Introduction
Prostate cancer (PCa) is the most common non-cutaneous cancer in men worldwide.(1) Prostate-specific antigen (PSA) testing serves as the principal method for the initial detection of PCa; however, its use is still a subject of debate. PSA is an enzyme produced by the prostate epithelial cells. While it is specific to the prostate, it is not specific to cancer. Non-cancerous diseases such as prostatitis or benign prostatic hyperplasia (BPH) can also lead to increased levels of PSA.(2) Concise guidelines for early PCa detection are needed since our elderly population is increasing, in whom PCa-related mortality is the highest.(3) In this review, we summarise the latest local and international guidelines regarding PSA screening and discuss some of the controversies around PSA testing.
Controversy Regarding PSA Screening
The United States Preventive Services Task Force (USPSTF) recommendation of 2008 assigned a grade D (not recommended) for PSA screening in men aged >75 and a grade D for all men regardless of age in their 2012 recommendation.(4) The USPSTF published a draft update in April 2017, which reversed the 2012 guidelines against PCa screening.(4) A grade C (no recommendation for or against) guideline was issued for men 55–69 of age to undergo screening based on an individualised approach.(4) The final guideline was published in May 2018 and continued to stand by a grade D recommendation for men aged 70 and older.(4) These drastic changes in guidelines were a source of mass confusion, and these recommendations are still being challenged.(5)
There is a well-established argument against using PSA for PCa screening. The notion is supported by the fact that an increased level of PSA can be caused by factors other than PCa, such as benign prostatic hyperplasia (BPH), prostatitis, trauma, transurethral manipulation, and sexual intercourse.(6) The specificity and sensitivity of PSA (≥4 ng/mL) to identify PCa are 0.20 and 0.93, respectively.(7) Additionally, overtreatment and overdiagnosis of cases that would have been inconsequential are additional drawbacks of PSA screening.(4) Patient anxiety, pain, haematuria, bleeding per rectum, haematospermia, prostatitis, epididymitis, urinary tract infection, urinary retention, and potential sepsis may result from an unnecessary prostate biopsy.(6) The extent of harm caused by treatment varies depending on the treatment modality; however, the most prevalent side effects often encompass impotence and urine incontinence.(6) The potential occurrence of false-positive outcomes in digital rectal exams (DRE) and PSA testing is linked to heightened anxiety in males, underscoring the psychological consequences of PCa screening.(6)
Data supporting the use of PSA screening for prostate cancer is conflicting, and therefore, shared decision-making is crucial.(8) European Randomized Study of Screening for Prostate Cancer (ERSPC) trials, at the 11-year follow-up, demonstrated that prostate cancer-related mortality was reduced by 25%–31% due to screening with PSA.(6,9) Advocates for PSA screening base their arguments on the results of the ERSPC trial, where the most recent follow-up at 16 years showed an increased benefit as follow-up progressed.(6) Van Poppel et al. re-evaluated the randomised trials arguing against PSA screening and concluded that PSA screening reduces prostate cancer-specific mortality.(3) Conversely, the Prostate, Lung, Colorectal and Ovarian (PLCO) trials identified no difference among screening and non-screening populations, though substantial contamination among groups was demonstrated.(6,9) In fact, on per-protocol analysis of the PLCO study, results were comparable to that of the ERSPC trial.
Current Published/In-Press International Prostate Cancer Screening Guidelines (Table 1.)
Current approaches recognise PSA testing as a powerful stratification tool for obtaining a baseline in healthy men.(3) PSA testing is inexpensive, non-invasive, and has proven effective in reducing prostate cancer-related mortality.(3) Thus, it should not be dismissed and should serve as an essential first step in the assessment of well-informed men about their prostate cancer risk.(3) Correcting the PSA level for patients on 5α-reductase inhibitors (e.g. dutasteride or finasteride) is essential, as it can reduce the PSA by ≥50% after six months of therapy.(2,10) The German Prostate Cancer Early Detection Study Based on a Baseline PSA Value in Young Men (PROBASE) trial found that screening using DRE detected only 0.05% of prostate cancer in patients aged 45, which is almost four times lower than the detection rate of PSA screening in these patients.(11)
Trends are moving towards a risk-stratified approach to effectively identify clinically significant prostate cancer in individuals at risk to reduce PCa-related mortality.(3) Shared decision-making must be prioritised between the patient and clinician before ordering a PSA test during the PCa screening process.(12) Overdiagnosis and overtreatment can be prevented by discontinuation of screening in patients with a significantly low risk of PCa or in those that would not have a survival advantage if treated for localised prostate cancer.(12) There needs to be more consistency between the current guidelines, but we recommend following the local guidelines.
The South African Prostate Cancer Screening Guidelines, 2024
The newly updated local guidelines aim to implement PCa screening for the appropriate patient and indication at a primary level.(13) While a PCa screening programme would be ideal due to the increased rates of advanced PCa in black and coloured populations, unfortunately, there are resource and logistical barriers.(13)
The local guidelines advise screening with PSA in asymptomatic, well-informed men with a >10-year life expectancy, in line with their preferences and personal values.(13) PSA screening also should be initiated in other select patient cohorts (Table 1).
PSA screening recommendations of the current published local and international guidelines (2,12–15,17)
| Guideline | Screening recommendation |
|---|---|
| The South African Prostate Cancer Screening Guidelines, 2024 | |
| The European Association of Urology (EAU), 2024 | PSA screening should take place in the following patients: Screening is discouraged in patients with a life expectancy of less than 15 years. |
| The National Comprehensive Cancer Network (NCCN), 2023 | |
| The American Urological Association (AUA), 2023 | |
| Navigating the National Institute for Health and CareExcellence (NICE) NG12 and Prostate Cancer RiskManagement Programme (PCRMP), 2022 | Asymptomatic men at increased risk should be screened as stipulated in the EAU guidelines from the age of 45. |
| The United States Preventative Services Task Force (USPSTF) Recommendation Statement, 2018 |
It is not recommended to screen for PCa in patients who are likely to refuse treatment, even if a treatable cancer is detected.(13) PCa screening is discouraged in patients with a life expectancy of less than 10 years or patients aged >70 years.(13) PSA screening should be deferred when the following factors are present: acute urinary retention (defer for 6 weeks), recent transurethral resection of the prostate (defer for 6 weeks), bacterial prostatitis (defer for 6–8 weeks), urethral instrumentation (defer for 6 weeks).(13)
The European Association of Urology (EAU) guidelines, 2024
The recently updated 2024 EAU guidelines strongly recommend that patients should not be subjected to PSA testing without proper counselling on the potential harms and benefits.(2) PSA testing should be offered to the following well-informed men who are at increased risk of having PCa: men aged 50 and older, men 45 years and older with a positive family history of PCa, men aged 45 of African descent, and men from 40 years of age who have breast cancer gene 2 (BRCA2) mutations.(2) Early diagnosis of prostate cancer has no benefit in men with a life expectancy of less than 15 years, and therefore, screening should be discouraged.(2) Findings from five randomised controlled trials (RCTs) concluded that screening increases the diagnosis of prostate cancer and detects more localised disease than advanced prostate cancer.(2)
The EAU guidelines have a PSA threshold of 3 ng/mL.(2) If the patient screens negative, the PSA and DRE must be repeated using a risk-adapted strategy based on their baseline PSA.(2) A baseline PSA of <1 ng/mL at 40 years or <2 ng/mL at 60 years indicates a decreased risk of prostate cancer metastasis or death from prostate cancer in the patient's lifetime. Therefore, the interval of retesting can be every two years for those at risk, and for those at low risk, the interval can be up to eight years.(2) Long-term quality of life and survival benefits are clear in extending the PSA re-testing (to eight years) in low-risk groups.(2) A repeat PSA test within a few weeks is recommended in men with a moderately increased PSA (3–10 ng/mL) to confirm the elevated value before continuing diagnostic tests.(2) After recognition of the harms associated with overdiagnosis and overtreatment, there has been a redesign of the early detection pathway, namely using MRI and/or risk calculators as an indication for biopsy, identifying specific groups at risk, active surveillance for the low-risk groups, and individualised re-testing intervals.(2)
The National Comprehensive Cancer Network (NCCN) guidelines, 2023
NCCN guidelines on early PCa detection advise on screening of prostate cancer with PSA testing in patients aged 45–75 with average or high risk.(14) They do not recommend testing of PSA in individuals over the age of 75.(14) Screening in patients over 75 should be limited to individuals with excellent health and few or no comorbid conditions, especially if there is no baseline PSA or an upward trend in PSA levels.(14) The panel agreed on a retesting interval of 8 years in patients who are ≥55 years old with a baseline PSA of <1 ng/mL.(14) It is recommended that patients at increased risk with a baseline PSA ≤3 ng/mL undergo retesting at 1- to 2-year intervals.(14)
The American Urological Association (AUA) guidelines, 2023
The American Urological Association guidelines of 2023 advise using PSA as the baseline screening test in patients for whom screening would be appropriate after engaging in shared decision-making.(12) The PSA should be repeated in men with a newly elevated value before ordering imaging, a secondary biomarker, or performing a biopsy.(12) Screening can start between the ages of 45–50.(12) Patients at increased risk should be offered screening at age 40–45.(12) Patients aged 50–69 should be offered PSA screening every 2–4 years.(12) Validated risk calculators should be used as adjuncts to decide the need for a biopsy.(12) The AUA guidelines emphasise PSA-based screening as part of early detection.(12)
Navigating the National Institute for Health and Care Excellence (NICE) NG12 and Prostate Cancer Risk Management Programme (PCRMP) guidelines, 2022
Prostate Cancer United Kingdom agrees with the EAU guidelines to screen asymptomatic men with a higher risk of prostate cancer.(15) The PCRMP is currently under review and confirms that early prostate cancer is usually asymptomatic and that any asymptomatic men with a PSA of 3 or more will need referral for further diagnostic evaluation.(15) The NICE NG12 guidelines published age-specific thresholds for PSA values, which could cause confusion at the primary level, and around 16% of significant cancers would be missed.(15) This would significantly impact older groups of men >60 years old.(15)
The United States Preventive Services Task Force (USPSTF) Recommendation Statement, 2018
In the years following the 2012 USPSTF recommendation, there was an evident decrease in PSA testing, and the incidence of PCa also decreased.(5) A population-based cohort study analysing data from PCa patients during 2004–2018 suggests an increased rate of metastatic prostate cancer, which followed the USPSTF updates of 2008 and 2012.(16) Following the draft update in 2017, reversing trends regarding PSA screening were seen.(4) The USPSTF recommends that the periodic screening for patients between 55 and 69 years should be individualised, and potential harms and benefits should be discussed before testing the PSA level.(17) USPTF advises against the screening of prostate cancer in patients aged 70 and older.(17) PSA-based screening is helpful in African American men, given the higher rates of aggressive prostate cancer, and might contribute to a mortality benefit when screening starts before the age of 55.(17) An updated recommendation statement is in progress.
The Future of Prostate Cancer Screening
PSA testing will be risk-adapted in the future of prostate cancer screening. This method will efficiently prevent unnecessary investigations in low-risk cases and enable the detection of clinically significant prostate cancer in its early stages.(3) Further risk stratification can be done by reflex testing, utilising different risk calculators or biomarkers, such as the Prostate Health Index (PHI) or 4K score, and evaluating the patient's family history.(3)
Examples of risk calculators include the Prostate Cancer Prevention Trial Risk Calculator 2.0 (PCPTRC), which has been replaced by the new Prostate Biopsy Collaborative Group (PBCG) risk calculator, but its validity in racial minority groups is questionable.(18) The ERSPC risk calculator estimates the probability of prostate cancer on biopsy by incorporating biochemical, clinical, and ultrasonographic features.(19) It has been validated in a South African cohort and missed no clinically significant cancer while preventing 50 unnecessary biopsies.(19) Novel nomograms have been reported, including those using machine learning algorithms.(20)
The introduction of novel prostate biomarkers in the screening setting has been previously reported. The Chun nomogram, which incorporates prostate cancer antigen 3 (PCA3), outperformed other risk calculators (PCPT, PCPT 2.0, and ERSPC) with a c-index of 0.93 (confidence interval 95%) in a South African setting.(21) The PCA3 assay is helpful in the ‘grey zone’ of PSA values between 4 and 10 ng/mL, with a sensitivity of 85.7% and a specificity of 64.7%.(22) The PCA3 assay could play an influential role in a specific subset of our population, which includes men with a high-volume gland (PCA3 performs independent of the prostate volume), men with negative biopsies, men with an altered baseline PSA, and well-informed men who request the test.(22) Although PCA3 has its role in specific subsets of the South African population, it has not proven to outperform the PSA test, especially across the risk spectrum of our population.(22)
The rise of novel biomarkers will assist in deciding which patients should undergo further diagnostic evaluation.(6) Trends towards adding percent free PSA (%fPSA) and PSA density (PSAD) can potentially reduce overdiagnosis by reducing the number of unnecessarily performed biopsies.(23) Percent-free PSA has been approved by the Food and Drug Administration to detect PCa in men aged 50 and older with a baseline PSA between 4 and 10 ng/mL.(6) These markers and PSA kinetics have also been utilised in the machine learning setting.(24) Magnetic resonance imaging (MRI) is a powerful prebiopsy tool in patients whose PSA is within the ‘grey area’ of 4–10 ng/mL to decrease unnecessary biopsies and to detect prostate cancer.(25)
The Stockholm-3 (STHLM-3) test appears promising as a first-line screening test combining serum biomarkers, clinical variables, and a polygenic risk score.(12) However, further research is needed to confirm its validity in more diverse populations.(12) Recent studies evaluating the mRNA expression in prebiopsy urine, isolation-by-SizE-of-Tumor-Cells (ISET®)-circulating tumour cells (CTC) blood test, and immunocytochemistry-PSA-marker confirm these novel biomarkers might replace conventional PSA testing.(6) Artificial neural networking is currently used to identify and validate biomarkers in prostate cancer surveillance.(26)
Conclusion
Although PSA testing is a subject of controversy, it should not impede screening for clinically significant PCa in eligible patients until more advanced biomarkers demonstrate superiority over PSA testing. It is imperative to practice shared decision-making and provide each patient with guidance concerning the advantages and disadvantages of PSA screening. With novel biomarkers, risk calculators, better imaging modalities, and the ever-expanding role of artificial intelligence in medicine, the landscape of PCa screening will continue to evolve. Although the need for adherence to well-established national guidelines in this evolving dilemma is paramount, we should always strive to manage the patient before the PSA!