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Background: Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer. Methods: Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium. Results: In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I. Conclusions: These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease.

Using prostate-specific antigen (PSA) for prostate cancer (PCa) screening led to overinvestigation and overdiagnosis of indolent PCa. We aimed to investigate the value of prostate health index (PHI) and magnetic resonance imaging (MRI) prostate in an Asian PCa screening program. Men aged 50-75 years were prospectively recruited from a community-based PSA screening program. Men with PSA 4.0-10.0 ng ml -1 had PHI result analyzed. MRI prostate was offered to men with PSA 4.0-50.0 ng ml -1. A systematic prostate biopsy was offered to men with PSA 4.0-9.9 ng ml -1 and PHI ≥35, or PSA 10.0-50.0 ng ml -1. Additional targeted prostate biopsy was offered if they had PI-RADS score ≥3. Clinically significant PCa (csPCa) was defined as the International Society of Urological Pathology (ISUP) grade group (GG) ≥2 or ISUP GG 1 with involvement of ≥30% of total systematic cores. In total, 12.8% (196/1536) men had PSA ≥4.0 ng ml -1. Among 194 men with PSA 4.0-50.0 ng ml -1, 187 (96.4%) received MRI prostate. Among them, 28.3% (53/187) had PI-RADS ≥3 lesions. Moreover, 7.0% (107/1536) men were indicated for biopsy and 94.4% (101/107) men received biopsy. Among the men received biopsy, PCa, ISUP GG ≥2 PCa, and csPCa was diagnosed in 42 (41.6%), 24 (23.8%), and 34 (33.7%) men, respectively. Compared with PSA/PHI pathway in men with PSA 4.0-50.0 ng ml -1, additional MRI increased diagnoses of PCa, ISUP GG ≥2 PCa, and csPCa by 21.2% (from 33 to 40), 22.2% (from 18 to 22), and 18.5% (from 27 to 32), respectively. The benefit of additional MRI was only observed in PSA 4.0-10.0 ng ml -1, and the number of MRI needed to diagnose one additional ISUP GG ≥2 PCa was 20 in PHI ≥35 and 94 in PHI <35. Among them, 45.4% (89/196) men with PSA ≥4.0 ng ml -1 avoided unnecessary biopsy with the use of PHI and MRI. A screening algorithm with PSA, PHI, and MRI could effectively diagnose csPCa while reducing unnecessary biopsies. The benefit of MRI prostate was mainly observed in PSA 4.0-9.9 ng ml -1

Over the last three decades, the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US-based Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening have steered the conversation around the early detection of prostate cancer. These two randomized trials assessed the effect of screening on prostate cancer disease-specific mortality. Elevated PSA levels were followed by a systematic sextant prostate biopsy. Standard repeat testing intervals were applied. After controversies from 2009 to 2016 due to contradicting results of the two trials, the results aligned in 2016 and showed that early PSA detection reduces prostate cancer-specific mortality. However, overdiagnosis rates of up to 50% were reported, and this sparked an intense debate on harms and benefits for almost 20 years. The balance between harms and benefits is highly debated and has initiated further research to investigate new ways of early detection. In the meantime, the knowledge and tools for the diagnostic algorithm improved. This is a continuously ongoing effort which focuses on individual risk-based screening algorithms that preserve the benefits of the purely PSA-based screening algorithms, while reducing the side effects. An important push towards investigating new techniques for early detection came from the European Commission on the 20th of September 2022. The European Commission published its updated recommendation to investigate prostate, lung, and gastric cancer early detection programs. This opened a new window of opportunity to move away from the trial setting to population-based early detection settings. With this review, we aim to review 30 years of historical evidence of prostate cancer screening, which led to the initiation of the 'The Prostate Cancer Awareness and Initiative for Screening in the European Union' (PRAISE-U) project, which aims to encourage the early detection and diagnosis of PCa through customized and risk-based screening programs.

Background: Lymphoceles, lymph fluid-filled collections within the body lacking epithelial lining, are a common complication after pelvic lymph node dissection (PLND) during robot-assisted radical prostatectomy (RARP). In this study, we investigate the incidence of imaging confirmed symptomatic lymphoceles (SLC) in a centralized high-volume operating centre and assess predictive factors and treatment.Methods: We retrospectively analysed the incidence, risk factors and treatment of a consecutive series of patients who underwent PLND during RARP between September 2018 and January 2021 in a specialised operation clinic. We compared baseline patients’ characteristics and pathological data between men who developed an SLC and those who did not. A multivariable model for the occurrence of an SLC was created using predetermined, clinically relevant variables to investigate predictive factors. Results: We analysed the records of 404 patients. The median follow-up length was 29 months. A total of 30 (7.4%) patients with an SLC were identified. The median time until SLC presentation was 12 weeks [interquartile range (IQR), 4–31 weeks], one-third of SLCs presented after 180 days. Percutaneous drainage was performed in 17 patients (57%). On multivariable analysis, only body mass index (BMI) significantly increased the odds of an SLC [per 5 odds ratio (OR) =1.7; 95% confidence interval (CI): 1.0–3.0, P=0.04]. Conclusions: SLCs present significant consequences, as more than half of patients with an SLC were treated with percutaneous drainage. Many patients presented later than the centralized surgeons’ postoperative follow-up, a drawback of centralized care. An increased BMI was a significant predictor for SLC.

Background and Objective: Active surveillance (AS) has been established as an important treatment option for patients with localised prostate cancer (PCa). Current evidence suggests that health literacy is an important facilitator or barrier to choosing and adhering to AS. We aim to understand how the level of health literacy has an impact on choosing and adhering to AS for PCa patients. Methods: We performed a narrative literature review in accordance with the Narrative Review guidelines through the MEDLINE online database via PubMed using two different search strategies to identify the relevant literature. We looked at literature until August 2022. A narrative synthesis was performed to identify if there is any evidence on how studies report health literacy as an outcome in the AS population and if there are any interventions targeting health literacy. Key Content and Findings: We identified 18 studies which looked at health literacy in the PCa context. Health literacy was measured in the context of comprehension of information of patients across PCa stages, decision making across PCa stages and quality of life (QoL) across PCa stages. Lower health literacy had a negative impact on the identified themes. Nine of the identified studies used validated health literacy measures. Interventions targeting health literacy have been used to improve health literacy with a positive impact across the patient journey. Conclusions: Health literacy plays an important role in enabling men to take an active part in their treatment journey. In this review, we presented how health literacy is measured and which interventions targeting health literacy are implemented across PCa. These examples of interventions targeting health literacy should be studied further and translated into the AS setting to improve treatment decision making and adherence to AS.

An updated Council of the EU recommendation on cancer screening was adopted in December 2022 during the Czech EU presidency. The recommendation included prostate cancer as a suitable target disease for organised screening, and invited countries to proceed with piloting and further research. To support further discussions and actions to promote early detection of prostate cancer, an international conference in November 2022 (Prostaforum 2022) resulted in a joint declaration. Here we describe the EU policy background, summarise the preparation of the declaration and the key underlying evidence and expert recommendations, and report the text of the declaration. The declaration summarises the striking inequalities in prostate cancer burden in Europe and calls on all stakeholders to consider and support concrete steps for advancement of organised early detection of prostate cancer. Our aim is to request endorsement of the text and potential initiation of practical actions by all stakeholders to support the aims of the declaration. Patient summary: Prostate cancer is among the most frequent cancers and is one of the most common causes of cancer death among men. The European Union has recommended new pilot programmes for prostate cancer screening. The Prostaforum 2022 declaration invites all stakeholders to support this new recommendation with specific steps.

In response to the rising incidence of indolent, low-risk prostate cancer (PCa) due to increased prostate-specific antigen (PSA) screening in the 1990s, active surveillance (AS) emerged as a treatment modality to combat overtreatment by delaying or avoiding unnecessary definitive treatment and its associated morbidity. AS consists of regular monitoring of PSA levels, digital rectal exams, medical imaging, and prostate biopsies, so that definitive treatment is only offered when deemed necessary. This paper provides a narrative review of the evolution of AS since its inception and an overview of its current landscape and challenges. Although AS was initially only performed in a study setting, numerous studies have provided evidence for the safety and efficacy of AS which has led guidelines to recommend it as a treatment option for patients with low-risk PCa. For intermediate-risk disease, AS appears to be a viable option for those with favourable clinical characteristics. Over the years, the inclusion criteria, follow-up schedule and triggers for definitive treatment have evolved based on the results of various large AS cohorts. Given the burdensome nature of repeat biopsies, risk-based dynamic monitoring may further reduce overtreatment by avoiding repeat biopsies in selected patients.

Background: The European Association of Urology guidelines recommend a risk-based strategy for prostate cancer screening based on the first prostate-specific antigen (PSA) level and age. Objective: To analyze the impact of the first PSA level on prostate cancer (PCa) detection and PCa-specific mortality (PCSM) in a population-based screening trial (repeat screening every 2–4 yr). Design, setting, and participants: We evaluated 25 589 men aged 55–59 yr, 16 898 men aged 60–64 yr, and 12 936 men aged 65–69 yr who attended at least one screening visit in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial (screening arm: repeat PSA testing every 2–4 yr and biopsy in cases with elevated PSA; control arm: no active screening offered) during 16-yr follow-up (FU). Outcome measurements and statistical analysis: We assessed the actuarial probability for any PCa and for clinically significant (cs)PCa (Gleason ≥7). Cox proportional-hazards regression was performed to assess whether the association between baseline PSA and PCSM was comparable for all age groups. A Lorenz curve was computed to assess the association between baseline PSA and PCSM for men aged 60–61 yr. Results and limitations: The overall actuarial probability at 16 yr ranged from 12% to 16% for any PCa and from 3.7% to 5.7% for csPCa across the age groups. The actuarial probability of csPCa at 16 yr ranged from 1.2–1.5% for men with PSA <1.0 ng/ml to 13.3–13.8% for men with PSA ≥3.0 ng/ml. The association between baseline PSA and PCSM differed marginally among the three age groups. A Lorenz curve for men aged 60–61 yr showed that 92% of lethal PCa cases occurred among those with PSA above the median (1.21 ng/ml). In addition, for men initially screened at age 60–61 yr with baseline PSA <2 ng/ml, further continuation of screening is unlikely to be beneficial after the age of 68–70 yr if PSA is still <2 ng/ml. No case of PCSM emerged in the sub

Background: Considering the long natural history of prostate cancer (PCa), long-term results of the European Randomised Study of Screening for PCa (ERSPC) are crucial. Objective: To provide an update on the effect of prostate-specific antigen (PSA)-based screening on PCa-specific mortality (PCSM), metastatic disease, and overdiagnosis in the Dutch arm of the ERSPC. Design, setting, and participants: Between 1993 and 2000, a total of 42 376 men, aged 55–74 yr, were randomised to a screening or a control arm. The main analysis was performed with men aged 55–69 yr (n = 34 831). Men in the screening arm were offered PSA-based screening with an interval of 4 yr. Outcome measurements and statistical analysis: Intention-to-screen analyses with Poisson regression were used to calculate rate ratios (RRs) of PCSM and metastatic PCa. Results and limitations: After a median follow-up of 21 yr, the RR of PCSM was 0.73 (95% confidence interval [CI]: 0.61–0.88) favouring screening. The numbers of men needed to invite (NNI) and needed to diagnose (NND) to prevent one PCa death were 246 and 14, respectively. For metastatic PCa, the RR was 0.67 (95% CI: 0.58–0.78) favouring screening. The NNI and NND to prevent one metastasis were 121 and 7, respectively. No statistical difference in PCSM (RR of 1.18 [95% CI: 0.87–1.62]) was observed in men aged ≥70 yr at the time of randomisation. In the screening arm, higher rates of PCSM and metastatic disease were observed in men who were screened only once and in a selected group of men above the screening age cut-off of 74 yr. Conclusions: The current analysis illustrates that with a follow-up of 21 yr, both absolute metastasis and mortality reduction continue to increase, resulting in a more favourable harm-benefit ratio than demonstrated previously. These data do not support starting screening at the age of 70–74 yr and show that repeated screening is essential. Patient summary: Prostate-specific antigen–based prostate cancer screening red

Background: The ERSPC study has demonstrated that prostate-specific antigen (PSA)-based screening results in a relative increase in diagnosis of (low-risk) prostate cancer (PCa) and a reduction in metastatic disease and PCa mortality. Objective: To evaluate the burden of PCa among men randomized to active screening compared to those in the control arm in ERSPC Rotterdam. Design, setting, and participants: We analyzed data for participants in the Dutch section of the ERSPC, including 21 169 men randomized to the screening arm and 21 136 randomized to the control arm. Men in the screening arm were invited for PSA-based screening every 4 yr, and transrectal ultrasound–guided prostate biopsy was recommended for those with PSA ≥3.0 ng/ml. Outcome measurements and statistical analysis: We analyzed detailed follow-up and mortality data up to January 1, 2019, to a maximum of 21 yr, using multistate models. Results and limitations: At 21 yr, 3046 men (14%) had been diagnosed with nonmetastatic PCa and 161 (0.76%) with metastatic PCa in the screening arm. In the control arm, 1698 men (8.0%) had been diagnosed with nonmetastatic PCa and 346 (1.6%) with metastatic PCa. In comparison to the control arm, men in the screening arm were diagnosed with PCa almost 1 yr earlier and if diagnosed with nonmetastatic PCa lived on average for almost 1 yr longer without disease progression. Among those who experienced biochemical recurrence (18–19% after nonmetastatic PCa), progression to metastatic disease or death was quicker in the control arm: men in the screening arm lived for 7.17 yr without progression, while the progression-free interval was only 1.59 yr for men in the control arm over a 10-yr time period. Among those who experienced metastatic disease, men in both study arms lived for 5 yr over a 10-yr time period. Conclusions: PCa diagnosis was earlier after study entry for men in the PSA-based screening arm. However, disease progression was not as fast in the screening arm as i

Background: Our objective was to assess the accuracy of transabdominal ultrasound (TAUS) measured prostate volume in the primary care setting with transrectal ultrasound (TRUS) measured prostate volume by the urologist as the reference test. Furthermore, our objective was to assess whether risk-stratification using TAUS prostate volume by the primary care physician could reduce unnecessary referrals to the urologist. Methods: Men in two Dutch primary care offices with a prostate cancer (PCa) screening request received a digital rectal examination (DRE), prostate specific-antigen (PSA), and TAUS prostate volume measurement by the general practitioner, followed by Rotterdam Prostate Cancer Risk Calculator (RPCRC) risk assessment. The examination was repeated by a urologist using TRUS. A prostate biopsy was performed in case of a RPCRC positive biopsy advice. A non-inferiority analysis was performed comparing TAUS and TRUS prostate volume differences. A risk-based referral strategy using TAUS and the RPCRC in the primary care setting was compared with the standard referral strategy based on PSA (≥3 ng/mL) and DRE. Results: A total of 105 men were included with a median PSA of 1.9 ng/mL. The mean prostate volumes measured by TAUS and TRUS were 55 and 45 mL, respectively. The mean overestimation of the prostate volume by TAUS as compared to the reference test was 9.9 mL (95% CI: 5.9–13.8). According to Dutch standard practice, 41 out of 105 (39%) men would have been referred to the urologist. Stratification in primary care based on the RPCRC using TAUS prostate volume would have avoided 29 out of the 41 (71%) referrals, at the expense of non-referral of 5 out of 11 (45%) men with a biopsy indication, according to the urologist. Conclusions: RPCRC-based risk stratification in primary care using TAUS prostate volume measurement is feasible and may prevent unnecessary referrals to the urologist and reduce costs. The accuracy of the risk assessment with TAUS might be impr

Background: Evidence-practice gaps exist in urology. We previously surveyed European Association of Urology (EAU) guidelines for strong recommendations underpinned by high-certainty evidence that impact patient experience for which practice variations were suspected. The recommendation “Do not offer neoadjuvant androgen deprivation therapy (ADT) before surgery for patients with prostate cancer” was prioritised for further investigation. ADT before surgery is neither clinically effective nor cost effective and has serious side effects. The first step in improving implementation problems is to understand their extent. A clear picture of practice regarding ADT before surgery across Europe is not available. Objective: To assess current ADT use before prostate cancer surgery in Europe. Design, setting, and participants: This was an observational cross-sectional study. We retrospectively audited recent ADT practices in a multicentre international setting. We used nonprobability purposive sampling, aiming for breadth in terms of low- versus high-volume, academic, versus community and public versus private centres. Outcome measurements and statistical analysis: Our primary outcome was adherence to the ADT recommendation. Descriptive statistics and a multilevel model were used to investigate differences between countries across different factors (volume, centre type, and funding type). Subgroup analyses were performed for patients with low, intermediate, and high risk, and for those with locally advanced prostate cancer. We also collected reasons for nonadherence. Results and limitations: We included 6598 patients with prostate cancer from 187 hospitals in 31 countries from January 1, 2017 to May 1, 2020. Overall, nonadherence was 2%, (range 0–32%). Most of the variability was found in the high-risk subgroup, for which nonadherence was 4% (range 0–43%). Reasons for nonadherence included attempts to improve oncological outcomes or preoperative tumour parameters; attempts t

Objective: To evaluate the feasibility of multivariable risk stratification for early prostate cancer (PCa) detection in a primary healthcare diagnostic facility with regard to its effects on the referral rate and subsequent PCa diagnoses compared to a PSA threshold of 3.0 ng/mL as the current referral indicator. Patients and Methods: In 2014, the Erasmus MC Cancer Institute and the primary healthcare diagnostic facility STAR-SHL (located in Rotterdam city centre) initiated this observational study, in which general practitioners (GPs) could refer men who wished to undergo PCa screening to STAR-SHL for consultation by specially trained personnel. Referral recommendations to secondary healthcare were based on the outcome of application of the Rotterdam Prostate Cancer Risk Calculator (RPCRC) and were compared to the current Dutch GPs' PSA referral threshold of 3.0 ng/mL. For data collection on PCa diagnoses, the study cohort was linked to the Dutch nationwide pathology databank (PALGA). Results: Between January 2014 and February 2021, 507 men were referred for consultation and in 495 men prostate-specific antigen (PSA) was tested. The median (interquartile range) follow-up from consultation to PALGA linkage was 43 (25–65) months. In total, 279 men (56%) had a PSA level ≥3.0 ng/mL, of whom 68% (95% confidence interval [95% CI] 63–74) were considered at low risk according to the RPCRC. Within 1 year after consultation, one of these men (0.52%; 95% CI 0.092–2.9) was diagnosed with clinically significant (cs)PCa (i.e., International Society of Urological Pathology Grade Group ≥2). Thereafter, another four (2.1%; 95% CI 0.82–5.3) low-risk men were diagnosed with csPCa. Of the high-risk men who were biopsied within 1 year after consultation (n = 61), 77% (95% CI 65–86) were diagnosed with PCa and 49% (95% CI 37–61) with csPCa. Conclusion: In a primary healthcare diagnostic facility, the RPCRC could reduce up to 68% of referrals to secondary healthca

Currently available data from long-running single- and multi-center active surveillance (AS) studies show that AS has excellent cancer-specific survival rates. For AS to be effective the ‘right’ patients should be selected for which up until 5-to-10 years ago systematic prostate biopsies were used. Because the systematic prostate strategy relies on sampling efficiency for the detection of prostate cancer (PCa), it is subject to sampling error. Due to this sampling error, many of the Gleason 3+3 PCas that were included on AS in the early days and were classified as low-risk, may in fact have had a higher Gleason score. Subsequently, AS-criteria were more strict to overcome or limit the number of men missing the potential window of curability in case their tumor would be reclassified. Five to ten years ago the prostate biopsy landscape changed drastically by the addition of magnetic resonance imaging (MRI) into the diagnostic PCa-care pathway, which has by now trickled down into the EAU guidelines. At the moment, the EAU guidelines recommend performing a (multi-parametric) MRI before prostate biopsy and combine systematic and targeted prostate biopsy when the MRI is positive (i.e. PIRADS ≥3). So because of the introduction of the MRI into the diagnostic PCa-care pathway, literature is showing that more Gleason 3+4 PCas are being diagnosed. But can it not be that the inclusion of MRI into the diagnostic PCa-care pathway causes risk inflation, resulting in men earlier eligible for AS, now being labelled ineligible for AS? Would it not be possible to include these current Gleason 3+4 PCas on AS? The authors hypothesize that the improved accuracy that comes with the introduction of MRI into the diagnostic PCa-care pathway permits to widen both the AS-inclusion and follow-up criteria. Maintaining our inclusion criteria for AS from the systematic biopsy era will unnecessarily and undesirably expose patients to the increased risk of overtreatment. The evidence behind the

BACKGROUND Evidence-practice gaps exist in urology. We previously surveyed European Association of Urology (EAU) guidelines for strong recommendations underpinned by high-certainty evidence that impact patient experience for which practice variations were suspected. The recommendation "Do not offer neoadjuvant androgen deprivation therapy (ADT) before surgery for patients with prostate cancer" was prioritised for further investigation. ADT before surgery is neither clinically effective nor cost effective and has serious side effects. The first step in improving implementation problems is to understand their extent. A clear picture of practice regarding ADT before surgery across Europe is not available. OBJECTIVE To assess current ADT use before prostate cancer surgery in Europe. DESIGN, SETTING, AND PARTICIPANTS This was an observational cross-sectional study. We retrospectively audited recent ADT practices in a multicentre international setting. We used nonprobability purposive sampling, aiming for breadth in terms of low- versus high-volume, academic, versus community and public versus private centres. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Our primary outcome was adherence to the ADT recommendation. Descriptive statistics and a multilevel model were used to investigate differences between countries across different factors (volume, centre type, and funding type). Subgroup analyses were performed for patients with low, intermediate, and high risk, and for those with locally advanced prostate cancer. We also collected reasons for nonadherence. RESULTS AND LIMITATIONS We included 6598 patients with prostate cancer from 187 hospitals in 31 countries from January 1, 2017 to May 1, 2020. Overall, nonadherence was 2%, (range 0-32%). Most of the variability was found in the high-risk subgroup, for which nonadherence was 4% (range 0-43%). Reasons for nonadherence included attempts to improve oncological outcomes or preoperative tumour parameters; attempts to contro