Widespread, organised prostate cancer screening was introduced in the late 1980s and early 1990s using a blood-based prostate-specific antigen (PSA) test, which is a cheap, simple and effective method of assessing prostate gland activity. The benefits of PSA testing were clearly demonstrated in large randomized controlled trials, such as the European Randomized study of Screening for Prostate Cancer (ERSPC) which showed a 20% reduction in prostate cancer-related deaths after 16 years of follow-up.2 This reduction is likely even greater after correcting for contamination (i.e. PSA testing in the control arm) and non-participation (i.e. men in the screening arm not accepting the PSA test invitation). However, the results of these trials were heavily criticised based on the observed high overdiagnosis (i.e. repeat tests and biopsies in men without prostate cancer) and overtreatment (i.e. treatment with surgery or radiotherapy in men with either a short life expectancy/multiple comorbidities or indolent prostate cancer who would not benefit from active treatment but suffer unnecessary side effects and a detrimental impact on their quality of life). These criticisms led to a reversal in guidance and a halt to widespread organised PSA testing.
It is worth highlighting that the screening protocol used in ERSPC, although standard practice at the time (almost three decades ago), was based on limited knowledge regarding the best use of PSA testing and is therefore outdated. In this protocol, a fixed PSA threshold was applied and all men with an elevated PSA proceeded to biopsy. In the event of a positive diagnosis, all men were offered active treatment such as radical prostatectomy or radiotherapy since ERSPC was conducted prior to the introduction of active surveillance protocols. Indeed, the rate of prostate cancer diagnosis per biopsy recorded in the screening group of ERSPC was 25%, meaning that 75% of men with an elevated PSA received an unnecessary biopsy.2
The overdiagnosis/overtreatment seen in these early trials has fuelled a longstanding debate over the harms and benefits of PSA testing, and a reluctance to revisit the potential benefits of such a simple test, even in the face of three decades of research and a vastly improved understanding of the biology of prostate cancer, facilitating a far more intelligent approach to prostate cancer screening. Firstly, risk groups for developing prostate cancer have now been refined based on age, family history and genetics, enabling us to safely target a narrower population for the application of prostate cancer screening protocols. Secondly, the introduction of risk calculators and multiparametric magnetic resonance imaging (mpMRI) permit the effective identification of men considered as low risk of significant prostate cancer who can be spared further tests and biopsies, as well as the anxiety of a prostate cancer diagnosis. Finally, the introduction of active surveillance for those with a favourable grading has broken the link between diagnosis and treatment in prostate cancer, although this approach is still often underutilised.
Given these advances, the EAU has proposed a risk-adapted strategy for the early detection of prostate cancer which embraces all of these tools to provide an intelligent use of PSA testing that effectively identifies men with significant prostate cancer who require active treatment whilst significantly reducing overdiagnosis and overtreatment of men unlikely to either develop or suffer symptoms of prostate cancer in their lifetimes.3 Using this contemporary protocol, for men with an elevated PSA test result, more than 70% will be identified as low risk using risk calculators and mpMRI, and can therefore safely avoid further tests and biopsies. The remaining 30% of patients considered as intermediate or high risk would then proceed to biopsy, resulting in a prostate cancer diagnosis per biopsy rate of around 80%,4 which is in stark contrast to that reported in ERSPC (25%),2 and clearly demonstrates the dramatic reduction in overdiagnosis (i.e. unnecessary biopsies) that could be achieved using this protocol. Finally, among men with a positive prostate cancer diagnosis, around 25% would be eligible for active surveillance based on a favourable grading, thereby significantly reducing the overtreatment seen using outdated protocols such as ERSPC. These improvements will not only help to reduce late-stage diagnoses and improve prostate cancer-related mortality rates but will also have a significant positive impact on quality of life for all men who have a PSA test by the safe avoidance of further tests in men with no/insignificant prostate cancer and the earlier diagnosis of men with significant prostate cancer which would help to improve the chances of cure.
Unfortunately, there is ongoing reluctance to implement this modern-day protocol and insistence on waiting for results from further large-scale, randomized controlled trials to provide more evidence. However, such trials would take 10-15 years to report results and we cannot and should not wait that long, given the current unfavourable trends in prostate cancer morbidity/mortality. Rather, we should embrace the tools we have at our disposal today to improve the early detection of prostate cancer using the EAU’s risk-adapted approach, with results from ongoing trials used to further refine this protocol in the future.
Written by: Hendrik Van Poppel, Department of Urology, KU Leuven, Leuven, Belgium.
References:
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34.
- Hugosson J, Roobol MJ, Månsson M, et al. A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer. Eur Urol. 2019;76(1):43-51.
- Van Poppel H, Roobol MJ, Chapple CR, et al. Prostate-specific Antigen Testing as Part of a Risk-Adapted Early Detection Strategy for Prostate Cancer: European Association of Urology Position and Recommendations for 2021. Eur Urol. 2021.
- Collen S, Van Poppel H. Early detection and diagnosis of prostate cancer in well informed men: the way forward for Europe. Belgian Journal of Medical Oncology. 2020;14.
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