The use of PSA, biomarkers, risk calculators and mpMRI in the early detection of prostate cancer.

Henk Benjamin Luiting, Monique J Roobol


Prostate cancer (PCa) is the most common cause of cancer in men in the developed world and the fifth leading cause of cancer death among men. In 1991 the use of prostate-specific antigen (PSA) level in serum was described to detect prostate cancer at an early stage, where curative treatment is still possible. To answer the question whether PSA-based screening could reduce PCa-specific mortality, two large randomized controlled trials were set up in 1993 namely; the Prostate, Lung, Colorectal and Ovary (PLCO) Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC). After years of research followed by years of debate, the general consensus is that PSA-based screening can reduce PCa-specific mortality. Unfortunately, purely PSA-based screening results in harms like unnecessary biopsies, overdiagnosis of low-risk prostate cancer and subsequent overtreatment. In a purely PSA-based screening protocol, harms tend to outweigh the benefits. Therefore, further refinement of the screening algorithm is indicated. Risk calculators, contemporary biomarkers and imaging techniques like mpMRI can be used to  reduce the harms of PSA-based screening by improving the specificity of the PSA tests. In current practice, PSA tests, in general, are used on patient request. This so called opportunistic screening is mostly applied in elderly men who benefit least from PCa screening. Hence, further development and implementation of risk calculators, contemporary biomarkers and mpMRI is needed and will undoubtedly lead to a more favorable harm-benefit trade-off for prostate cancer screening. Pilot studies for the implementation of organized PCa screening programs should be started to determine the harm-benefit trade-off of these new modalities and to determine cost-effectiveness. A well-organized contemporary screening program is preferred above the current ineffective opportunistic screening practices.


Prostate cancer, urology, screening, PSA

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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Sep.

Siegel RL, Jemal A, Wender RC, Gansler T, Ma J, Brawley OW. An assessment of progress in cancer control. CA Cancer J Clin. 2018 Jul.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018 Jan;68(1):7-30.

Neppl-Huber C, Zappa M, Coebergh JW, Rapiti E, Rachtan J, Holleczek B, et al. Changes in incidence, survival and mortality of prostate cancer in Europe and the United States in the PSA era: additional diagnoses and avoided deaths. Ann Oncol. 2012 May;23(5):1325-34.

Kontis V, Bennett JE, Mathers CD, Li G, Foreman K, Ezzati M. Future life expectancy in 35 industrialised countries: projections with a Bayesian model ensemble. Lancet. 2017 04;389(10076):1323-35.

Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med. 1991 Apr;324(17):1156-61.

Gupta N, Sudhakar DVS, Gangwar PK, Sankhwar SN, Gupta NJ, Chakraborty B, et al. Mutations in the prostate specific antigen (PSA/KLK3) correlate with male infertility. Sci Rep. 2017 Sep;7(1):11225.

Tomao L, Sbardella D, Gioia M, Di Masi A, Marini S, Ascenzi P, et al. Characterization of the prostate-specific antigen (PSA) catalytic mechanism: a pre-steady-state and steady-state study. PLoS One. 2014;9(7):e102470.

Lee C, Keefer M, Zhao ZW, Kroes R, Berg L, Liu XX, et al. Demonstration of the role of prostate-specific antigen in semen liquefaction by two-dimensional electrophoresis. J Androl. 1989 1989 Nov-Dec;10(6):432-8.

Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). National Cancer Institute, Division of Cancer Prevention. Available online: (accessed: June 20, 2018).

ERSPC Background. Available online: (accessed: june 20, 2018).

Andriole GL, Crawford ED, Grubb RL, Buys SS, Chia D, Church TR, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009 Mar;360(13):1310-9.

Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009 Mar;360(13):1320-8.

Bokhorst LP, Zappa M, Carlsson SV, Kwiatkowski M, Denis L, Paez A, et al. Correlation between stage shift and differences in mortality in the European Randomised study of Screening for Prostate Cancer (ERSPC). BJU Int. 2016 11;118(5):677-80.

Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Zappa M, Nelen V, 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. Lancet. 2014 Dec;384(9959):2027-35.

Ciatto S, Zappa M, Villers A, Paez A, Otto SJ, Auvinen A. Contamination by opportunistic screening in the European Randomized Study of Prostate Cancer Screening. BJU Int. 2003 Dec;92 Suppl 2:97-100.

Andriole GL, Crawford ED, Grubb RL, Buys SS, Chia D, Church TR, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst. 2012 Jan;104(2):125-32.

Pinsky PF, Blacka A, Kramer BS, Miller A, Prorok PC, Berg C. Assessing contamination and compliance in the prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Clin Trials. 2010 Aug;7(4):303-11.

Gulati R, Tsodikov A, Wever EM, Mariotto AB, Heijnsdijk EA, Katcher J, et al. The impact of PLCO control arm contamination on perceived PSA screening efficacy. Cancer Causes Control. 2012 Jun;23(6):827-35.

Schröder FH, Roobol MJ. ERSPC and PLCO prostate cancer screening studies: what are the differences? Eur Urol. 2010 Jul;58(1):46-52.

Otto SJ, van der Cruijsen IW, Liem MK, Korfage IJ, Lous JJ, Schröder FH, et al. Effective PSA contamination in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. Int J Cancer. 2003 Jun;105(3):394-9.

de Koning HJ, Liem MK, Baan CA, Boer R, Schröder FH, Alexander FE, et al. Prostate cancer mortality reduction by screening: power and time frame with complete enrollment in the European Randomised Screening for Prostate Cancer (ERSPC) trial. Int J Cancer. 2002 Mar;98(2):268-73.

Tsodikov A, Gulati R, Heijnsdijk EAM, Pinsky PF, Moss SM, Qiu S, et al. Reconciling the Effects of Screening on Prostate Cancer Mortality in the ERSPC and PLCO Trials. Ann Intern Med. 2017 Oct;167(7):449-55.

Roobol MJ, Kerkhof M, Schröder FH, Cuzick J, Sasieni P, Hakama M, et al. Prostate cancer mortality reduction by prostate-specific antigen-based screening adjusted for nonattendance and contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC). Eur Urol. 2009 Oct;56(4):584-91.

Bokhorst LP, Bangma CH, van Leenders GJ, Lous JJ, Moss SM, Schröder FH, et al. Prostate-specific antigen-based prostate cancer screening: reduction of prostate cancer mortality after correction for nonattendance and contamination in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. Eur Urol. 2014 Feb;65(2):329-36.

Hugosson J, Carlsson S, Aus G, Bergdahl S, Khatami A, Lodding P, et al. Mortality results from the Göteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 2010 Aug;11(8):725-32.

Hugosson J, Godtman RA, Carlsson SV, Aus G, Grenabo Bergdahl A, Lodding P, et al. Eighteen-year follow-up of the Göteborg Randomized Population-based Prostate Cancer Screening Trial: effect of sociodemographic variables on participation, prostate cancer incidence and mortality. Scand J Urol. 2018 Feb;52(1):27-37.

Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med. 2012 Mar;366(11):981-90.

Loeb S, Vellekoop A, Ahmed HU, Catto J, Emberton M, Nam R, et al. Systematic review of complications of prostate biopsy. Eur Urol. 2013 Dec;64(6):876-92.

Draisma G, Boer R, Otto SJ, van der Cruijsen IW, Damhuis RA, Schröder FH, et al. Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst. 2003 Jun;95(12):868-78.

Resnick MJ, Koyama T, Fan KH, Albertsen PC, Goodman M, Hamilton AS, et al. Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med. 2013 Jan;368(5):436-45.

Heijnsdijk EA, Wever EM, Auvinen A, Hugosson J, Ciatto S, Nelen V, et al. Quality-of-life effects of prostate-specific antigen screening. N Engl J Med. 2012 Aug;367(7):595-605.

Martin RM, Donovan JL, Turner EL, Metcalfe C, Young GJ, Walsh EI, et al. Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer Mortality: The CAP Randomized Clinical Trial. JAMA. 2018 03;319(9):883-95.

Klotz L, Vesprini D, Sethukavalan P, Jethava V, Zhang L, Jain S, et al. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J Clin Oncol. 2015 Jan;33(3):272-7.

Tosoian JJ, Mamawala M, Epstein JI, Landis P, Wolf S, Trock BJ, et al. Intermediate and Longer-Term Outcomes From a Prospective Active-Surveillance Program for Favorable-Risk Prostate Cancer. J Clin Oncol. 2015 Oct;33(30):3379-85.

Bokhorst LP, Valdagni R, Rannikko A, Kakehi Y, Pickles T, Bangma CH, et al. A Decade of Active Surveillance in the PRIAS Study: An Update and Evaluation of the Criteria Used to Recommend a Switch to Active Treatment. Eur Urol. 2016 12;70(6):954-60.

Drost FH, Rannikko A, Valdagni R, Pickles T, Kakehi Y, Remmers S, et al. Can active surveillance really reduce the harms of overdiagnosing prostate cancer? A reflection of real life clinical practice in the PRIAS study. Transl Androl Urol. 2018 Feb;7(1):98-105.

Thompson IM, Ankerst DP, Chi C, Lucia MS, Goodman PJ, Crowley JJ, et al. Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. JAMA. 2005 Jul;294(1):66-70.

Schröder FH, Roobol-Bouts M, Vis AN, van der Kwast T, Kranse R. Prostate-specific antigen-based early detection of prostate cancer--validation of screening without rectal examination. Urology. 2001 Jan;57(1):83-90.

Aus G, Damber JE, Khatami A, Lilja H, Stranne J, Hugosson J. Individualized screening interval for prostate cancer based on prostate-specific antigen level: results of a prospective, randomized, population-based study. Arch Intern Med. 2005 Sep;165(16):1857-61.

Hugosson J. Stopping screening, when and how? Transl Androl Urol. 2018 Feb;7(1):46-53.

Carlsson S, Assel M, Ulmert D, Gerdtsson A, Hugosson J, Vickers A, et al. Screening for Prostate Cancer Starting at Age 50-54 Years. A Population-based Cohort Study. Eur Urol. 2017 01;71(1):46-52.

Roobol MJ. Digital rectal examination can detect early prostate cancer. Evid Based Med. 2015 Jun;20(3):119.

Walsh AL, Considine SW, Thomas AZ, Lynch TH, Manecksha RP. Digital rectal examination in primary care is important for early detection of prostate cancer: a retrospective cohort analysis study. Br J Gen Pract. 2014 Dec;64(629):e783-7.

Roobol MJ, Steyerberg EW, Kranse R, Wolters T, van den Bergh RC, Bangma CH, et al. A risk-based strategy improves prostate-specific antigen-driven detection of prostate cancer. Eur Urol. 2010 Jan;57(1):79-85.

Finne P, Finne R, Bangma C, Hugosson J, Hakama M, Auvinen A, et al. Algorithms based on prostate-specific antigen (PSA), free PSA, digital rectal examination and prostate volume reduce false-positive PSA results in prostate cancer screening. Int J Cancer. 2004 Aug;111(2):310-5.

Chun FK, Steuber T, Erbersdobler A, Currlin E, Walz J, Schlomm T, et al. Development and internal validation of a nomogram predicting the probability of prostate cancer Gleason sum upgrading between biopsy and radical prostatectomy pathology. Eur Urol. 2006 May;49(5):820-6.

Karakiewicz PI, Benayoun S, Kattan MW, Perrotte P, Valiquette L, Scardino PT, et al. Development and validation of a nomogram predicting the outcome of prostate biopsy based on patient age, digital rectal examination and serum prostate specific antigen. J Urol. 2005 Jun;173(6):1930-4.

Ankerst DP, Hoefler J, Bock S, Goodman PJ, Vickers A, Hernandez J, et al. Prostate Cancer Prevention Trial risk calculator 2.0 for the prediction of low- vs high-grade prostate cancer. Urology. 2014 Jun;83(6):1362-7.

Louie KS, Seigneurin A, Cathcart P, Sasieni P. Do prostate cancer risk models improve the predictive accuracy of PSA screening? A meta-analysis. Ann Oncol. 2015 May;26(5):848-64.

Stephan C, Cammann H, Semjonow A, Diamandis EP, Wymenga LF, Lein M, et al. Multicenter evaluation of an artificial neural network to increase the prostate cancer detection rate and reduce unnecessary biopsies. Clin Chem. 2002 Aug;48(8):1279-87.

Nam RK, Toi A, Klotz LH, Trachtenberg J, Jewett MA, Appu S, et al. Assessing individual risk for prostate cancer. J Clin Oncol. 2007 Aug;25(24):3582-8.

Pereira-Azevedo N, Verbeek JFM, Nieboer D, Bangma CH, Roobol MJ. Head-to-head comparison of prostate cancer risk calculators predicting biopsy outcome. Transl Androl Urol. 2018 Feb;7(1):18-26.

Parekh DJ, Punnen S, Sjoberg DD, Asroff SW, Bailen JL, Cochran JS, et al. A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer. Eur Urol. 2015 Sep;68(3):464-70.

de la Calle C, Patil D, Wei JT, Scherr DS, Sokoll L, Chan DW, et al. Multicenter Evaluation of the Prostate Health Index to Detect Aggressive Prostate Cancer in Biopsy Naïve Men. J Urol. 2015 Jul;194(1):65-72.

Nordström T, Vickers A, Assel M, Lilja H, Grönberg H, Eklund M. Comparison Between the Four-kallikrein Panel and Prostate Health Index for Predicting Prostate Cancer. Eur Urol. 2015 Jul;68(1):139-46.

Van Neste L, Hendriks RJ, Dijkstra S, Trooskens G, Cornel EB, Jannink SA, et al. Detection of High-grade Prostate Cancer Using a Urinary Molecular Biomarker-Based Risk Score. Eur Urol. 2016 11;70(5):740-8.

Dani H, Loeb S. The role of prostate cancer biomarkers in undiagnosed men. Curr Opin Urol. 2017 May;27(3):210-6.

Grönberg H, Adolfsson J, Aly M, Nordström T, Wiklund P, Brandberg Y, et al. Prostate cancer screening in men aged 50-69 years (STHLM3): a prospective population-based diagnostic study. Lancet Oncol. 2015 Dec;16(16):1667-76.

Ström P, Nordström T, Aly M, Egevad L, Grönberg H, Eklund M. The Stockholm-3 Model for Prostate Cancer Detection: Algorithm Update, Biomarker Contribution, and Reflex Test Potential. Eur Urol. 2018 Jan.

Eggener S. Prostate Cancer Screening Biomarkers: An Emerging Embarrassment of 'Riches'? Eur Urol. 2016 07;70(1):54-5.

Roobol MJ, Schröder FH, Hugosson J, Jones JS, Kattan MW, Klein EA, et al. Importance of prostate volume in the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculators: results from the prostate biopsy collaborative group. World J Urol. 2012 Apr;30(2):149-55.

Shariat SF, Roehrborn CG. Using biopsy to detect prostate cancer. Rev Urol. 2008;10(4):262-80.

Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch MG, De Santis M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol. 2017 04;71(4):618-29.

Taneja S, Bjurlin M, Carter B. Optimal Techniques of Prostate Biopsy and Specimen Handling. [08-08-2018]; Available from:

Poyet C, Nieboer D, Bhindi B, Kulkarni GS, Wiederkehr C, Wettstein MS, et al. Prostate cancer risk prediction using the novel versions of the European Randomised Study for Screening of Prostate Cancer (ERSPC) and Prostate Cancer Prevention Trial (PCPT) risk calculators: independent validation and comparison in a contemporary European cohort. BJU Int. 2016 Mar;117(3):401-8.

Eichler K, Hempel S, Wilby J, Myers L, Bachmann LM, Kleijnen J. Diagnostic value of systematic biopsy methods in the investigation of prostate cancer: a systematic review. J Urol. 2006 May;175(5):1605-12.

Ahmed HU, El-Shater Bosaily A, Brown LC, Gabe R, Kaplan R, Parmar MK, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017 02;389(10071):815-22.

Verbeek JFM, Roobol MJ, group ERs. What is an acceptable false negative rate in the detection of prostate cancer? Transl Androl Urol. 2018 Feb;7(1):54-60.

Schoots IG, Roobol MJ, Nieboer D, Bangma CH, Steyerberg EW, Hunink MG. Magnetic resonance imaging-targeted biopsy may enhance the diagnostic accuracy of significant prostate cancer detection compared to standard transrectal ultrasound-guided biopsy: a systematic review and meta-analysis. Eur Urol. 2015 Sep;68(3):438-50.

Moldovan PC, Van den Broeck T, Sylvester R, Marconi L, Bellmunt J, van den Bergh RCN, et al. What Is the Negative Predictive Value of Multiparametric Magnetic Resonance Imaging in Excluding Prostate Cancer at Biopsy? A Systematic Review and Meta-analysis from the European Association of Urology Prostate Cancer Guidelines Panel. Eur Urol. 2017 Aug;72(2):250-66.

Alberts AR, Schoots IG, Bokhorst LP, van Leenders GJ, Bangma CH, Roobol MJ. Risk-based Patient Selection for Magnetic Resonance Imaging-targeted Prostate Biopsy after Negative Transrectal Ultrasound-guided Random Biopsy Avoids Unnecessary Magnetic Resonance Imaging Scans. Eur Urol. 2016 06;69(6):1129-34.

Grönberg H, Eklund M, Picker W, Aly M, Jäderling F, Adolfsson J, et al. Prostate Cancer Diagnostics Using a Combination of the Stockholm3 Blood Test and Multiparametric Magnetic Resonance Imaging. Eur Urol. 2018 Jul.

Alberts AR, Roobol MJ, Verbeek JFM, Schoots IG, Chiu PK, Osses DF, et al. Prediction of high-grade prostate cancer following multiparametric magnetic resonance imaging: improving the European Randomized study of Screening for Prostate Cancer Risk Calculators. Eur Urol. 2018. (in press). .

Han S, Woo S, Kim YJ, Suh CH. Impact of. Eur Urol. 2018 Apr.

Lopci E, Saita A, Lazzeri M, Lughezzani G, Colombo P, Buffi NM, et al. Ga-PSMA Positron Emission Tomography/Computerized Tomography for Primary Diagnosis of Prostate Cancer in Men with Contraindications to or Negative Multiparametric Magnetic Resonance Imaging: A Prospective Observational Study. J Urol. 2018 Jul;200(1):95-103.

Kweldam CF, van der Kwast T, van Leenders GJ. On cribriform prostate cancer. Transl Androl Urol. 2018 Feb;7(1):145-54.

Arnsrud Godtman R, Holmberg E, Lilja H, Stranne J, Hugosson J. Opportunistic testing versus organized prostate-specific antigen screening: outcome after 18 years in the Göteborg randomized population-based prostate cancer screening trial. Eur Urol. 2015 Sep;68(3):354-60.

Heijnsdijk EA, de Carvalho TM, Auvinen A, Zappa M, Nelen V, Kwiatkowski M, et al. Cost-effectiveness of prostate cancer screening: a simulation study based on ERSPC data. J Natl Cancer Inst. 2015 Jan;107(1):366.

Heijnsdijk EAM, Bangma CH, Borràs JM, de Carvalho TM, Castells X, Eklund M, et al. Summary statement on screening for prostate cancer in Europe. Int J Cancer. 2018 Feb;142(4):741-6.



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