Guidelines on Prostate Cancer A. Heidenreich (chairman), M. Bolla, S. Joniau, T.H. van der Kwast, V. Matveev, M.D. Mason, N. Mottet, H-P. Schmid, T. Wiegel, F. Zattoni © European Association of Urology 2009 TABLE OF CONTENTS PAGE 1 BACKGROUND 7 1.1 Reference 7 2. BACKGROUND 8 2.1 References 8 3. CLASSIFICATION 8 3.1 Gleason score 9 3.2 References 9 4. RISK FACTORS 9 4.1 References 10 5. SCREENING AND EARLY DETECTION 10 5.1 References 11 6. DIAGNOSIS 13 6.1 Digital rectal examination (DRE) 13 6.2 Prostate specific antigen (PSA) 13 6.2.1 Free/total PSA ratio (f/t PSA) 13 6.2.2 PSA velocity (PSAV), PSA doubling time (PSADT) 14 6.2.3 PCA3 marker 14 6.3 Transrectal ultrasonography (TRUS) 14 6.4 Prostate biopsy 14 6.4.1 Baseline biopsy 14 6.4.2 Repeat biopsy 14 6.4.3 Saturation biopsy 14 6.4.4 Sampling sites and number of cores 14 6.4.5 Diagnostic transurethral resection of the prostate (TURP) 15 6.4.6 Seminal vesicle biopsy 15 6.4.7 Transition zone biopsy 15 6.4.8 Antibiotics 15 6.4.9 Local anaesthesia 15 6.4.10 Fine-needle aspiration biopsy 15 6.4.11 Complications 15 6.5 Pathology of prostate needle biopsies 15 6.5.1 Grossing and processing 15 6.5.2 Microscopy and reporting 16 6.6 Pathohistology of radical prostatectomy (RP) specimens 17 6.6.1 Processing of the RP specimen 17 6.6.2 RP specimen report 17 6.6.2.1 Gleason score 18 6.6.2.2 Interpreting the Gleason score 18 6.6.2.3 Definition of extraprostatic extension 18 6.6.3 Prostate cancer volume 19 6.6.4 Surginal margin status 19 6.6.5 Other factors 19 6.7 References 19 7. STAGING 24 7.1 T-staging 24 7.2 N-staging 26 7.3 M-staging 27 7.4 Guidelines for the staging of prostate cancer (PCa) 28 7.5 References 28 2 UPDATE MARCH 2009 8. TREATMENT: DEFERRED TREATMENT (WATCHFUL WAITING [WW] / ACTIVE MONITORING 33 8.1 Introduction 33 8.1.1 Definition 33 8.2 Deferred treatment of localised PCa (stage T1-T2, Nx-N0, M0) 34 8.2.1 Watchful waiting (WW) 34 8.2.2 Active surveillance 36 8.3 Deferred treatment for locally advanced PCa (stage T3-T4, Nx-N0, M0) 37 8.4 Deferred treatment for metastatic PCa (stage M1) 38 8.5 Summary of deferred treatment 38 8.5.1 Indications 38 8.5.2 Options 38 8.6 References 39 9. TREATMENT: RADICAL PROSTATECTOMY 42 9.1 Introduction 42 9.2 Low-risk localised PCa: cT1-T2a AND Gleason score 2-6 and PSA < 10 43 9.2.1 Stage T1a-T1b PCa 43 9.2.2 Stage T1c and T2a PCa 43 9.3 Intermediate-risk localised PCa: cT2b-T2c OR Gleason score = 7 or PSA 10-20 43 9.3.1 Oncological results of RP in low- and intermediate risk PCa 44 9.4 High-risk localised PCa: cT3a OR Gleason score 8-10 or PSA > 20 44 9.4.1 Locally-advanced PCa: cT3a 44 9.4.2 High-grade PCa: Gleason score 8-10 45 9.4.3 PCa with PSA > 20 45 9.5 Very high-risk localised PCa: cT3b-T4 N0 or any T, N1 46 9.5.1 cT3b-T4 N0 46 9.5.2 Any T, N1 46 9.5.2.1 Indication and extent of extended pelvic lymph node dissection (eLND) 46 9.5.2.2 Therapeutic role of eLND 47 9.5.2.3 Morbidity 47 9.5.2.4 Summary of eLND 47 9.6 Summary of RP in high-risk localised disease 47 9.7 Neoadjuvant hormonal therapy and RP 47 9.7.1 Summary of neoadjuvant and adjuvant hormonal treatment and RP 48 9.8 Complications and functional outcome 48 9.9 Summary of indications for nerve-sparing surgery 48 9.10 Guidelines and recommendations for RP 49 9.11 References 49 10. TREATMENT: DEFINITIVE RADIATION THERAPY 56 10.1 Introduction 56 10.2 Technical aspects: three dimensional conformal radiotherapy and intensity modulated external beam radiotherapy 56 10.3 Localised prostate cancer T1-2c N0, M0 56 10.3.1 T1a-T2a, N0, M0 and Gleason score ≤ 6 and PSA < 10 ng/mL (low-risk group) 56 10.3.2 T2b or PSA 10-20 ng/mL, or Gleason score 7 (intermediate-risk group) 57 10.3.3 T2c or Gleason score > 7 or PSA > 20 ng/mL (high-risk group) 57 10.3.4 Prophylactic irradiation of pelvic lymph nodes in high-risk localised prostate cancer 57 10.4 Innovative techniques 58 10.4.1 Intensity modulated radiotherapy 58 10.4.2 Proton beam and carbon ion beam therapy 58 10.5 Transperineal brachytherapy 59 10.6 Late toxicity 60 10.7 Immediate post-operative external irradiation for pathological tumour stage T3 N0 M0 61 10.8 Locally advanced prostate cancer: T3-4 N0, M0 62 10.8.1 Neoadjuvant and concomitant hormonal therapy 62 10.8.2 Concomitant and long-term adjuvant hormonal therapy 62 10.8.3 Long-term adjuvant hormonal therapy 63 10.8.4 Neoadjuvant, concomitant and long-term adjuvant hormonal therapy 63 UPDATE MARCH 2009 3 10.8.5 Short-term or long-term adjuvant hormonal treatment 63 10.8.6 Dose escalation with hormonal therapy 63 10.9 Very high-risk prostate cancer: c or pN1 M0 63 10.10 Summary of definitive radiation therapy 64 10.11 References 64 11. EXPERIMENTAL LOCAL TREATMENT OF PROSTATE CANCER 70 11.1 Background 70 11.2 Cryosurgery of the prostate (CSAP) 70 11.2.1 Indication for CSAP 71 11.2.2 Results of modern cryosurgery for PCa 71 11.2.3 Complications of CSAP for primary treatment of PCa 71 11.2.4 Summary of CSAP 72 11.3 High-intensity focused ultrasound (HIFU) of the prostate 72 11.3.1 Results of HIFU in PCa 72 11.3.2 Complications of HIFU 73 11.4 Radiofrequency interstitial tumour ablation (RITA) 73 11.5 Summary of experimental therapeutic options to treat clinically localized PCa 73 11.6 References 73 12. HORMONAL THERAPY 74 12.1 Introduction 74 12.2 Basics of hormonal control of the prostate 75 12.3 Different types of hormonal therapy 75 12.3.1 Testosterone-lowering therapy (castration) 75 12.3.1.1 Bilateral orchiectomy 75 12.3.1.2 Oestrogens 75 12.3.1.3 LHRH agonists 76 12.3.1.4 LHRH antagonists 77 12.3.2 Anti-androgens 78 12.3.2.1 Steroidal anti-androgens 78 Cyproterone acetate (CPA) 78 Megestrol acetate and medroxyprogesterone acetate 78 12.3.2.2 Non-steroidal anti-androgens 78 Nilutamide 79 Flutamide 79 Bicalutamide 79 12.3.3 Combination therapies 81 12.3.3.1 Complete androgen blockade 81 12.3.3.2 Minimal androgen blockade (or peripheral androgen blockade) 81 12.3.3.3 Intermittent vs continuous androgen deprivation therapy 81 12.3.3.4 Immediate vs deferred ADT 83 12.4 Indications for hormonal therapy 84 12.5 Contraindications for various therapies 84 12.6 Outcome 85 12.7 Side-effects, QoL and cost of hormonal therapy 85 12.7.1 Side-effects 85 12.7.2 Quality of Life (QoL) 86 12.7.3 Cost-effectiveness of hormonal therapy options 87 12.8 Summary of hormonal therapy 87 12.9 References 88 13. SUMMARY OF GUIDELINES ON PRIMARY TREATMENT OF PCa 98 14 FOLLOW-UP: AFTER PRIMARY TREATMENT WITH CURATIVE INTENT 99 14.1 Definition 99 14.2 Why follow-up? 99 14.3 How to follow-up? 99 14.3.1 PSA monitoring 99 14.3.2 Definition of PSA progression 99 4 UPDATE MARCH 2009 14.3.3 PSA monitoring after radical prostatectomy 100 14.3.4 PSA monitoring after radiation therapy 100 14.3.5 Digital rectal examination (DRE) 100 14.3.6 Transrectal ultrasonography (TRUS) and biopsy 100 14.3.7 Bone scintigraphy 100 14.3.8 Computed tomography (CT) and magnetic resonance imaging (MRI) 100 14.4 When to follow-up? 101 14.5 Guidelines for follow-up after treatment with curative intent 101 14.6 References 101 15. FOLLOW-UP AFTER HORMONAL TREATMENT 103 15.1 Introduction 103 15.2 Purpose of follow-up 103 15.3 Methods of follow-up 103 15.3.1 Prostate-specific antigen monitoring 103 15.3.2 Creatinine, haemoglobin and liver function monitoring 103 15.3.3 Bone scan, ultrasound and chest X-ray 104 15.4 When to follow-up 104 15.4.1 Stage M0 patients 104 15.4.2 Stage M1 patients 104 15.4.3 Hormone-refractory patients 104 15.5 Guidelines for follow-up after hormonal treatment 104 15.6 References 105 16. TREATMENT OF BIOCHEMICAL FAILURE AFTER TRATMENT WITH CURATIVE INTENT 106 16.1 Background 106 16.2 Definitions 106 16.2.1 Definition of treatment failure 106 16.2.2 Definition of recurrence 106 16.3 Local or systemic relapse 106 16.3.1 Definition of local and systemic failure 107 16.4 Evaluation of PSA progression 108 16.5 Diagnostic procedures in patients with PSA relapse 109 16.6 Treatment of PSA-only recurrences 109 16.6.1 Radiation therapy for PSA-only recurrence after radical prostatectomy (RP) 109 16.6.2 Hormonal therapy 110 16.6.3 Observation 111 16.6.4 Management of PSA relapse after radical prostatectomy 111 16.7 Management of PSA failures after radiation therapy 111 16.7.1 Salvage cryosurgical ablation of the prostate (CSAP) for radiation failures 112 16.7.2 Salvage brachytherapy for radiation failures 112 16.7.3 Observation 112 16.7.4 Management of PSA-relapse after radiation therapy 113 16.8 Guidelines for second-line therapy after treatment with curative intent 113 16.9 References 113 17.