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Systematic Review of Cost-Effectiveness Models in Prostate Cancer: Exploring New Developments in Testing and Diagnosis

Open AccessPublished:September 21, 2021DOI:https://doi.org/10.1016/j.jval.2021.07.002

      Abstract

      Objectives

      Recent innovations in prostate cancer diagnosis include new biomarkers and more accurate biopsy methods. This study assesses the evidence base on cost-effectiveness of these developments (eg, Prostate Health Index and magnetic resonance imaging [MRI]-guided biopsy) and identifies areas of improvement for future cost-effectiveness models.

      Methods

      A systematic review using the National Health Service Economic Evaluation Database, MEDLINE, Embase, Health Technology Assessment databases, National Institute for Health and Care Excellence guidelines, and United Kingdom National Screening Committee guidance was performed, between 2009 and 2021. Relevant data were extracted on study type, model inputs, modeling methods and cost-effectiveness conclusions, and results narratively synthesized.

      Results

      A total of 22 model-based economic evaluations were included. A total of 11 compared the cost-effectiveness of new biomarkers to prostate-specific antigen testing alone and all found biomarkers to be cost saving. A total of 8 compared MRI-guided biopsy methods to transrectal ultrasound-guided methods and found MRI-guided methods to be most cost-effective. Newer detection methods showed a reduction in unnecessary biopsies and overtreatment. The most cost-effective follow-up strategy in men with a negative initial biopsy was uncertain. Many studies did not model for stage or grade of cancer, cancer progression, or the entire testing and treatment pathway. Few fully accounted for uncertainty.

      Conclusions

      This review brings together the cost-effectiveness literature for novel diagnostic methods in prostate cancer, showing that most studies have found new methods to be more cost-effective than standard of care. Several limitations of the models were identified, however, limiting the reliability of the results. Areas for further development include accurately modeling the impact of early diagnostic tests on long-term outcomes of prostate cancer and fully accounting for uncertainty.

      Keywords

      Introduction

      Prostate cancer is the second most commonly occurring cancer in men worldwide and the fourth most commonly occurring cancer overall.
      Prostate cancer statistics. World Cancer Research Fund, American Institute for Cancer Research.
      Detection of early disease has historically been achieved using a prostate-specific antigen (PSA) blood test followed by transrectal ultrasound (TRUS)-guided biopsy. Nevertheless, PSA is not a specific marker for prostate cancer, and TRUS-guided prostate biopsy is associated with infection and other adverse effects and can lead to false negative results in up to 25% of cases.
      • Rosario D.J.
      • Lane J.A.
      • Metcalfe C.
      • et al.
      Short term outcomes of prostate biopsy in men tested for cancer by prostate specific antigen: prospective evaluation within ProtecT study.
      ,
      • Roehl K.A.
      • Antenor J.A.
      • Catalona W.J.
      Serial biopsy results in prostate cancer screening study.
      Therefore, current diagnostic methods lead to overdetection of cancers that may not progress to become clinically important in a man’s lifetime, but can also miss aggressive, potentially fatal prostate cancer.
      • Ahmed H.U.
      • El-Shater Bosaily A.
      • Brown L.C.
      • et al.
      Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study.
      ,
      • Martin R.M.
      • Donovan J.L.
      • Turner E.L.
      • et al.
      Effect of a low-intensity PSA-based screening intervention on prostate cancer mortality: the CAP randomized clinical trial.
      Overdetection can have a significant effect on the quality of life (QOL) of the men affected owing to the adverse effects associated with testing and unnecessary treatment.
      • Heijnsdijk E.A.
      • Wever E.M.
      • Auvinen A.
      • et al.
      Quality-of-life effects of prostate-specific antigen screening.
      It is also a poor use of limited healthcare resources. In the absence of robust evidence, current UK policy does not advocate population screening. Several large trials, including the European Randomised Study of Screening for Prostate Cancer (ERSPC),
      • Schröder F.H.
      • Hugosson J.
      • Roobol M.J.
      • et al.
      Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up.
      the US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial,
      • Andriole G.L.
      • Crawford E.D.
      • Grubb 3rd, R.L.
      • et al.
      Mortality results from a randomized prostate-cancer screening trial [published correction appears in N Engl J Med. 2009;360(17):1797].
      and the UK Cluster Randomized Trial of PSA Testing for Prostate Cancer trial,
      • Martin R.M.
      • Donovan J.L.
      • Turner E.L.
      • et al.
      Effect of a low-intensity PSA-based screening intervention on prostate cancer mortality: the CAP randomized clinical trial.
      have found limited mortality benefit of PSA-based screening when considered overall.
      • Ilic D.
      • Djulbegovic M.
      • Jung J.H.
      • et al.
      Prostate cancer screening with prostate-specific antigen (PSA) test: a systematic review and meta-analysis.
      Therefore, as it stands, the benefits of screening seem insufficient to outweigh the potential harms of overtreatment.
      Recent years have seen the development of biomarker tests to complement PSA-based testing, for example, the Prostate Health Index (PHI), 4Kscore, SelectMDx, and PCA3. These tests act as additional reflex tests to aid the decision about when a man should be referred for prostate biopsy. Multiparametric magnetic resonance imaging (MRI) is another recent development that, when used as a triage test after PSA or other biomarker testing, might allow men with no or likely indolent cancer to avoid unnecessary biopsy and improve diagnostic accuracy with respect to more aggressive disease.

      Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-targeted or standard biopsy for prostate-cancer diagnosis. 2018;378(19):1767-1777.

      ,
      • Ahdoot M.
      • Wilbur A.R.
      • Reese S.E.
      • et al.
      MRI-targeted, systematic, and combined biopsy for prostate cancer diagnosis.
      Therefore, there is potential for a reduction in overdiagnosis and higher specificity for potentially lethal cancer.
      • Ahmed H.U.
      • El-Shater Bosaily A.
      • Brown L.C.
      • et al.
      Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study.
      Nevertheless, it is not yet clear whether these new developments should be implemented either individually or in combination with one another at a national level within a screening program.
      As innovations that aim to address the overdiagnosis associated with prostate cancer screening become available, healthcare policy makers must make informed decisions regarding their use in national screening strategies. As such, it is essential to establish the cost-effectiveness of these developments and their combinations, to make rational decisions about the allocation of limited healthcare resources.
      This systematic review aimed to identify published economic models assessing the impact of these innovations on the costs and outcomes of prostate cancer diagnosis. The population of interest was men at risk of developing prostate cancer, the interventions reviewed were novel biomarkers and MRI-guided biopsy techniques as prostate cancer diagnostic tools, the alternatives against which the interventions were compared were standard diagnostic tools such as the PSA test, TRUS-guided biopsy, or no intervention, and the outcome considered was the cost-effectiveness of these interventions in comparison with each other. This review also determines the current evidence base and provides an overview of model characteristics. It provides information on novel tests, how they have been modeled, and the data available to populate such models, which will assist the development of new cost-effectiveness models in prostate cancer screening. It assesses the limitations of available models, highlighting ways in which a future model may improve on these, and provides overall conclusions on the cost-effectiveness of these new diagnostic tools.

      Methods

       Study Selection

      Study selection proceeded from title/abstract screening against the eligibility criteria through full-text review to data extraction. E.K. was involved at all stages. A second reviewer (J.M.) independently screened 10% of the titles and abstracts and performed data extraction on 20% of the included studies. Studies were categorized according to model-based economic evaluations of new (1) biomarkers/tests/risk models for screening in prostate cancer, (2) biopsy methods for definitive diagnosis after an initial triage screening test in prostate cancer, and (3) follow-up testing and diagnostic strategies for men initially found to have no or low-risk prostate cancer.

       Search Strategy

      In April 2021, studies were identified by searching the National Health Service Economic Evaluation Database (2009-2014), MEDLINE, Embase, Health Technology Assessment databases, National Institute for Health and Care Excellence (NICE) guidelines, UK National Screening Committee guidance, and reference lists from relevant studies. The review was restricted to evidence from January 2009 onward to reflect current practice in screening and testing for prostate cancer and because the aim was to identify novel tests in prostate cancer diagnosis. Search terms included free text and medical subject headings terms (Appendix 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.07.002). The search was limited to English language publications.

       Eligibility Criteria

      Studies were included if they were model-based economic evaluations of screening or diagnostic strategies for prostate cancer beyond the standard PSA test plus TRUS-guided biopsy. Cost-effectiveness, cost-utility, cost-consequence, and cost-benefit analyses were considered. Models could use primary data from a trial or secondary data from the literature. They could compare any novel test or diagnostic strategy for diagnosing or ruling out prostate cancer or any subsequent follow-up regime (aside from PSA testing) when prostate cancer has not been identified at initial biopsy. Models from any country or type of health system were considered.

       Data Extraction

      Data extraction forms were developed and pilot-tested on a random sample (5%) of included studies and refined accordingly. The data extraction form is shown in Appendix 2 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.07.002.
      Information extracted from each study included context (ie, perspective and country), characteristics of the tests compared (ie, frequency of testing and threshold for a positive result), the population the strategy was applied to (ie, screening start and stop age and the prevalence of prostate cancer), outcome measures (eg, cost per quality-adjusted life-year [QALY] gained), and cost-effectiveness result. Information was also extracted on characteristics of the model including model type (eg, decision tree, Markov model) and structure (how clinical pathways are represented), sensitivity analyses (including the extent to which uncertainty in the cost-effectiveness result had been quantified), the source of evidence for utility values assigned to health states and costs included in the model, and the source of evidence for accuracy of tests.

       Quality Assessment

      The purpose of the review was to determine the current evidence base and provide an overview of the characteristics of available models. Therefore, a formal quality checklist was not used to exclude studies from the review. Nevertheless, existing economic evaluation checklists were used as a guide to reporting the studies.
      • Philips Z.
      • Bojke L.
      • Sculpher M.
      • Claxton K.
      • Golder S.
      Good practice guidelines for decision-analytic modelling in health technology assessment: a review and consolidation of quality assessment.
      ,
      • Karnon J.
      • Goyder E.
      • Tappenden P.
      • et al.
      A review and critique of modelling in prioritising and designing screening programmes.
      The quality of the included economic evaluations was assessed using the Consolidated Health Economic Evaluation Reporting Standards checklist.
      • Husereau D.
      • Drummond M.
      • Petrou S.
      • et al.
      Consolidated Health Economic Evaluation Reporting Standards (CHEERS)--explanation and elaboration: a report of the ISPOR health economic evaluation publication guidelines good reporting practices task force.
      A score of 0, 1, or 2 was allocated for each criterion corresponding to a decision of criterion not met, criterion met, or criterion not applicable. Risk of bias was assessed using the Bias in Economic Evaluation checklist.
      • Adarkwah C.C.
      • van Gils P.F.
      • Hiligsmann M.
      • Evers S.M.
      Risk of bias in model-based economic evaluations: the ECOBIAS checklist.
      Every item was rated as yes, no, partly, unclear, or not applicable.
      The review follows the reporting standards for reviews of economic evaluations.
      • van Mastrigt G.A.
      • Hiligsmann M.
      • Arts J.J.
      • et al.
      How to prepare a systematic review of economic evaluations for informing evidence-based healthcare decisions: a five-step approach (part 1/3).
      • Thielen F.W.
      • Van Mastrigt G.
      • Burgers L.T.
      • et al.
      How to prepare a systematic review of economic evaluations for clinical practice guidelines: database selection and search strategy development (part 2/3).
      • Wijnen B.
      • Van Mastrigt G.
      • Redekop W.K.
      • Majoie H.
      • De Kinderen R.
      • Evers S.
      How to prepare a systematic review of economic evaluations for informing evidence-based healthcare decisions: data extraction, risk of bias, and transferability (part 3/3).

      Results

      In total, 1075 studies were identified. Most studies were excluded at the abstract stage because they were not model-based economic evaluations or did not compare tests for diagnosing prostate cancer. After removing duplicates and checking for eligibility, 55 full-text articles were retrieved (Fig. 1). Of the 55 full-text articles, 22 studies were included in the review. A total of 16 articles were excluded because these were conference abstracts and the rest were excluded because they (1) were background articles rather than original studies, (2) had the wrong study design, for example, cost-comparison rather than cost-effectiveness analyses, or (3) had the wrong population, for example, men with biochemical recurrence after radical prostatectomy.
      Figure thumbnail gr1
      Figure 1Studies included and excluded from the review.

       Study Type

      Of the 22 studies, 11 compared the cost-effectiveness of new urinary or blood biomarkers to each other or to the standard of care (a PSA test alone) (Table 1). Another 8 studies compared different approaches with prostate biopsy. A total of 3 studies compared follow-up strategies in men who have a negative initial biopsy result. The studies were based in the United States (n = 6), United Kingdom (n = 6), The Netherlands (n = 4), Hong Kong (n = 1), Germany (n = 1), China (n = 1), Sweden (n = 1), and Canada (n = 1). One study compared results for France, Germany, Spain, and Italy.
      • Govers T.M.
      • Hessels D.
      • Vlaeminck-Guillem V.
      • et al.
      Cost-effectiveness of SelectMDx for prostate cancer in four European countries: a comparative modeling study.
      All but 3 studies
      • Bouttell J.
      • Teoh J.
      • Chiu P.K.
      • et al.
      Economic evaluation of the introduction of the Prostate Health Index as a rule-out test to avoid unnecessary biopsies in men with prostate specific antigen levels of 4-10 in Hong Kong.
      • Schiffer E.
      • Bick C.
      • Grizelj B.
      • Pietzker S.
      • Schöfer W.
      Urinary proteome analysis for prostate cancer diagnosis: cost-effective application in routine clinical practice in Germany.
      • Kim L.
      • Boxall N.
      • George A.
      • et al.
      Clinical utility and cost modelling of the phi test to triage referrals into image-based diagnostic services for suspected prostate cancer: the PRIM (Phi to RefIne Mri) study.
      performed a cost-utility analysis where outcomes were measured in QALYs. The other 3 were cost-consequence analyses reporting the number of tests and biopsies performed and expected overall diagnostic costs.
      • Bouttell J.
      • Teoh J.
      • Chiu P.K.
      • et al.
      Economic evaluation of the introduction of the Prostate Health Index as a rule-out test to avoid unnecessary biopsies in men with prostate specific antigen levels of 4-10 in Hong Kong.
      ,
      • Schiffer E.
      • Bick C.
      • Grizelj B.
      • Pietzker S.
      • Schöfer W.
      Urinary proteome analysis for prostate cancer diagnosis: cost-effective application in routine clinical practice in Germany.
      Table 1Characteristics of studies included after full-text screening
      AuthorYearCountryPatient populationAgeAssumed prevalence of PCa, %Strategies compared
      Biomarkers
      Bouttell et al
      • Bouttell J.
      • Teoh J.
      • Chiu P.K.
      • et al.
      Economic evaluation of the introduction of the Prostate Health Index as a rule-out test to avoid unnecessary biopsies in men with prostate specific antigen levels of 4-10 in Hong Kong.
      2019Hong KongNormal DRE, PSA 4-10 ng/mLNR10.9
      • 1.
        Biopsy all
      • 2.
        Biopsy only if PHI >25
      • 3.
        Biopsy only if PHI >35
      • 4.
        Biopsy only if PHI >55
      Govers et al
      • Govers T.M.
      • Caba L.
      • Resnick M.J.
      Cost-effectiveness of urinary biomarker panel in prostate cancer risk assessment.
      2018USElevated PSA or abnormal DRENR46.4
      • 1.
        Biopsy all
      • 2.
        Biopsy only if SelectMDx +
      Sathianathen al
      • Sathianathen N.J.
      • Kuntz K.M.
      • Alarid-Escudero F.
      • et al.
      Incorporating biomarkers into the primary prostate biopsy setting: a cost-effectiveness analysis.
      2018USPSA >3 ng/mL5029
      • 1.
        Biopsy all
      • 2.
        Biopsy only if SelectMDx +
      • 3.
        Biopsy only if PHI +
      • 4.
        Biopsy only if EPI +
      • 5.
        Biopsy only if 4Kscore +
      Dijkstra et al
      • Dijkstra S.
      • Govers T.M.
      • Hendriks R.J.
      • et al.
      Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.
      2017HollandPSA >3 ng/mLNR44.4
      • 1.
        Biopsy all
      • 2.
        Biopsy only if SelectMDx +
      Heijnsdijk et al
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      2016HollandPSA >3 ng/mL50-75NR
      • 1.
        Biopsy all
      • 2.
        Biopsy only if PHI >25
      Schiffer et al
      • Schiffer E.
      • Bick C.
      • Grizelj B.
      • Pietzker S.
      • Schöfer W.
      Urinary proteome analysis for prostate cancer diagnosis: cost-effective application in routine clinical practice in Germany.
      2012GermanyPSA >4 and/or suspicious DRE in a urological outpatient center setting6624
      • 1.
        Biopsy all
      • 2.
        Biopsy only if UPA-PC +
      Nichol et al
      • Nichol M.B.
      • Wu J.
      • Huang J.
      • Denham D.
      • Frencher S.K.
      • Jacobsen S.J.
      Cost-effectiveness of Prostate Health Index for prostate cancer detection.
      2011USPSA 2-10 ng/mL50-7525
      • 1.
        Biopsy all
      • 2.
        Biopsy only if PHI +
      PSA 4-10 ng/mL50-7525
      PHI+ at PSA 2-10 ng/mL50-7529.6
      PHI+ at PSA 4-10 ng/mL50-7530.3
      PSA >10 ng/mL50-7566.70
      Kim et al
      • Kim L.
      • Boxall N.
      • George A.
      • et al.
      Clinical utility and cost modelling of the phi test to triage referrals into image-based diagnostic services for suspected prostate cancer: the PRIM (Phi to RefIne Mri) study.
      2020UKReferred from primary care for elevated PSA66NR
      • 1.
        mpMRI and biopsy all
      • 2.
        mpMRI all and biopsy if positive
      • 3.
        mpMRI all and biopsy if PSA density ≥0.15
      • 4.
        mpMRI all and biopsy if PSA density ≥0.1
      • 5.
        PHI all and mpMRI and biopsy if PHI ≥25
      • 6.
        PHI all and mpMRI and biopsy if PHI ≥30
      Teoh et al
      • Teoh J.Y.
      • Leung C.H.
      • Wang M.H.
      • et al.
      The cost-effectiveness of Prostate Health Index for prostate cancer detection in Chinese men.
      2020ChinaPatients with normal DRE undergoing opportunistic PSA testing50-75NR
      • 1.
        Biopsy if PSA 4-10 ng/mL
      • 2.
        Biopsy only if PSA 4-10 ng/mL and PHI >35
      Karlsson et al
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      2021SwedenAll men55-69NR
      • 1.
        No screening
      • 2.
        Quadrennial screening for men at the age of 55-69 years with PSA test alone
      • 3.
        Quadrennial screening for men at the age of 55-69 years with PSA test and reflex Stockholm3 test for PSA values above 1, 1.5, and 2 ng/mL, respectively
      Govers et al
      • Govers T.M.
      • Hessels D.
      • Vlaeminck-Guillem V.
      • et al.
      Cost-effectiveness of SelectMDx for prostate cancer in four European countries: a comparative modeling study.
      2019France, Germany, Italy, and SpainMen who, under current guideline concordant management, would undergo initial TRUS-guided biopsyNRFrance: 47

      Germany: 49

      Italy: 37

      Spain: 33
      • 1.
        Biopsy all
      • 2.
        Biopsy only if SelectMDx +
      Biopsy methods
      Barnett et al
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Wei J.T.
      • Montie J.E.
      • Denton B.T.
      Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer.
      2018USBiopsy-naive men with PSA >4 ng/mL55-69NR
      • 1.
        Standard biopsy for all
      • 2.
        MRI, if positive targeted fusion biopsy
      • 3.
        MRI, if positive combined biopsy
      For 2 and 3 additional strategies of no further biopsy or additional standard biopsy if negative
      Pahwa et al
      • Pahwa S.
      • Schiltz N.K.
      • Ponsky L.E.
      • Lu Z.
      • Griswold M.A.
      • Gulani V.
      Cost-effectiveness of MR imaging-guided strategies for detection of prostate cancer in biopsy-naive men.
      2017USBiopsy-naive men recommended for prostate biopsy on basis of abnormal DRE or elevated PSA41-5037
      • 1.
        Standard biopsy for all
      • 2.
        MRI + cognitively guided biopsy
      • 3.
        MR imaging/US fusion biopsy
      • 4.
        in-gantry MR imaging-guided biopsy
      For 2-4 additional strategies of no further biopsy or additional standard biopsy if negative
      51-6044
      41-7050
      61-7065
      Venderink et al
      • Venderink W.
      • Govers T.M.
      • de Rooij M.
      • Fütterer J.J.
      • Sedelaar J.P.M.
      Cost-effectiveness comparison of imaging-guided prostate biopsy techniques: systematic transrectal ultrasound, direct in-bore MRI, and image fusion.
      2017HollandBiopsy-naive men with elevated PSA or abnormal DRENR25
      • 1.
        TRUS-guided biopsy for all
      • 2.
        mpMRI, if suspicious MRI TRUS fusion-guided biopsy
      • 3.
        Direct in-bore MRI-guided biopsy
      Cerantola et al
      • Cerantola Y.
      • Dragomir A.
      • Tanguay S.
      • Bladou F.
      • Aprikian A.
      • Kassouf W.
      Cost-effectiveness of multiparametric magnetic resonance imaging and targeted biopsy in diagnosing prostate cancer.
      2016CanadaBiopsy-naive men with clinical suspicion of PCa (based on DRE and PSA values 4-10 ng/mL) with life expectancy of 20 years60-6524
      • 1.
        TRUS-guided biopsy for all
      • 2.
        MRI-targeted biopsy
      de Rooij et al
      • de Rooij M.
      • Crienen S.
      • Witjes J.A.
      • Barentsz J.O.
      • Rovers M.M.
      • Grutters J.P.
      Cost-effectiveness of magnetic resonance (MR) imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer: a modelling study from a health care perspective.
      2013Hollandelevated PSA level ( > 4 ng/mL)6025
      • 1.
        TRUS-guided biopsy for all
      • 2.
        MRI-guided biopsy
      Faria et al
      • Faria R.
      • Soares M.O.
      • Spackman E.
      • et al.
      Optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate MR imaging study (PROMIS).
      2018UKMen at risk of PCa referred to secondary care for further investigationNR38383 clinically feasible combinations of mpMRI, TRUS-guided biopsy, and TPMB, in addition to the use of TRUS-guided biopsy and TPMB in isolation
      Barnett et al
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Kunju L.P.
      • Denton B.T.
      • Piert M.
      18F-choline PET/mpMRI for detection of clinically significant prostate cancer: part 2. Cost-effectiveness analysis.
      2019USBiopsy-naive men with elevated PSA levels ( >4 ng/mL)55-69NR
      • 1.
        Standard biopsy for all
      • 2.
        mpMRI, if positive combined biopsy
      • 3.
        Hybrid 18F-choline PET/mpMRI, if positive combined biopsy
      For 2 and 3 additional strategies of using Likert or PI-RADSv2 scores to determine positive results and no further biopsy or additional standard biopsy if negative
      Callender et al
      • Callender T.
      • Emberton M.
      • Morris S.
      • Pharoah P.D.P.
      • Pashayan N.
      Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer.
      2021UKAll men55-69NR
      • 1.
        No screening
      • 2.
        Age-based screening with biopsy if PSA ≥3
      • 3.
        Age-based screening with MRI if PSA ≥3 and biopsy if abnormal findings
      • 4.
        Risk-stratified screening with biopsy if PSA ≥3
      • 5.
        Risk-stratified screening with MRI if PSA ≥3 and biopsy if abnormal findings
      Follow-up strategies in men with negative biopsies
      NICE Guideline
      NICE Guideline Updates Team (UK)
      Prostate cancer: diagnosis and management. National Institute for Health and Care Excellence.
      2019UKRaised PSA, negative MRI, and/or negative prostate biopsy66-7558.2Different follow-up strategies, including screening test (PSA density, velocity, doubling time, % free forms) PCA3 or PHI, at different frequencies and different thresholds for triggering further investigation; diagnostic stage possibly including MRI techniques
      Nicholson et al
      • Nicholson A.
      • Mahon J.
      • Boland A.
      • et al.
      The clinical effectiveness and cost-effectiveness of the PROGENSA (R) prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation.
      2015UKMen referred for second biopsy because, after negative initial biopsy result, clinicians still suspect malignant PCa presentNR24
      • 1.
        clinical assessment
      • 2.
        clinical assessment + PCA3
      • 3.
        clinical assessment + PHI
      • 4.
        clinical assessment + PCA3 + PHI
      • 5.
        clinical assessment + mpMRI
      • 6.
        clinical assessment + mpMRI + PCA3
      • 7.
        clinical assessment + mpMRI + PHI
      • 8.
        clinical assessment + mpMRI + PCA3 + PHI
      Mowatt et al
      • Mowatt G.
      • Scotland G.
      • Boachie C.
      • et al.
      The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation.
      2013UKSuspected PCa with a prior negative/inconclusive biopsy, with indications for repeat biopsy (ie, sustained suspicion of PCa as a result of clinical and/or pathological findings)6024
      • 1.
        TRUS-guided biopsy for all
      • 2.
        T2-MRI
      • 3.
        MRS
      • 4.
        DCE-MRI
      • 5.
        T2-MRI or MRS
      • 6.
        T2-MRI or DCE-MRI
      DCE-MRI indicates dynamic contrast-enhanced magnetic resonance imaging; DRE, digital rectal examination; EPI, ExoDx® Prostate(IntelliScore); mpMRI, multiparametric magnetic resonance imaging; MR, magnetic resonance; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NR, not reported; PCa, prostate cancer; PET, positron emission tomography; PHI, Prostate Health Index; PI-RADSv2, Prostate Imaging-Reporting and Data System version 2; PSA, prostate-specific antigen; TPMB, transperineal mapping biopsy; TRUS, transrectal ultrasound; UPA-PC, urinary proteome analysis for prostate cancer diagnosis; UK, United Kingdom; US, United States.

       Strategies compared—biomarkers

      The novel diagnostic strategies that were compared with PSA-based testing alone included PHI,
      • Bouttell J.
      • Teoh J.
      • Chiu P.K.
      • et al.
      Economic evaluation of the introduction of the Prostate Health Index as a rule-out test to avoid unnecessary biopsies in men with prostate specific antigen levels of 4-10 in Hong Kong.
      ,
      • Kim L.
      • Boxall N.
      • George A.
      • et al.
      Clinical utility and cost modelling of the phi test to triage referrals into image-based diagnostic services for suspected prostate cancer: the PRIM (Phi to RefIne Mri) study.
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      • Nichol M.B.
      • Wu J.
      • Huang J.
      • Denham D.
      • Frencher S.K.
      • Jacobsen S.J.
      Cost-effectiveness of Prostate Health Index for prostate cancer detection.
      PCA3, SelectMDx,
      • Dijkstra S.
      • Govers T.M.
      • Hendriks R.J.
      • et al.
      Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.
      ,
      • Govers T.M.
      • Caba L.
      • Resnick M.J.
      Cost-effectiveness of urinary biomarker panel in prostate cancer risk assessment.
      Stockholm3,
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      and urinary proteome analysis.
      • Schiffer E.
      • Bick C.
      • Grizelj B.
      • Pietzker S.
      • Schöfer W.
      Urinary proteome analysis for prostate cancer diagnosis: cost-effective application in routine clinical practice in Germany.
      The definitions of these biomarker tests are given in Appendix Table S1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.07.002. Most studies considered only 1 novel test, except Sathianathen et al
      • Sathianathen N.J.
      • Kuntz K.M.
      • Alarid-Escudero F.
      • et al.
      Incorporating biomarkers into the primary prostate biopsy setting: a cost-effectiveness analysis.
      who compared PHI, the 4Kscore, ExoDx Prostate(IntelliScore), and SelectMDx.
      • Kim L.
      • Boxall N.
      • George A.
      • et al.
      Clinical utility and cost modelling of the phi test to triage referrals into image-based diagnostic services for suspected prostate cancer: the PRIM (Phi to RefIne Mri) study.
      ,
      • Sathianathen N.J.
      • Kuntz K.M.
      • Alarid-Escudero F.
      • et al.
      Incorporating biomarkers into the primary prostate biopsy setting: a cost-effectiveness analysis.
      Of the 11 studies comparing different biomarkers, 9 referred to TRUS-guided biopsy to confirm diagnosis, 1 to multiparametric MRI,
      • Kim L.
      • Boxall N.
      • George A.
      • et al.
      Clinical utility and cost modelling of the phi test to triage referrals into image-based diagnostic services for suspected prostate cancer: the PRIM (Phi to RefIne Mri) study.
      and 1 did not report the biopsy method assumed.
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      Only 3 studies
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      ,
      • Nichol M.B.
      • Wu J.
      • Huang J.
      • Denham D.
      • Frencher S.K.
      • Jacobsen S.J.
      Cost-effectiveness of Prostate Health Index for prostate cancer detection.
      ,
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      that compared biomarkers modeled repeat PSA/biomarker testing, assuming annual
      • Nichol M.B.
      • Wu J.
      • Huang J.
      • Denham D.
      • Frencher S.K.
      • Jacobsen S.J.
      Cost-effectiveness of Prostate Health Index for prostate cancer detection.
      or 4-yearly screening.
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      ,
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      These intervals were chosen in accordance with the American Urological Association 2009 recommendations (annual screening for men aged 40 years and older with shared decision making)
      • Greene K.L.
      • Albertsen P.C.
      • Babaian R.J.
      • et al.
      Prostate specific antigen best practice statement: 2009 update.
      and the screening protocol used in ERSPC (4 yearly).
      • Schröder F.H.
      • Hugosson J.
      • Roobol M.J.
      • et al.
      Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up.

       Strategies compared—biopsy methods

      Men with a suspicion of prostate cancer indicated by a PSA test or other biomarker are generally referred for a TRUS-guided biopsy. The different biopsy methods the 7 studies identified compared included MRI-targeted methods and template mapping biopsy.
      • Faria R.
      • Soares M.O.
      • Spackman E.
      • et al.
      Optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate MR imaging study (PROMIS).
      The definitions of biopsy methods are given in Appendix Table S2 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.07.002. Different strategies were compared, including using MRI to decide whether a TRUS-guided biopsy is necessary and to target biopsy and strategies starting with TRUS-guided biopsy and using MRI to decide whether a repeat biopsy is necessary. A total of 3 of the studies comparing biopsy methods
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Kunju L.P.
      • Denton B.T.
      • Piert M.
      18F-choline PET/mpMRI for detection of clinically significant prostate cancer: part 2. Cost-effectiveness analysis.
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Wei J.T.
      • Montie J.E.
      • Denton B.T.
      Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer.
      • Callender T.
      • Emberton M.
      • Morris S.
      • Pharoah P.D.P.
      • Pashayan N.
      Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer.
      modeled repeat screening, assuming that men would be screened every 2 years based on the 2013 American Urological Association guideline
      • Carter H.B.
      • Albertsen P.C.
      • Barry M.J.
      • et al.
      Early detection of prostate cancer: AUA guideline.
      or every 4 years based on the ERSPC protocol.
      • Schröder F.H.
      • Hugosson J.
      • Roobol M.J.
      • et al.
      Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up.

       Strategies compared—follow-up strategies in men with negative biopsies

      A total of 3 studies
      NICE Guideline Updates Team (UK)
      Prostate cancer: diagnosis and management. National Institute for Health and Care Excellence.
      • Nicholson A.
      • Mahon J.
      • Boland A.
      • et al.
      The clinical effectiveness and cost-effectiveness of the PROGENSA (R) prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation.
      • Mowatt G.
      • Scotland G.
      • Boachie C.
      • et al.
      The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation.
      compared follow-up strategies for men with raised PSA and negative MRI, negative prostate biopsy or negative MRI and negative biopsy. The strategies included various biomarkers (PSA, PSA velocity, PSA density, % free PSA, PSA doubling time, PSA density in transition zone, PCA3, PHI) and MRI techniques.

       Model Inputs

       Accuracy data

      All but 6 studies
      • Nichol M.B.
      • Wu J.
      • Huang J.
      • Denham D.
      • Frencher S.K.
      • Jacobsen S.J.
      Cost-effectiveness of Prostate Health Index for prostate cancer detection.
      ,
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      ,
      • Callender T.
      • Emberton M.
      • Morris S.
      • Pharoah P.D.P.
      • Pashayan N.
      Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer.
      ,
      • Nicholson A.
      • Mahon J.
      • Boland A.
      • et al.
      The clinical effectiveness and cost-effectiveness of the PROGENSA (R) prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation.
      ,
      • Cerantola Y.
      • Dragomir A.
      • Tanguay S.
      • Bladou F.
      • Aprikian A.
      • Kassouf W.
      Cost-effectiveness of multiparametric magnetic resonance imaging and targeted biopsy in diagnosing prostate cancer.
      ,
      • Teoh J.Y.
      • Leung C.H.
      • Wang M.H.
      • et al.
      The cost-effectiveness of Prostate Health Index for prostate cancer detection in Chinese men.
      explicitly reported the sensitivity and specificity of the tests. The assumed sensitivity of a standard biopsy ranged from 0.9 based on ERSPC data
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      ,
      • Postma R.
      • Schröder F.H.
      • van Leenders G.J.
      • et al.
      Cancer detection and cancer characteristics in the European Randomized study of Screening for Prostate Cancer (ERSPC) --section Rotterdam: a comparison of two rounds of screening.
      to 0.46 based on de Rooij et al.
      • Sathianathen N.J.
      • Kuntz K.M.
      • Alarid-Escudero F.
      • et al.
      Incorporating biomarkers into the primary prostate biopsy setting: a cost-effectiveness analysis.
      ,
      • de Rooij M.
      • Crienen S.
      • Witjes J.A.
      • Barentsz J.O.
      • Rovers M.M.
      • Grutters J.P.
      Cost-effectiveness of magnetic resonance (MR) imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer: a modelling study from a health care perspective.
      ,
      • Pahwa S.
      • Schiltz N.K.
      • Ponsky L.E.
      • Lu Z.
      • Griswold M.A.
      • Gulani V.
      Cost-effectiveness of MR imaging-guided strategies for detection of prostate cancer in biopsy-naive men.
      The biomarkers were generally assumed to be either particularly sensitive, that is, good at correctly identifying those with the disease, or particularly specific, that is, good at correctly identifying those without the disease. PHI at a threshold of 20, for example, had the highest reported sensitivity (1, but specificity of 0.08) and also the highest reported specificity (0.974, but sensitivity of 0.129).
      • Bouttell J.
      • Teoh J.
      • Chiu P.K.
      • et al.
      Economic evaluation of the introduction of the Prostate Health Index as a rule-out test to avoid unnecessary biopsies in men with prostate specific antigen levels of 4-10 in Hong Kong.
      ,
      • Chiu P.K.
      • Roobol M.J.
      • Teoh J.Y.
      • et al.
      Prostate Health Index (PHI) and prostate-specific antigen (PSA) predictive models for prostate cancer in the Chinese population and the role of digital rectal examination-estimated prostate volume.
      The MRI-targeted biopsy methods generally had a better balance of sensitivity and specificity, ranging from a sensitivity of 0.965 (specificity of 0.597) for MRI using a Prostate Imaging-Reporting and Data System threshold of ≥3
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Wei J.T.
      • Montie J.E.
      • Denton B.T.
      Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer.
      ,
      • Grey A.D.
      • Chana M.S.
      • Popert R.
      • Wolfe K.
      • Liyanage S.H.
      • Acher P.L.
      Diagnostic accuracy of magnetic resonance imaging (MRI) prostate imaging reporting and data system (PI-RADS) scoring in a transperineal prostate biopsy setting.
      to 0.770 (specificity 0.68) using fusion biopsy.
      • Sathianathen N.J.
      • Kuntz K.M.
      • Alarid-Escudero F.
      • et al.
      Incorporating biomarkers into the primary prostate biopsy setting: a cost-effectiveness analysis.
      ,
      • Siddiqui M.M.
      • Rais-Bahrami S.
      • Turkbey B.
      • et al.
      Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer.
      ,
      • Venderink W.
      • Govers T.M.
      • de Rooij M.
      • Fütterer J.J.
      • Sedelaar J.P.M.
      Cost-effectiveness comparison of imaging-guided prostate biopsy techniques: systematic transrectal ultrasound, direct in-bore MRI, and image fusion.
      Appendix Table S3 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.07.002 details the accuracy estimates used along with their evidence sources.

       Quality of life

      As detailed in Table 2, all but 3 studies assigned disutilities to various aspects associated with testing including screening attendance, the biopsy procedure, diagnosis of cancer, treatment, active surveillance, advanced or metastatic cancer, posttreatment or recovery, adverse events associated with biopsy and treatment, and palliative therapy. A total of 9 studies
      • Heijnsdijk E.A.
      • Wever E.M.
      • Auvinen A.
      • et al.
      Quality-of-life effects of prostate-specific antigen screening.
      ,
      • Govers T.M.
      • Hessels D.
      • Vlaeminck-Guillem V.
      • et al.
      Cost-effectiveness of SelectMDx for prostate cancer in four European countries: a comparative modeling study.
      ,
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      ,
      • Dijkstra S.
      • Govers T.M.
      • Hendriks R.J.
      • et al.
      Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.
      ,
      • Govers T.M.
      • Caba L.
      • Resnick M.J.
      Cost-effectiveness of urinary biomarker panel in prostate cancer risk assessment.
      ,
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Wei J.T.
      • Montie J.E.
      • Denton B.T.
      Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer.
      ,
      • Callender T.
      • Emberton M.
      • Morris S.
      • Pharoah P.D.P.
      • Pashayan N.
      Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer.
      ,
      • Nicholson A.
      • Mahon J.
      • Boland A.
      • et al.
      The clinical effectiveness and cost-effectiveness of the PROGENSA (R) prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation.
      ,
      • Venderink W.
      • Govers T.M.
      • de Rooij M.
      • Fütterer J.J.
      • Sedelaar J.P.M.
      Cost-effectiveness comparison of imaging-guided prostate biopsy techniques: systematic transrectal ultrasound, direct in-bore MRI, and image fusion.
      sourced all utility estimates used in their model from Heijnsdijk et al
      • Heijnsdijk E.A.
      • Wever E.M.
      • Auvinen A.
      • et al.
      Quality-of-life effects of prostate-specific antigen screening.
      who in turn obtained their utility estimates from the Cost-Effectiveness Analysis Registry and various additional studies.
      • Essink-Bot M.L.
      • de Koning H.J.
      • Nijs H.G.
      • Kirkels W.J.
      • van der Maas P.J.
      • Schröder F.H.
      Short-term effects of population-based screening for prostate cancer on health-related quality of life.
      • de Haes J.C.
      • de Koning H.J.
      • van Oortmarssen G.J.
      • van Agt H.M.
      • de Bruyn A.E.
      • van der Maas P.J.
      The impact of a breast cancer screening programme on quality-adjusted life-years.
      • Korfage I.J.
      • de Koning H.J.
      • Roobol M.
      • Schröder F.H.
      • Essink-Bot M.L.
      Prostate cancer diagnosis: the impact on patients’ mental health.
      • Stewart S.T.
      • Lenert L.
      • Bhatnagar V.
      • Kaplan R.M.
      Utilities for prostate cancer health states in men aged 60 and older.
      • Konski A.
      • Sherman E.
      • Krahn M.
      • et al.
      Economic analysis of a phase III clinical trial evaluating the addition of total androgen suppression to radiation versus radiation alone for locally advanced prostate cancer (Radiation Therapy Oncology Group protocol 86-10).
      • Calvert N.W.
      • Morgan A.B.
      • Catto J.W.
      • et al.
      Effectiveness and cost-effectiveness of prognostic markers in prostate cancer.

      Bennett CL, Matchar D, McCrory D, McLeod DG, Crawford ED, Hillner BE. Cost-effective models for flutamide for prostate carcinoma patients: are they helpful to policy makers? 1996;77(9):1854-1861.

      • Zeliadt S.B.
      • Etzioni R.D.
      • Penson D.F.
      • Thompson I.M.
      • Ramsey S.D.
      Lifetime implications and cost-effectiveness of using finasteride to prevent prostate cancer.
      • Cooperberg M.R.
      • Carroll P.R.
      • Klotz L.
      Active surveillance for prostate cancer: progress and promise.
      • Konski A.
      • Watkins-Bruner D.
      • Brereton H.
      • Feigenberg S.
      • Hanks G.
      Long-term hormone therapy and radiation is cost-effective for patients with locally advanced prostate carcinoma.
      • Moeremans K.
      • Caekelbergh K.
      • Annemans L.
      Cost-effectiveness Analysis of bicalutamide (Casodex) for adjuvant treatment of early prostate cancer.
      • Penson D.F.
      • Ramsey S.
      • Veenstra D.
      • Clarke L.
      • Gandhi S.
      • Hirsch M.
      The cost-effectiveness of combined androgen blockade with bicalutamide and luteinizing hormone releasing hormone agonist in men with metastatic prostate cancer.
      • Ramsey S.
      • Veenstra D.
      • Clarke L.
      • Gandhi S.
      • Hirsch M.
      • Penson D.
      Is combined androgen blockade with bicalutamide cost-effective compared with combined androgen blockade with flutamide?.
      The other studies sourced their utility estimates from various unrelated publications, also in different countries and settings. Where utility estimates were sourced from studies directly measuring health-related QOL, the most common methods used were standard gamble
      • Stewart S.T.
      • Lenert L.
      • Bhatnagar V.
      • Kaplan R.M.
      Utilities for prostate cancer health states in men aged 60 and older.
      ,
      • Krahn M.D.
      • Bremner K.E.
      • Tomlinson G.
      • Naglie G.
      Utility and health-related quality of life in prostate cancer patients 12 months after radical prostatectomy or radiation therapy.
      ,
      • Volk R.J.
      • Cantor S.B.
      • Cass A.R.
      • Spann S.J.
      • Weller S.C.
      • Krahn M.D.
      Preferences of husbands and wives for outcomes of prostate cancer screening and treatment.
      and time trade-off
      • Shimizu F.
      • Fujino K.
      • Ito Y.M.
      • et al.
      Factors associated with variation in utility scores among patients with prostate cancer.
      ,
      • Brooks R.
      EuroQol: the current state of play.
      and the most common instruments used were EQ-5D
      • Essink-Bot M.L.
      • de Koning H.J.
      • Nijs H.G.
      • Kirkels W.J.
      • van der Maas P.J.
      • Schröder F.H.
      Short-term effects of population-based screening for prostate cancer on health-related quality of life.
      ,
      • Torvinen S.
      • Färkkilä N.
      • Sintonen H.
      • Saarto T.
      • Roine R.P.
      • Taari K.
      Health-related quality of life in prostate cancer.
      • Donovan J.L.
      • Hamdy F.C.
      • Lane J.A.
      • et al.
      Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer.
      • Ware J.
      • Snow K.K.
      • Kosinski M.
      • Gandek B.
      SF-36 health survey: manual and interpretation guide. The Health Institute, New England Medical Center.
      and 12-item Short Form Medical Survey.
      • Ara R.
      • Brazier J.
      • Peasgood T.
      • Paisley S.
      The identification, review and synthesis of health state utility values from the literature.
      ,
      • Ades A.E.
      • Lu G.
      • Claxton K.
      Expected value of sample information calculations in medical decision modeling.
      None of the included studies provided the Ara et al
      Principles of epidemiology in public health practice: an introduction to applied epidemiology and biostatistics: lesson 1: introduction to epidemiology. Centers for Disease Control and Prevention.
      recommended level of detail on health state utility values that are sourced from the literature, that is, detail on searches, inclusion/exclusion criteria, the quality and relevance of included studies, and a justification for the utility values chosen. Only 5 studies fully reported the uncertainty in the disutility estimates used.
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Kunju L.P.
      • Denton B.T.
      • Piert M.
      18F-choline PET/mpMRI for detection of clinically significant prostate cancer: part 2. Cost-effectiveness analysis.
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Wei J.T.
      • Montie J.E.
      • Denton B.T.
      Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer.
      • Callender T.
      • Emberton M.
      • Morris S.
      • Pharoah P.D.P.
      • Pashayan N.
      Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer.
      ,
      • de Rooij M.
      • Crienen S.
      • Witjes J.A.
      • Barentsz J.O.
      • Rovers M.M.
      • Grutters J.P.
      Cost-effectiveness of magnetic resonance (MR) imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer: a modelling study from a health care perspective.
      ,
      • Pahwa S.
      • Schiltz N.K.
      • Ponsky L.E.
      • Lu Z.
      • Griswold M.A.
      • Gulani V.
      Cost-effectiveness of MR imaging-guided strategies for detection of prostate cancer in biopsy-naive men.
      Table 2Disutility estimates used for prostate cancer states, tests, and treatments in the identified economic models (annual values)
      StudyBiopsyDiagnosisRPRTASAdvanced cancerPosttreatmentAEsOtherSourceReport uncertainty
      Barnett et al
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Wei J.T.
      • Montie J.E.
      • Denton B.T.
      Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer.
      0.0060.0170.247-0.030.30.050.0161 (postbiopsy infection)0.0002 (PSA screening)

      0.00077 (MRI)

      0.60 (palliative therapy)
      • Heijnsdijk E.A.
      • Wever E.M.
      • Auvinen A.
      • et al.
      Quality-of-life effects of prostate-specific antigen screening.
      ,
      • Li C.k.
      • Tong B.C.Y.
      • You J.H.S.
      Cost-effectiveness of culture-guided antimicrobial prophylaxis for the prevention of infections after prostate biopsy.
      Yes
      Cerantola et al
      • Cerantola Y.
      • Dragomir A.
      • Tanguay S.
      • Bladou F.
      • Aprikian A.
      • Kassouf W.
      Cost-effectiveness of multiparametric magnetic resonance imaging and targeted biopsy in diagnosing prostate cancer.
      ------0.08-0.22 (relapse)
      • Cooperberg M.R.
      • Ramakrishna N.R.
      • Duff S.B.
      • et al.
      Primary treatments for clinically localised prostate cancer: a comprehensive lifetime cost-utility analysis.
      No
      de Rooij et al
      • de Rooij M.
      • Crienen S.
      • Witjes J.A.
      • Barentsz J.O.
      • Rovers M.M.
      • Grutters J.P.
      Cost-effectiveness of magnetic resonance (MR) imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer: a modelling study from a health care perspective.
      --0.330.270.16----
      • Stewart S.T.
      • Lenert L.
      • Bhatnagar V.
      • Kaplan R.M.
      Utilities for prostate cancer health states in men aged 60 and older.
      Yes
      Dijkstra et al
      • Dijkstra S.
      • Govers T.M.
      • Hendriks R.J.
      • et al.
      Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.
      0.0060.0170.2280.2470.03-0.05--
      • Heijnsdijk E.A.
      • Wever E.M.
      • Auvinen A.
      • et al.
      Quality-of-life effects of prostate-specific antigen screening.
      No
      Faria et al
      • Faria R.
      • Soares M.O.
      • Spackman E.
      • et al.
      Optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate MR imaging study (PROMIS).
      0.007 (TPM biopsy)----0.137---
      • Li C.k.
      • Tong B.C.Y.
      • You J.H.S.
      Cost-effectiveness of culture-guided antimicrobial prophylaxis for the prevention of infections after prostate biopsy.
      , PROMIS IPD
      • Ahmed H.U.
      • El-Shater Bosaily A.
      • Brown L.C.
      • et al.
      Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study.
      ,
      • Torvinen S.
      • Färkkilä N.
      • Sintonen H.
      • Saarto T.
      • Roine R.P.
      • Taari K.
      Health-related quality of life in prostate cancer.
      Only for TPM biopsy
      Govers et al
      • Govers T.M.
      • Hessels D.
      • Vlaeminck-Guillem V.
      • et al.
      Cost-effectiveness of SelectMDx for prostate cancer in four European countries: a comparative modeling study.
      ,
      • Govers T.M.
      • Caba L.
      • Resnick M.J.
      Cost-effectiveness of urinary biomarker panel in prostate cancer risk assessment.
      0.0060.0170.2280.2470.03-0.05--
      • Heijnsdijk E.A.
      • Wever E.M.
      • Auvinen A.
      • et al.
      Quality-of-life effects of prostate-specific antigen screening.
      No
      Heijnsdijk et al
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      0.0060.0170.2470.2280.030.30.05-0.0002 (screening attendance)

      0.60 (palliative therapy)
      • Heijnsdijk E.A.
      • Wever E.M.
      • Auvinen A.
      • et al.
      Quality-of-life effects of prostate-specific antigen screening.
      No
      Mowatt et al
      • Mowatt G.
      • Scotland G.
      • Boachie C.
      • et al.
      The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation.
      -----0.365-0.16 (urinary incontinence)

      0.17 (bowel problem)

      0.12 (erectile dysfunction)
      0.11 (localized [undiagnosed])

      0.1 (localized [diagnosed])

      0.19 (locally advanced [undiagnosed])

      0.18 (locally advanced [diagnosed])
      • Krahn M.
      • Ritvo P.
      • Irvine J.
      • et al.
      Patient and community preferences for outcomes in prostate cancer: implications for clinical policy.
      ,
      • Volk R.J.
      • Cantor S.B.
      • Cass A.R.
      • Spann S.J.
      • Weller S.C.
      • Krahn M.D.
      Preferences of husbands and wives for outcomes of prostate cancer screening and treatment.
      ,
      • Shimizu F.
      • Fujino K.
      • Ito Y.M.
      • et al.
      Factors associated with variation in utility scores among patients with prostate cancer.
      Only for cancer states
      NICE Guideline
      NICE Guideline Updates Team (UK)
      Prostate cancer: diagnosis and management. National Institute for Health and Care Excellence.
      0.004, 0.007 (template mapping biopsy)----0.137--0.027 (low risk)

      0.029 (intermediate risk)

      0.027 (high risk)
      • Heijnsdijk E.A.
      • Wever E.M.
      • Auvinen A.
      • et al.
      Quality-of-life effects of prostate-specific antigen screening.
      ,
      • Li C.k.
      • Tong B.C.Y.
      • You J.H.S.
      Cost-effectiveness of culture-guided antimicrobial prophylaxis for the prevention of infections after prostate biopsy.
      ,
      • Brown L.C.
      • Ahmed H.U.
      • Faria R.
      • et al.
      Multiparametric MRI to improve detection of prostate cancer compared with transrectal ultrasound-guided prostate biopsy alone: the PROMIS study.
      ,
      • Torvinen S.
      • Färkkilä N.
      • Sintonen H.
      • Saarto T.
      • Roine R.P.
      • Taari K.
      Health-related quality of life in prostate cancer.
      ,
      • Donovan J.L.
      • Hamdy F.C.
      • Lane J.A.
      • et al.
      Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer.
      No
      Nichol et al
      • Nichol M.B.
      • Wu J.
      • Huang J.
      • Denham D.
      • Frencher S.K.
      • Jacobsen S.J.
      Cost-effectiveness of Prostate Health Index for prostate cancer detection.
      0.027-------0.2 (PCa)
      • Krahn M.D.
      • Mahoney J.E.
      • Eckman M.H.
      • Trachtenberg J.
      • Pauker S.G.
      • Detsky A.S.
      Screening for prostate cancer: a decision analytic view.
      ,
      • Bremner K.E.
      • Chong C.A.K.Y.
      • Tomlinson G.
      • Alibhai S.M.H.
      • Krahn M.D.
      A review and meta-analysis of prostate cancer utilities.
      ,
      • Stewart S.T.
      • Lenert L.
      • Bhatnagar V.
      • Kaplan R.M.
      Utilities for prostate cancer health states in men aged 60 and older.
      Only for PCa
      Nicholson et al
      • Nicholson A.
      • Mahon J.
      • Boland A.
      • et al.
      The clinical effectiveness and cost-effectiveness of the PROGENSA (R) prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation.
      0.006--------
      • Heijnsdijk E.A.
      • Wever E.M.
      • Auvinen A.
      • et al.
      Quality-of-life effects of prostate-specific antigen screening.
      No
      Pahwa et al
      • Pahwa S.
      • Schiltz N.K.
      • Ponsky L.E.
      • Lu Z.
      • Griswold M.A.
      • Gulani V.
      Cost-effectiveness of MR imaging-guided strategies for detection of prostate cancer in biopsy-naive men.
      0.027Only lifetime QALYs reported
      • Krahn M.D.
      • Mahoney J.E.
      • Eckman M.H.
      • Trachtenberg J.
      • Pauker S.G.
      • Detsky A.S.
      Screening for prostate cancer: a decision analytic view.
      Yes
      Sathianathen et al
      • Sathianathen N.J.
      • Kuntz K.M.
      • Alarid-Escudero F.
      • et al.
      Incorporating biomarkers into the primary prostate biopsy setting: a cost-effectiveness analysis.
      0.004-0.14-0.030.420.05--
      • Heijnsdijk E.A.
      • Wever E.M.
      • Auvinen A.
      • et al.
      Quality-of-life effects of prostate-specific antigen screening.
      ,
      • Krahn M.D.
      • Mahoney J.E.
      • Eckman M.H.
      • Trachtenberg J.
      • Pauker S.G.
      • Detsky A.S.
      Screening for prostate cancer: a decision analytic view.
      ,
      • Krahn M.D.
      • Bremner K.E.
      • Tomlinson G.
      • Naglie G.
      Utility and health-related quality of life in prostate cancer patients 12 months after radical prostatectomy or radiation therapy.
      Yes
      Venderink et al
      • Venderink W.
      • Govers T.M.
      • de Rooij M.
      • Fütterer J.J.
      • Sedelaar J.P.M.
      Cost-effectiveness comparison of imaging-guided prostate biopsy techniques: systematic transrectal ultrasound, direct in-bore MRI, and image fusion.
      0.0060.020.250.230.030.550.05--
      • Heijnsdijk E.A.
      • Wever E.M.
      • Auvinen A.
      • et al.
      Quality-of-life effects of prostate-specific antigen screening.
      No
      Barnett et al
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Kunju L.P.
      • Denton B.T.
      • Piert M.
      18F-choline PET/mpMRI for detection of clinically significant prostate cancer: part 2. Cost-effectiveness analysis.
      0.005770.01670.247-0.030.30.050.0161 (postbiopsy infection)0.0002 (PSA screening)

      0.00077 (PET/mpMRI)

      0.60 (palliative therapy)
      • Heijnsdijk E.A.
      • Wever E.M.
      • Auvinen A.
      • et al.
      Quality-of-life effects of prostate-specific antigen screening.
      ,
      • Li C.k.
      • Tong B.C.Y.
      • You J.H.S.
      Cost-effectiveness of culture-guided antimicrobial prophylaxis for the prevention of infections after prostate biopsy.
      ,
      • Grann V.R.
      • Patel P.R.
      • Jacobson J.S.
      • et al.
      Comparative effectiveness of screening and prevention strategies among BRCA1/2-affected mutation carriers.
      Yes
      Callender et al
      • Callender T.
      • Emberton M.
      • Morris S.
      • Pharoah P.D.P.
      • Pashayan N.
      Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer.
      --------0.07 (PCa)
      • Rosario D.J.
      • Lane J.A.
      • Metcalfe C.
      • et al.
      Short term outcomes of prostate biopsy in men tested for cancer by prostate specific antigen: prospective evaluation within ProtecT study.
      Yes
      Teoh et al
      • Teoh J.Y.
      • Leung C.H.
      • Wang M.H.
      • et al.
      The cost-effectiveness of Prostate Health Index for prostate cancer detection in Chinese men.
      0.0270.2 (PCa)
      • Nichol M.B.
      • Wu J.
      • Huang J.
      • Denham D.
      • Frencher S.K.
      • Jacobsen S.J.
      Cost-effectiveness of Prostate Health Index for prostate cancer detection.
      ,
      • Bremner K.E.
      • Chong C.A.K.Y.
      • Tomlinson G.
      • Alibhai S.M.H.
      • Krahn M.D.
      A review and meta-analysis of prostate cancer utilities.
      ,
      • Stewart S.T.
      • Lenert L.
      • Bhatnagar V.
      • Kaplan R.M.
      Utilities for prostate cancer health states in men aged 60 and older.
      ,
      • Cooperberg M.R.
      • Carroll P.R.
      • Klotz L.
      Active surveillance for prostate cancer: progress and promise.
      No
      Karlsson et al
      • Mowatt G.
      • Scotland G.
      • Boachie C.
      • et al.
      The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation.
      0.10.20.33 (part 1), 0.23 (part 2)0.27 (part 1), 0.22 (part 2)0.030.60.050.60 (palliative therapy), 0.01 (PSA test)
      • Heijnsdijk E.A.
      • Wever E.M.
      • Auvinen A.
      • et al.
      Quality-of-life effects of prostate-specific antigen screening.
      No
      Note. “-”, not applicable as disutility not applied in model.
      AE indicates adverse event; AS, active surveillance; IPD, individual participant data; mpMRI, multiparametric magnetic resonance imaging; MRI, magnetic resonance imaging; NICE, National Institute for Health and Care Excellence; PCa, prostate cancer; PET, positron emission tomography; PROMIS, Patient-Reported Outcomes Measurement Information System; PSA, prostate-specific antigen; QALY, quality-adjusted life-year; RP, radical prostatectomy; RT, radiotherapy; TPM, transperineal mapping.

       Resource use

      Most studies took a healthcare provider perspective for the analysis (only including costs incurred to the provider rather than any wider patient or societal costs). A total of 2 studies stated that a societal perspective was taken but did not detail the societal costs that were included.
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      ,
      • Nichol M.B.
      • Wu J.
      • Huang J.
      • Denham D.
      • Frencher S.K.
      • Jacobsen S.J.
      Cost-effectiveness of Prostate Health Index for prostate cancer detection.
      Another 2 studies included productivity costs in terms of missed days of work when a patient undergoes a test or treatment.
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      ,
      • Pahwa S.
      • Schiltz N.K.
      • Ponsky L.E.
      • Lu Z.
      • Griswold M.A.
      • Gulani V.
      Cost-effectiveness of MR imaging-guided strategies for detection of prostate cancer in biopsy-naive men.
      No study gave a justification for the perspective taken. The main costs included were the cost of testing, biopsy, and subsequent management strategy. Thirteen studies included costs of complications arising from biopsy.
      • Govers T.M.
      • Hessels D.
      • Vlaeminck-Guillem V.
      • et al.
      Cost-effectiveness of SelectMDx for prostate cancer in four European countries: a comparative modeling study.
      ,
      • Bouttell J.
      • Teoh J.
      • Chiu P.K.
      • et al.
      Economic evaluation of the introduction of the Prostate Health Index as a rule-out test to avoid unnecessary biopsies in men with prostate specific antigen levels of 4-10 in Hong Kong.
      ,
      • Kim L.
      • Boxall N.
      • George A.
      • et al.
      Clinical utility and cost modelling of the phi test to triage referrals into image-based diagnostic services for suspected prostate cancer: the PRIM (Phi to RefIne Mri) study.
      ,
      • Dijkstra S.
      • Govers T.M.
      • Hendriks R.J.
      • et al.
      Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.
      ,
      • Govers T.M.
      • Caba L.
      • Resnick M.J.
      Cost-effectiveness of urinary biomarker panel in prostate cancer risk assessment.
      ,
      • Faria R.
      • Soares M.O.
      • Spackman E.
      • et al.
      Optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate MR imaging study (PROMIS).
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Kunju L.P.
      • Denton B.T.
      • Piert M.
      18F-choline PET/mpMRI for detection of clinically significant prostate cancer: part 2. Cost-effectiveness analysis.
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Wei J.T.
      • Montie J.E.
      • Denton B.T.
      Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer.
      ,
      NICE Guideline Updates Team (UK)
      Prostate cancer: diagnosis and management. National Institute for Health and Care Excellence.
      • Nicholson A.
      • Mahon J.
      • Boland A.
      • et al.
      The clinical effectiveness and cost-effectiveness of the PROGENSA (R) prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation.
      • Mowatt G.
      • Scotland G.
      • Boachie C.
      • et al.
      The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation.
      ,
      • Pahwa S.
      • Schiltz N.K.
      • Ponsky L.E.
      • Lu Z.
      • Griswold M.A.
      • Gulani V.
      Cost-effectiveness of MR imaging-guided strategies for detection of prostate cancer in biopsy-naive men.
      ,
      • Venderink W.
      • Govers T.M.
      • de Rooij M.
      • Fütterer J.J.
      • Sedelaar J.P.M.
      Cost-effectiveness comparison of imaging-guided prostate biopsy techniques: systematic transrectal ultrasound, direct in-bore MRI, and image fusion.
      Only 7 studies explicitly stated that costs associated with complications arising from treatment were included.
      • Govers T.M.
      • Hessels D.
      • Vlaeminck-Guillem V.
      • et al.
      Cost-effectiveness of SelectMDx for prostate cancer in four European countries: a comparative modeling study.
      ,
      • Dijkstra S.
      • Govers T.M.
      • Hendriks R.J.
      • et al.
      Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.
      ,
      • Govers T.M.
      • Caba L.
      • Resnick M.J.
      Cost-effectiveness of urinary biomarker panel in prostate cancer risk assessment.
      ,
      • Faria R.
      • Soares M.O.
      • Spackman E.
      • et al.
      Optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate MR imaging study (PROMIS).
      ,
      NICE Guideline Updates Team (UK)
      Prostate cancer: diagnosis and management. National Institute for Health and Care Excellence.
      ,
      • Mowatt G.
      • Scotland G.
      • Boachie C.
      • et al.
      The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation.
      ,
      • Venderink W.
      • Govers T.M.
      • de Rooij M.
      • Fütterer J.J.
      • Sedelaar J.P.M.
      Cost-effectiveness comparison of imaging-guided prostate biopsy techniques: systematic transrectal ultrasound, direct in-bore MRI, and image fusion.

       Modeling Methods

       Model type

      Table 3 details model characteristics including model type, time horizon, and cycle length. A total of 8 combined decision tree/Markov cohort models were identified. In 5 of these, the decision tree reflected the diagnostic process and the Markov model reflected treatment.
      • Govers T.M.
      • Caba L.
      • Resnick M.J.
      Cost-effectiveness of urinary biomarker panel in prostate cancer risk assessment.
      ,
      • Faria R.
      • Soares M.O.
      • Spackman E.
      • et al.
      Optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate MR imaging study (PROMIS).
      ,
      • Teoh J.Y.
      • Leung C.H.
      • Wang M.H.
      • et al.
      The cost-effectiveness of Prostate Health Index for prostate cancer detection in Chinese men.
      ,
      • de Rooij M.
      • Crienen S.
      • Witjes J.A.
      • Barentsz J.O.
      • Rovers M.M.
      • Grutters J.P.
      Cost-effectiveness of magnetic resonance (MR) imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer: a modelling study from a health care perspective.
      In the others, the decision tree captured both diagnosis and treatment and the Markov model was used for posttreatment states.
      • Dijkstra S.
      • Govers T.M.
      • Hendriks R.J.
      • et al.
      Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.
      ,
      • Sathianathen N.J.
      • Kuntz K.M.
      • Alarid-Escudero F.
      • et al.
      Incorporating biomarkers into the primary prostate biopsy setting: a cost-effectiveness analysis.
      ,
      • Venderink W.
      • Govers T.M.
      • de Rooij M.
      • Fütterer J.J.
      • Sedelaar J.P.M.
      Cost-effectiveness comparison of imaging-guided prostate biopsy techniques: systematic transrectal ultrasound, direct in-bore MRI, and image fusion.
      The treatment allocation assumed in the studies that modeled this is shown in Appendix Table S4 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.07.002. A total of 8 cohort Markov models,
      • Schiffer E.
      • Bick C.
      • Grizelj B.
      • Pietzker S.
      • Schöfer W.
      Urinary proteome analysis for prostate cancer diagnosis: cost-effective application in routine clinical practice in Germany.
      ,
      • Nichol M.B.
      • Wu J.
      • Huang J.
      • Denham D.
      • Frencher S.K.
      • Jacobsen S.J.
      Cost-effectiveness of Prostate Health Index for prostate cancer detection.
      ,
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Kunju L.P.
      • Denton B.T.
      • Piert M.
      18F-choline PET/mpMRI for detection of clinically significant prostate cancer: part 2. Cost-effectiveness analysis.
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Wei J.T.
      • Montie J.E.
      • Denton B.T.
      Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer.
      • Callender T.
      • Emberton M.
      • Morris S.
      • Pharoah P.D.P.
      • Pashayan N.
      Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer.
      ,
      NICE Guideline Updates Team (UK)
      Prostate cancer: diagnosis and management. National Institute for Health and Care Excellence.
      ,
      • Mowatt G.
      • Scotland G.
      • Boachie C.
      • et al.
      The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation.
      ,
      • Cerantola Y.
      • Dragomir A.
      • Tanguay S.
      • Bladou F.
      • Aprikian A.
      • Kassouf W.
      Cost-effectiveness of multiparametric magnetic resonance imaging and targeted biopsy in diagnosing prostate cancer.
      2 continuous time discrete-event microsimulation models (the MIcrosimulation SCreening Analysis model)
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      and the Prostata model,
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      and 4 decision tree models
      • Bouttell J.
      • Teoh J.
      • Chiu P.K.
      • et al.
      Economic evaluation of the introduction of the Prostate Health Index as a rule-out test to avoid unnecessary biopsies in men with prostate specific antigen levels of 4-10 in Hong Kong.
      ,
      • Kim L.
      • Boxall N.
      • George A.
      • et al.
      Clinical utility and cost modelling of the phi test to triage referrals into image-based diagnostic services for suspected prostate cancer: the PRIM (Phi to RefIne Mri) study.
      ,
      • Nicholson A.
      • Mahon J.
      • Boland A.
      • et al.
      The clinical effectiveness and cost-effectiveness of the PROGENSA (R) prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation.
      ,
      • Pahwa S.
      • Schiltz N.K.
      • Ponsky L.E.
      • Lu Z.
      • Griswold M.A.
      • Gulani V.
      Cost-effectiveness of MR imaging-guided strategies for detection of prostate cancer in biopsy-naive men.
      were also identified. No study provided a justification for choosing one model type over another.
      Table 3Model characteristics
      StudyModel typeProgression modeledHealth states in Markov modelDefinition of low-risk cancerDefinition of intermediate risk cancerDefinition of high-risk cancerTime horizonCycle lengthDSAPSA
      Dijkstra et al
      • Dijkstra S.
      • Govers T.M.
      • Hendriks R.J.
      • et al.
      Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.
      Decision tree/MarkovNoHigh-grade PCa, low-grade PCa, missed PCaG ≤ 6-G ≥ 718 years1 yearYesNo
      Sathianathen et al
      • Sathianathen N.J.
      • Kuntz K.M.
      • Alarid-Escudero F.
      • et al.
      Incorporating biomarkers into the primary prostate biopsy setting: a cost-effectiveness analysis.
      Decision tree/MarkovNoNR---Lifetime6 monthsYesYes
      Govers et al
      • Govers T.M.
      • Caba L.
      • Resnick M.J.
      Cost-effectiveness of urinary biomarker panel in prostate cancer risk assessment.
      Decision tree/MarkovNoHigh-grade PCa, low-grade PCa, missed PCaG ≤ 6-G ≥ 7Lifetime1 yearYesNo
      Faria et al
      • Faria R.
      • Soares M.O.
      • Spackman E.
      • et al.
      Optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate MR imaging study (PROMIS).
      Decision tree/MarkovYesProgression free, metastaticPSA < 10, G < 6PSA 10-15 or G7G > 8LifetimeNRYesYes
      Venderink et al
      • Venderink W.
      • Govers T.M.
      • de Rooij M.
      • Fütterer J.J.
      • Sedelaar J.P.M.
      Cost-effectiveness comparison of imaging-guided prostate biopsy techniques: systematic transrectal ultrasound, direct in-bore MRI, and image fusion.
      Decision tree/MarkovNoStatus after prostatectomy, status after radiotherapy, status after active surveillance---18 years1 yearYesNo
      de Rooij et al
      • de Rooij M.
      • Crienen S.
      • Witjes J.A.
      • Barentsz J.O.
      • Rovers M.M.
      • Grutters J.P.
      Cost-effectiveness of magnetic resonance (MR) imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer: a modelling study from a health care perspective.
      Decision tree/MarkovNoAlive, deadG3 + 3 or small size 3 + 4-Large tumors with a G3 + 3 or ≥3 + 410 years1 yearYesNo
      NICE Guideline
      NICE Guideline Updates Team (UK)
      Prostate cancer: diagnosis and management. National Institute for Health and Care Excellence.
      Decision tree/MarkovYesLow risk, intermediate, high risk, metastaticG ≤ 6, PSA ≤ 10G = 7 or 10 ≤ PSA < 20G ≥ 8 and PSA > 20Lifetime3 monthsYesYes
      Nichol et al
      • Nichol M.B.
      • Wu J.
      • Huang J.
      • Denham D.
      • Frencher S.K.
      • Jacobsen S.J.
      Cost-effectiveness of Prostate Health Index for prostate cancer detection.
      Markov cohortNoAlive, dead---Lifetime1 yearYesYes
      Schiffer et al
      • Schiffer E.
      • Bick C.
      • Grizelj B.
      • Pietzker S.
      • Schöfer W.
      Urinary proteome analysis for prostate cancer diagnosis: cost-effective application in routine clinical practice in Germany.
      Markov cohortNoNR---Up to treatmentNRYesYes
      Barnett et al
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Wei J.T.
      • Montie J.E.
      • Denton B.T.
      Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer.
      Markov cohortYesG < 7, G = 7, G > 7, extraprostatic or lymph node positiveG < 7G = 7G > 7Until death1 yearYesNo
      Cerantola et al
      • Cerantola Y.
      • Dragomir A.
      • Tanguay S.
      • Bladou F.
      • Aprikian A.
      • Kassouf W.
      Cost-effectiveness of multiparametric magnetic resonance imaging and targeted biopsy in diagnosing prostate cancer.
      Markov cohortNoMRGTB/TRUSGB; follow-up of PCa-naive patients with DRE, PSA, and TRUSGB as required; low-risk PCa; intermediate/high-risk PCa; active surveillance; curative-intended treatment; biochemical recurrence after curative treatment; metastatic/castration-resistant PCa---5, 10, 15, and 20 years1 yearYesNo
      Mowatt et al
      • Mowatt G.
      • Scotland G.
      • Boachie C.
      • et al.
      The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation.
      Markov cohortYesLocalized (T1-T2) (low risk); localized (intermediate risk); localized (high risk); locally advanced (T3); metastaticG ≤ 6, PSA ≤ 10, ≤ T1aG ≤ 7, PSA ≤ 20, ≤ T2bG > 7, PSA > 20, > T2b30 years3 monthsYesYes
      Pahwa et al
      • Pahwa S.
      • Schiltz N.K.
      • Ponsky L.E.
      • Lu Z.
      • Griswold M.A.
      • Gulani V.
      Cost-effectiveness of MR imaging-guided strategies for detection of prostate cancer in biopsy-naive men.
      Decision treeNo-G ≤ 6-G ≥ 7Until death-YesNo
      Nicholson et al
      • Nicholson A.
      • Mahon J.
      • Boland A.
      • et al.
      The clinical effectiveness and cost-effectiveness of the PROGENSA (R) prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation.
      Decision treeNo----3 years-YesYes
      Bouttell et al
      • Bouttell J.
      • Teoh J.
      • Chiu P.K.
      • et al.
      Economic evaluation of the introduction of the Prostate Health Index as a rule-out test to avoid unnecessary biopsies in men with prostate specific antigen levels of 4-10 in Hong Kong.
      Decision treeNo----Up to biopsy-YesYes
      Heijnsdijk et al
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      MicrosimulationYesT1 G < 7, G = 7, G > 7; T2 G < 7, G = 7, G > 7; T3+ G < 7, G = 7, G > 7, each state can be local or metastatic---Lifetime-YesNo
      Barnett et al
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Kunju L.P.
      • Denton B.T.
      • Piert M.
      18F-choline PET/mpMRI for detection of clinically significant prostate cancer: part 2. Cost-effectiveness analysis.
      Markov cohortYesG < 7, G = 7, G > 7, extraprostatic or lymph node positiveG < 7G = 7G > 7Until death1 yearYesNo
      Callender et al
      • Callender T.
      • Emberton M.
      • Morris S.
      • Pharoah P.D.P.
      • Pashayan N.
      Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer.
      Markov cohortNoHealthy, PCa---Lifetime1 yearYesYes
      Kim et al
      • Kim L.
      • Boxall N.
      • George A.
      • et al.
      Clinical utility and cost modelling of the phi test to triage referrals into image-based diagnostic services for suspected prostate cancer: the PRIM (Phi to RefIne Mri) study.
      Decision treeNo----Up to diagnosis-YesNo
      Teoh et al
      • Teoh J.Y.
      • Leung C.H.
      • Wang M.H.
      • et al.
      The cost-effectiveness of Prostate Health Index for prostate cancer detection in Chinese men.
      Decision tree/MarkovNoPCa, no PCa---25 years1 yearYesYes
      Karlsson et al
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      MicrosimulationYesT1-T2 G < 7, G = 7, G > 7; T3+ G < 7, G = 7, G > 7; Metastatic G < 7, G = 7, G > 7,---Lifetime-YesYes
      Govers et al
      • Govers T.M.
      • Hessels D.
      • Vlaeminck-Guillem V.
      • et al.
      Cost-effectiveness of SelectMDx for prostate cancer in four European countries: a comparative modeling study.
      Decision tree/Markov modelNoTreatment, no treatment, delayed treatmentG ≤ 7G≥718 years1 yearYesNo
      Note. “-”, not included in the model.
      DRE indicates digital rectal examination; DSA deterministic sensitivity analysis; G, Gleason grade; MRGTB, magnetic resonance imaging-guided transrectal ultrasound biopsy; NR, not reported; PCa, prostate cancer; PSA, probabilistic sensitivity Analysis; TRUSGB, transrectal ultrasound-guided guided biopsy.
      The decision trees generally used data on disease prevalence and accuracy of the tests to categorize men into true positives, false positives, true negatives, and false negatives
      • Bouttell J.
      • Teoh J.
      • Chiu P.K.
      • et al.
      Economic evaluation of the introduction of the Prostate Health Index as a rule-out test to avoid unnecessary biopsies in men with prostate specific antigen levels of 4-10 in Hong Kong.
      ,
      • Dijkstra S.
      • Govers T.M.
      • Hendriks R.J.
      • et al.
      Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.
      ,
      • Venderink W.
      • Govers T.M.
      • de Rooij M.
      • Fütterer J.J.
      • Sedelaar J.P.M.
      Cost-effectiveness comparison of imaging-guided prostate biopsy techniques: systematic transrectal ultrasound, direct in-bore MRI, and image fusion.
      with some also incorporating the clinical significance of cancer.
      • Dijkstra S.
      • Govers T.M.
      • Hendriks R.J.
      • et al.
      Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.
      ,
      • Govers T.M.
      • Caba L.
      • Resnick M.J.
      Cost-effectiveness of urinary biomarker panel in prostate cancer risk assessment.
      ,
      • Faria R.
      • Soares M.O.
      • Spackman E.
      • et al.
      Optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate MR imaging study (PROMIS).
      ,
      • de Rooij M.
      • Crienen S.
      • Witjes J.A.
      • Barentsz J.O.
      • Rovers M.M.
      • Grutters J.P.
      Cost-effectiveness of magnetic resonance (MR) imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer: a modelling study from a health care perspective.
      ,
      • Pahwa S.
      • Schiltz N.K.
      • Ponsky L.E.
      • Lu Z.
      • Griswold M.A.
      • Gulani V.
      Cost-effectiveness of MR imaging-guided strategies for detection of prostate cancer in biopsy-naive men.
      The Markov models captured cancer progression and survival. All but 4 studies developed a de novo model.
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      ,
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      ,
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Wei J.T.
      • Montie J.E.
      • Denton B.T.
      Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer.
      ,
      • Callender T.
      • Emberton M.
      • Morris S.
      • Pharoah P.D.P.
      • Pashayan N.
      Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer.
      Cycle length varied from 3 months to 1 year. The only study that reported a justification for the cycle length chosen was the NICE guideline, which stated that the guideline development committee confirmed that a cycle length of 3 months is sufficient to reflect possible clinical events a person with prostate cancer may experience.
      NICE Guideline Updates Team (UK)
      Prostate cancer: diagnosis and management. National Institute for Health and Care Excellence.

       Sensitivity analyses

      All studies conducted a deterministic sensitivity analysis where input parameters or sets of parameters were varied to see the impact on results. Half (11 of 22) of the studies also performed a probabilistic sensitivity analysis where repeated simulations sampled all parameters from their respective distributions to observe the impact on results.
      • Nichol M.B.
      • Wu J.
      • Huang J.
      • Denham D.
      • Frencher S.K.
      • Jacobsen S.J.
      Cost-effectiveness of Prostate Health Index for prostate cancer detection.
      ,
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      ,
      • Sathianathen N.J.
      • Kuntz K.M.
      • Alarid-Escudero F.
      • et al.
      Incorporating biomarkers into the primary prostate biopsy setting: a cost-effectiveness analysis.
      ,
      • Faria R.
      • Soares M.O.
      • Spackman E.
      • et al.
      Optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate MR imaging study (PROMIS).
      ,
      • Callender T.
      • Emberton M.
      • Morris S.
      • Pharoah P.D.P.
      • Pashayan N.
      Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer.
      ,
      NICE Guideline Updates Team (UK)
      Prostate cancer: diagnosis and management. National Institute for Health and Care Excellence.
      • Nicholson A.
      • Mahon J.
      • Boland A.
      • et al.
      The clinical effectiveness and cost-effectiveness of the PROGENSA (R) prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation.
      • Mowatt G.
      • Scotland G.
      • Boachie C.
      • et al.
      The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation.
      ,
      • Teoh J.Y.
      • Leung C.H.
      • Wang M.H.
      • et al.
      The cost-effectiveness of Prostate Health Index for prostate cancer detection in Chinese men.
      ,
      • de Rooij M.
      • Crienen S.
      • Witjes J.A.
      • Barentsz J.O.
      • Rovers M.M.
      • Grutters J.P.
      Cost-effectiveness of magnetic resonance (MR) imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer: a modelling study from a health care perspective.
      ,
      • Pahwa S.
      • Schiltz N.K.
      • Ponsky L.E.
      • Lu Z.
      • Griswold M.A.
      • Gulani V.
      Cost-effectiveness of MR imaging-guided strategies for detection of prostate cancer in biopsy-naive men.
      No study performed a Value of Information analysis to determine the value of further research in prostate cancer screening.
      • Shimizu F.
      • Fujino K.
      • Ito Y.M.
      • et al.
      Factors associated with variation in utility scores among patients with prostate cancer.

       Model structure

      The structure of a model relates to how different health states are categorized and how patients move between health states. Related to this, the natural history of a disease refers to how a disease progresses in a person over time in the absence of treatment.
      • Brooks R.
      EuroQol: the current state of play.
      Only 7 of the included models
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      ,
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      ,
      • Faria R.
      • Soares M.O.
      • Spackman E.
      • et al.
      Optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate MR imaging study (PROMIS).
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Kunju L.P.
      • Denton B.T.
      • Piert M.
      18F-choline PET/mpMRI for detection of clinically significant prostate cancer: part 2. Cost-effectiveness analysis.
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Wei J.T.
      • Montie J.E.
      • Denton B.T.
      Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer.
      ,
      NICE Guideline Updates Team (UK)
      Prostate cancer: diagnosis and management. National Institute for Health and Care Excellence.
      ,
      • Mowatt G.
      • Scotland G.
      • Boachie C.
      • et al.
      The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation.
      took account of how prostate cancer progresses through different health states and how the introduction of a new test might affect this, and all of these captured this progression differently. The health states included in the models are shown in Table 3. Heijnsdijk et al
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      and Karlsson et al
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      used the most detailed breakdown with both T-stage and Gleason grade modeled. In comparison, the only health states modeled in Faria et al
      • Faria R.
      • Soares M.O.
      • Spackman E.
      • et al.
      Optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate MR imaging study (PROMIS).
      were progression free and metastatic cancer. A total of 8 studies modeled survival time from diagnosis only,
      • Govers T.M.
      • Hessels D.
      • Vlaeminck-Guillem V.
      • et al.
      Cost-effectiveness of SelectMDx for prostate cancer in four European countries: a comparative modeling study.
      ,
      • Dijkstra S.
      • Govers T.M.
      • Hendriks R.J.
      • et al.
      Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.
      ,
      • Govers T.M.
      • Caba L.
      • Resnick M.J.
      Cost-effectiveness of urinary biomarker panel in prostate cancer risk assessment.
      ,
      • Callender T.
      • Emberton M.
      • Morris S.
      • Pharoah P.D.P.
      • Pashayan N.
      Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer.
      ,
      • Cerantola Y.
      • Dragomir A.
      • Tanguay S.
      • Bladou F.
      • Aprikian A.
      • Kassouf W.
      Cost-effectiveness of multiparametric magnetic resonance imaging and targeted biopsy in diagnosing prostate cancer.
      ,
      • Teoh J.Y.
      • Leung C.H.
      • Wang M.H.
      • et al.
      The cost-effectiveness of Prostate Health Index for prostate cancer detection in Chinese men.
      ,
      • de Rooij M.
      • Crienen S.
      • Witjes J.A.
      • Barentsz J.O.
      • Rovers M.M.
      • Grutters J.P.
      Cost-effectiveness of magnetic resonance (MR) imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer: a modelling study from a health care perspective.
      ,
      • Venderink W.
      • Govers T.M.
      • de Rooij M.
      • Fütterer J.J.
      • Sedelaar J.P.M.
      Cost-effectiveness comparison of imaging-guided prostate biopsy techniques: systematic transrectal ultrasound, direct in-bore MRI, and image fusion.
      with no progression through health states. A total of 4 did not model beyond diagnosis.
      • Husereau D.
      • Drummond M.
      • Petrou S.
      • et al.
      Consolidated Health Economic Evaluation Reporting Standards (CHEERS)--explanation and elaboration: a report of the ISPOR health economic evaluation publication guidelines good reporting practices task force.
      ,
      • van Mastrigt G.A.
      • Hiligsmann M.
      • Arts J.J.
      • et al.
      How to prepare a systematic review of economic evaluations for informing evidence-based healthcare decisions: a five-step approach (part 1/3).
      ,
      • Kim L.
      • Boxall N.
      • George A.
      • et al.
      Clinical utility and cost modelling of the phi test to triage referrals into image-based diagnostic services for suspected prostate cancer: the PRIM (Phi to RefIne Mri) study.
      In addition, the definition of clinically significant cancer varied across studies (Table 3). Of all the models, 6 did not consider stages or grade of cancer, only the presence or absence of cancer.
      • Nichol M.B.
      • Wu J.
      • Huang J.
      • Denham D.
      • Frencher S.K.
      • Jacobsen S.J.
      Cost-effectiveness of Prostate Health Index for prostate cancer detection.
      ,
      • Govers T.M.
      • Caba L.
      • Resnick M.J.
      Cost-effectiveness of urinary biomarker panel in prostate cancer risk assessment.
      ,
      • Sathianathen N.J.
      • Kuntz K.M.
      • Alarid-Escudero F.
      • et al.
      Incorporating biomarkers into the primary prostate biopsy setting: a cost-effectiveness analysis.
      ,
      • Callender T.
      • Emberton M.
      • Morris S.
      • Pharoah P.D.P.
      • Pashayan N.
      Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer.
      ,
      • Teoh J.Y.
      • Leung C.H.
      • Wang M.H.
      • et al.
      The cost-effectiveness of Prostate Health Index for prostate cancer detection in Chinese men.
      ,
      • Venderink W.
      • Govers T.M.
      • de Rooij M.
      • Fütterer J.J.
      • Sedelaar J.P.M.
      Cost-effectiveness comparison of imaging-guided prostate biopsy techniques: systematic transrectal ultrasound, direct in-bore MRI, and image fusion.

       Reporting of overdiagnosis and mechanism of screening benefit

      Overdiagnosis and overtreatment owing to the identification of cancers that would never progress to cause prostate cancer related death or illness in a man’s lifetime are key factors to consider when testing men for prostate cancer. Only 3 studies
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      ,
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      ,
      • Callender T.
      • Emberton M.
      • Morris S.
      • Pharoah P.D.P.
      • Pashayan N.
      Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer.
      provided estimates of the impact of screening on overdiagnosis. Both Heijnsdijk et al
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      and Karlsson et al
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      defined overdiagnosed cancers as additional cancers detected through screening that were not detected in the “no screening” arm. Heijnsdijk et al
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      estimated that 5% fewer overdiagnosed cancers would be detected through the use of PHI compared with PSA, and Karlsson et al
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      predicted 15% fewer overdiagnosed cancers through the use of Stockholm3 when PSA values were above 2 ng/mL compared with PSA alone. Callender et al
      • Callender T.
      • Emberton M.
      • Morris S.
      • Pharoah P.D.P.
      • Pashayan N.
      Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer.
      estimated age-specific overdiagnosis by multiplying the number of cases by an equation derived from Pashayan et al,
      • Pashayan N.
      • Duffy S.W.
      • Pharoah P.
      • et al.
      Mean sojourn time, overdiagnosis, and reduction in advanced stage prostate cancer due to screening with PSA: implications of sojourn time on screening.
      defined as the probability that a PSA-detected case would have taken longer than the remaining lifetime to progress to clinical cancer. They found that MRI-first risk-stratified screening was associated with a 10.4% to 72.6% lower probability of overdiagnosis in screen-detected cases, depending on the 10-year absolute risk thresholds at which individuals were eligible for screening.
      In addition, different approaches to measuring the benefit of screening in nonoverdiagnosed men are possible and the choice of method may affect results. Stage-shift screening models assume that the benefit associated with screening is due to a shift to a less advanced stage at diagnosis resulting in improved survival. Cure models assume that if cancers are detected earlier they can be treated and that curative treatment has the potential to prevent cancer-specific mortality.

      Wever EM, Hugosson J, Heijnsdijk EA, Bangma CH, Draisma G, de Koning HJ. To be screened or not to be screened Modeling the consequences of PSA screening for the individual. Br J Cancer;107(5):778-784.

      Only 1 study, Heijnsdijk et al,
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      explicitly stated that the assumed mechanism of benefit of screening in their model was as a cure proportion, which assumes that a percentage of men are cured owing to screening and therefore avoid a death from prostate cancer. The other studies did not consider overdiagnosis nor give any detail on the mechanism of benefit of screening assumed.

       Cost-Effectiveness Results

      To aid comparison, all reported costs were inflated to the 2020 price year and converted to US dollars, taking purchasing power parities between countries into account. This was done using the web-based tool developed by the Campbell and Cochrane Economics Methods Group and the Evidence for Policy and Practice Information and Coordinating Center. In reality, the costs are not comparable because different countries have different healthcare systems, care pathways, and negotiated prices. Therefore, original costs are also reported.

       Biomarkers

      Of the 11 studies that compared PSA testing with testing with a new biomarker, 6 studies found that introducing the new biomarker saves costs and increases QALYs
      • Govers T.M.
      • Hessels D.
      • Vlaeminck-Guillem V.
      • et al.
      Cost-effectiveness of SelectMDx for prostate cancer in four European countries: a comparative modeling study.
      ,
      • Nichol M.B.
      • Wu J.
      • Huang J.
      • Denham D.
      • Frencher S.K.
      • Jacobsen S.J.
      Cost-effectiveness of Prostate Health Index for prostate cancer detection.
      • Dijkstra S.
      • Govers T.M.
      • Hendriks R.J.
      • et al.
      Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.
      • Govers T.M.
      • Caba L.
      • Resnick M.J.
      Cost-effectiveness of urinary biomarker panel in prostate cancer risk assessment.
      ,
      • Sathianathen N.J.
      • Kuntz K.M.
      • Alarid-Escudero F.
      • et al.
      Incorporating biomarkers into the primary prostate biopsy setting: a cost-effectiveness analysis.
      ,
      • Teoh J.Y.
      • Leung C.H.
      • Wang M.H.
      • et al.
      The cost-effectiveness of Prostate Health Index for prostate cancer detection in Chinese men.
      (Table 4). A total of 3 did not measure QALYs but found that diagnostic costs were reduced,
      • Bouttell J.
      • Teoh J.
      • Chiu P.K.
      • et al.
      Economic evaluation of the introduction of the Prostate Health Index as a rule-out test to avoid unnecessary biopsies in men with prostate specific antigen levels of 4-10 in Hong Kong.
      • Schiffer E.
      • Bick C.
      • Grizelj B.
      • Pietzker S.
      • Schöfer W.
      Urinary proteome analysis for prostate cancer diagnosis: cost-effective application in routine clinical practice in Germany.
      • Kim L.
      • Boxall N.
      • George A.
      • et al.
      Clinical utility and cost modelling of the phi test to triage referrals into image-based diagnostic services for suspected prostate cancer: the PRIM (Phi to RefIne Mri) study.
      and one found that the introduction of a new test increased both costs and QALYs.
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      Of the studies that considered progression through stages or grades of cancer, Heijnsdijk et al
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      found that PSA + PHI testing saves costs compared with PSA testing alone and results in the same QALYs
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      and Karlsson et al
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      estimated an incremental cost-effectiveness ratio (ICER) of €5663 for screening using Stockholm3 when PSA values were above 2 ng/mL compared with PSA alone. The results from all studies were generally driven by a decrease in negative biopsies.
      Table 4Cost-effectiveness results from studies; where >2 interventions were compared, the ICER for the most cost-effective intervention is presented.
      AuthorTests comparedDifference in costs
      Costs are in reported currency with USD 2020 costs in brackets to aid comparison.
      Difference in QALYs
      NA indicates not applicable because the study was not a cost-utility analysis. NR indicates not reported because the study did not report differences between interventions.
      ICERProbability cost-effective
      Bouttell et al
      • Bouttell J.
      • Teoh J.
      • Chiu P.K.
      • et al.
      Economic evaluation of the introduction of the Prostate Health Index as a rule-out test to avoid unnecessary biopsies in men with prostate specific antigen levels of 4-10 in Hong Kong.
      PHI vs PSA−HK$5500 (−$943)NANANR
      Heijnsdijk et al
      • Heijnsdijk E.A.M.
      • Denham D.
      • de Koning H.J.
      The cost-effectiveness of prostate cancer detection with the use of Prostate Health Index.
      PHI vs PSA-€33 (-$47)0NANR
      Nichol et al
      • Nichol M.B.
      • Wu J.
      • Huang J.
      • Denham D.
      • Frencher S.K.
      • Jacobsen S.J.
      Cost-effectiveness of Prostate Health Index for prostate cancer detection.
      PHI vs PSA−$201 to −$1199 (−$243 to −$1447)0.01-0.08Dominates77%-70% or 78%-71% % at a range of $0-$200 000 WTP using PSA thresholds ≥2 ng/mL and ≥4 ng/mL, respectively
      Govers et al
      • Govers T.M.
      • Caba L.
      • Resnick M.J.
      Cost-effectiveness of urinary biomarker panel in prostate cancer risk assessment.
      SelectMDx vs PSA−$1694 (−$1854)0.045DominatesNR
      Dijkstra et al
      • Dijkstra S.
      • Govers T.M.
      • Hendriks R.J.
      • et al.
      Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.
      SelectMDx vs PSA−€128 (−$170)0.025DominatesNR
      Schiffer et al
      • Schiffer E.
      • Bick C.
      • Grizelj B.
      • Pietzker S.
      • Schöfer W.
      Urinary proteome analysis for prostate cancer diagnosis: cost-effective application in routine clinical practice in Germany.
      UPA-PC vs PSA−€297 (−$440)NANANR
      Kim et al
      • Kim L.
      • Boxall N.
      • George A.
      • et al.
      Clinical utility and cost modelling of the phi test to triage referrals into image-based diagnostic services for suspected prostate cancer: the PRIM (Phi to RefIne Mri) study.
      MRI + biopsy only if PHI ≥ 30 vs MRI + biopsy for all−£191 (−$280)NANRNR
      Teoh et al
      • Teoh J.Y.
      • Leung C.H.
      • Wang M.H.
      • et al.
      The cost-effectiveness of Prostate Health Index for prostate cancer detection in Chinese men.
      PHI vs PSA$4562 (−$4657)0.35DominatesNR
      Karlsson et al
      • Karlsson A.A.
      • Hao S.
      • Jauhiainen A.
      • et al.
      The cost-effectiveness of prostate cancer screening using the Stockholm3 test.
      Stockholm3 if PSA > 2 ng/mL vs PSA€14 ($18)1€5663 ($7082)97% at WTP €50 000
      Govers et al
      • Govers T.M.
      • Hessels D.
      • Vlaeminck-Guillem V.
      • et al.
      Cost-effectiveness of SelectMDx for prostate cancer in four European countries: a comparative modeling study.
      SelectMDx vs PSAFrance: −€1217 (−$1620)

      Germany: −€439 (−$605)

      Italy: −€757 (−$1089)

      Spain: −€247 (−$405)
      France 0.036

      Germany 0.026

      Italy 0.043

      Spain 0.028
      DominatesNR
      Venderink et al
      • Venderink W.
      • Govers T.M.
      • de Rooij M.
      • Fütterer J.J.
      • Sedelaar J.P.M.
      Cost-effectiveness comparison of imaging-guided prostate biopsy techniques: systematic transrectal ultrasound, direct in-bore MRI, and image fusion.
      MRI TRUS fusion biopsy vs TRUS-guided biopsy€175 ($236)0.1263€1386 ($1869)NR
      Cerantola et al
      • Cerantola Y.
      • Dragomir A.
      • Tanguay S.
      • Bladou F.
      • Aprikian A.
      • Kassouf W.
      Cost-effectiveness of multiparametric magnetic resonance imaging and targeted biopsy in diagnosing prostate cancer.
      MRI cognitive-targeted biopsy vs TRUS-guided biopsy−CAD$2187 (−$1960)0.168DominatesNR
      de Rooij et al
      • de Rooij M.
      • Crienen S.
      • Witjes J.A.
      • Barentsz J.O.
      • Rovers M.M.
      • Grutters J.P.
      Cost-effectiveness of magnetic resonance (MR) imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer: a modelling study from a health care perspective.
      MRI-targeted biopsy vs TRUS-guided biopsy€31 ($42)0.10€323 ($442)80% at WTP higher than €2000
      Faria et al
      • Faria R.
      • Soares M.O.
      • Spackman E.
      • et al.
      Optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate MR imaging study (PROMIS).
      mpMRI guided biopsy vs TRUS-guided biopsyNRNR£7076 ($10 519)NR
      Pahwa et al
      • Pahwa S.
      • Schiltz N.K.
      • Ponsky L.E.
      • Lu Z.
      • Griswold M.A.
      • Gulani V.
      Cost-effectiveness of MR imaging-guided strategies for detection of prostate cancer in biopsy-naive men.
      MRI cognitive-targeted biopsy vs TRUS-guided biopsy−$1771 (−$1882)0.198Dominates94.05% at WTP $50 000 and 93.9% at WTP $100 000
      Mowatt et al
      • Mowatt G.
      • Scotland G.
      • Boachie C.
      • et al.
      The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation.
      T2-MRI vs TRUS-guided biopsy£7 ($12)0.00054£12 315 ($21 013)34% at WTP £30 000
      Barnett et al
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Wei J.T.
      • Montie J.E.
      • Denton B.T.
      Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer.
      Combined (standard + targeted fusion) biopsy vs TRUS-guided biopsyNRNR$23 483 ($24 340)NR
      Nicholson et al
      • Nicholson A.
      • Mahon J.
      • Boland A.
      • et al.
      The clinical effectiveness and cost-effectiveness of the PROGENSA (R) prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation.
      clinical assessment + mpMRI vs clinical assessment£113 449 ($180, 497)3.35£33 911 ($53 952)100% at WTP £37 000
      Barnett et al
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Kunju L.P.
      • Denton B.T.
      • Piert M.
      18F-choline PET/mpMRI for detection of clinically significant prostate cancer: part 2. Cost-effectiveness analysis.
      hybrid 18F-choline

      PET/mpMRI with Likert scoring vs TRUS-guided biopsy
      NRNR$35 108 ($35 841)NR
      Callender et al
      • Callender T.
      • Emberton M.
      • Morris S.
      • Pharoah P.D.P.
      • Pashayan N.
      Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer.
      MRI-first risk-stratified screening at 10-year absolute risk threshold of 7.5% vs no screening£28 ($35)0.0042NRNR
      ICER indicates incremental cost-effectiveness ratio; mpMRI, multiparametric magnetic resonance imaging; MRI, magnetic resonance imaging; NA, not available; NR, not reported; PET, positron emission tomography; PHI, Prostate Health Index; PSA, prostate-specific antigen; QALY, quality-adjusted life-year; TRUS, transrectal ultrasound; UPA-PC, urinary proteome analysis for prostate cancer diagnosis; USD, US dollars; WTP, willingness to pay.
      Costs are in reported currency with USD 2020 costs in brackets to aid comparison.
      NA indicates not applicable because the study was not a cost-utility analysis. NR indicates not reported because the study did not report differences between interventions.

       Biopsy methods

      A total of 7 of the 8 studies that compared MRI-guided biopsy strategies to each other and to TRUS-guided biopsy found at least 1 MRI-guided strategy to be cost-effective (increased costs but also increased QALYs). The exception was Cerantola et al
      • Cerantola Y.
      • Dragomir A.
      • Tanguay S.
      • Bladou F.
      • Aprikian A.
      • Kassouf W.
      Cost-effectiveness of multiparametric magnetic resonance imaging and targeted biopsy in diagnosing prostate cancer.
      who found that MRI-guided biopsy dominated TRUS-guided biopsy (reduced costs and increased QALYs). ICERs for MRI-guided biopsy methods compared with standard methods ranged from €323 per QALY in a study conducted from a The Netherlands perspective
      • de Rooij M.
      • Crienen S.
      • Witjes J.A.
      • Barentsz J.O.
      • Rovers M.M.
      • Grutters J.P.
      Cost-effectiveness of magnetic resonance (MR) imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer: a modelling study from a health care perspective.
      to $35 108 per QALY in a US study,
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Kunju L.P.
      • Denton B.T.
      • Piert M.
      18F-choline PET/mpMRI for detection of clinically significant prostate cancer: part 2. Cost-effectiveness analysis.
      ,
      • Barnett C.L.
      • Davenport M.S.
      • Montgomery J.S.
      • Wei J.T.
      • Montie J.E.
      • Denton B.T.
      Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer.
      both indicating cost-effectiveness according to the generally accepted cost-effectiveness thresholds in the respective countries.,
      • Muurinen J.M.
      Demand for health: a generalised Grossman model.
      The increased QALYs and reduced costs were generally owing to an avoidance of the adverse effects and resource use associated with overdiagnosis.

       Follow-up strategies

      A total of 2 of the studies comparing follow-up strategies in men with a previous negative biopsy did not identify a clear indication of cost-effectiveness for any strategy. The NICE guideline
      NICE Guideline Updates Team (UK)
      Prostate cancer: diagnosis and management. National Institute for Health and Care Excellence.
      concluded that PSA velocity, density, and % free PSA may be the best indicators to trigger further diagnostics in higher risk populations, however the “no screening” strategy seemed optimal for the lowest-risk subpopulation who had MRI Likert scores of 1 or 2 (very unlikely/unlikely that the patient has prostate cancer that needs to be treated) and 2 previous negative biopsies. Nicholson et al
      • Nicholson A.
      • Mahon J.
      • Boland A.
      • et al.
      The clinical effectiveness and cost-effectiveness of the PROGENSA (R) prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation.
      found no strategy to be cost-effective. Mowatt et al
      • Mowatt G.
      • Scotland G.
      • Boachie C.
      • et al.
      The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation.
      found the base-case ICER for T2-MRI to be below the UK willingness to pay threshold (£30 000 per QALY) for all cohorts modeled.

       Assessing uncertainty in cost-effectiveness results

      A total of 5 studies found that the results were sensitive to the potential of the tests to identify cancer, particularly clinically significant cancer.
      • Dijkstra S.
      • Govers T.M.
      • Hendriks R.J.
      • et al.
      Cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics - a decision analytical model.
      ,
      • Govers T.M.
      • Caba L.
      • Resnick M.J.
      Cost-effectiveness of urinary biomarker panel in prostate cancer risk assessment.
      ,
      • Faria R.
      • Soares M.O.
      • Spackman E.
      • et al.
      Optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate MR imaging study (PROMIS).