EAU - EANM - ESTRO - ESUR - SIOG Guidelines on Prostate Cancer N. Mottet (Chair), R.C.N. van den Bergh, E. Briers (Patient Representative), P. Cornford (Vice-chair), M. De Santis, S. Fanti, S. Gillessen, J. Grummet, A.M. Henry, T.B. Lam, M.D. Mason, T.H. van der Kwast, H.G. van der Poel, O. Rouvière, D. Tilki, T. Wiegel Guidelines Associates: T. Van den Broeck, M. Cumberbatch, N. Fossati, T. Gross, M. Lardas, M. Liew, L. Moris, I.G. Schoots, P-P.M. Willemse © European Association of Urology 2019 TABLE OF CONTENTS PAGE 1. INTRODUCTION 9 1.1 Aims and scope 9 1.2 Panel composition 9 1.2.1 Acknowledgement 9 1.3 Available publications 9 1.4 Publication history and summary of changes 9 1.4.1 Publication history 9 1.4.2 Summary of changes 9 2. METHODS 12 2.1 Data identification 12 2.2 Review 13 2.3 Future goals 13 3. EPIDEMIOLOGY AND AETIOLOGY 13 3.1 Epidemiology 13 3.2 Aetiology 14 3.2.1 Family history / genetics 14 3.2.2 Risk factors 14 3.2.2.1 Metabolic syndrome 14 3.2.2.1.1 Diabetes/metformin 14 3.2.2.1.2 Cholesterol/statins 14 3.2.2.1.3 Obesity 14 3.2.2.2 Dietary factors 14 3.2.2.3 Hormonally active medication 15 3.2.2.3.1 5-alpha-reductase inhibitors 15 3.2.2.3.2 Testosterone 15 3.2.2.4 Other potential risk factors 15 3.2.3 Summary of evidence and guidelines for epidemiology and aetiology 16 4. CLASSIFICATION AND STAGING SYSTEMS 16 4.1 Classification 16 4.2 Gleason score and International Society of Urological Pathology 2014 grade 17 4.3 Prognostic relevance of stratification 17 5. DIAGNOSTIC EVALUATION 18 5.1 Screening and early detection 18 5.1.1 Screening 18 5.1.2 Early detection 19 5.1.3 Guidelines for screening and early detection 20 5.2 Clinical diagnosis 20 5.2.1 Digital rectal examination 20 5.2.2 Prostate-specific antigen 20 5.2.2.1 PSA density 20 5.2.2.2 PSA velocity and doubling time 21 5.2.2.3 Free/total PSA ratio 21 5.2.2.4 Additional serum testing 21 5.2.2.5 Urine tests: PCA3 marker/SelectMDX/Mi Prostate score (MiPS)/ExoDX 21 5.2.2.6 Guidelines for risk-assessment of asymptomatic men 22 5.2.3 Baseline biopsy 22 5.2.4 The role of imaging in clinical diagnosis 22 5.2.4.1 Transrectal ultrasound (TRUS) and ultrasound-based techniques 22 5.2.4.2 Multiparametric magnetic resonance imaging (mpMRI) 22 5.2.4.2.1 mpMRI performance in detecting ISUP grade > 2 PCa 22 5.2.4.2.2 mpMRI performance in detecting ISUP grade group 1 PCa 22 5.2.4.2.3 Does MRI-TBx improve the detection of ISUP grade > 2 as compared to systematic biopsy? 23 2 PROSTATE CANCER - UPDATE MARCH 2019 5.2.4.2.4 Does MRI-TBx reduce the detection of ISUP grade 1 PCa as compared to systematic biopsy? 23 5.2.4.2.5 The added value of systematic and targeted biopsy 23 5.2.4.2.6 Number of biopsy procedures potentially avoided in the ‘MR pathway’ 24 5.2.4.2.7 Other considerations 24 5.2.4.2.7.1 mpMRI reproducibility 24 5.2.4.2.7.2 Targeted biopsy accuracy and reproducibility 24 5.2.4.2.7.3 Role of risk-stratification 25 5.2.4.3 Summary of evidence and practical considerations on pre-biopsy mpMRI 25 5.2.4.4 Summary of evidence and guidelines for imaging 25 5.2.5 Repeat biopsy 26 5.2.5.1 Repeat biopsy after previously negative biopsy 26 5.2.5.1.1 Tests to select men for a repeat biopsy 26 5.2.5.2 Saturation biopsy 26 5.2.6 Prostate biopsy procedure 27 5.2.6.1 Sampling sites and number of cores 27 5.2.6.2 Antibiotics prior to biopsy 27 5.2.6.3 Local anaesthesia prior to biopsy 27 5.2.6.4 Complications 27 5.2.6.5 Seminal vesicle biopsy 27 5.2.6.6 Transition zone biopsy 27 5.2.6.7 Fine-needle aspiration biopsy 28 5.2.7 Pathology of prostate needle biopsies 28 5.2.7.1 Processing 28 5.2.7.2 Microscopy and reporting 28 5.2.7.3 Tissue-based prognostic biomarker testing 29 5.2.7.4 Histopathology of radical prostatectomy specimens 29 5.2.7.4.1 Processing of radical prostatectomy specimens 29 5.2.7.4.1.1 Guidelines for processing prostatectomy specimens 29 5.2.7.4.2 Radical prostatectomy specimen report 29 5.2.7.4.3 ISUP grade in prostatectomy specimens 30 5.2.7.4.4 Definition of extraprostatic extension 30 5.2.7.4.5 PCa volume 31 5.2.7.4.6 Surgical margin status 31 5.2.8 Guidelines for the clinical diagnosis of prostate cancer 31 5.3 Diagnosis – Clinical Staging 31 5.3.1 T-staging 31 5.3.1.1 TRUS 31 5.3.1.2 mpMRI 32 5.3.2 N-staging 32 5.3.2.1 Computed tomography (CT) and magnetic resonance imaging 32 5.3.2.2 Choline PET/CT 32 5.3.2.3 Prostate-specific membrane antigen-based PET/CT 32 5.3.3 M-staging 33 5.3.3.1 Bone scan 33 5.3.3.2 Fluoride PET and PET/CT, choline PET/CT and MRI 33 5.3.3.3 Prostate-specific membrane antigen-based PET/CT 33 5.3.4 Summary of evidence and practical considerations on initial N/M staging 34 5.3.5 Guidelines for staging of prostate cancer 34 5.4 Evaluating life expectancy and health status 34 5.4.1 Introduction 34 5.4.2 Life expectancy 34 5.4.3 Health status screening 35 5.4.3.1 Comorbidity 35 5.4.3.2 Nutritional status 35 5.4.3.3 Cognitive function 35 5.4.3.4 Physical function 35 PROSTATE CANCER - UPDATE MARCH 2019 3 5.4.4 Conclusion 36 5.4.5 Guidelines for evaluating health status and life expectancy 38 6. TREATMENT 38 6.1 Treatment modalities 38 6.1.1 Deferred treatment (active surveillance/watchful waiting) 38 6.1.1.1 Definitions 38 6.1.1.2 Active surveillance 39 6.1.1.3 Watchful Waiting 39 6.1.1.3.1 Introduction 39 6.1.1.3.2 Outcome of watchful waiting compared with active treatment 39 6.1.1.4 The ProtecT study 40 6.1.2 Radical prostatectomy 40 6.1.2.1 Surgical techniques 41 6.1.2.1.1 Pelvic lymph node dissection 41 6.1.2.1.2 Sentinel node biopsy analysis 41 6.1.2.1.3 Nerve-sparing surgery 41 6.1.2.1.4 Neoadjuvant androgen deprivation therapy 41 6.1.2.1.5 Lymph-node-positive patients during radical prostatectomy 42 6.1.2.2 Comparing effectiveness of radical prostatectomy vs. other interventions for localised disease 42 6.1.2.2.1 Radical prostatectomy vs. deferred treatment 42 6.1.2.2.2 Radical prostatectomy vs. radiotherapy 42 6.1.2.3 Acute complications of surgery 42 6.1.2.3.1 Early complications of extended lymph node dissection 43 6.1.3 Radiotherapy 43 6.1.3.1 External Beam Radiation Therapy: 43 6.1.3.1.1 Technical aspects: intensity-modulated external-beam radiotherapy and volumetric arc external-beam radiotherapy 43 6.1.3.1.2 Dose escalation 43 6.1.3.1.3 Hypofractionation 44 6.1.3.1.4 Neoadjuvant or adjuvant hormone therapy plus radiotherapy 46 6.1.3.1.5 Combined dose-escalated radiotherapy and androgen- deprivation therapy 47 6.1.3.2 Proton beam therapy 48 6.1.3.3 Brachytherapy 48 6.1.3.3.1 Low-dose rate brachytherapy 48 6.1.3.3.2 High-dose rate brachytherapy 48 6.1.3.4 Acute side-effects of external beam radiotherapy and brachytherapy 49 6.1.4 Hormonal therapy 49 6.1.4.1 Introduction 49 6.1.4.1.1 Different types of hormonal therapy 49 6.1.4.1.1.1 Testosterone-lowering therapy (castration) 49 6.1.4.1.1.1.1 Castration level 49 6.1.4.1.1.1.2 Bilateral orchiectomy 49 6.1.4.1.1.2 Oestrogens 49 6.1.4.1.1.3 Luteinising-hormone-releasing hormone agonists 50 6.1.4.1.1.4 Luteinising-hormone-releasing hormone antagonists 50 6.1.4.1.1.5 Anti-androgens 50 6.1.4.1.1.5.1 Steroidal anti-androgens 50 6.1.4.1.1.5.1.1 Cyproterone acetate 50 6.1.4.1.1.5.2 Non-steroidal anti-androgens 50 6.1.4.1.1.5.2.1 Nilutamide 51 6.1.4.1.1.5.2.2 Flutamide 51 6.1.4.1.1.5.2.3 Bicalutamide 51 4 PROSTATE CANCER - UPDATE MARCH 2019 6.1.4.1.1.6 New compounds 51 6.1.4.1.1.6.1 Abiraterone acetate 51 6.1.4.1.1.6.2 Enzalutamide 51 6.1.4.1.1.6.3 Apalutamide 51 6.1.5 Investigational therapies 51 6.1.5.1 Background 51 6.1.5.2 Cryotherapy 51 6.1.5.3 High-intensity focused ultrasound 52 6.1.5.4 Focal therapy 52 6.1.6 General guidelines for active treatment 53 6.1.7 Discussing treatment options 53 6.2 Treatment by disease stages 53 6.2.1 Treatment of low-risk disease 53 6.2.1.1 Active surveillance 53 6.2.1.1.1 Selection criteria for active survillance based on clinical and pathological variables 53 6.2.1.1.2 Biological markers 53 6.2.1.1.3 Imaging for treatment selection 54 6.2.1.1.3.1 mpMRI in men eligible for active surveillance based on systematic biopsy findings only 54 6.2.1.1.3.1.1 Reduction of systematic biopsies in MRI-negative men on active surveillance.