European Urology Today: March 2023 - Congress-edition

What is the best method of risk stratification before biopsy? Algorithm for further risk stratification ready to be tested in pilots across Europe

But this doesn’t mean that the knowledge gained so far is useless and that we should wash our hands of the matter. On the contrary, letting prostate cancer run its course leads to a high disease-specific mortality rate. To illustrate this, in the seventies, before the PSA discovery, two out of three prostate cancer patients died of their disease [4]. More recently, after the recommendation against prostate cancer screening a stage migration to advanced prostate cancer stages was observed in, amongst others, the USA and Germany [5, 6], requiring expensive and invasive treatments with a negative impact on quality of life [7]. To combat what is by now the second leading cause of male cancer death [8], we need to make a start with a risk-based screening strategy for prostate cancer that is the best way to go according to current available knowledge. We can build on the important lessons learned from the past and focus on the favourable short-term outcomes from ongoing state-of-the-art screening trials, as long as we remain aware of the pitfalls and keep validating and updating the implemented tools and strategies. “In the seventies, before the PSA discovery, two out of three prostate cancer patients died of their disease.” Pilot testing by the PRAISE-U consortium Next month, the EAU-led Prostate cancer Awareness and Initiative for Screening in the European Union (PRAISE-U) initiative will start. The main aims of the PRAISE-U consortium are to gain insight into the state-of-play of and need for population-based prostate cancer screening in the 27 EU member states, and to initiate several nationally tailored pilot testing sites throughout Europe. Analyses arising from these pilot studies will focus on aspects like acceptance, logistical capacity, quality control, avoiding unnecessary prostate biopsy, overdiagnosis, and cost effectiveness. Risk-based screening strategy The European Association of Urology (EAU) position paper published a flexible algorithm to conduct a risk-based prostate cancer screening strategy, which is used by the PRAISE-U consortium as a starting point [9, 10]. This strategy aims to leverage the proven benefit of PSA testing while reducing unnecessary diagnostic procedures and combatting overdiagnosis by using new risk stratification tools. Some steps in the algorithm have already been validated, while others are still being investigated.

improves the detection of clinically significant prostate cancer and reduces overdiagnosis (variation 2-5) [15]. However, the availability of high-quality MRI and expert readers can sometimes be limited. Fortunately, attractive alternatives have been developed. The Göteborg trial compared multiparametric MRI, as today’s golden standard for prostate cancer imaging, with the less expensive bi-parametric MRI [16]. Their promising results regarding cancer detection encourage research in prospective, multicenter and multiobserver settings to work towards large-scale implementation [17, 18]. However, another important lesson that we have learned from this trial is that performing MRI in all men with elevated PSA levels (variation 2) result in many negative MRI outcomes (75-77%). In the light of the present and future financial pressure on the European healthcare system [19], avoiding unnecessary MRIs by pre-risk stratification is an essential step. In 2018, Mannaerts et al. found that with a risk-based patient selection strategy using the RPCRC in a clinical cohort, one-third of MRI scans can be avoided [20]. Such a strategy (variation 3) is currently being applied in a screening cohort by the ProScreen trial using the 4Kscore and the STHLM3-MRI study with favourable (preliminary) results [21, 22]. “The PRAISE-U consortium will assess national needs among the EU member states and coordinate pilot testing sites to gain insight into the feasibility and effectiveness of different risk-based prostate cancer screening strategies.” Since, on the one hand, not all significant cancers are visible on MRI, and on the other, the detection rate of significant cancer is relatively low in equivocal lesions (PIRADS 3), risk-stratification after MRI is also preferred. Several MRI informed risk calculators have been developed (Table 1) and compared, of which one appears to be clinical useful according to decision curve analysis [23, 24]. Application of the model in a clinical cohort could reduce 28% of biopsy procedures at the cost of missing only 2.6% of clinically significant cancers. The Organised PCa Testing (OPT) project in Sweden is currently investigating such an approach in a screening setting, with PSA-density as a stratification tool (variation 4) [25].

Renée Hogenhout , MD/PhD candidate Dept. of Urology, Erasmus MC Cancer Institute, Rotterdam (NL)

Table 1 – Discriminative ability for csPCa detection of several stratification tools

Co-author: Prof. Dr. Monique J. Roobol, Professor Decision Making in Urology.

availability. Although many variations are therefore possible, the essence of a risk-based prostate cancer screening programme is to break the link between elevated PSA and immediate biopsy to reduce unnecessary biopsy procedures and overdiagnosis. Table 1 shows that PSA density alone as a simple biomarker already provides a huge improvement in discriminative ability in significant prostate cancer detection compared to PSA only. Depending on availability, risk stratification can be further extended with risk calculators whether or not they are enhanced with MRI data or advanced (genetic) blood biomarkers further increasing the discriminative ability. Several variations of the algorithm (variation 5) are presented in figure 1. Every variation has its own pros and cons compared to the one-size-fits- all strategy (variation 0). In general, with any strategy, some clinically significant prostate cancers will be missed simply because men are excluded from biopsy based on probabilities. No prediction comes with 100% certainty. On the other hand, overdiagnosis can never be ruled out completely against an acceptable percentage of missed significant cancers. A safety net for those false negatives is, therefore, mandatory (i.e. re-entering the algorithm) and active surveillance should be offered to overdiagnosed men. “The essence of a risk-based prostate cancer screening programme is to break the link between elevated PSA and immediate biopsy to reduce unnecessary biopsy procedures and overdiagnosis.” The simplest pathway is to apply risk stratification with clinical variables, for example by using a risk calculator (variation 1). Most risk calculators are accessible to every clinician (e.g. online, mobile application), easy to use, inexpensive and noninvasive. The general condition is that the risk calculator’s performance must be evaluated within the target population and recalibrated if necessary. Several risk calculators, the so-called traditional RCs (i.e. not MRI-informed), have been developed. Of these, the Rotterdam Prostate Cancer Risk Calculator (RPCRC) and the Prostataclass showed the highest discriminative ability (AUC=0.79) [11]. To illustrate clinical implication, using the RPCRC avoids one-third of the biopsy procedures (cut-off 12.5%) [12]. Other well-known tools with good performance representing variation 1 are the STHLM3 model [13] and the 4Kscore [14], which combine clinical variables with other blood biomarkers. A comment should be made, however, on the price of these last two scores, especially if they were to be applied on a population-based level. "In the light of the present and future financial pressure on the European healthcare system, avoiding unnecessary MRIs by pre-risk stratification is an essential step." Meanwhile, MRI has taken an important role in the diagnostic process of prostate cancer. Performing MRI before biopsy is highly recommended as it

On the 20th of September 2022, after three decades of research, the European Commission added prostate, lung and gastric cancer to the list to be addressed by the cancer screening recommendations, on top of cervical, colorectal and breast cancer. This gives the green light to implement good quality prostate cancer screening programmes throughout Europe. But what is a good quality programme? Rapid technological developments in the detection of prostate cancer, a generally slow-growing disease The strict answer is that we do not know, and in a world of exponentially increasing technological advancements, we will probably never know. Especially with prostate cancer being a slow-growing process, we are constantly overtaken by time. This conundrum makes it difficult, or even nearly impossible, to translate the long-term outcomes of new tools to current practice in time. By the time the long-term outcomes of a certain newly developed tool or screening strategy become available, it might be replaced by the next. A prime example is the traditional PSA-based screening strategy that was used by the European Randomized Study of Screening for Prostate Cancer (ERSPC) [1] and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening trial [2]. Elevated PSA levels were followed by systematic sextant prostate biopsy (a one-size-fits-all strategy). We had to wait for almost two decades before the data of these trials became mature enough to publish the first results. Those results showed us that screening indeed could avoid suffering and dying from prostate cancer, which opened the way for further research. However, sextant biopsy was replaced by laterally-directed biopsy, and later on by MRI-targeted biopsy to improve cancer detection, causing a stage shift and making long-term outcomes from the ERSPC and PLCO not fully translatable to the present time [3]. Also, the reported overdiagnosis resulting from this strategy (~50% [1]) is no longer current with the rise of risk calculators and MRI as a stratification tool.

Conclusion The European Commission has given the green light

to implement good quality prostate cancer screening programmes across Europe. The

The flexible algorithm for further risk stratification can be easily adapted according to local resource

PRAISE-U consortium will assess national needs among the EU member states and coordinate pilot testing sites to gain insight into the feasibility and effectiveness of different risk-based prostate cancer screening strategies. Many stratification tools have been developed and proven their usefulness, however mainly in a clinical setting and in the short term. Validation studies of these tools in a screening setting are ongoing with promising preliminary results. Some pieces of the puzzle have been slotted into place while others are yet to be laid. But at the same time that knowledge gaps are being filled, new ones will always arise due to the rapid technical developments in the detection of prostate cancer which is a generally slow-growing disease. It is a continuous, dynamic process that started three decades ago and will never end. However, an important step is now being taken with the implementation of these pilot testing sites that build on the valuable knowledge gained so far, fulfilling a crucial monitoring role and strive for continuous improvement.

PSA

Risk stratification

One-size-fits-all strategy

MRI

Risk stratification

Biopsy

General pros and cons: • Missing csPCa in all strategies since men are excluded from biopsy  safety net (re-entry algorithm) • Still overdiagnosis in all strategies, but less compared to one-size-fits-all  active surveillance

+ No extra tools required ‒ Unnecessary biopsies ‒ Undersampling (Sbx only) ‒ Overdiagnosis E.g. ERSPC, PLCO

+ No e.g. RC required + Better sampling (Tbx) ‒ Unnecessary MRIs ‒ Unnecessary biopsies in PIRADS 3 E.g. Göteborg, PROBASE

+ Better sampling (Tbx) + No unnecessary biopses in PIRADS 3 ‒ Unnecessary MRIs E.g. OPT, RPCRC-MRI, PSA-density

References can be requested from the corresponding authors.

+ No MRI required ‒ Still unnecessary biopsies ‒ Missing csPCa ‒ Undersampling (Sbx only) E.g. RPCRC, prostataclass, STHLM3, 4Kscore

+ Efficient use of stratification and diagnostic tools + Better sampling (Tbx) ‒ Most stratification tools required

+ No e.g. MRI informed RC required + Better sampling (Tbx) ‒ Unnecessary biopsies in PIRADS 3 E.g. ProScreen, STHLM3-MRI

Sunday 12 March 08:33 - 08:41 Plenary Session: The right management of prostate cancer: Early detection and active surveillance Yellow Area, eURO Auditorium 1

Figure 1 – Variations on the EAU’s risk-adapted early prostate cancer detection strategy (variation 5) aiming to improve the one-size-fits-all strategy (variation 0).

European Urology Today

February/March 2023