–73.10.1007/s13277-013-1249-2Search in Google Scholar PubMed
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