Publications by authors named "Monique J Roobol"

338 Publications

The Key Role of Patient Involvement in the Development of Core Outcome Sets in Prostate Cancer.

Eur Urol Focus 2021 Sep 30. Epub 2021 Sep 30.

Translational and Oncology Research, Faculty of Life Sciences and Medicine, King's College London, London, UK.

Patients are the stewards of their own care and hence their voice is important when designing and implementing research. Patients should be involved not only as participants in research that impacts their care, as the recipients of that care and any associated harms, but also as research collaborators in prioritising important questions from the patient perspective and designing the research and the ways in which is it most appropriate to involve patients. The PIONEER Consortium, an international multistakeholder collaboration lead by the European Association of Urology, has developed a core outcome set (COS) for localised and metastatic prostate cancer relevant to all stakeholders in particular patients. Throughout the work of PIONEER, patient representatives were involved as collaborators in setting the research agenda, and a wider group of patients was involved as participants in developing COSs, for instance in consensus meetings on choosing important outcomes and appropriate definitions. This publication showcases the process for COS development and highlights the most important recommendations to ultimately inform future research projects co-created between patients and other stakeholders. PATIENT SUMMARY: An important step in involving patients in the selection of outcomes for clinical trials, clinical audits, and real-world evidence is the development of a core outcome set (COS) that is relevant to all stakeholders. This report highlights the patient participation throughout our PIONEER COS development. TAKE HOME  MESSAGE: An important step in involving patients in the selection of outcomes for clinical trials, clinical audits, and real-world evidence is to develop a core outcome set (COS) that is relevant to all stakeholders. As part of the work of the PIONEER Consortium, we aim to highlight the patient participation throughout our PIONEER COS development.
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http://dx.doi.org/10.1016/j.euf.2021.09.008DOI Listing
September 2021

Interaction of MRI and active surveillance in prostate cancer: Time to re-evaluate the active surveillance inclusion criteria.

Urol Oncol 2021 Sep 2. Epub 2021 Sep 2.

Department of Urology, Erasmus Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands.

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 addition of MRI-targeted biopsies to systematic biopsies calls upon the re-evaluation of the AS inclusion criteria and research from one-size-fits-all protocols used so far, into the direction of more dynamic and individual risk-based AS-approaches.
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http://dx.doi.org/10.1016/j.urolonc.2021.08.008DOI Listing
September 2021

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 Aug 15. Epub 2021 Aug 15.

Department of Urology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.

Background: Recommendations against prostate-specific antigen (PSA) testing in 2012 have increased advanced-stage diagnosis and prostate cancer-specific mortality rates.

Objective: To present the position of the European Association of Urology (EAU) in 2021 and provide recommendations for the use of PSA testing as part of a risk-adapted strategy for the early detection of prostate cancer.

Evidence Acquisition: The authors combined their review of relevant literature, including the EAU prostate cancer guidelines 2021 update, with their own knowledge to provide an expert opinion, representing the EAU's position in 2021.

Evidence Synthesis: The EAU has developed a risk-adapted early prostate cancer detection strategy for well-informed men based on PSA testing, risk calculators, and multiparametric magnetic resonance imaging, which can differentiate significant from insignificant prostate cancer. This approach largely avoids the overdiagnosis/overtreatment of men unlikely to experience disease-related symptoms during their lifetime and facilitates an early diagnosis of men with significant cancer to receive active treatment. It also reduces advanced-stage diagnosis, thereby potentially reducing prostate cancer-specific mortality and improving quality of life. Education is required among urologists, general practitioners, radiologists, policy makers, and healthy men, including endorsement by the European Commission to adapt the European Council's screening recommendations in its 2022 plan and requests to individual countries for its incorporation into national cancer plans.

Conclusions: This risk-adapted approach for the early detection of prostate cancer will reverse current unfavourable trends and ultimately save lives.

Patient Summary: The European Association of Urology has developed a patient information leaflet and algorithm for the early diagnosis of prostate cancer. It can identify men who do not need magnetic resonance imaging or a biopsy and those who would not show any symptoms versus those with more aggressive disease who require further tests/treatment. We need to raise awareness of this algorithm to ensure that all well-informed men at risk of significant prostate cancer are offered a prostate-specific antigen test. TAKE  HOME MESSAGE: A risk-adapted early prostate cancer detection strategy, incorporating prostate-specific antigen testing, multiparametric magnetic resonance imaging, risk calculators, and biomarkers, will avoid overdiagnosis/overtreatment of insignificant cancers and ensure early detection and treatment of significant cancers, thereby improving quality of life and reducing prostate cancer-related deaths.
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http://dx.doi.org/10.1016/j.eururo.2021.07.024DOI Listing
August 2021

A comparison of prostate cancer prediction models in men undergoing both magnetic resonance imaging and transperineal biopsy: Are the models still relevant?

BJU Int 2021 Aug 9. Epub 2021 Aug 9.

Department of Urology, Westmead Hospital, Westmead, NSW, Australia.

Objective: To externally validate and compare the performance of the European Randomized Study of Screening for Prostate Cancer risk calculator 3/4 (ERSPC-RC3/4), the Prostate Biopsy Collaborative Group risk calculator (PBCG-RC) and the van Leeuwen model to determine which prediction model would perform the best in a contemporary Australian cohort undergoing transperineal (TP) biopsy.

Materials And Methods: A retrospective review identified all patients undergoing TP biopsy across two centres. Of the 797 patients identified, 373 had the data required to test all three risk calculators. The probability of high-grade prostate cancer, defined as International Society of Urological Pathology Grade Group >1, was calculated for each patient. For each prediction model discrimination was assessed using area under the receiver-operating characteristic curve (AUC), calibration using numerical and graphical summaries, and net benefit using decision curve analysis.

Results: Assessment of model discrimination for detecting high-grade prostate cancer showed AUCs of 0.79 (95% confidence interval [CI] 0.74-0.84) for the ERSPC-RC3/4, 0.81 (95% CI 0.77-0.86) for the van Leeuwen model, and 0.68 (95% CI 0.63-0.74) for the PBCG-RC, compared to 0.58 (95% CI 0.52-0.65) for prostate-specific antigen alone. The ERSPC-RC3/4 was the best calibrated in the moderate-risk range of 10-40%, whilst the van Leeuwen model was the best calibrated in the low-risk range of 0-10%. The van Leeuwen model demonstrated the greatest net benefit from 10% risk onwards, followed closely by the ERSPC-RC3/4 and then the PBCG-RC.

Conclusion: The ERPSC-RC3/4 demonstrated good performance and was comparable to the van Leeuwen model with regard to discrimination, calibration and net benefit for an Australian population undergoing TP prostate biopsy. It is one of the most accessible risk calculators with an easy-to-use online platform, therefore, we recommend that Australian urologists use the ERSPC-RC3/4 to predict risk in the clinical setting.
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http://dx.doi.org/10.1111/bju.15554DOI Listing
August 2021

A European Model for an Organised Risk-stratified Early Detection Programme for Prostate Cancer.

Eur Urol Oncol 2021 Aug 4. Epub 2021 Aug 4.

Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands.

Context: Overdiagnosis as the argument to stop prostate cancer (PCa) screening is less valid since the introduction of new technologies such as risk calculators (RCs) and magnetic resonance imaging (MRI). These new technologies result in fewer unnecessary biopsy procedures and fewer cases of both overdiagnosis and underdetection. Therefore, we can now adequately respond to the growing and urgent need for a structured risk assessment to detect PCa early.

Objective: To provide expert discussion on the existing evidence for a previously published risk-stratified strategy regarding an organised population-based early detection programme for PCa.

Evidence Acquisition: The proposed algorithm for early detection of PCa emerged from expert consensus by the authors based on available evidence derived from a nonsystematic review of the current literature using Medline/PubMed, Cochrane Library database, ClinicalTrials.gov, ISRCTN Registry, and the European Association of Urology guidelines on PCa.

Evidence Synthesis: Although not confirmed by the highest level of evidence, current literature and guidelines point towards an algorithm for early detection of PCa that starts with risk-based prostate-specific antigen (PSA) testing, followed by multivariable risk stratification with RCs. All men who are classified to be at intermediate and high risk are then offered prostate MRI. The combined data from RCs and MRI results can be used to select men for prostate biopsy. Low-risk men return to a risk-based safety net that includes individualised PSA-interval tests and, if necessary, repeated MRI. Depending on local availability, the use of the different risk stratification tools may be adapted.

Conclusions: We present a risk-stratified algorithm for an organised population-based early detection programme for clinically significant PCa. Although the proposed strategy has not yet been analysed prospectively, it exploits and may even improve the most important available benefits of "PSA-only" screening studies, while at the same time reduces unnecessary biopsies and overdiagnosis by using new risk stratification tools.

Patient Summary: This paper presents a personalised strategy that enables selective early detection of prostate cancer by combining prostate-specific antigen (interval) testing' prediction models (risk calculators), and magnetic resonance imaging scans. This will likely lead to reduced prostate cancer-related morbidity and mortality, while reducing the need for prostate biopsy and limiting overdiagnosis.
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http://dx.doi.org/10.1016/j.euo.2021.06.006DOI Listing
August 2021

External Validation of Two Nomograms Developed for Ga-PSMA-11 Applied to the Prostate-specific Membrane Antigen Tracer F-DCFPyl: Is Prediction of the Optimal Timing of Salvage Therapy Feasible?

Eur Urol Open Sci 2021 Jun 29;28:47-51. Epub 2021 Apr 29.

Department of Urology, The Netherlands Cancer Institute, Prostate Cancer Network Netherlands, Amsterdam, The Netherlands.

Two nomograms have been developed to predict the outcome of positron emission tomography (PET)/computed tomography (CT) imaging withGa-labeled ligands for prostate-specific membrane antigen (Ga-PSMA) for patients with rising prostate-specific antigen after radical prostatectomy (RP). These nomograms quantify the ability of PSMA PET/CT to detect prostate cancer recurrences, and therefore provide critical information in determining the optimal timing for PSMA PET/CT in guiding salvage therapies. We validated the ability of these nomograms to accurately predict PET/CT outcome using another ligand tracer, F-DCFPyL. The external validation cohort consisted of 157 men from the Prostate Cancer Network Netherlands who underwent F-DCFPyL PET/CT to guide salvage therapies after RP. The nomogram of Rauscher et al (predicting a positive scan) showed accurate prediction of 50-80% (discrimination 0.68, 95% confidence interval [CI] 0.59-0.76). The nomogram of Luiting et al (predicting recurrence outside the prostatic fossa) showed accurate prediction for predicted probability values between 15% and 65%, with a small degree of overestimation for predicted probability values between 30% and 50% (discrimination 0.74, 95% CI 0.28-1.24). According to calibration curves, discrimination results, and decision curve analysis, we conclude that clinicians can use these Ga-PSMA-based nomograms to predict F-DCFPyL PET/CT outcome. These nomograms improve shared decision-making in determining the optimal time to initiate PSMA PET/CT-guided salvage therapies.

Patient Summary: Prediction tools developed for prostate scans (positron emission tomography, PET) using one type of radioactive tracer (chemicals labeled with gallium-68) are also accurate in predicting scan findings with another tracer (a chemical labeled with fluorine-18). Our study confirms that these tools can be used to guide decisions on the timing of treatments for prostate cancer recurrence.
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http://dx.doi.org/10.1016/j.euros.2021.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317859PMC
June 2021

Active surveillance for prostate cancer-will the discoveries of the last 5 years change the future?

Authors:
Monique J Roobol

Transl Androl Urol 2021 Jun;10(6):2828-2831

Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands.

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http://dx.doi.org/10.21037/tau-20-1321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261427PMC
June 2021

Active surveillance for prostate cancer.

Transl Androl Urol 2021 Jun;10(6):2809-2819

Department of Surgery (Urology Service), Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Many men diagnosed with localized prostate cancer can postpone definitive treatment without raising their risk of metastasis or death from disease. Active surveillance (AS) is a method of monitoring select men, with the option of switching to active treatment upon signs of progression, thereby avoiding the well-known side-effects of surgery and radiotherapy. This review analyzes the data from long-running AS cohorts to determine the safety and efficacy of AS. We conducted a narrative review of recently published data, including 14 articles from 13 AS cohorts. The cohorts used varying inclusion criteria, with reported differences in clinical T stage and Gleason Score (Grade Group), among other features. Some studies (n=5) limited their cohorts to low-risk patients, while others (n=8) also included intermediate-risk patients. The heterogeneity of the cohorts produced mixed results, with the risk of prostate cancer metastasis ranging from 0.1-1.0% at 10 years and the risk of prostate cancer mortality ranging from 0-1.9% at 10 years. However, the majority of studies reported risks of less than 0.5% at 10 years for both metastasis and death. For most cohorts, half of men remained untreated for 5-10 years, with estimates ranging from 37% receiving active treatment in the Toronto cohort to 73% in the Prostate Cancer Research International AS (PRIAS) study. Current data do not support the use of negative magnetic resonance imaging (MRI) to avoid scheduled biopsy. Taken together, the data collected from these AS cohorts suggests that AS is a safe approach for men with low-grade prostate cancer and some men with intermediate risk disease. AS should be more broadly implemented for eligible patients to avoid the decreases in quality of life from undergoing active treatment. Studies expanding the inclusion criteria and further defining a subset of men with favorable intermediate-risk prostate cancer who might safely benefit from AS are needed to assess the long-term outcomes of using AS in intermediate-risk groups.
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http://dx.doi.org/10.21037/tau-20-1370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261451PMC
June 2021

Using the Movember Foundation's GAP3 cohort to measure the effect of active surveillance on patient-reported urinary and sexual function-a retrospective study in low-risk prostate cancer patients.

Transl Androl Urol 2021 Jun;10(6):2719-2727

Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands.

Background: Active surveillance (AS) for low-risk prostate cancer (PCa) is intended to overcome potential side-effects of definitive treatment. Frequent prostate biopsies during AS may, however, impact erectile (EF) and urinary function (UF). The objective of this study was to test the influence of prostate biopsies on patient-reported EF and UF using multicenter data from the largest to-date AS-database.

Methods: In this retrospective study, data analyses were performed using the Movember GAP3 database (v3.2), containing data from 21,169 AS participants from 27 AS-cohorts worldwide. Participants were included in the study if they had at least one follow-up prostate biopsy and completed at least one patient reported outcome measure (PROM) related to EF [Sexual Health Inventory for Men (SHIM)/five item International Index of Erectile Function (IIEF-5)] or UF [International Prostate Symptom Score (IPSS)] during follow-up. The longitudinal effect of the number of biopsies on either SHIM/IIEF-5 or IPSS were analyzed using linear mixed models to adjust for clustering at patient-level. Analyses were stratified by center; covariates included age and Gleason Grade group at diagnosis, and time on AS.

Results: A total of 696 participants completed the SHIM/IIEF-5 3,175 times, with a median follow-up of 36 months [interquartile range (IQR) 20-55 months]. A total of 845 participants completed the IPSS 4,061 times, with a median follow-up of 35 months (IQR 19-56 months). The intraclass correlation (ICC) was 0.74 for the SHIM/IIEF-5 and 0.68 for the IPSS, indicating substantial differences between participants' PROMs. Limited heterogeneity between cohorts in the estimated effect of the number of biopsies on either PROM were observed. A significant association was observed between the number of biopsies and the SHIM/IIEF-5 score, but not for the IPSS score. Every biopsy was associated with a decrease in the SHIM/IIEF-5 score of an average 0.67 (95% CI, 0.47-0.88) points.

Conclusions: Repeated prostate biopsy as part of an AS protocol for men with low-risk PCa does not have a significant association with self-reported UF but does impact self-reported sexual function. Further research is, however, needed to understand whether the effect on sexual function implies a negative clinical impact on their quality of life and is meaningful from a patient's perspective. In the meantime, clinicians and patients should anticipate a potential decline in erectile function and hence consider incorporating the risk of this harm into their discussion about opting for AS and also when deciding on the stringency of follow-up biopsy schedules with long-term AS.
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http://dx.doi.org/10.21037/tau-20-1255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261406PMC
June 2021

A first step towards a global nomogram to predict disease progression for men on active surveillance.

Transl Androl Urol 2021 Mar;10(3):1102-1109

Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA.

Background: Signs of disease progression (28%) and conversion to active treatment without evidence of disease progression (13%) are the main reasons for discontinuation of active surveillance (AS) in men with localised prostate cancer (PCa). We aimed to develop a nomogram to predict disease progression in these patients.

Methods: As a first step in the development of a nomogram, using data from Movembers' GAP3 Consortium (n=14,380), we assessed heterogeneity between centres in terms of risk of disease progression. We started with assessment of baseline hazards for disease progression based on grouping of centres according to follow-up protocols [high: yearly; intermediate: ~2 yearly; and low: at year 1, 4 & 7 (i.e., PRIAS)]. We conducted cause-specific random effect Cox proportional hazards regression to estimate risk of disease progression by centre in each group.

Results: Disease progression rates varied substantially between centres [median hazard ratio (MHR): 2.5]. After adjustment for various clinical factors (age, year of diagnosis, Gleason grade group, number of positive cores and PSA), substantial heterogeneity in disease progression remained between centres.

Conclusions: When combining worldwide data on AS, we noted unexplained differences of disease progression rate even after adjustment for various clinical factors. This suggests that when developing a global nomogram, local adjustments for differences in risk of disease progression and competing outcomes such as conversion to active treatment need to be considered.
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http://dx.doi.org/10.21037/tau-20-1082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039580PMC
March 2021

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Nat Commun 2021 02 23;12(1):1236. Epub 2021 Feb 23.

Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS (PHS, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10). Comparing the 80/20 PHS percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
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http://dx.doi.org/10.1038/s41467-021-21287-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902617PMC
February 2021

Risk-Based Selection for Active Surveillance: Results of the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) Initiative.

J Urol 2021 Jul 22;206(1):62-68. Epub 2021 Feb 22.

Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands.

Purpose: We sought to identify and validate known predictors of disease reclassification at 1 or 4 years to support risk-based selection of patients suitable for active surveillance.

Materials And Methods: An individual participant data meta-analysis using data from 25 established cohorts within the Movember Foundations GAP3 Consortium. In total 5,530 men were included. Disease reclassification was defined as any increase in Gleason grade group at biopsy at 1 and 4 years. Associations were estimated using random effect logistic regression models. The discriminative ability of combinations of predictors was assessed in an internal-external validation procedure using the AUC curve.

Results: Among the 5,570 men evaluated at 1 year, we found 815 reclassifications to higher Gleason grade group at biopsy (pooled reclassification rate 13%, range 0% to 31%). Important predictors were age, prostate specific antigen, prostate volume, T-stage and number of biopsy cores with prostate cancer. Among the 1,515 men evaluated at 4 years, we found 205 reclassifications (pooled reclassification rates 14%, range 3% to 40%), with similar predictors. The average areas under the receiver operating characteristic curve at internal-external validation were 0.68 and 0.61 for 1-year and 4-year reclassification, respectively.

Conclusions: Disease reclassification occurs typically in 13% to 14% of biopsies at 1 and 4 years after the start of active surveillance with substantial between-study heterogeneity. Current guidelines might be extended by considering prostate volume to improve individualized selection for active surveillance. Additional predictors are needed to improve patient selection for active surveillance.
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http://dx.doi.org/10.1097/JU.0000000000001700DOI Listing
July 2021

Impact of cancer screening on metastasis: A prostate cancer case study.

J Med Screen 2021 Feb 9:969141321989738. Epub 2021 Feb 9.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Background: Trials of cancer screening present results in terms of deaths prevented, but metastasis is also a key endpoint that screening seeks to prevent. We developed a framework for projecting overall (de novo and progressive) metastases prevented in a screening trial using prostate cancer screening as a case study.

Methods: Mechanistic simulation model in which screening shifts a fraction of cases that would be metastatic at diagnosis to being non-metastatic. This shift increases the incidence of non-overdiagnosed, organ-confined cases. We use estimates of the risk of metastatic progression for these cases to project how many progress to metastasis after diagnosis and tally the projected de novo and progressive metastatic cases with and without screening. We use data on stage shift from the European Randomized Study of Screening for Prostate Cancer (ERSPC) and data on the risk of metastatic progression from the Scandinavian Prostate Cancer Group-4 trial. We estimate the relative risk and absolute risk reductions in metastatic disease at diagnosis and compare these with reductions in overall metastases.

Results: Assuming no effect of screening beyond initial stage shift at diagnosis, the model projects a 43% reduction in metastasis at diagnosis but a 22% reduction in the cumulative probability of metastasis over 12 years in favor of screening. These results are consistent with the empirical findings from the ERSPC.

Conclusion: Any reduction in metastatic disease at diagnosis under screening is likely to be an overly optimistic predictor of the impact of screening on overall metastasis and disease-specific mortality.
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http://dx.doi.org/10.1177/0969141321989738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349931PMC
February 2021

Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Prostate Cancer Prostatic Dis 2021 06 8;24(2):532-541. Epub 2021 Jan 8.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).

Materials And Method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.

Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.

Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
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http://dx.doi.org/10.1038/s41391-020-00311-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157993PMC
June 2021

Urine spermine and multivariable Spermine Risk Score predict high-grade prostate cancer.

Prostate Cancer Prostatic Dis 2021 06 6;24(2):542-548. Epub 2021 Jan 6.

SH Ho Urology Centre, Division of Urology, Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China.

Background: To investigate the role of urine spermine and Spermine Risk Score in prediction of high-grade prostate cancer (HGPCa, ISUP grade group ≥2).

Methods: Nine hundred and five consecutive men with elevated PSA were prospectively recruited from two hospitals. Core analyses focused on consecutive men with PSA 4-20 ng/mL (n = 600). Pre-biopsy urine without prior prostatic massage was analyzed for spermine level with ultra-high performance liquid chromatography with triple quadrupole mass spectrometer (UPLC-MS/MS). The proportions of PCa and HGPCa were compared across different spermine ranges. Logistic regressions were used to form different models, and their performances were compared using area under curve (AUC) and decision curve analysis (DCA).

Results: PCa and HGPCa were diagnosed in 30.8% (185/600) and 17.2% (103/600) men, respectively, and were significantly associated with lower urine spermine levels. Between the lowest and highest quartiles of spermine results, a threefold increase in PCa risk (49.3% vs. 16.7%) and 3.5-fold increase in ISUP grade group ≥2 PCa risk (31.3% vs. 8.7%) were observed. Multivariate analysis showed PSA, prostate volume (PV), digital rectal examination (DRE), and spermine, which were independent predictors for PCa and HGPCa, and a Spermine Risk Score with these factors achieved the highest AUC of 0.78 for PCa and 0.82 for HGPCa. At 90% sensitivity for HGPCa, 36.7% biopsies and 24.4% ISUP grade group 1 diagnoses could have been avoided, with a negative predictive value of 95.4%. DCA revealed net clinical benefit of the Spermine Risk Score. Internal validation with bootstrapping showed good discrimination and calibration.

Conclusion: Urine spermine and Spermine Risk Score identified men at higher risk of HGPCa and reduced unnecessary biopsies.
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http://dx.doi.org/10.1038/s41391-020-00312-1DOI Listing
June 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

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

Eur Urol 2021 03 29;79(3):327-329. Epub 2020 Dec 29.

Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands.

The burden of prostate cancer is increasing. Therefore, we need to implement a contemporary, organized, risk-stratified program for early detection to reduce both the harm from the disease and potential overdiagnosis and overtreatment, while avoiding underdiagnosis to considerably improve the harm-to-benefit ratio.
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http://dx.doi.org/10.1016/j.eururo.2020.12.010DOI Listing
March 2021

Equivocal PI-RADS Three Lesions on Prostate Magnetic Resonance Imaging: Risk Stratification Strategies to Avoid MRI-Targeted Biopsies.

J Pers Med 2020 Dec 10;10(4). Epub 2020 Dec 10.

Department of Urology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.

We aimed to investigate the relation between largest lesion diameter, prostate-specific antigen density (PSA-D), age, and the detection of clinically significant prostate cancer (csPCa) using first-time targeted biopsy (TBx) in men with Prostate Imaging-Reporting and Data System (PI-RADS) 3 index lesions. A total of 292 men (2013-2019) from two referral centers were included. A multivariable logistic regression analysis was performed. The discrimination and clinical utility of the built model was assessed by the area under the receiver operation curve (AUC) and decision curve analysis, respectively. A higher PSA-D and higher age were significantly related to a higher risk of detecting csPCa, while the largest index lesion diameter was not. The discrimination of the model was 0.80 (95% CI 0.73-0.87). When compared to a biopsy-all strategy, decision curve analysis showed a higher net benefit at threshold probabilities of ≥2%. Accepting a missing ≤5% of csPCa diagnoses, a risk-based approach would result in 34% of TBx sessions and 23% of low-risk PCa diagnoses being avoided. In men with PI-RADS 3 index lesions scheduled for first-time TBx, the balance between the number of TBx sessions, the detection of low-risk PCa, and the detection of csPCa does not warrant a biopsy-all strategy. To minimize the risk of missing the diagnosis of csPCa but acknowledging the need of avoiding unnecessary TBx sessions and overdiagnosis, a risk-based approach is advisable.
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http://dx.doi.org/10.3390/jpm10040270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768373PMC
December 2020

Europa Uomo Patient Reported Outcome Study (EUPROMS): Descriptive Statistics of a Prostate Cancer Survey from Patients for Patients.

Eur Urol Focus 2020 Dec 3. Epub 2020 Dec 3.

Department of Urology, Erasmus University Medical Center Rotterdam, The Netherlands.

Background: Europa Uomo initiated the Europa Uomo Patient Reported Outcome Study (EUPROMS) to collect prostate cancer (PCa) patient-reported outcome (PRO) data as a primary endpoint.

Objective: To inform future PCa patients about the impact of PCa treatment through self-reported PRO data of fellow patients collected outside a clinical trial setting.

Design, Setting, And Participants: A cross-sectional survey was conducted among PCa patients currently receiving or having received treatment. The EUPROMS survey contained the EQ-5D-5 L (generic health), the EORTC-QLQ-C30 (cancer-specific quality of life (QoL), and the Expanded Prostate cancer Index Composite short form 26 (EPIC-26; prostate-specific health) questionnaires.

Outcome Measurements And Statistical Analysis: Descriptive statistics were used to assess the demographic and clinical characteristics, and to analyze the PROs of EQ-5D-5L, EORTC-QLQ-C30, and EPIC-26.

Results And Limitations: Between August 21 and November 19, 2019, 2943 men from 24 European countries completed the EUPROMS survey. The median age of the respondents was 71 yr (interquartile range 65-75 yr); 81.9% was living with a spouse. In total, 1937 (65.8%) men underwent a single treatment, and 636 (21.6%), 300 (10.2%), and 70 (2.4%) underwent two, three, and four treatments, respectively. Fatigue scores are highest for men who underwent radiotherapy or chemotherapy. Progression of disease leads to more insomnia. Surgery affects urinary incontinence the most. Self-reported sexual function amounts to 27/100, with the lowest scores being reported for men who underwent surgery and radiotherapy (15/100). Overall, patients who received two or more treatments reported lower scores for all indices.

Conclusions: The EUPROMS survey provided a cross-sectional picture of the current PCa patient population and their reported QoL. Initial treatment is often followed by subsequent treatments, affecting mainly sexual function, as well as fatigue and insomnia. QoL of men undergoing chemotherapy is worse for almost all domains. These data can inform physicians and patients on the true impact of PCa treatment.

Patient Summary: Patient-reported quality of life in the Europa Uomo Patient Reported Outcome Study (EUPROMS) survey-a more informal setting as compared with clinical trials-reveals that prostate cancer treatment affects mainly sexual function, fatigue, and insomnia.
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http://dx.doi.org/10.1016/j.euf.2020.11.002DOI Listing
December 2020

Prostate Specific Membrane Antigen Positron Emission Tomography/Computerized Tomography in the Evaluation of Initial Response in Candidates Who Underwent Salvage Radiation Therapy after Radical Prostatectomy for Prostate Cancer.

J Urol 2021 Apr 18;205(4):1100-1109. Epub 2020 Nov 18.

Amsterdam University Medical Center, VU University, Department of Urology, Prostate Cancer Network Amsterdam, Amsterdam, The Netherlands.

Purpose: We assessed predictors of short-term oncologic outcomes of patients who underwent salvage radiation therapy for biochemical recurrence after robot-assisted laparoscopic radical prostatectomy without evidence of metastases on prostate specific membrane antigen positron emission tomography/computerized tomography.

Materials And Methods: We retrospectively analyzed 194 patients with biochemical recurrence after robot-assisted laparoscopic radical prostatectomy who underwent prostate specific membrane antigen positron emission tomography/computerized tomography prior to salvage radiation therapy. Patients with lymph node or distant metastases on restaging imaging or at the time of extended pelvic lymph node dissection during robot-assisted laparoscopic radical prostatectomy were excluded, as were patients who received androgen deprivation therapy during or prior to salvage radiation therapy. A multivariable logistic regression analysis was performed to assess predictors of treatment response, defined as prostate specific antigen value ≤0.1 ng/ml after salvage radiation therapy.

Results: Overall treatment response after salvage radiation therapy was 75% (146/194 patients). On multivariable analysis, prostate specific antigen value at initiation of salvage radiation therapy (OR 0.42, 95% CI 0.27-0.62, p <0.001), pathological T stage (pT3a vs pT2 OR 0.28, 95% CI 0.11-0.69, p=0.006; pT3b vs pT2 OR 0.26, 95% CI 0.09-0.71, p=0.009) and local recurrent disease on imaging (OR 5.53, 95% CI 1.96-18.52, p=0.003) were predictors of treatment response.

Conclusions: Salvage radiation therapy in patients without evidence of metastases on prostate specific membrane antigen positron emission tomography/computerized tomography showed a good overall treatment response of 75%. Higher treatment response rates were observed in patients with lower prostate specific antigen values at initiation of salvage radiation therapy, those with local recurrent disease on imaging and those with lower pathological T stage (pT2 vs pT3a/b).
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http://dx.doi.org/10.1097/JU.0000000000001437DOI Listing
April 2021

Restricting False-positive Magnetic Resonance Imaging Scans to Reduce Overdiagnosis of Prostate Cancer.

Eur Urol 2021 01 6;79(1):30-32. Epub 2020 Nov 6.

Department of Radiology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

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http://dx.doi.org/10.1016/j.eururo.2020.10.013DOI Listing
January 2021

Comparison of biopsy under-sampling and annual progression using hidden markov models to learn from prostate cancer active surveillance studies.

Cancer Med 2020 12 6;9(24):9611-9619. Epub 2020 Nov 6.

Department of Urology, University of Michigan, Ann Arbor, MI, USA.

This study aimed to estimate the rates of biopsy undersampling and progression for four prostate cancer (PCa) active surveillance (AS) cohorts within the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) consortium. We used a hidden Markov model (HMM) to estimate factors that define PCa dynamics for men on AS including biopsy under-sampling and progression that are implied by longitudinal data in four large cohorts included in the GAP3 database. The HMM was subsequently used as the basis for a simulation model to evaluate the biopsy strategies previously proposed for each of these cohorts. For the four AS cohorts, the estimated annual progression rate was between 6%-13%. The estimated probability of a biopsy successfully sampling undiagnosed non-favorable risk cancer (biopsy sensitivity) was between 71% and 80%. In the simulation study of patients diagnosed with favorable risk cancer at age 50, the mean number of biopsies performed before age 75 was between 4.11 and 12.60, depending on the biopsy strategy. The mean delay time to detection of non-favorable risk cancer was between 0.38 and 2.17 years. Biopsy undersampling and progression varied considerably across study cohorts. There was no single best biopsy protocol that is optimal for all cohorts, because of the variation in biopsy under-sampling error and annual progression rates across cohorts. All strategies demonstrated diminishing benefits from additional biopsies.
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http://dx.doi.org/10.1002/cam4.3549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774732PMC
December 2020

The Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

Cancers (Basel) 2020 Nov 4;12(11). Epub 2020 Nov 4.

Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.
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http://dx.doi.org/10.3390/cancers12113254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694218PMC
November 2020

IMAGINE-IMpact Assessment of Guidelines Implementation and Education: The Next Frontier for Harmonising Urological Practice Across Europe by Improving Adherence to Guidelines.

Eur Urol 2021 02 29;79(2):173-176. Epub 2020 Oct 29.

Department of Urology, Scientific Institute and University Vita-Salute San Raffaele Hospital, Milan, Italy.

Adherence to national and international clinical practice guidelines is suboptimal throughout Europe. The European Association of Urology Guidelines Office project "IMAGINE" (IMpact Assessment of Guidelines Implementation and Education) has been developed to measure baseline adherence to urological guideline recommendations across Europe and to identify issues that drive nonadherence.
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http://dx.doi.org/10.1016/j.eururo.2020.10.011DOI Listing
February 2021

Health-related quality of life in Japanese low-risk prostate cancer patients choosing active surveillance: 3-year follow-up from PRIAS-JAPAN.

World J Urol 2021 Jul 20;39(7):2491-2497. Epub 2020 Oct 20.

Department of Urology, Kagawa University Faculty of Medicine, 1750-1 Ikenobe, Kita-gun, Miki-cho, Kagawa, 761-0793, Japan.

Purpose: To evaluate the health-related quality of life (HRQoL) of Japanese men on active surveillance (AS) in the Prostate cancer Research International Active Surveillance study in Japan (PRIAS-JAPAN).

Methods: Participants were included in the PRIAS-JAPAN HRQoL study between January 2010 and March 2016. Their general HRQoL was assessed using a validated Japanese version of the Short-Form 8 Health Survey (SF-8) at enrolment and annually thereafter until discontinuation of AS. The SF-8 mental component summary (MCS) and physical component summary (PCS) of men on AS were compared with scores of the general population (norm-based score [NBS]: 50) and MCS and PCS scores for men following AS were analysed over time. We tested whether MCS and PCS scores over time explained discontinuation of AS.

Results: Five hundred and twenty-five patients enrolled, and the median age at baseline was 68 years. At enrolment and after 1-, 2-, and 3-year follow-ups, the PCS and MCS scores were significantly higher than the NBS of the general Japanese population except for the median PCS at 3 years. We found that age at diagnosis and time on AS negatively affected the PCS score of men on AS, while every additional year on AS led to a 0.27 point increase in MCS scores. Neither PCS nor MCS were predictors for discontinuation of AS.

Conclusion: Japanese men following an AS strategy for 3 years reported better HRQoL compared with the general population, indicating that monitoring Japanese low-risk prostate cancer patients can be an effective treatment strategy.

Study Registration: Clinical trial registry-UMIN (University Hospital Medical Information Network); UMIN000002874 (2009/12/11).
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http://dx.doi.org/10.1007/s00345-020-03494-4DOI Listing
July 2021

Assessment of harms, benefits, and cost-effectiveness of prostate cancer screening: A micro-simulation study of 230 scenarios.

Cancer Med 2020 10 19;9(20):7742-7750. Epub 2020 Aug 19.

Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

Background: Prostate cancer screening incurs a high risk of overdiagnosis and overtreatment. An organized and age-targeted screening strategy may reduce the associated harms while retaining or enhancing the benefits.

Methods: Using a micro-simulation analysis (MISCAN) model, we assessed the harms, benefits, and cost-effectiveness of 230 prostate-specific antigen (PSA) screening strategies in a Dutch population. Screening strategies were varied by screening start age (50, 51, 52, 53, 54, and 55), stop age (51-69), and intervals (1, 2, 3, 4, 8, and single test). Costs and effects of each screening strategy were compared with a no-screening scenario.

Results: The most optimum strategy would be screening with 3-year intervals at ages 55-64 resulting in an incremental cost-effectiveness ratio (ICER) of €19 733 per QALY. This strategy predicted a 27% prostate cancer mortality reduction and 28 life years gained (LYG) per 1000 men; 36% of screen-detected men were overdiagnosed. Sensitivity analyses did not substantially alter the optimal screening strategy.

Conclusions: PSA screening beyond age 64 is not cost-effective and associated with a higher risk of overdiagnosis. Similarly, starting screening before age 55 is not a favored strategy based on our cost-effectiveness analysis.
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http://dx.doi.org/10.1002/cam4.3395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571827PMC
October 2020

Active surveillance for low-risk prostate cancer - in pursuit of a standardized protocol.

Cent European J Urol 2020 25;73(2):123-126. Epub 2020 Jun 25.

Division of Urology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

Introduction: Active surveillance (AS) is a management option recommended by most guidelines for low risk clinically-localized prostate cancer (LR-CLPC). Data shows that AS is being increasingly adopted into clinical practice worldwide. Our aim was to review the up-to date guidelines and observational studies in regards to AS in LR-CLRPC to gain insight into principles of contemporary clinical practice.

Material And Methods: Several guidelines on the management of low-risk prostate cancer were reviewed for evidence-based recommendations regarding the protocol of AS. We reviewed the available literature for most recent studies on AS in LR-CLPC.

Results: No uniform protocol of AS in LR-CLPC has been recommended up to date and available guidelines significantly differ in terms of protocol schedules and the role of particular tools in monitoring for disease progression. Nevertheless, recent studies on AS in LR-CLPC, in which various protocols were adopted, have demonstrated promising outcomes in regards to cancer-specific survival (99-100% at 5 years, 98.1-99.9% at 10 years, and 94.3-96% at 15 years), with high rates of men remaining within the protocols (23-39% at 10 years).

Conclusions: This article is a call for focusing further research on development and recommending a precise and standardized, evidence-based protocol for AS in LR-CLPC.
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http://dx.doi.org/10.5173/ceju.2020.0167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407781PMC
June 2020
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