For many cancer types finding and treating the disease early, before it has spread, can improve treatment and survival outcomes. Early detection and treatment of aggressive prostate cancers which are life-threatening offers a survival benefit for affected men. However, most prostate cancers usually progress slowly or not at all and will not require treatment. Overdiagnosis of slow progressing cancer exposes affected men to unnecessary treatment side effects.
Currently there is no test available to distinguish between aggressive and indolent prostate cancers at early stage. Using PSA testing to assess prostate cancer risk in asymptomatic men is a complex and controversial issue.
The most complicating factors are the limitations and potential harms of using the PSA test as a screening tool and the risk of significant adverse effects associated with treatment. The PSA test is limited as it is not cancer-specific and the mortality benefit isn’t clear. The US Preventive Services Task Force found PSA-based screening programs had no significant effect on prostate cancer mortality among men aged 55 to 69 years in the United States. However, the European Randomized Study of Screening for Prostate Cancer (ERSPC) found a 27% reduction in prostate cancer mortality in men aged 55-69 years who undergo PSA testing. Accepted criteria for systematic use of a population screening tool include evidence that early detection of the disease, with subsequent early treatment, has benefits to health and can lengthen life, and that the benefits of screening and any subsequent treatment outweigh any known or possible harm resulting from screening. As screening using the PSA test does not meet this criteria, Australian and international health authorities do not recommend it as a population screening tool.
Risk assessment tools for prostate cancer
The PSA blood test is commonly used to assess whether an asymptomatic man may have prostate cancer before referring him for more invasive diagnostic procedures such as biopsy. Other tests for prostate cancer include digital rectal examination (DRE) and transrectal ultrasonography of the prostate (TRUS), however these are generally used to complement the PSA test. In 2016, the Australian clinical practice guidelines recommended that asymptomatic men interested in undergoing testing for early diagnosis of prostate cancer should be advised against DRE as a routine addition to PSA testing in the primary care setting.
Prostate-specific antigen test
The PSA test measures the amount of prostate specific antigen, a chemical produced by the prostate gland, in blood. As this test is prostate-specific (i.e. reflects multiple biological effects in the prostate other than cancer), and not cancer-specific, the test has limitations.
High PSA levels may indicate prostate cancer, but may also indicate benign (non-cancerous) conditions such as benign prostatic enlargement, urinary tract infections and prostatitis. Most men who have a positive result from PSA testing do not have prostate cancer. PSA tests should only be used to test asymptomatic men after discussion about the benefits and harms with a health professional. Clinical practice guidelines on PSA Testing and Early Management of Test-Detected Prostate Cancer provides evidence-based recommendations for PSA testing and support for the appropriate use of PSA testing in Australia.
Digital rectal examination
DRE involves manual examination of the prostate gland through the rectum to check any abnormality in size, shape or texture. However, it is not possible to feel the entire prostate meaning some cancers are missed. The use of DRE and PSA testing increases detection rates of prostate cancer, but at a cost of two or more extra false positives per cancer detected. For asymptomatic men interested in undergoing testing for early detection of prostate cancer, DRE is not recommended as a routine addition to PSA testing in the primary care setting.
Multi-parametric magnetic resonance imaging (mMRI)
Multi-parametric magnetic resonance imaging (mpMRI) combines the anatomical images of T1- and T2-weighted imaging with two or more functional sequences. The use of mpMRI has the potential to improve diagnosis and treatment of prostate cancer by providing information on tumour location, volume, grade and stage, reducing the risk of false positive PSA test. However, mpMRI is not recommended to replace the PSA test and should only be conducted by the treating urologist. Further evaluation is required to determine the optimal techniques, indications and interpretation of mpMRI.
Transrectal ultrasonography and biopsy
Transrectal ultrasound (TRUS) biopsy has been used for primary investigation of a positive PSA test, although use has decreased, from 63% in 2015 to 50% in 2017. At the same time, transperineal biopsy use is increasing (24% in 2015 to 38% in 2017). Sepsis and infection are significant complications associated with TRUS biopsy. There is evidence that transperineal biopsy may have a reduced rate of sepsis and infection, although the accuracy at detecting prostate cancers appears similar. Transperineal biopsies can also be targeted after an MRI scan, potentially diagnosing more clinically relevant prostate cancers.
Future prospects for tests
Prostate-specific membrane antigen (PSMA) poistron-emission-tomography (PET)/CT imaging has is increasingly being used in the detection of metastatic disease, particularly among patients with biochemical recurrence after local treatment. There is a prospective, multicentre, cross-sectional study underway to determine the accuracy of PSMA-PET/CT in detecting clinically significant prostate cancer.
Benefits and harms of using the PSA test to detect prostate cancer early
The key potential benefit of screening for prostate cancer would be a lower risk of death from prostate cancer in those who are screened systematically compared to those who are not. The ERSPC reported that the risk of dying from prostate cancer reduced by 27% among men who had undergone PSA testing. The US Preventive Services Task Force concluded that PSA-based screening programs in men aged 55 to 69 years may prevent approximately 1.3 deaths from prostate cancer over approximately 13 years per 1000 men screened. However there is no benefit for men aged over 70 years. The National Health and Medicine Research Council endorsed Clinical Practice Guidelines suggests that prostate cancer-specific mortality may be reduced if asymptomatic men aged 55 to 69 years undergo PSA testing but it is unclear what screening strategy is effective and the degree of reduction in prostate cancer-specific mortality.
Meta-analyses pooling the results of large randomised trials have found no significant reduction in mortality as a result of screening, despite increased detection of early-stage prostate cancers. These analyses have been criticised, however, because of heterogeneity in the quality of the studies pooled.
Preliminary research shows that the limited benefits of the PSA test can be increased significantly if health professionals comply fully with the Australian clinical practice guidelines at all points in the clinical pathway.
PSA testing for prostate cancer can cause harm in a number of ways. The main harms are due to the limitations of the PSA test, subsequent diagnostic investigations and, by extension, overdiagnosis and treatment side effects.
The PSA test is not accurate for detecting prostate cancer: most men with elevated PSA levels do not have cancer (a 'false positive') while cancers that are present may be missed (a 'false negative'). Abnormal or elevated PSA will normally lead to a biopsy. Approximately 66-75% of follow-up biopsies do not detect cancer and indicate that the elevated PSA test result was a false positive. Although a small percentage of biopsies result in serious complications requiring hospitalisation (1%), common complications include pain and discomfort as well as infection, bleeding and urinary difficulties. Consequently, significant numbers of men undergo unnecessary investigations following a false positive test result, subjecting themselves to procedural risks, financial costs and anxiety. Alternatively, a small percent may be falsely reassured that they do not have prostate cancer.
Over-diagnosis is defined as the detection, due to screening (or ineffective use of early detection tests in ad hoc screening), of a tumour that would not otherwise be diagnosed within the patient’s lifetime. As current available tests do not distinguish between aggressive and indolent cancers, overdiagnosis is a major potential harm of screening. Rates of overdiagnosis with prostate cancer testing have been estimated to be up to 50%.
Active surveillance is a method of delayed curative treatment for men with low-risk prostate cancer. Between 2015-2017, 66% of men chose active surveillance or watchful waiting. However, 34% of men with low-risk disease still choose immediate treatment and are therefore exposed to serious adverse effects and reduced quality of life. A recent data synthesis found that following radical prostatectomy one in three men would experience erectile dysfunction and one in six would experience urinary incontinence. One in seven men undergoing radiation therapy would experience long-term erectile dysfunction and more men would experience long-term bothersome bowel symptoms than from conservative management (including active surveillance or watchful waiting).
In addition to the quality-of-life costs of overdiagnosis incurred by individual men, the economic costs to the health system of treating large numbers of indolent cancers detected by PSA testing would be significant.
Quality of life issues
Irrespective of the risk it poses to life expectancy, a diagnosis of prostate cancer at any age can have a major impact on a man’s quality of life. Depression, anxiety, stress, fatigue, pain and psychosocial factors all affect the patient diagnosed with prostate cancer.
Side effects from prostate cancer treatment have also been shown to adversely affect the quality of life of prostate cancer survivors. Significant numbers of men treated for prostate cancer, and their partners, have reported reduced quality of life as a result of common side effects such sexual dysfunction and incontinence.
- Grossman DC, Curry SJ, Owens DK, Bibbins-Domingo K, Caughey AB, Davidson KW, et al. Screening for Prostate Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 2018 May 8;319(18):1901-1913 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29801017.
- 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 6;384(9959):2027-35 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25108889.
- Prostate Cancer Foundation of Australia and Cancer Council Australia PSA Testing Guidelines Expert Advisory Panel. Clinical practice guidelines for PSA testing and early management of test-detected prostate cancer. [homepage on the internet] Sydney: Cancer Council Australia; 2015 [cited 2021]. Available from: http://wiki.cancer.org.au/australiawiki/index.php?oldid=211982.
- American Cancer Society. American Cancer Society Recommendations for Prostate Cancer Early Detection. [homepage on the internet] American Cancer Society; 2016 [cited 2021]. Available from: https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/acs-recommendations.html.
- American Urological Association 2015. Early Detection of Prostate Cancer. AUA Guideline J Urol 2013 [cited 2021];190:419 Available from: https://www.auanet.org/guidelines/guidelines/prostate-cancer-early-detection-guideline.
- Rendon RA, Mason RJ, Marzouk K, Finelli A, Saad F, So A, et al. Recommendations of the Canadian Urological Association on the screening and early diagnosis of prostate cancer. Can Urol Assoc J 2017 Oct;11(10):298-309 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29381452.
- Canadian Task Force on Preventive Health Care. Recommendations on screening for prostate cancer with the prostate-specific antigen test. CMAJ 2014 [cited 2021] Available from: https://www.cmaj.ca/content/cmaj/186/16/1225.full.pdf.
- Heidenreich A, Abrahamsson PA, Artibani W, Catto J, Montorsi F, Van Poppel H, et al. Early detection of prostate cancer: European Association of Urology recommendation. Eur Urol 2013 Sep;64(3):347-54 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23856038.
- Prostate Cancer Foundation of Australia and Cancer Council Australia PSA Testing Guidelines Expert Advisory Panel. Role of digital rectal examination. [homepage on the internet] Sydney: Cancer Council Australia; [cited 2021]. Available from: http://wiki.cancer.org.au/australiawiki/index.php?oldid=122827.
- Croswell JM, Kramer BS, Crawford ED. Screening for prostate cancer with PSA testing: current status and future directions. Oncology (Williston Park) 2011 May;25(6):452-60, 463 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21717898.
- Thompson IM, Tangen CM, Goodman PJ, Lucia MS, Parnes HL, Lippman SM, et al. Finasteride improves the sensitivity of digital rectal examination for prostate cancer detection. J Urol 2007 May;177(5):1749-52 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17437804.
- Pedler K, Kitzing Y, Varol C, Arianayagan M. The current status of MRI in prostate cancer. AFP 2015 [cited 2021];44(4) Available from: https://www.racgp.org.au/afp/2015/april/the-current-status-of-mri-in-%E2%80%A8prostate-cancer/.
- Drost FH, Osses DF, Nieboer D, Steyerberg EW, Bangma CH, Roobol MJ, et al. Prostate MRI, with or without MRI-targeted biopsy, and systematic biopsy for detecting prostate cancer. Cochrane Database Syst Rev 2019 Apr 25;4:CD012663 Available from: http://www.ncbi.nlm.nih.gov/pubmed/31022301.
- O'Callaghan M, Pase M, Frydenberg M, Mark S, Moretti K, Maqsood S, et al. Prostate cancer in Australian and New Zealand Men, Patters of cancer within PCOR-ANZ 2015-2017. Melbourne, VIC: Monash University and Movember; 2020 Mar [cited 2021] Available from: https://prostatecancerregistry-org.s3.amazonaws.com/pcor_cms/media/filer_public/eb/e2/ebe2352f-ff5f-4aeb-88fb-fbf623da0e90/pcor-anz_2019_annual_report.pdf.
- Grummet J, Gorin MA, Popert R, et al. “TREXIT 2020”: Why the time to abandon transrectal prostate biopsy starts now. Prostate Cancer Prostatic Dis 2020 Jan 13 [cited 2020 Feb 3];doi: 10.1038/s41391-020-0204-8 [Epub ahead of print] Available from: https://www.nature.com/articles/s41391-020-0204-8.
- Garcia C, Witner M, Bergensen P, et al. Does transperineal prostate biopsy reduce complications compared with transrectal biopsy? A systematic review and meta-analysis of randomised controlled trials. The Journal of Urology 2016 [cited 2021];195(4, Suppl 1): e328 Available from: https://www.auajournals.org/doi/full/10.1016/j.juro.2016.02.2879.
- Perera M, Papa N, Roberts M, Williams M, Udovicich C, Vela I, et al. Gallium-68 Prostate-specific Membrane Antigen Positron Emission Tomography in Advanced Prostate Cancer-Updated Diagnostic Utility, Sensitivity, Specificity, and Distribution of Prostate-specific Membrane Antigen-avid Lesions: A Systematic Review and Meta-analysis. Eur Urol 2020 Apr;77(4):403-417 Available from: http://www.ncbi.nlm.nih.gov/pubmed/30773328.
- Rauscher I, Düwel C, Haller B, Rischpler C, Heck MM, Gschwend JE, et al. Efficacy, Predictive Factors, and Prediction Nomograms for 68Ga-labeled Prostate-specific Membrane Antigen-ligand Positron-emission Tomography/Computed Tomography in Early Biochemical Recurrent Prostate Cancer After Radical Prostatectomy. Eur Urol 2018 May;73(5):656-661 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29358059.
- van Leeuwen PJ, Emmett L, Ho B, Delprado W, Ting F, Nguyen Q, et al. Prospective evaluation of 68Gallium-prostate-specific membrane antigen positron emission tomography/computed tomography for preoperative lymph node staging in prostate cancer. BJU Int 2017 Feb;119(2):209-215 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27207581.
- Fendler WP, Calais J, Eiber M, Flavell RR, Mishoe A, Feng FY, et al. Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial. JAMA Oncol 2019 Jun 1;5(6):856-863 Available from: http://www.ncbi.nlm.nih.gov/pubmed/30920593.
- Emmett L, Metser U, Bauman G, Hicks RJ, Weickhardt A, Davis ID, et al. Prospective, Multisite, International Comparison of 18F-Fluoromethylcholine PET/CT, Multiparametric MRI, and 68Ga-HBED-CC PSMA-11 PET/CT in Men with High-Risk Features and Biochemical Failure After Radical Prostatectomy: Clinical Performance and Patient Outcomes. J Nucl Med 2019 Jun;60(6):794-800 Available from: http://www.ncbi.nlm.nih.gov/pubmed/30442757.
- van Leeuwen PJ, Stricker P, Hruby G, Kneebone A, Ting F, Thompson B, et al. (68) Ga-PSMA has a high detection rate of prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage radiation treatment. BJU Int 2016 May;117(5):732-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26683282.
- Roach PJ, Francis R, Emmett L, Hsiao E, Kneebone A, Hruby G, et al. The Impact of 68Ga-PSMA PET/CT on Management Intent in Prostate Cancer: Results of an Australian Prospective Multicenter Study. J Nucl Med 2018 Jan;59(1):82-88 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28646014.
- Emmett L, van Leeuwen PJ, Nandurkar R, Scheltema MJ, Cusick T, Hruby G, et al. Treatment Outcomes from 68Ga-PSMA PET/CT-Informed Salvage Radiation Treatment in Men with Rising PSA After Radical Prostatectomy: Prognostic Value of a Negative PSMA PET. J Nucl Med 2017 Dec;58(12):1972-1976 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28747524.
- Morigi JJ, Stricker PD, van Leeuwen PJ, Tang R, Ho B, Nguyen Q, et al. Prospective Comparison of 18F-Fluoromethylcholine Versus 68Ga-PSMA PET/CT in Prostate Cancer Patients Who Have Rising PSA After Curative Treatment and Are Being Considered for Targeted Therapy. J Nucl Med 2015 Aug;56(8):1185-90 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26112024.
- Amin A, Blazevski A, Thompson J, Scheltema MJ, Hofman MS, Murphy D, et al. Protocol for the PRIMARY clinical trial, a prospective, multicentre, cross-sectional study of the additive diagnostic value of gallium-68 prostate-specific membrane antigen positron-emission tomography/computed tomography to multiparametric magnetic resonance imaging in the diagnostic setting for men being investigated for prostate cancer. BJU Int 2020 Apr;125(4):515-524 Available from: http://www.ncbi.nlm.nih.gov/pubmed/31957122.
- Chou R, Croswell JM, Dana T, Bougatsos C, Blazina I, Fu R, et al. Screening for prostate cancer: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2011 Dec 6;155(11):762-71 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21984740.
- Djulbegovic M, Beyth RJ, Neuberger MM, Stoffs TL, Vieweg J, Djulbegovic B, et al. Screening for prostate cancer: systematic review and meta-analysis of randomised controlled trials. BMJ 2010 Sep 14;341:c4543 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20843937.
- Ilic D, Neuberger MM, Djulbegovic M, Dahm P. Screening for prostate cancer. Cochrane Database Syst Rev 2013 Jan 31;(1):CD004720 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23440794.
- Roobol MJ, Carlsson S, Hugosson J. Meta-analysis finds screening for prostate cancer with PSA does not reduce prostate cancer-related or all-cause mortality but results likely due to heterogeneity - the two highest quality studies identified do find prostate cancer-related mortality reductions. Evid Based Med 2011 Feb;16(1):20-1 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21228057.
- National Health and Medical Research Council. PSA Testing for Prostate Cancer in Asymptomatic Men: Evidence Evaluation Report. Canberra: National Health and Medical Research Council; 2013 [cited 2021] Available from: https://www.nhmrc.gov.au/sites/default/files/documents/reports/clinical%20guidelines/men4d-psa-testing-asymptomatic.pdf.
- Fenton JJ, Weyrich MS, Durbin S, Liu Y, Bang H, Melnikow J. Prostate-Specific Antigen-Based Screening for Prostate Cancer: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2018 May 8;319(18):1914-1931 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29801018.
- Loeb S, Bjurlin MA, Nicholson J, Tammela TL, Penson DF, Carter HB, et al. Overdiagnosis and overtreatment of prostate cancer. Eur Urol 2014 Jun;65(6):1046-55 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24439788.
- Sanda MG, Dunn RL, Michalski J, Sandler HM, Northouse L, Hembroff L, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008 Mar 20;358(12):1250-61 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18354103.
- Clark JA, Inui TS, Silliman RA, Bokhour BG, Krasnow SH, Robinson RA, et al. Patients' perceptions of quality of life after treatment for early prostate cancer. J Clin Oncol 2003 Oct 15;21(20):3777-84 Available from: http://www.ncbi.nlm.nih.gov/pubmed/14551296.