Early Detection of Prostate Cancer in 2020 and Beyond: Facts and Recommendations for the European Union and the European Commission.

The urological community has the obligation to grasp every means to reduce mortality from urological cancers. Prostate cancer is the most frequent male cancer and is the second most lethal cancer in men in an increasing number of countries. The disease has a particularly long palliative period with a huge impact on quality of life and healthcare costs. The simple PSA blood test has enormous potential as it reflects prostate gland activity. It may be used to detect prostate cancer in an early stage when it can still be cured. Although it leads to a higher diagnosis rate, it has been shown to significantly reduce cancer mortality and metastasis rates. PSA for early detection of prostate cancer is currently poorly used, both on an individual level, as well as early detection or screening for prostate cancer. To have most men worldwide benefit from the advantages of early detection of prostate cancer and to minimize the side effects, we need to act now to improve early detection protocols with new developments. The data from randomized trials should be updated with findings from studies analyzing a sub-step of the screening model.

The European Randomized Study of Screening for Prostate Cancer (ERSPC) showed that repeated screening using PSA significantly reduces prostate cancer-specific mortality after 10-15 years by around 20% on a population level when compared to standard of care. When corrected for contamination (PSA check in men allocated to the study control arm) and non-participants (men not accepting the screening invitation) the reduction on an individual level may increase to up to 50%. Using earlier, but still, highly relevant endpoints such as metastasis rates, even higher rates of reduction may be achieved. Other large screening trials were hampered by high contamination rates (such as PLCO) or had low acceptance rates combined with one-time screening only (such as the CAP trial). When used properly, PSA screening dramatically reduces the burden of prostate cancer for patients and healthcare systems.

The ERSPC was started in the early nineties of the previous century, shortly after PSA became available. To put the time period into perspective, this is even long before large-scale internet was available. It used a screening protocol that was state-of-the-art at that time but now deemed outdated. For every man, the same screening interval was used, and a singular fixed PSA threshold was applied to stratify between normal and abnormal. After biopsy indication, a systematic lateralized sextant biopsy protocol was applied, and after diagnosis of localized prostate cancer, most men received active therapy, risking side effects of the therapies available at that time. The first results of the ERSPC were published in 2009, more than 15 years after study initiation when participants had a median follow-up of around 9 years. It showed a relative reduction in prostate cancer mortality of 20%. In the absence of level 1 evidence on a more modern screening strategy, the results of the historical screening protocol as used in ERSPC are still used as the basis for scientific considerations on screening.

The balance in benefits and side effects of early detection for the individual man and screening on a population level has been one of the most extensively debated issues in urology. Recommendations on screening differ per country and have also changed over the years. This ambiguity towards screening has resulted in uncertainty among both men at risk for prostate cancer and health care professionals. In this no-man’s-land, an unwanted situation has been created, in which factors such as socioeconomic status and coincidental attitude towards screening of the general practitioner decide whether PSA is offered, rather than medical considerations. Besides the fact that this denies men the advantages of PSA, it also leads to PSA checks and potential side effects in men who have a small chance of benefitting from PSA (for example >75 years). The look-away attitude towards PSA may cause more harm than good.

The methods and tools available for screening have changed dramatically in the past 30 years and are now hard to compare to the classic screening algorithms. Risk-groups for developing significant prostate cancer have now been defined more sharply and not only based on age but also family history or genetics. Follow-up intervals for repeat screening can now be individualized based on the first measurement and can be varied between 1 and 8 years. The indication for biopsy has been totally overthrown, now using risk calculators and MRI to decide on biopsies instead of a singular PSA value only. The biopsy strategy itself has been perfected, now using more systematic cores, a volume-dependent number of systematic cores, and of course MRI lesion-targeted biopsies. Finally, the link between diagnosis and treatment has been broken by using active surveillance in many low-risk cases avoiding or postponing radical therapy, and in men in whom radical therapy is elected, more modern surgical and radiation options are available. These improvements lead to less unnecessary repeat PSA, less unnecessary biopsy procedures and its side effects, less insignificant cancers detected, improved risk stratification, less unnecessary treatments, and milder side effects. Never has a screening trial been completed incorporating all these modern tools and approaches. Although MRI-based screening trials are underway, it will take many years before they have matured enough to compare to ERSPC. However, all these developments point to the same direction; the detection of clinically significant disease (a strong intermediate indicator for metastatic disease and disease-specific mortality) are preserved or even slightly improved, while the number of unnecessary screening tests, biopsies, and treatments are strongly reduced. So, an important reduction will be achieved in the disadvantages of different steps of the screening process, while the advantages regarding mortality and metastasis reduction are minimally preserved.

Screening protocols will always keep changing. It is not possible to await randomized evidence for every alteration in the protocol. The value of screening has already been proven, even when using an outdated protocol. Numerous dramatic improvements have now become available to improve our strategy and minimize the burden of screening. Our article attempts to provide a realistic modern protocol for early detection of prostate cancer, implementing the most important improvements; an individualized screening interval, risk stratification before biopsy, and active surveillance. Although further refinement may be required in the future (for example by using targeted biopsies only), and protocols may need to be adapted per region (mainly regarding availability of MRI), we believe this protocol provides a good basis for individuals considering PSA testing and policymakers deciding on the implementation of population-based screening. The potential of PSA is enormous. Screening using PSA works. Side effects of screening have been minimized. We are obliged to every man to exploit and harness the power of PSA.

Written by: Roderick van den Bergh, Antonius Hospital, Utrecht, The Netherlands, Monique Roobol, Erasmus MC, Rotterdam, The Netherlands, and Hein van Poppel, EAU Policy Office Chairman, KU Leuven, Belgium

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