EAU - EANM - ESTRO -

ESUR - ISUP - SIOG

Guidelines on
Prostate Cancer
N. Mottet (Chair), P. Cornford (Vice-chair), R.C.N. van den Bergh,
E. Briers, Expert Patient Advocate (European Prostate Cancer
Coalition/Europa UOMO), D. Eberli, G. De Meerleer,
M. De Santis, S. Gillessen, J. Grummet, A.M. Henry,
T.H. van der Kwast, G.J.L.H. van Leenders, M.D. Mason,
S. O’Hanlon, I.M. van Oort, D.E. Oprea-Lager, G. Ploussard,
O. Rouvière, I.G. Schoots. J. Stranne, D. Tilki, T. Wiegel
Guidelines Associates: T. Van den Broeck, A. Farolfi, G. Gandaglia,
N. Grivas, M. Lardas, M. Liew, E. Linares Espinós, P-P.M. Willemse

© European Association of Urology 2023

TABLE OF CONTENTS PAGE
1. INTRODUCTION 11
1.1 Aims and scope 11
1.2 Panel composition 11
1.3 Available publications 11
1.4 Publication history and summary of changes 11
1.4.1 Publication history 11
1.4.2 Summary of changes 11

2. METHODS 16
2.1 Data identification 16
2.2 Review 17
2.3 Future goals 17

3. EPIDEMIOLOGY AND AETIOLOGY 17

3.1 Epidemiology 17
3.2 Aetiology 18
3.2.1 Family history/hereditary prostate cancer 18
3.2.1.1 Germline mutations and prostate cancer 18
3.2.2 Risk factors 19
3.2.2.1 Metabolic syndrome 19
3.2.2.1.1 Diabetes/metformin 19
3.2.2.1.2 Cholesterol/statins 19
3.2.2.1.3 Obesity 20
3.2.2.2 Dietary factors 20
3.2.2.3 Hormonally active medication 20
3.2.2.3.1 5-alpha-reductase inhibitors (5-ARIs) 20
3.2.2.3.2 Testosterone 20
3.2.2.4 Other potential risk factors 20
3.2.3 Summary of evidence for epidemiology and aetiology 21

4. CLASSIFICATION AND STAGING SYSTEMS 21

4.1 Classification 21
4.2 Gleason score and International Society of Urological Pathology 2019 grade 22
4.3 Clinically significant prostate cancer 23
4.4 Prognostic relevance of stratification 24
4.5 Guidelines for classification and staging systems 24

5. DIAGNOSTIC EVALUATION 24
5.1 Screening and individual early detection 24
5.1.1 Screening 24
5.1.2 Individual early detection 26
5.1.2.1 Risk assessment, co-morbidity and life-expectancy 26
5.1.2.2 Initial risk assessment by PSA and DRE 26
5.1.2.3 Risk assessment to determine the need for biopsy 26
5.1.3 Genetic testing for inherited prostate cancer 27
5.1.4 Guidelines for germline testing 27
5.1.5 Guidelines for screening and individual early detection 27
5.2 Clinical diagnosis 28
5.2.1 Digital rectal examination 28
5.2.2 Prostate-specific antigen 28
5.2.2.1 Repeat PSA testing 28
5.2.2.2 PSA density 29
5.2.2.3 Free/total PSA ratio 29
5.2.3 Other blood and urine biomarkers 29
5.2.3.1 Blood based biomarkers: PHI/4K score/IsoPSA 29
5.2.3.2 Urine biomarkers: PCA3/SelectMDX/Mi Prostate score (MiPS)/ExoDX 29
5.2.3.3 Biomarkers to select men for a repeat biopsy 30
5.2.4 Imaging 30

2 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

 5.2.4.1 Transrectal ultrasound and ultrasound-based techniques 30
5.2.4.2 Magnetic resonance imaging 30
5.2.4.2.1 MRI diagnostic performance in detecting PCa 30
5.2.4.2.2 Targetted biopsy improves the detection of ISUP
grade > 2 cancer as compared to systemic biopsy. 31
5.2.4.2.3 Reduced detection of ISUP grade 1 cancers by
MRI-targeted biopsy without systematic biopsy 31
5.2.4.2.4 Added value of systematic biopsy and targeted biopsy 31
5.2.4.2.5 Avoiding biopsies in the ‘MR pathway’ 32
5.2.4.2.6 Practical considerations 33
5.2.4.2.6.1 Prostate MRI reproducibility 33
5.2.4.2.6.2 Targeted biopsy accuracy and
reproducibility 33
5.2.4.2.6.3 Risk-stratification 33
5.2.4.2.6.4 Potential cancer grade shift, induced by
improved diagnosis by MRI and
MRI-targeted biopsy 35
5.2.4.3 Guidelines for MRI imaging in biopsy decision 35
5.2.5 Baseline biopsy decision 35
5.2.6 Repeat biopsy decision 36
5.2.6.1 Repeat biopsy after previously negative biopsy 36
5.2.6.2 Saturation biopsy 36
5.2.7 Prostate biopsy procedure 36
5.2.8 Summary of evidence and guidelines for prostate biopsies 36
5.2.8.1 Antibiotics prior to biopsy 37
5.2.8.1.1 Transperineal prostate biopsy 37
5.2.8.1.2 Transrectal prostate biopsy 37
5.2.8.2 Summary of evidence and recommendations for performing prostate
biopsy 38
5.2.8.3 Local anaesthesia prior to biopsy 40
5.2.8.4 Complications 40
5.2.8.5 Seminal vesicle biopsy 40
5.2.8.6 Transition zone biopsy 40
5.2.9 Pathology of prostate needle biopsies 41
5.2.9.1 Processing 41
5.2.9.2 Microscopy and reporting 41
5.2.9.2.1 Recommended terminology for reporting prostate
biopsies 41
5.2.9.2.2 Recommended item list for reporting prostate cancer
biopsies 42
5.2.9.3 Tissue-based prognostic biomarker testing 42
5.2.9.4 Histopathology of radical prostatectomy specimens 42
5.2.9.4.1 Processing of radical prostatectomy specimens 42
5.2.9.4.2 Radical prostatectomy specimen report 43
5.2.9.4.3 ISUP grade in prostatectomy specimens 43
5.2.9.4.4 Definition of extra-prostatic extension 44
5.2.9.4.5 PCa volume 44
5.2.9.4.6 Surgical margin status 44
5.3 Diagnosis - Clinical Staging 44
5.3.1 T-staging 44
5.3.1.1 US-based techniques and CT 44
5.3.1.2 MRI 44
5.3.2 N-staging 45
5.3.2.1 Computed tomography and MRI 45
5.3.2.2 Risk calculators incorporating MRI findings and clinical data 45
5.3.2.3 Choline PET/CT 45
5.3.2.4 Prostate-specific membrane antigen-based PET/CT 45
5.3.2.5 Risk calculators incorporating MRI and PSMA findings 46
5.3.3 M-staging 46
5.3.3.1 Bone scan 46

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 3

 5.3.3.2 Fluoride PET/CT, choline PET/CT and MRI 46
5.3.3.3 PSMA PET/CT 46
5.3.4 Summary of evidence and practical considerations on initial N/M staging 47
5.3.5 Summary of evidence and guidelines for staging of prostate cancer 47
5.4 Estimating life expectancy and health status 47
5.4.1 Introduction 47
5.4.2 Life expectancy 48
5.4.3 Health status screening 48
5.4.3.1 Co-morbidity 49
5.4.3.2 Nutritional status 49
5.4.3.3 Cognitive function 49
5.4.3.4 Physical function 49
5.4.3.5 Shared decision-making 49
5.4.4 Conclusion 49
5.4.5 Guidelines for evaluating health status and life expectancy 52

6. TREATMENT 52
6.1 Treatment modalities 52
6.1.1 Deferred treatment (active surveillance/watchful waiting) 52
6.1.1.1 Active surveillance 53
6.1.1.2 Watchful Waiting 54
6.1.2 Radical prostatectomy 55
6.1.2.1 Introduction 55
6.1.2.2 Pre-operative preparation 55
6.1.2.2.1 Pre-operative patient education 55
6.1.2.2.2 Pre-operative pelvic floor exercises 55
6.1.2.2.3 Prophylactic antibiotics 55
6.1.2.2.4 Neoadjuvant androgen deprivation therapy 55
6.1.2.2.5 Timing of radical prostatectomy 56
6.1.2.3 Surgical techniques 56
6.1.2.3.1 Robotic anterior versus Retzius-sparing dissection 56
6.1.2.3.2 Pelvic lymph node dissection 57
6.1.2.3.2.1 Early complications of extended pelvic
lymph node dissection 57
6.1.2.3.2.2 Sentinel node biopsy analysis 58
6.1.2.3.3 Prostatic anterior fat pad dissection and histologic
analysis 58
6.1.2.3.4 Management of the dorsal venous complex 58
6.1.2.3.5 Nerve-sparing surgery 58
6.1.2.3.6 Lymph-node-positive patients during radical
prostatectomy 59
6.1.2.3.7 Removal of seminal vesicles 59
6.1.2.3.8 Techniques of vesico-urethral anastomosis 59
6.1.2.3.9 Bladder neck management 60
6.1.2.3.10 Urethral length preservation 60
6.1.2.3.11 Cystography prior to catheter removal 60
6.1.2.3.12 Urinary catheter 60
6.1.2.3.13 Use of a pelvic drain 61
6.1.2.4 Acute and chronic complications of radical protatectomy 61
6.1.2.4.1 Effect of anterior and posterior reconstruction on
continence 62
6.1.2.4.2 Deep venous thrombosis prophylaxis 62
6.1.3 Radiotherapy 63
6.1.3.1 External beam radiation therapy 63
6.1.3.1.1 Technical aspects 63
6.1.3.1.2 Dose escalation 63
6.1.3.1.3 Hypofractionation 65
6.1.3.1.4 Neoadjuvant or adjuvant hormone therapy plus
radiotherapy 66

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 6.1.3.1.5 Combined dose-escalated radiotherapy and androgen-
deprivation therapy 68
6.1.3.2 Proton beam therapy 69
6.1.3.3 Spacer during external beam radiation therapy 69
6.1.3.4 Brachytherapy 69
6.1.3.4.1 Low-dose rate brachytherapy 69
6.1.3.4.2 High-dose rate brachytherapy 70
6.1.3.5 Acute side effects of external beam radiotherapy and brachytherapy 70
6.1.4 Hormonal therapy 71
6.1.4.1 Introduction 71
6.1.4.1.1 Different types of hormonal therapy 71
6.1.4.1.1.1 Testosterone-lowering therapy (castration) 71
6.1.4.1.1.1.1 Castration level 71
6.1.4.1.1.1.2 Bilateral orchiectomy 71
6.1.4.1.1.1.3 Oestrogens 71
6.1.4.1.1.1.4 Luteinising-hormone-releasing
hormone agonists 71
6.1.4.1.1.1.5 Luteinising-hormone-releasing
hormone antagonists 72
6.1.4.1.1.1.6 Anti-androgens 72
6.1.4.1.1.1.6.1 Steroidal anti-androgens 72
6.1.4.1.1.1.6.2 Non-steroidal anti-androgens 72
6.1.4.1.1.2 New androgen receptor pathway inhibitors 72
6.1.4.1.1.2.1 Abiraterone acetate 73
6.1.4.1.1.2.2 Apalutamide, darolutamide,
enzalutamide 73
6.1.4.2 Non-hormonal non-cytotoxic drug treatments 73
6.1.4.2.1 PARP inhibitors 73
6.1.4.2.2 Immune checkpoint inhibitors 73
6.1.4.3 Radiopharmaceutical therapy 73
6.1.5 Investigational therapies 73
6.1.5.1 Background 73
6.1.5.2 Whole-gland therapies 74
6.1.5.2.1 Cryotherapy for whole-gland treatment 74
6.1.5.2.2 High-intensity focused ultrasound for whole-gland
treatment 74
6.1.5.3 Focal therapy for whole-gland treatment 74
6.1.6 General guidelines for the treatment of prostate cancer 76
6.2 Treatment by disease stages 76
6.2.1 Treatment of low-risk disease 76
6.2.1.1 Active surveillance 76
6.2.1.1.1 Active surveillance - inclusion criteria 76
6.2.1.1.2 Tissue-based prognostic biomarker testing for selection
for active surveillance 77
6.2.1.1.3 Magnetic resonance imaging for selection for active
surveillance 77
6.2.1.1.4 Follow-up during active surveillance 77
6.2.1.1.5 Active Surveillance - change in treatment 78
6.2.1.2 Alternatives to active surveillance 78
6.2.1.2.1 Androgen deprivation monotherapy 79
6.2.1.3 Summary of evidence and guidelines for follow-up during active
surveillance 79
6.2.1.4 Summary of evidence and guidelines for the management of low-risk
disease 79
6.2.2 Treatment of intermediate-risk disease 80
6.2.2.1 Active Surveillance 80
6.2.2.2 Radical prostatectomy 81
6.2.2.3 Radiation therapy 81
6.2.2.3.1 Recommended IMRT/VMAT for intermediate-risk PCa 81
6.2.2.3.2 Brachytherapy for intermediate-risk PCa 82

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 5

 6.2.2.4 Other options for the primary treatment of intermediate-risk PCa
(experimental therapies) 82
6.2.2.4.1 Focal therapy 82
6.2.2.4.2 Androgen deprivation therapy monotherapy 82
6.2.2.5 Guidelines for the treatment of intermediate-risk disease 82
6.2.3 Treatment of high-risk localised disease 83
6.2.3.1 Radical prostatectomy 83
6.2.3.1.1 ISUP grade 4–5 83
6.2.3.1.2 Prostate-specific antigen > 20 ng/mL 83
6.2.3.1.3 Radical prostatectomy in cN0 patients with
pathologically confirmed LN invasion (pN1) 83
6.2.3.2 External beam radiation therapy 83
6.2.3.2.1 Lymph node irradiation in cN0 84
6.2.3.2.2 Brachytherapy boost 84
6.2.3.3 Options other than surgery or radiotherapy for the primary treatment
of localised PCa 84
6.2.3.4 Guidelines for radical and palliative treatment of high-risk localised
disease 84
6.2.4 Treatment of locally-advanced PCa 84
6.2.4.1 Radical prostatectomy 85
6.2.4.2 Radiotherapy for locally-advanced PCa 85
6.2.4.3 Treatment of cN1 M0 PCa 85
6.2.4.4 Options other than surgery or radiotherapy for primary treatment 87
6.2.4.4.1 Investigational therapies 87
6.2.4.4.2 Androgen deprivation therapy monotherapy 87
6.2.4.5 Guidelines for radical- and palliative treatment of locally-advanced
disease 87
6.2.5 Adjuvant treatment after radical prostatectomy 87
6.2.5.1 Introduction 87
6.2.5.2 Risk factors for relapse 87
6.2.5.2.1 Biomarker-based risk stratification after radical
prostatectomy 88
6.2.5.3 Immediate (adjuvant) post-operative external irradiation after RP
(cN0 or pN0) 88
6.2.5.4 Comparison of adjuvant- and salvage radiotherapy 88
6.2.5.5 Adjuvant systemic therapy in N0 disease 90
6.2.5.6 Adjuvant treatment in pN1 disease 90
6.2.5.6.1 Adjuvant androgen ablation alone 90
6.2.5.6.2 Adjuvant radiotherapy combined with ADT in pN1
disease 90
6.2.5.6.3 Observation of pN1 patients after radical prostatectomy
and extended lymph node dissection 91
6.2.5.7 Guidelines for adjuvant treatment for pN0 and pN1 disease after
radical prostatectomy 91
6.2.6 Persistent PSA after radical prostatectomy 91
6.2.6.1 Natural history of persistently elevated PSA after RP 91
6.2.6.2 Imaging in patients with persistently elevated PSA after RP 92
6.2.6.3 Impact of post-operative RT and/or ADT in patients with persistent
PSA 92
6.2.6.4 Conclusion 93
6.2.6.5 Recommendations for the management of persistent PSA after
radical prostatectomy 93
6.3 Management of PSA-only recurrence after treatment with curative intent 93
6.3.1 Background 93
6.3.1.1 PSA velocity and doubling time 93
6.3.2 Controversies in the definitions of clinically relevant PSA relapse 94
6.3.3 Natural history of biochemical recurrence 94
6.3.4 The role of imaging in PSA-only recurrence 95
6.3.4.1 Assessment of metastases (including nodal) 95
6.3.4.1.1 Bone scan and abdominopelvic CT 95

6 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

 6.3.4.1.2 Choline PET/CT 95
6.3.4.1.3 Fluoride PET/CT 95
6.3.4.1.4 Fluciclovine PET/CT 95
6.3.4.1.5 Prostate-specific membrane antigen based PET/CT 96
6.3.4.1.6 Whole-body and axial MRI 96
6.3.4.2 Assessment of local recurrences 96
6.3.4.2.1 Local recurrence after radical prostatectomy 96
6.3.4.2.2 Local recurrence after radiation therapy 97
6.3.4.3 Summary of evidence of imaging in case of biochemical recurrence 97
6.3.4.4 Summary of evidence and guidelines for imaging in patients with
biochemical recurrence 97
6.3.5 Treatment of PSA-only recurrences 97
6.3.5.1 Treatment of PSA-only recurrences after radical prostatectomy 97
6.3.5.1.1 Salvage radiotherapy for PSA-only recurrence after
radical prostatectomy (cTxcN0M0, without PET/CT) 97
6.3.5.1.2 Salvage radiotherapy combined with androgen
deprivation therapy (cTxcN0, without PET/CT) 99
6.3.5.1.2.1 Target volume, dose, toxicity 101
6.3.5.1.2.2 Salvage radiotherapy with or without ADT
(cTx cN0/1) with PET/CT 102
6.3.5.1.2.3 Nodal-directed therapy for rcN1
(with PET/CT) 103
6.3.5.1.3 Salvage lymph node dissection 103
6.3.5.2 Management of PSA failures after radiation therapy 103
6.3.5.2.1 Salvage radical prostatectomy 104
6.3.5.2.1.1 Oncological outcomes 104
6.3.5.2.1.2 Morbidity 104
6.3.5.2.1.3 Summary of salvage radical prostatectomy 104
6.3.5.2.2 Salvage cryoablation of the prostate 104
6.3.5.2.2.1 Oncological outcomes 104
6.3.5.2.3 Salvage re-irradiation 105
6.3.5.2.3.1 Salvage brachytherapy for radiotherapy
failure 105
6.3.5.2.3.2 Salvage stereotactic ablative body
radiotherapy for radiotherapy failure 106
6.3.5.2.3.2.1 Oncological outcomes and morbidity 106
6.3.5.2.3.2.2 Morbidity 106
6.3.5.2.3.2.3 Summary of salvage stereotactic
ablative body radiotherapy 106
6.3.5.2.4 Salvage high-intensity focused ultrasound 106
6.3.5.2.4.1 Oncological outcomes 106
6.3.5.2.4.2 Morbidity 107
6.3.5.2.4.3 Summary of salvage high-intensity focused
ultrasound 107
6.3.6 Hormonal therapy for relapsing patients 107
6.3.7 Observation 108
6.3.8 Guidelines for second-line therapy after treatment with curative intent 108
6.4 Treatment: Metastatic prostate cancer 108
6.4.1 Introduction 108
6.4.2 Prognostic factors 109
6.4.3 First-line hormonal treatment 109
6.4.3.1 Non-steroidal anti-androgen monotherapy 109
6.4.3.2 Intermittent versus continuous androgen deprivation therapy 109
6.4.3.3 Early versus deferred androgen deprivation therapy 110
6.4.4 Combination therapies 110
6.4.4.1 ‘Combined’ androgen blockade with older generation NSAA
(bicalutamide, flutamide, nilutamide) 110
6.4.4.2 Androgen deprivation combined with other agents 110
6.4.4.2.1 Androgen deprivation therapy combined with
chemotherapy 110

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 7

 6.4.4.2.2 Combination with an ARPI alone (abiraterone,
apalutamide, enzalutamide) 112
6.4.4.2.3 Combination with docetaxel and an ARPI 114
6.4.5 Treatment selection and patient selection 114
6.4.6 Treatment of the primary tumour in newly diagnosed metastatic disease 114
6.4.7 Metastasis-directed therapy in M1-patients 115
6.4.8 Guidelines for the first-line treatment of hormone-sensitive metastatic disease 115
6.5 Treatment: Castration-resistant PCa (CRPC) 116
6.5.1 Definition of CRPC 116
6.5.2 Management of mCRPC - general aspects 116
6.5.2.1 Molecular diagnostics 116
6.5.3 Treatment decisions and sequence of available options 116
6.5.4 Non-metastatic CRPC 116
6.5.5 Metastatic CRPC 117
6.5.5.1 Conventional androgen deprivation in CRPC 117
6.5.6 First-line treatment of metastatic CRPC 118
6.5.6.1 Abiraterone 118
6.5.6.2 Enzalutamide 118
6.5.6.3 Docetaxel 118
6.5.6.4 Sipuleucel-T 118
6.5.6.5 Ipatasertib 118
6.5.6.6 Combinations 119
6.5.7 Second-line treatment for mCRPC and sequence 120
6.5.7.1 Cabazitaxel 120
6.5.7.2 Abiraterone acetate after docetaxel 120
6.5.7.3 Enzalutamide after docetaxel 121
6.5.7.4 Radium-223 121
6.5.8 Treatment after docetaxel and one line of hormonal treatment for mCRPC 121
6.5.8.1 Hormonal treatment 121
6.5.8.2 Radiopharmaceuticals 122
6.5.8.2.1 Introduction 122
6.5.8.2.2 PSMA-based therapy 122
6.5.8.3 PARP inhibitors for mCRPC 123
6.5.8.4 Sequencing treatment 123
6.5.8.4.1 ARPI -> ARPI (chemotherapy-naive patients) 123
6.5.8.4.2 ARPI -> PARP inhibitor/olaparib 123
6.5.8.4.3 Docetaxel for mHSPC -> docetaxel rechallenge 123
6.5.8.4.4 ARPI -> docetaxel or docetaxel -> ARPI followed by
PARP inhibitor 124
6.5.8.4.5 ARPI before or after docetaxel 124
6.5.8.4.6 ARPI –> docetaxel -> cabazitaxel or docetaxel –>
ARPI -> cabazitaxel 124
6.5.8.5 Platinum chemotherapy 125
6.5.9 Monitoring of treatment 125
6.5.10 When to change treatment 126
6.5.11 Symptomatic management in metastatic CRPC 126
6.5.11.1 Common complications due to bone metastases 126
6.5.11.2 Preventing skeletal-related events 126
6.5.11.2.1 Bisphosphonates 126
6.5.11.2.2 RANK ligand inhibitors 127
6.5.12 Summary of evidence and guidelines for life-prolonging treatments of
castrate-resistant disease 127
6.5.13 Guidelines for systematic treatments of castrate-resistant disease 127
6.5.14 Guideline for non-metastatic castrate-resistant disease 128
6.5.15 Guidelines for supportive care of castrate-resistant disease 128
6.6 Summary of guidelines for the treatment of prostate cancer 128
6.6.1 General guidelines recommendations for the treatment of prostate cancer 129
6.6.2 Guidelines recommendations for fist-line treatment of various disease stages 129
6.6.3 Guidelines for metastatic disease, second-line and palliative treatments 132

8 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

7. FOLLOW-UP 135
7.1 Follow-up: After local treatment 135
7.1.1 Definition 135
7.1.2 Why follow-up? 135
7.1.3 How to follow-up? 135
7.1.3.1 Prostate-specific antigen monitoring 135
7.1.3.1.1 Active surveillance follow-up 135
7.1.3.1.2 Prostate-specific antigen monitoring after radical
prostatectomy 135
7.1.3.1.3 Prostate-specific antigen monitoring after radiotherapy 136
7.1.3.2 Digital rectal examination 136
7.1.3.3 Transrectal ultrasound, bone scintigraphy, CT, MRI and PET/CT 136
7.1.3.4 Functional follow-up 136
7.1.4 How long to follow-up? 136
7.1.5 Summary of evidence and guidelines for follow-up after treatment with
curative intent 137
7.2 Follow-up: During first line hormonal treatment (androgen sensitive period) 137
7.2.1 Introduction 137
7.2.2 Purpose of follow-up 137
7.2.3 General follow-up of men on ADT 137
7.2.3.1 Testosterone monitoring 137
7.2.3.2 Liver function monitoring 138
7.2.3.3 Serum creatinine and haematological parameters 138
7.2.3.4 Monitoring of metabolic complications 138
7.2.3.5 Monitoring bone problems 138
7.2.3.6 Monitoring lifestyle, cognition, fatigue and sexual function 138
7.2.4 Methods of follow-up in men on ADT without metastases 139
7.2.4.1 Prostate-specific antigen monitoring 139
7.2.4.2 Imaging 139
7.2.5 Methods of follow-up in men under ADT for hormone-sensitive metastatic PCa 139
7.2.5.1 PSA monitoring 139
7.2.5.2 Imaging as a marker of response in metastatic PCa 139
7.2.6 Guidelines for follow-up during hormonal treatment 140

8. QUALITY OF LIFE OUTCOMES IN PROSTATE CANCER 140

8.1 Introduction 140
8.2 Adverse effects of PCa therapies 140
8.2.1 Surgery 140
8.2.2 Radiotherapy 141
8.2.2.1 Side effects of external beam radiotherapy 141
8.2.2.2 Side effects from brachytherapy 141
8.2.3 Local primary whole-gland treatments other than surgery or radiotherapy 141
8.2.3.1 Cryosurgery 141
8.2.3.2 High-intensity focused ultrasound 141
8.2.4 Hormonal therapy 141
8.2.4.1 Sexual function 142
8.2.4.2 Hot flushes 142
8.2.4.3 Non-metastatic bone fractures 142
8.2.4.4 Metabolic effects 142
8.2.4.5 Cardiovascular morbidity 143
8.2.4.6 Fatigue 143
8.2.4.7 Neurological side effects 143
8.3 Overall quality of life in men with PCa 143
8.3.1 Long-term (> 12 months) quality of life outcomes in men with localised disease 144
8.3.1.1 Men undergoing local treatments 144
8.3.1.2 Guidelines for quality of life in men undergoing local treatments 145
8.3.2 Improving quality of life in men who have been diagnosed with PCa 146
8.3.2.1 Men undergoing local treatments 146
8.3.2.2 Men undergoing systemic treatments 146
8.3.2.3 Decision regret 147

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 9

 8.3.2.4 Decision aids in prostate cancer 147
8.3.2.5 Guidelines for quality of life in men undergoing systemic treatments 148

9. REFERENCES 148

10. CONFLICT OF INTEREST 233

11. CITATION INFORMATION 233

10 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

1. INTRODUCTION
1.1 Aims and scope
The Prostate Cancer (PCa) Guidelines Panel have prepared this guidelines document to assist medical
professionals in the evidence-based management of PCa.
It must be emphasised that clinical guidelines present the best evidence available to the experts
but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never
replace clinical expertise when making treatment decisions for individual patients, but rather help to focus
decisions - also taking personal values and preferences/individual circumstances of patients into account.
Guidelines are not mandates and do not purport to be a legal standard of care.

1.2 Panel composition

The PCa Guidelines Panel consists of an international multidisciplinary group of urologists, radiation
oncologists, medical oncologists, radiologists, pathologists, a geriatrician and a patient representative.

All imaging sections in the text have been developed jointly with the European Society of Urogenital Radiology
(ESUR) and the European Association of Nuclear Medicine (EANM). Representatives of the ESUR and the
EANM in the PCa Guidelines Panel are (in alphabetical order): Dr. A. Farolfi, Dr. D. Oprea-Lager, Prof.Dr. O.
Rouvière and Dr. I.G. Schoots.
All radiotherapy (RT) sections have been developed jointly with the European Society for
Radiotherapy & Oncology (ESTRO). Representatives of ESTRO in the PCa Guidelines Panel are (in alphabetical
order): Prof.Dr. G. De Meerleer, Prof.Dr. A.M. Henry, Prof.Dr. M.D. Mason and Prof.Dr. T. Wiegel.
The International Society of Urological Pathology is represented by Prof.Dr. T. van der Kwast and
Prof.Dr. A. van Leenders.
Dr. S. O’Hanlon, consultant geriatrician, representing the International Society of Geriatric Oncology
(SOIG) contributed to the sections addressing life expectancy, health status and quality of life (QoL) in
particular.
Dr. E. Briers, expert Patient Advocate Hasselt-Belgium representing the patient voice as delegated
by the European Prostate Cancer Coalition/Europa UOMO.
All experts involved in the production of this document have submitted potential conflict of interest
statements which can be viewed on the EAU website Uroweb: https://uroweb.org/guideline/prostate-cancer/.

1.3 Available publications

A quick reference document (Pocket guidelines) is available. This is an abridged version which may require
consultation together with the full text version. Several scientific publications are available [1, 2] as are a
number of translations of all versions of the PCa Guidelines. All documents can be accessed on the EAU
website: http://uroweb.org/guideline/prostate-cancer/.

1.4 Publication history and summary of changes

1.4.1 Publication history
The EAU PCa Guidelines were first published in 2001. This 2023 document presents a limited update of the
2022 EAU-EANM-ESTRO-ESUR-ISUP-SIOG PCa Guidelines.

1.4.2 Summary of changes

The literature for the complete document has been assessed and updated based upon a review of all
recommendations and creation of appropriate GRADE forms. Evidence summaries and recommendations have
been amended throughout the current document and several new sections have been added.

All chapters of the 2022 PCa Guidelines have been updated. New data have been included in the following
sections, resulting in new sections, and new and revised recommendations:

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 11

 Table 4.3: E
 AU risk groups for biochemical recurrence of localised and locally-advanced prostate
cancer
Definition
Low-risk Intermediate-risk High-risk
PSA < 10 ng/mL PSA 10–20 ng/mL PSA > 20 ng/mL any PSA
and GS < 7 (ISUP grade 1) or GS 7 (ISUP grade 2/3) or GS > 7 (ISUP grade 4/5) any GS (any ISUP
and cT1-2a* or cT2b* or cT2c* grade)*
cT3-4* or cN+**
Localised Locally advanced
GS = Gleason score; ISUP = International Society of Urological Pathology; PSA = prostate-specific antigen.
* Based on digital rectal examination.
** Based on CT/bone scan.

5.1.5 Guidelines for screening and individual early detection

Recommendations Strength rating

In asymptomatic men with a prostate-specific antigen (PSA) level between Weak
3–10 ng/mL and a normal digital rectal examination (DRE), repeat the PSA test
prior to further investigations.
In asymptomatic men with a PSA level between 3–10 ng/mL and a normal DRE, use Strong
one of the following tools for biopsy indication:
• risk-calculator, provided it is correctly calibrated to the population prevalence;
• magnetic resonance imaging of the prostate
• an additional serum, urine biomarker test Weak

5.2.8.2 S
 ummary of evidence and recommendations for performing prostate biopsy
(in line with the EAU Urological Infections Guidelines Panel)

Summary of evidence LE
A meta-analysis of eight studies including 1,596 patients showed significantly reduced 1a
infectious complications in patients undergoing transperineal biopsy as compared to
transrectal biopsy.
A meta-analysis of eight non-RCTS reported comparable rates of post-biopsy infections in 1a
patients undergoing transperineal biopsy irrespective if antibiotic prophylaxis was given or not.
A meta-analysis of eleven RCTs including 2,036 men showed that use of a rectal povidone- 1a
iodine preparation before transrectal biopsy, in addition to antimicrobial prophylaxis, resulted
in a significantly lower rate of infectious complications.

Figure 5.1: Prostate biopsy workflow to reduce infectious complications*

Indicaon for prostate biopsy?

Transperineal biopsy feasible?

Yes No

Transperineal biopsy - 1st choice ( ) Transrectal biopsy – 2nd choice ( )

with: with:
• perineal cleansing1 • povidone-iodine rectal preparaon
• anbioc prophylaxis1 • anbioc prophylaxis2

Fluoroquinolones licensed?3

No Yes

1. Targeted prophylaxis1,7: based on rectal Duraon of anbioc prophylaxis ≥ 24 hrs

swab or stool cultures ( )

2. Augmented prophylaxis1,2,4: two or more 1. Targeted prophylaxis6,7 ( ): based

different classes of anbiocs on rectal swab or stool cultures
3. Alternave anbiocs5 ( ): 2. Augmented prophylaxis2,4,6,8 ( ):
• fosfomycin trometamol (e.g. 3 g before • Fluoroquinolone plus aminoglycoside
and 3 g 24-48 hrs aŽer biopsy)* • Fluoroquinolone plus cephalosporin
• cephalosporin (e.g. ceŽriaxone 1 g i.m.;
cefixime 400 mg p.o. for 3 days starng 3. Fluoroquinolone prophylaxis5
24 hrs before biopsy) ( ; )
• aminoglycoside (e.g. gentamicin 3 mg/kg
i.v.; amikacin 15 mg/kg i.m.)

12 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

 5.3.5 Summary of evidence and guidelines for staging of prostate cancer

Recommendation Strength rating

Any risk group staging
Treatment should not be changed based on PSMA PET/CT findings, in view of Strong
current available data.

6.1.6 General guidelines for the treatment of prostate cancer*

Recommendations Strength rating

Offer a watchful waiting policy to asymptomatic patients with clinically localised Strong
disease and with a life expectancy < 10 years (based on co-morbidities and age).
Surgical treatment
Radical prostatectomy (RP) can be safely delayed for at least 3 months from Weak
diagnosis in any risk category.
When a lymph node dissection (LND) is deemed necessary based on a nomogram, Strong
perform an extended LND template for optimal staging.
Radiotherapeutic treatment
Offer moderate hypofractionation (HFX) with IMRT/VMAT plus IGRT to the prostate Strong
to patients with localised disease (60 Gy/20 fractions in 4 weeks or 70 Gy/28
fractions in 6 weeks).
Offer low-dose rate (LDR) brachytherapy monotherapy to patients with good urinary Strong
function and low-risk or NCCN favourable intermediate-risk disease.
Offer LDR or high-dose rate (HDR) brachytherapy boost combined with IMRT/ Weak
VMAT plus IGRT to patients with good urinary function and NCCN unfavourable
intermediate-risk or high-risk disease and/or locally-advanced disease.
Active therapeutic options outside surgery or radiotherapy
Only offer focal therapy with high-intensity focused ultrasound or cryotherapy within Strong
a clinical trial or prospective registry.
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR
abdomen/pelvis.

6.2.1.3 Summary of evidence and guidelines for follow-up during active surveillance

Summary of evidence LE
Serial magnetic resonance imaging can improve the detection of aggressive cancers during 3
follow-up.
A progression on MRI mandates a repeat biopsy before a change in treatment strategy.
A stationary MRI does not make repeat biopsy superfluous.

Recommendations Strength rating

Base follow-up during active surveillance (AS) on a strict protocol including digital Strong
rectal examination (at least once yearly), prostate-specific antigen (PSA) (at least
once every 6 months) and repeated biopsy every 2 to 3 years.
Perform magnetic resonance imaging (MRI) and repeat biopsy if PSA is rising (PSA- Strong
doubling time < 3 years).
Re-classify patients with low-volume ISUP grade group 2 disease included in Weak
AS protocols, if repeat non-MRI-based systematic biopsies performed during
monitoring reveal > 3 positive cores or maximum CI > 50%/core of ISUP 2 disease.
Base change in treatment on biopsy progression, not on progression on MRI and/ Weak
or PSA.
Patients with a PI-RADS 1-2 findings on MRI and a low PSA density (< 0.15) may be Weak
excepted from repeat biopsy.

6.2.1.4 Summary of evidence and guidelines for the management of low-risk disease*

Summary of evidence LE
Active surveillance or WW is SOC, based on life expectancy. 2a
All active treatment options present a risk of over-treatment. 1a

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 13

 Recommendations Strength rating
Watchful Waiting
Manage patients with a life expectancy < 10 years by watchful waiting. Strong
Active surveillance (AS)
Manage patients with a life expectancy > 10 years and low-risk disease by AS. Strong
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR
abdomen/pelvis.

6.2.2.5 Guidelines for the treatment of intermediate-risk disease*

Recommendations Strength rating

Watchful Waiting (WW)
Offer WW in asymptomatic patients with life expectancy < 10 years. Strong
Radical prostatectomy (RP)
Offer RP to patients with a life expectancy of > 10 years. Strong
Radical prostatectomy can be safely delayed for at least 3 months. Weak
Offer nerve-sparing surgery to patients with a low risk of extra-capsular disease on Strong
that side.
Radiotherapeutic treatment
Offer LDR brachytherapy boost combined with IMRT/VMAT plus IGRT to patients Weak
with good urinary function and NCCN unfavourable intermediate-risk disease, in
combination with short-term ADT (4–6 months).
Offer high-dose rate (HDR) brachytherapy boost combined with IMRT/VMAT plus Weak
IGRT to patients with good urinary function and NCCN unfavourable intermediate-
risk disease, in combination with short-term ADT (4–6 months).
Other therapeutic options
Only offer whole-gland ablative therapy (such as cryotherapy, high-intensity focused Strong
ultrasound, etc.) or focal ablative therapy within clinical trials or registries.
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR
abdomen/pelvis.

6.2.3.4 Guidelines for radical and palliative treatment of high-risk localised disease*

Recommendations Strength rating

Watchful Waiting
Offer WW to asymptomatic patients with life expectancy < 10 years. Strong
Radical prostatectomy (RP)
Radical prostatectomy can be safely delayed for at least 3 months. Weak
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR
abdomen/pelvis.

6.2.4.5 Guidelines for radical- and palliative treatment of locally-advanced disease*

Recommendations Strength rating

Radical prostatectomy (RP)
Offer RP to patients with cN0 disease as part of multi-modal therapy. Weak
Radiotherapeutic treatment
Offer IMRT/VMAT plus IGRT to the prostate in combination with long-term ADT and Strong
2 years of abiraterone to cN0M0 patients with > 2 high-risk factors (cT3-4, Gleason
> 8 or PSA > 40 ng/mL).
Offer IMRT/VMAT plus IGRT to the prostate plus pelvis in combination with Strong
long-term ADT and 2 years of abiraterone to cN1M0 patients.
Offer patients with cN1 disease a local treatment (either RP or IMRT/VMAT plus Strong
IGRT) plus long-term ADT.
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR
abdomen/pelvis.

14 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

 6.2.5.7 Guidelines for adjuvant treatment for pN0 and pN1 disease after radical prostatectomy*

Recommendations Strength rating

In pN0 patients with ISUP grade group 4–5 and pT3 ± positive margins, offer adjuvant Strong
intensity-modulated radiation therapy (IMRT)/volumetric modulated arc therapy (VMAT)
plus image-guided radiation therapy (IGRT).
In pN1 patients, after an extended lymph node dissection, discuss three Weak
management options, based on nodal involvement characteristics:
1. Offer adjuvant ADT;
2. Offer adjuvant ADT with additional IMRT/VMAT plus IGRT;
3. Offer observation (expectant management) to a patient after eLND and
< 2 nodes and a PSA < 0.1 ng/mL.
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR
abdomen/pelvis.

6.4.8 Guidelines for the first-line treatment of hormone-sensitive metastatic disease*

Recommendations Strength rating

At the start of ADT offer luteinising hormone-releasing hormone (LHRH) antagonists Strong
or orchiectomy to patients with impending clinical complications like spinal cord
compression or bladder outlet obstruction.
Offer docetaxel only in combination with ADT plus abiraterone or darolutamide to Strong
patients with M1 disease and who are fit for docetaxel.
Offer ADT combined with non-curative prostate radiotherapy (using doses up to Strong
the equivalent of 72 Gy in 2 Gy fractions) to patients whose first presentation is M1
disease and who have low volume of disease by CHAARTED criteria/M1a disease.
*All the following statements are based on metastatic disease defined by bone scintigraphy and CT
scan/MRI.

• Section 6.6: Two new flowcharts were introduced

Figure 6.1: Treatment non-metastasized (M0) – asymptomatic disease#

Eligible for ac
ve Radical prostatectomy +/- ePLND
surveillance? (ePLND based on nomogram risk)
Prostate cancer - All low-risk
adenocarcinoma Candidate for disease. EBRT1 + ADT (4–6 mo)
cura
ve yes no Intermediate
- non- - Selected pts with (76–78 Gy, moderate hypofraconaon (3 Gy – 60 Gy or 2.5 Gy – 70
treatment? ≤ 1 element of int risk
metastasized (PSA 10–20 or Gy)
(life expectancy risk disease (if GG2
(M0) GG 2–3 or Favourable LDR brachytherapy
based on age and in system. cores:
- asymptoma
c comorbidity*) < 10% paern 4, cT2b**) **** (consider urinary funcon and prostate volume)
disease ≤ 3 pos; no GG3,
no IDC / cribriform Unfavourable LDR or HDR brachytherapy boost + EBRT 1 + ADT (4–6 mo)
growth) **** (consider urinary funcon and prostate volume)

no yes
Radical prostatectomy + ePLND
Watchful Acƒve (risk for needing mulmodal treatment)
waiƒng surveillance
High risk EBRT1 + ADT (2–3 yrs)
localised (76–78 Gy)
(PSA >20 or
GG >3 or
LDR or HDR brachytherapy boost + EBRT 1 + ADT (2–3 yrs)
cT2c**)
(consider urinary funcon and prostate volume)

Two of: cT3–4**, EBRT 1 + ADT (3 years) + abiraterone (2 yrs)

GG 4, PSA 40 (consider urinary funcon)

Radical prostatectomy + ePLND

(high risk for needing mulmodal treatment)
Locally
advanced
(cT 3–4 cN0 EBRT1 + ADT (2–3 yrs)
**) (76–78 Gy)

LDR or HDR brachytherapy boost + EBRT 1 + ADT (2–3 yrs)

(consider urinary funcon and prostate volume)

Radical prostatectomy + ePLND

(high risk for needing mulmodal treatment)
cN1***
EBRT1 including pelvis + ADT (3 years) + abiraterone (2 yrs)
(consider urinary funcon)

* Rule of thumb: Life expectancy 10 years.

** Recommendation based on clinical staging using digital rectal examination, not imaging.
*** Recommendation based on staging using combination of bone scan and CT.
**** See text, dependent on GG and (biopsy) volume
1EBRT: IMRT/VMAT + IGRT of the prostate

= weak recommendation.
ADT = androgen deprivation therapy; EBRT =external beam radiotherapy; ECE = extracapsular extension;
ePLND = extended pelvic lymph node dissection; GG = grade group; HDR = high-dose rate; IDC = intraducal
carcinoma; IGRT = image-guided radiotherapy; IMRT = intensity-modulated radiotherapy; LDR = low-dose rate;
VMAT = volumetric modulated arc therapy.

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 15

 Figure 6.2: Treatment of metastasized (M1*) – disease, M+HSPC

Prostate Upfront EBRT1

yes
adenocarcinoma Connuous Adequate life of the primary tumour
metastasized castraon expectancy (If no previous local therapy)
(M1*)
Low volume
(not fulfilling high
volume criteria)
no

No upfront Upfront double combinaon

combinaon systemic therapy: connuous
therapy castraon +**:
Eligible for - abiraterone / prednisone
docetaxel ? - apalutamide
- enzalutamide

High volume
(≥ 4 bone mets
including ≥ 1 outside
vertebral column or Upfront triple combinaon
pelvis OR visceral systemic therapy: connuous
mets) castraon + **:
- docetaxel 6 x +
abiraterone / pred
- docetaxel 6 x + darolutamide

* Based on staging using combination of bone scan and CT.

** Alphabetical order
1EBRT: IMRT/VMAT + IGRT of the prostate (equivalent of up to 72 Gy in 2 Gy fractions).

= weak recommendation.
EBRT = external beam radiotherapy; IGRT = image-guided radiotherapy; IMRT = intensity-modulated
radiotherapy.

#Note:
 Please be aware that the various options in the following flowcharts present a generalised approach
only, and cannot take the management of individual patients into account, nor the availability of resources.

7.1.5 Summary of evidence for follow-up after treatment with curative intent

Summary of evidence LE
A detectable PSA, indicating a relaps of the disease, must be differentiated from a clinically 3
meaningful relapse. The PSA threshold that best predicts further metastases after RP is
> 0.4 ng/mL and > NADIR + 2 ng/mL after IMRT/VMAT plus IGRT (± ADT].

2. METHODS
2.1 Data identification
For the 2023 PCa Guidelines, new and relevant evidence has been identified, collated and appraised through
a structured assessment of the literature. A number of comprehensive searches were performd, covering all
sections of the PCa Guidelines. The search was limited to English language publications. Databases searched
included Medline, EMBASE and the Cochrane Libraries, covering a time frame between May 1st 2021 and
April 1st 2022. A total of 2,480 unique records were identified, retrieved and screened for relevance resulting
in 166 new publications having been included in the 2023 print. A detailed search strategy is available online:
https://uroweb.org/guideline/prostate-cancer/?type=appendices-publications.

Changes in recommendations were generally only considered on the basis of high-level evidence (i.e. systematic
reviews with meta-analysis, randomised controlled trials [RCTs], and prospective comparative studies) published
in the English language. Additional information can be found in the general Methodology section of this print and
online at the EAU website: https://uroweb.org/guidelines/policies-and-methodological-documents/.

For each recommendation within the guidelines there is an accompanying online strength rating form which
includes the assessment of the benefit to harms ratio and patients’ preferences for each recommendation.
The strength rating forms draws on the guiding principles of the GRADE methodology but do not purport to be
GRADE [3, 4]. These forms address a number of key elements namely:
1. the overall quality of the evidence which exists for the recommendation, references used in
this text are graded according to a classification system modified from the Oxford Centre for
Evidence-Based Medicine Levels of Evidence [5];
2. the magnitude of the effect (individual or combined effects);

16 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

 3. t he certainty of the results (precision, consistency, heterogeneity and other statistical or
study related factors);
4. the balance between desirable and undesirable outcomes;
5. the impact of patient values and preferences on the intervention;
6. the certainty of those patient values and preferences.

These key elements are the basis which panels use to define the strength rating of each recommendation.
The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [6]. The strength of each
recommendation is determined by the balance between desirable and undesirable consequences of alternative
management strategies, the quality of the evidence (including certainty of estimates), and nature and variability
of patient values and preferences. The strength rating forms will be available online.

A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address. In
addition, the International Society of Geriatric Oncology (SIOG), the European Society for Radiotherapy &
Oncology (ESTRO), the European Society for Urogenital Radiology (ESUR), the European Association of
Nuclear Medicine (EANM) and the International Society of Urological Pathology (ISUP) have endorsed the PCa
Guidelines.

2.2 Review
Publications ensuing from systematic reviews have all been peer-reviewed.

2.3 Future goals

Results of ongoing and new systematic reviews will be included in the 2024 update of the PCa Guidelines:
• A systematic review assessing the performance of risk stratification tools incorporating imaging,
biomarkers, biopsy involvement and/or MRI-targeted biopsies, compared to the classical risk
classifications (d’Amico, EAU, CAPRA and NCCN) recommended in current guidelines for predicting
biochemical recurrence, metastasis or death after local treatment for prostate cancer. Are the new
stratification tools preferred above the classical risk classifications?
• A systematic review assessing the outcomes of brachytherapy boost combined with external beam RT for
PCa.
• Care pathways for the various stages of PCa management are being developed. These pathways will, in
due time, inform treatment flowcharts and an interactive app.
• Assessment of individual patient life expectancy – development of a calculator.

3. EPIDEMIOLOGY AND AETIOLOGY

3.1 Epidemiology
Prostate cancer is the second most commonly diagnosed cancer in men, with an estimated 1.4 million
diagnoses worldwide in 2020 [7, 8]. A systematic review of autopsy studies reported a prevalence of PCa at
age < 30 years of 5% (95% confidence interval [CI]: 3–8%), increasing by an odds ratio (OR) of 1.7 (1.6–1.8) per
decade, to a prevalence of 59% (48–71%) by age > 79 years [9]. There is variation in the frequency of autopsy-
detected PCa between men with different ethnical backgrounds and geographical areas (e.g., 83 in white US
males vs. 41 in Japan at age 71–80) [10].

The variation in incidence of PCa diagnosis is even more pronounced between different geographical areas,
driven by rate of prostate-specific antigen (PSA) testing and influenced by (inter)national organisations‘
recommendations on screening (see Section 5.1) [11]. It is highest in Australia/New Zealand and Northern
America (age-standardised rates [ASR] per 100,000 of 111.6 and 97.2, respectively), and in Western and
Northern Europe (ASRs of 94.9 and 85, respectively). The incidence is low in Eastern and South-Central Asia
(ASRs of 10.5 and 4.5, respectively), but rising [12]. Rates in Eastern and Southern Europe were low but have
also shown a steady increase [8, 10]. Besides PSA testing, incidence is also dependent on the age of the
population, geography and ethnicity.
There is relatively less variation in mortality rates worldwide, although rates are generally high in
populations of African descent (e.g., Caribbean: ASR of 29 and Sub-Saharan Africa: ASRs ranging between 19
and 14), intermediate in the USA and very low in Asia (South-Central Asia: ASR of 2.9) [8, 13]. Mortality due to
PCa has decreased in most Western nations but the magnitude of the reduction varies between countries [7].

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 17

3.2 Aetiology
3.2.1 Family history/hereditary prostate cancer
Family history and ethnic background are associated with an increased PCa incidence suggesting a genetic
predisposition [14, 15]. Men of African ancestry in the Western world demonstrate more unfavourable
outcomes due to a combination of biological, environmental, social, and health care factors [16]. They are more
likely to be diagnosed with more advanced disease [17] and upgrade after prostatectomy was more frequent
as compared to Caucasian men (49% vs. 26%) [18]. Racial disparities in development of, prevention of, and
therapies for PCa may exist. It should be kept in mind that many PCa studies include either small percentages
of men from other origin than Caucasians or focus on highly specific other groups [19].

Only a small subpopulation of men with PCa have true hereditary disease (> 3 cases in the same family, PCa in
three successive generations, or > 2 men diagnosed with PCa < 55 yrs). Hereditary PCa (HPCa) is associated
with a six to seven year earlier disease onset but the disease aggressiveness and clinical course does not seem
to differ in other ways [14, 20]. In a large USA population database, HPCa (reported by 2.18% of participants)
showed a relative risk (RR) of 2.30 for diagnosis of any PCa, 3.93 for early-onset PCa, 2.21 for lethal PCa, and
2.32 for clinically significant PCa (csPCa) [21]. These increased risks with HPCa were higher than for familial
PCa (> 2 first- or second-degree relatives with PCa on the same side of the pedigree), or familial syndromes
such as hereditary breast- and ovarian cancer and Lynch syndrome. With the father as well as two brothers
affected, the probability of high-risk PCa at age 65 was 11.4% (vs. a population risk of 1.4%), and for any PCa
43.9% vs. 4.8%, in a Swedish population-based study [22].

3.2.1.1 Germline mutations and prostate cancer

Genome-wide association studies have identified more than 100 common susceptibility loci contributing to the
risk for (aggressive) PCa [23-27]. Clinical cohort studies have reported rates of 15% to 17% of cases harbour
any germline mutations independent of stage [28, 29]. Based on clinical genetic data from men with PCa
unselected for metastatic disease undergoing multigene testing across the US, it was found that 15.6% of men
with PCa have pathogenic variants identified in genes tested ([Breast Cancer genes] BRCA1, BRCA2, HOXB13,
MLH1, MSH2, PMS2, MSH6, EPCAM, ATM, CHEK2, NBN, and TP53), and 10.9% of men have germline
pathogenic variants in DNA repair genes (see Table 3.1) [28]. Pathogenic variants were most commonly
identified in BRCA2 (4.5%), CHEK2 (2.2%), ATM (1.8%), and BRCA1 (1.1%) [28].
The frequency and distribution of positive germline variants of 3,607 unselected PCa patients was
reported and showed that 620 (17.2%) had a pathogenic germline variant [29]. A carrier rate of 16.2% was
found in unselected patients at diagnosis of metastatic castrate-resistant PCa (mCRPC) who were screened for
DNA damage repair (DDR) mutations in 107 genes [30].
Among unselected men with metastatic PCa, an incidence of 11.8% was found for germline
mutations in genes mediating DNA-repair processes [31]. Targeted genomic analysis of genes associated with
an increased risk of PCa could offer options to identify families at high risk [32, 33].

A prospective cohort study of male BRCA1 and BRCA2 carriers confirmed BRCA2 association with aggressive
PCa [34]. An analysis of the outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers,
and 1,940 non-carriers) showed that PCa with germline BRCA1/2 mutations were more frequently associated
with ISUP > 4, T3/T4 stage, nodal involvement, and metastases at diagnosis than PCa in non-carriers [35].
BRCA-susceptibility gene mutation carriers were also reported to have worse outcome when compared to
non-carriers after local therapy [36]. In a retrospective study of 313 patients who died of PCa and 486 patients
with low-risk localised PCa, the combined BRCA1/2 and ATM mutation carrier rate was significantly higher in
lethal PCa patients (6.07%) than in localised PCa patients (1.44%) [37]. The rate of PCa among BRCA1 carriers
was more than twice as high (8.6% vs. 3.8%) compared to the general population, in contrast to findings of
the prospective IMPACT study (Identification of Men With a Genetic Predisposition to ProstAte Cancer (see
Chapter 5) [38].

18 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

Table 3.1: Germline mutations in DNA repair genes associated with increased risk of prostate cancer

Gene Location Prostate cancer risk Findings

BRCA2 13q12.3 - RR 2.5 to 4.6 [39, 40] • up to 12 % of men with metastatic PCa harbour
-P Ca at 55 years or germline mutations in 16 genes (including BRCA2
under: RR: 8–23 [5.3%]) [31]
[39, 41] • 2% of men with early-onset PCa harbour germline
mutations in the BRCA2 gene [39]
• BRCA2 germline alteration is an independent predictor
of metastases and worse PCa-specific survival [35, 42]
ATM 11q22.3 RR: 6.3 for metastatic • higher rates of lethal PCa among mutation carriers [37]
PCa [31] • up to 12% of men with metastatic PCa harbour germline
mutations in 16 genes (including ATM [1.6%]) [31]
CHEK2 22q12.1 OR 3.3 [43, 44] • up to 12% of men with metastatic PCa harbour germline
mutations in 16 genes (including CHEK2 [1.9%]) [31]
BRCA1 17q21 RR: 1.8–3.8 at 65 years • higher rates of lethal PCa among mutation carriers [37]
or under [45, 46] •u  p to 12% of men with metastatic PCa harbour germline
mutations in 16 genes (including BRCA1 [0.9%]) [31]
HOXB13 17q21.2 OR 3.4–7.9 [32, 47] • significantly higher PSA at diagnosis, higher Gleason
score and higher incidence of positive surgical margins
in the radical prostatectomy specimen than non-carriers
[48]
MMR genes 3p21.3 RR: 3.7 [49] • Mutations in MMR genes are responsible for Lynch
MLH1 2p21 syndrome [50]
MSH2 2p16 • MSH2 mutation carriers are more likely to develop PCa
MSH6 7p22.2 than other MMR gene mutation carriers [51]
PMS2
BRCA2 = breast cancer gene 2; ATM = ataxia telangiectasia mutated; CHEK2 = checkpoint kinase 2;
BRCA1 = breast cancer gene 1; GS = Gleason score; HOXB13 = homeobox B13; MMR = mismatch repair;
MLH1 = mutL homolog 1; MSH2 = mutS homolog 2; MSH6 = mutS homolog 6; OR = odds ratio;
PMS2 = post-meiotic segregation increased 2; PCa = prostate cancer; RR = relative risk.

3.2.2 Risk factors

A wide variety of exogenous/environmental factors have been discussed as being associated with the risk of
developing PCa or as being aetiologically important for the progression from latent to clinical PCa [52]. Asians
who immigrated to the USA have approximately half the risk of PCa when compared to their US born Asian-
descendant counterparts, implying a role of environmental or dietary factors [53]. However, currently there are
no known effective preventative dietary or pharmacological interventions.

3.2.2.1 Metabolic syndrome

The single components of metabolic syndrome (MetS), hypertension (p = 0.035) and waist circumference
> 102 cm (p = 0.007), have been associated with a significantly greater risk of PCa, but in contrast, having > 3
components of MetS is associated with a reduced risk (OR: 0.70, 95% CI: 0.60–0.82) [54, 55].

3.2.2.1.1 Diabetes/metformin
The association between metformin use and PCa is controversial. At population level, metformin users (but not
other oral hypoglycaemic agents) were found to be at a decreased risk of PCa diagnosis compared with never
users (adjusted OR: 0.84, 95% CI: 0.74–0.96) [56]. In 540 diabetic participants of the Reduction by Dutasteride
of Prostate Cancer Events (REDUCE) study, metformin use was not significantly associated with PCa and
therefore not advised as a preventive measure (OR: 1.19, p = 0.50) [57].

3.2.2.1.2 Cholesterol/statins
A meta-analysis of 14 large prospective studies did not show any association between blood total cholesterol,
high-density lipoprotein cholesterol, low-density lipoprotein cholesterol levels and the risk of developing either
overall PCa or high-grade PCa [54]. Results from the REDUCE study also did not show a preventive effect of
statins on PCa risk [55]. A meta-analysis suggested a lower risk of advanced PCa in statin users [58].

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3.2.2.1.3 Obesity
Within the REDUCE study, obesity was associated with lower risk of low-grade PCa in multivariable analyses
(OR: 0.79, p = 0.01), but increased risk of high-grade PCa (OR: 1.28, p = 0.042) [59]. This effect seems mainly
explained by environmental determinants of height/body mass index (BMI) rather than genetically elevated
height or BMI [60]. A systematic review showed an association between obesity and increased PC-specific
mortality [61].

3.2.2.2 Dietary factors

The association between a wide variety of dietary factors and PCa have been studied, but there is still a paucity
of quality evidence (Table 3.2). To date, the current body of evidence will not support a causal relationship
between specific (dietary and otherwise) factors and the development of PCa. Consequently, no effective
preventative strategies can be suggested.

Table 3.2: Main dietary factors that have been associated with PCa

Alcohol High alcohol intake, but also total abstention from alcohol has been associated with
a higher risk of PCa and PCa-specific mortality [62]. A meta-analysis shows a dose-
response relationship with PCa [63].
Coffee Coffee consumption may be associated with a reduced risk of PCa; with a pooled RR
of 0.91 for the highest category of coffee consumption [64].
Dairy A weak correlation between high intake of protein from dairy products and the risk of
PCa was found [65].
Fat No association between intake of long-chain omega-3 poly-unsaturated fatty acids
and PCa was found [66]. A relation between intake of fried foods and risk of PCa may
exist [67].
Tomatoes A trend towards a favourable effect of tomato intake (mainly cooked) and lycopenes on
(lycopenes/ PCa incidence has been identified in meta-analyses [68, 69]. Randomised controlled
carotenes) trials comparing lycopene with placebo did not identify a significant decrease in the
incidence of PCa [70].
Meat Meta-analyses show a potential association between red meat, total meat, and
processed meat consumption and PCa [71, 72].
Soy Phytoestrogen intake was significantly associated with a reduced risk of PCa in a
(phytoestrogens meta-analysis [73]. Total soy food intake has been associated with a reduced risk of
[isoflavones/ PCa, but also with an increased risk of advanced disease [74, 75].
coumestans])
Vitamin D A U-shaped association has been observed, with both low- and high vitamin-D
concentrations being associated with an increased risk of PCa, and more strongly for
high-grade disease [75, 76].
Vitamin E/Selenium An inverse association of blood, but mainly nail selenium levels (reflecting long-term
exposure) with aggressive PCa have been found [77, 78]. Selenium and Vitamin E
supplementation were, however, found not to affect PCa incidence [79].

3.2.2.3 Hormonally active medication

3.2.2.3.1 5-alpha-reductase inhibitors (5-ARIs)
Although it seems that 5-ARIs have the potential of preventing or delaying the development of PCa (decreasing
the risk by 25% but only for ISUP grade 1 cancer), this must be weighed against treatment-related side effects
as well as the potential small increased risk of high-grade PCas, although these do not seem to impact PCa
mortality [80-84] None of the available 5-ARIs have been approved by the European Medicines Agency (EMA)
for chemoprevention.

3.2.2.3.2 Testosterone
Hypogonadal men receiving testosterone supplements do not have an increased risk of PCa [85]. A pooled
analysis showed that men with very low concentrations of free testosterone (lowest 10%) have a below average
risk (OR: 0.77) of PCa [86].

3.2.2.4 Other potential risk factors

A significantly higher rate of ISUP > 2 PCa (hazard ratio [HR]: 4.04) was found in men with inflammatory
bowel disease when compared with the general population [87]. Balding was associated with a higher risk of
PCa death [88]. Gonorrhoea was significantly associated with an increased incidence of PCa (OR: 1.31, 95%

20 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

CI: 1.14–1.52) [89]. Occupational exposure may also play a role, based on a meta-analysis which revealed that
night-shift work is associated with an increased risk (2.8%, p = 0.030) of PCa [90]. Current cigarette smoking
was associated with an increased risk of PCa death (RR: 1.24, 95% CI: 1.18–1.31) and with aggressive tumour
features and worse prognosis, even after quitting smoking [91, 92]. A meta-analysis on Cadmium (Cd) found
a positive association (magnitude of risk unknown due to heterogeneity) between high Cd exposure and risk
of PCa for occupational exposure, but not for non-occupational exposure, potentially due to higher Cd levels
during occupational exposure [93]. Men positive for human papillomavirus-16 may be at increased risk [94].
Plasma concentration of the estrogenic insecticide chlordecone is associated with an increase in the risk of
PCa (OR: 1.77 for highest tertile of values above the limit of detection) [95].
A number of other factors previously linked to an increased risk of PCa have been disproved
including vasectomy [96] and self-reported acne [97]. There are conflicting data about the use of aspirin or non-
steroidal anti-inflammatory drugs and the risk of PCa and mortality [98, 99].
Ultraviolet radiation exposure decreased the risk of PCa (HR: 0.91, 95% CI: 0.88–0.95) [100]. A
review found a small but protective association of circumcision status with PCa [101]. Higher ejaculation
frequency (> 21 times a month vs. 4 to 7 times) has been associated with a 20% lower risk of PCa [102].

3.2.3 Summary of evidence for epidemiology and aetiology

Summary of evidence LE
Prostate cancer is a major health concern in men, with incidence mainly dependent on age. 3
Genetic factors are associated with risk of (aggressive) PCa. 3
A variety of dietary/exogenous/environmental factors have been associated with PCa incidence and 3
prognosis.
In hypogonadal men, testosterone supplements do not increase the risk of PCa. 2a
No conclusive data exist which could support specific preventive or dietary measures aimed at 1a
reducing the risk of developing PCa.

4. CLASSIFICATION AND STAGING SYSTEMS

4.1 Classification
The objective of a tumour classification system is to combine patients with a similar clinical outcome. This
allows for discussion about prognosis with patients, the design of clinical trials on relatively homogeneous
populations, the comparison of clinical and pathological data obtained from different hospitals across the
world, and the development of recommendations for the treatment of these patient populations. Throughout
these Guidelines the Union for International Cancer Control (UICC) 8th edition (2017), the Tumour, Node,
Metastasis (TNM) classification for staging of PCa (Table 4.1) [103] and the EAU risk group classification are
used [104]. The latter classification is based on the grouping of patients with a similar risk of biochemical
recurrence (BCR) after radical prostatectomy (RP) or external beam radiotherapy (EBRT). Changes in the
diagnostic pathway, such as imaging (e.g., Magnetic Resonance Imaging [MRI], Prostate-Specific Membrane
Antigen [PSMA] Positron Emission Tomography Computed Tomography [PET/CT] scan) and biopsy (e.g.,
increasing number of systematic biopsy cores, targeted biopsy) may cause a stage shift in risk classification
systems [105].

Although the 2017 American Joint Committee on Cancer (AJCC) staging 8th edition specifically states that
clinical staging should be based on digital rectal examination (DRE) only, such an explicit comment is not
made by the UICC. Since clinical stage as assessed by DRE only, it is included in the EAU (D’Amico) risk group
classification, cT-stage should be based on DRE findings and not on imaging. Additional staging information
based on imaging should be reported separately. A non-palpable PCa with bilateral positive biopsies and
extra-prostatic extension (EPE) on MRI would therefore be categorized as cT1c with a separate report of MRI
findings.

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Table 4.1: Clinical Tumour Node Metastasis (TNM) classification of PCa [103]

T - Primary Tumour (stage based on digital rectal examination [DRE] only)

TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Clinically inapparent tumour that is not palpable
T1a Tumour incidental histological finding in 5% or less of tissue resected
T1b Tumour incidental histological finding in more than 5% of tissue resected
T1c Tumour identified by needle biopsy (e.g. because of elevated prostate-specific antigen [PSA])
T2 Tumour that is palpable and confined within the prostate
T2a Tumour involves one half of one lobe or less
T2b Tumour involves more than half of one lobe, but not both lobes
T2c Tumour involves both lobes
T3 Tumour extends palpably through the prostatic capsule
T3a Extracapsular extension (unilateral or bilateral)
T3b Tumour invades seminal vesicle(s)
T4 Tumour is fixed or invades adjacent structures other than seminal vesicles: external sphincter, rectum,
levator muscles, and/or pelvic wall
N - Regional (pelvic) Lymph Nodes1
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
M - Distant Metastasis2
M0 No distant metastasis
M1 Distant metastasis
M1a Non-regional lymph node(s)
M1b Bone(s)
M1c Other site(s)
1 Metastasis no larger than 0.2 cm can be designated pNmi.
2 When more than one site of metastasis is present, the most advanced category is used. (p)M1c is the most
advanced category.

Pathological staging (pTNM) is based on histopathological tissue assessment and largely parallels the
clinical TNM, except for clinical stage T1 and T2 substages. Pathological stages pT1a/b/c do not exist and
histopathologically confirmed organ-confined PCas after RP are pathological stage pT2. The current UICC no
longer recognise pT2 substages [103].

Of note: the EANM recently proposed a ‘miTNM’ (molecular imaging TNM) classification, taking into
account PSMA PET/CT findings [106]. The prognosis of the miT, miN and miM substages is likely
to be better than their T, N and M counterparts due to the ‘Will Rogers phenomenon’; the extent of
this prognosis shift remains to be assessed as well as its practical interest and impact [107]. This
reclassification is not endorsed by the UICC or the AJCC.

4.2 Gleason score and International Society of Urological Pathology 2019 grade
In the original Gleason grading system, 5 Gleason grades (ranging from 1–5) based on histological tumour
architecture were distinguished, but in the 2005 and subsequent 2014 ISUP consensus meetings Gleason
grades 1 and 2 were eliminated [108, 109]. The 2005 ISUP modified Gleason score (GS) of biopsy-detected
PCa comprises the Gleason grade of the most extensive (primary) pattern, plus the second most common
(secondary) pattern, if two are present. If only one pattern is present, it needs to be doubled to yield the GS.
For three grades, the biopsy GS comprises the most common grade plus the highest grade, irrespective of
its extent. In case intraductal carcinoma is present intermixed with invasive PCa, it should be incorporated in
the GS based on its underlying architectural pattern [110]. In addition to reporting of the carcinoma features
for each biopsy side, an overall (or global) GS based on the carcinoma-positive biopsies can be provided.
The global GS takes into account the cumulative extent of each grade from all prostate biopsies (see Section
5.2.9.2). The 2014 and 2019 ISUP endorsed grading system limits the number of PCa grades, ranging them
from 1 to 5 (see Table 4.2) [109, 111].

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Table 4.2: International Society of Urological Pathology 2014 grade (group) system

Gleason score ISUP grade

2-6 1
7 (3+4) 2
7 (4+3) 3
8 (4+4 or 3+5 or 5+3) 4
9-10 (4+5 or 5+4 or 5+5) 5

4.3 Clinically significant prostate cancer

The descriptor ‘clinically significant’ is widely used to differentiate PCa that may cause morbidity or death in a
specific patient from types of PCa that do not. This distinction is particularly important as insignificant PCa that
does not cause harm is so common [9]. Unless this distinction is made, such cancers are at high risk of being
over-treated, with the treatment itself risking harmful side effects to patients. The over-treatment of insignificant
PCas has also been criticised as a major drawback of PSA testing and early detection [112]. Although
pathological factors are often used to delineate insignficant PCa, the definition of significant vs. insignificant is
a balance between tumour and patient factors. High-risk PCa is significant in almost all men, except when life
expectancy is limited. Low-risk PCa is insignificant in almost all men.

From a pathological point of view in large studies of RP specimens which showed only ISUP grade 1 disease,
EPE (0.3%) [113] and biochemical recurrence (3.5%) were rare, and seminal vesicle (SV) invasion or lymph
node (LN) metastasis did not occur at all [114, 115]. International Society of Urological Pathology grade 1
disease at RP itself can therefore be considered clinically insignificant. Whilst ISUP grade 1 bears the hallmarks
of cancer histologically, ISUP grade 1 at RP itself does not behave in a clinically malignant fashion [116]. It
is important to note that the studies showing absence of metastasis in ISUP grade 1 were all done on RP
specimens; ISUP grade 1 on biopsy is associated with low risk of developing metastasis and disease-specific
death, due to under-sampling of a higher grade component. Finally, modifications in PCa grading, MRI and
targeted biopsies led to a grade shift during the past 10–15 years; for instance the introduction of the ISUP
2005 led to 20% of pre-ISUP 2005 GS 6 tumours being upgraded to GS 7 or higher, which has to be taken into
account when interpreting older studies [117].

The current standard practice of MRI-targeted and template biopsies has reduced diagnostic inaccuracy [118],
however sampling error may still occur such that higher grade cancer could be missed. This should especially
be considered if the prior MRI showed a suspicious lesion, but only ISUP grade 1 was found at biopsy. Another
complexity in defining insignificant cancer is that ISUP grade 1 may progress to higher grades over time,
becoming clinically significant at a later biopsy [119].

Therefore, although ISUP grade 1 itself can be described as clinically insignificant, it is important to take
into account other factors, including age, imaging prior to biopsy and adequate sampling core number.
When combined with low-risk clinical factors (see Table 4.3), ISUP grade 1 represents low-risk PCa, with
its recommendation of preferred management being active surveillance (AS) or watchful waiting (WW) (see
Sections 6.1.1.1 & 6.1.1.2). It should be noted, therefore, that defining ISUP grade 1 as insignificant cancer
does not mean it should be ignored, but appropriately observed.

Epidemiological and autopsy data suggest that a proportion of ISUP grade 2 PCas would remain undetectable
during a man’s life [120] and therefore may be over-treated. In current guidelines deferred treatment may
be offered to select patients with intermediate-risk PCa [121], but clear evidence is lacking for appropriate
selection criteria [122].

Recent papers have defined clinically significant cancer differently, commonly using ISUP grade 2 and above
and even ISUP grade 3 and above, demonstrating the lack of consensus and evolution of its definition [123-126].
Some papers provide more than one definition within a single study [127, 128]. Since there is insufficient data
to relate modern histological grading to hard clinical endpoints, it is imperative that authors define and state it
in their own studies what they believe csPCa is, including exactly how the disease was diagnosed.

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Table 4.3: EAU risk groups for biochemical recurrence of localised and locally-advanced prostate cancer

Definition
Low-risk Intermediate-risk High-risk
PSA < 10 ng/mL PSA 10–20 ng/mL PSA > 20 ng/mL any PSA
and GS < 7 (ISUP grade 1) or GS 7 (ISUP grade 2/3) or GS > 7 (ISUP grade 4/5) any GS (any ISUP grade)*
and cT1-2a* or cT2b* or cT2c* cT3-4 or cN+**
Localised Locally advanced
GS = Gleason score; ISUP = International Society for Urological Pathology; PSA = prostate-specific antigen.
* Based on digital rectal examination.
** Based on CT/bone scan.

4.4 Prognostic relevance of stratification

TNM staging is a schematic representation of anatomic tumour extent and pathological tumour grade is
reflective of intrinsic features of tumour aggressiveness. EAU risk group classification, which is essentially
based on D’Amico’s classification system for PCa, combines clinical information on tumour extent, PSA and
pathology (Table 4.3) [104]. A more precise stratification of the clinically heterogeneous subset of intermediate-
risk group patients could provide a better framework for their management [129, 130]. Specifically the National
Cancer Center Network (NCCN) Guidelines subdivide intermediate-risk disease into favourable intermediate-
risk and unfavourable intermediate-risk, with unfavourable features including ISUP grade 3, and/or > 50%
positive biopsy cores and/or at least two intermediate-risk factors [121]. However, as yet, the best stratification
and optimal treatment remain controversial.

4.5 Guidelines for classification and staging systems

Recommendations Strength rating

Use the Tumour, Node, Metastasis (TNM) classification for staging of PCa. Strong
Clinical stage should be based on digital rectal examination (DRE) only; additional staging Strong
information based on imaging should be reported separately.
Use the International Society of Urological Pathology (ISUP) 2019 system for grading of PCa. Strong
Use the EAU risk group stratification for prognostic subgrouping of patients. Strong

5. DIAGNOSTIC EVALUATION
5.1 Screening and individual early detection
5.1.1 Screening
Population or mass screening is defined as the ‘systematic examination of asymptomatic men to identify
individuals at risk for a specific disease’ and is usually initiated by health authorities. The co-primary objectives
are:
• reduction in mortality due to PCa;
• a maintained QoL as expressed by QoL-adjusted gain in life years (QALYs).

Screening for PCa still is one of the most controversial topics in the urological literature [131]. A Cochrane
review of randomised PCa screening trials with PCa mortality as endpoint was published in 2013 [132]
and updated in 2018 [133, 134]. The main findings of the updated publication from the results of 5 RCTs,
randomising more than 721,718 men, are:
• Screening is associated with an increased diagnosis of PCa (Incidence ratio [IR]: 1.23 95% CI: 1.03–1.48).
• Screening is associated with detection of more localised disease (RR: 1.39, [1.09–1.79]) and less
advanced PCa (T3–4, N1, M1; RR: 0.85 [0.72–0.99]).
• No PCa-specific survival benefit was observed (IR: 0.96 [0.85–1.08]). This was the main endpoint in all
trials.
• No overall survival (OS) benefit was observed (IR: 0.99, 95% CI: 0.98–1.01). None of the trials were
designed/powered for this endpoint.

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The included studies are different regarding multiple aspects, including: trial size, time periods, age groups,
participation/compliance rates, previous screening rates (opportunistic testing in control arm, ‘contamination’),
one-time vs. repeat screening, and the applied diagnostic pathway. These differences account for discrepancies
in results between single studies and the Cochrane review aggregated findings.

The ERSPC (European Randomized Study of Screening for Prostate Cancer) started in the early 90’s, included
>182K European men, found a significant reduction in PCa mortality due to screening. ERSPC applied a mainly
PSA-based screening protocol (cut-off 3.0–4.0 ng/mL followed by systematic sextant prostate biopsy, every 2–4
years in men aged 50–74). The contamination rate was relatively low when compared to other large studies such
as the PLCO (Prostate Lung Colorectal & Ovarian) screening trial [135]. A limitation is the heterogenity in patient
groups and the applied screening protocols. Since 2013, data have been updated with 16 years of follow-up
[135]. With extended follow-up, the mortality reduction (21% and 29% after non-compliance adjustment) remains
unchanged. However, the number needed to screen (NNS) and to treat is decreasing and is now below the NNS
observed in breast cancer trials [135, 136] (Table 5.1).

Table 5.1: Follow-up data from the ERSPC study [135]

Years of follow-up Number needed to screen Number needed to treat

9 1,410 48
11 979 35
13 781 27
16 570 18

In the Göteborg screening trial, with 18 years of follow-up, the ratio of death from PCa for the screening group
compared with the control group was 0.65 (95% CI: 0.49–0.87) and for men starting screening at age 55–59 it
was 0.47 (95% CI: 0.29–0.78) [137]. The number needed to invite was 231; the number needed to diagnose 10.

A comparison of systematic and opportunistic screening suggested over-diagnosis and mortality reduction in
the systematic screening group compared to a higher over-diagnosis with only a marginal survival benefit, at
best, in the opportunistic screening regimen [138].

The benefit of screening in reducing PCa-specific mortality (PCSM) and the even more favourable impact on
metastases rates, is counter-balanced by the side effects of screening such as increased diagnosis rates,
which has led to over-treatment of mainly low-risk PCa, and subsequent treatment-related effects [139].
Regarding QoL, the beneficial effects of screening and the side effects seem to balance out, resulting in limited
overall impact on the invited population [139-141].

National USA recommendations against PSA-based screening resulted in a reduction in the use of PSA for
early detection and was associated with higher rates of advanced disease [11, 112, 142-147]. Initial widespread
aggressive screening in USA was associated with a decrease in PCa mortality, which has decreased for two
decades since the introduction of PSA testing [148-150]. The current USA national recommendation for men
< 70 years of age is that the decision to be screened should be an individual one [151-153].

Recognition of the harms of over-diagnosis and over-treatment had led to a redesign in the pathway for early
detection of PCa including identification of specific risk groups, individualised re-testing interval, improved
indication for biopsy using risk calculators and/or MRI, targeted biopsies, and the application of AS for low-risk
disease.

The inclusion of MRI may improve a screening protocol, as it reduces the number of men that undergo biopsies
while detecting more high-grade and less low-grade PCa [154-156]. The Stockholm-3 (STHLM3) screening
trial randomised men with a PSA > 3 ng/mL between standard biopsies (10–12 cores) or MRI and standard
plus targeted biopsies in the presence of a suspicious MRI. The percentage of men that underwent prostate
biopsies in the standard group was double that of the MRI group. In this non-inferiority trial, the intention-to-
treat (ITT) analysis found 18% and 21% clinically significant disease (ISUP Grade group > 1) and 12% and 4%
insignificant disease in the standard and the MRI group, respectively [154]. The IP1-PROSTAGRAM study (PSA
> 3 ng/mL; MRI Prostate Imaging – Reporting and Data System [PI-RADS] > 2), showed highest detection of
csPCa for MRI compared to transrectal ultrasound-guided prostate (TRUS) biopsy in a population screening
setting [155].

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The Identification of Men With a Genetic Predisposition to ProstAte Cancer (IMPACT) study, evaluates targeted
PCa screening using PSA in men aged 40–69 years with germline BRCA1/2 mutations (annually, biopsy
recommended if PSA > 3.0 ng/mL). After 3 years of screening, BRCA2 mutation carriers were associated with
a higher incidence of PCa, a younger age of diagnosis, and more clinically significant tumours compared with
non-carriers [26, 157]. The influence of BRCA1 mutations on PCa remained unclear. No differences in age or
tumour characteristics were detected between BRCA1 carriers and BRCA1 non-carriers. The mismatch repair
cohort of IMPACT in men with MSH2 and MSH6 pathogenic variants found a higher incidence of significant
PCa vs. non-carriers [158].

5.1.2 Individual early detection

Early detection may be initiated on an individual level in men with risk factors (age > 50; men from 45 years of
age and a family history of PCa; men of African descent from 45 years of age; men carrying BRCA2 mutations
from 40 years of age). Decreased disease-specific mortality on one side, but increased incidence with the risk
of over-treatment on the other side, should be discussed with men.

5.1.2.1 Risk assessment, co-morbidity and life-expectancy

Data from the Goteborg arm of the ERSPC trial suggest that the age at which early diagnosis should be
stopped remains controversial, but an individual’s life expectancy must definitely be taken into account. Men
who have less than a 15-year life expectancy are unlikely to benefit, based on data from the Prostate Cancer
Intervention Versus Observation Trial (PIVOT) and the ERSPC trials. Furthermore, although there is no simple
tool to evaluate individual life expectancy, co-morbidity is at least as important as age. A detailed review can be
found in Section 5.4 ‘Estimating life expectancy and health status’ and in the SIOG Guidelines [159].

5.1.2.2 Initial risk assessment by PSA and DRE

Informed men requesting an early diagnosis should be given a PSA test and undergo a DRE [160]. The
use of DRE alone in the primary care setting had a sensitivity and specificity below 60%, possibly due to
inexperience, and can therefore not be recommended to exclude PCa [161]. PSA measurement and DRE
need to be repeated [162], but the optimal intervals for PSA testing and DRE follow-up are unknown as they
varied between several prospective screening trials. A risk-adapted strategy might be a consideration, based
on the initial PSA level. Men with a baseline PSA < 1 ng/mL at 40 years and < 2 ng/mL at 60 years are at
decreased risk of PCa metastasis or death from PCa several decades later [50, 163]. The retesting interval
can therefore be every 2 years for those initially at risk, or postponed up to 8 years in those not at risk with an
initial PSA < 1 ng/mL at 40 years and a PSA < 2 ng/mL at 60 years of age and a negative family history [164].
An analysis of ERSPC data supports a recommendation for an 8-year screening interval in men with an initial
PSA concentration < 1 ng/mL; fewer than 1% of men with an initial PSA concentration < 1 ng/mL were found
to have a concentration above the biopsy threshold of 3 ng/mL at 4-year follow-up; the cancer detection rate
by 8 years was close to 1% [165]. The long-term survival and QoL benefits of extended PSA re-testing (every
8 years) remain to be proven at a population level.

5.1.2.3 Risk assessment to determine the need for biopsy

Multiple diagnostic tools are now available to determine the need for a biopsy to establish the diagnosis of a
PCa.

Risk calculators, combining clinical data (age, DRE findings, PSA level, prostate volume, etc.) may be useful
in helping to determine (on an individual basis) what the potential risk of cancer may be, thereby reducing
the number of unnecessary biopsies. The risk calculator selected should have been calibrated to the target
population; lack of calibration might represent a real limiting factor for its use [166]. Several tools developed
from cohort studies are available including (among others):
• the ERSPC cohort: http://www.prostatecancer-riskcalculator.com/seven-prostate-cancer-risk-calculators;
This calculator has been updated by incorporating the 2014 ISUP Pathology Gleason Grading and
Cribriform growth [167];
• the PCPT cohort: PCPTRC 2.0 http://myprostatecancerrisk.com/.

Prostate MRI stratifies patients with an indication for biopsy on a 1- to 5- risk scale of having csPCa. Prostate
MRI and related MRI-directed biopsies have shown to be at least as diagnostically effective as systematic
biopsies alone in diagnosing significant cancers [168] (see Section 5.2.4.2.4).

Moreover, in a prospective, multi-centre, non-randomised opportunistic early detection setting (PSA > 3 ng/mL),
the MRI-directed biopsy decision strategy avoided more men biopsied in comparison to a diagnostic pathway
using a risk calculator and then systematic biopsy (559/1015, 55% vs 403/950, 42%; difference -13%, 95%

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CI: -17% to -8.3%; p < 0.01); it also detected less ISUP grade 1 cancers (84/1015, 8.3% vs. 121/950, 13%;
difference 4.5%, 95% CI: 1.8–7.2%; p < 0.01) [169].

PSA-density (PSA-D) is the strongest predictor in risk calculators. Combinations of PSA-D and MRI have been
explored [170-175], showing guidance in biopsy-decisions whilst safely avoiding redundant biopsy testing (see
Section 5.2.4.2.6.3).

Urine and serum biomarkers as well as tissue-based biomarkers have been proposed for improving detection
and risk stratification of PCa patients, potentially avoiding unnecessary biopsies. However, further studies are
necessary to validate their efficacy [176]. At present there is too limited data to implement these markers into
routine screening protocols (see Section 5.2.3).

5.1.3 Genetic testing for inherited prostate cancer

Increasing evidence supports the implementation of genetic counselling and germline testing in early detection
and PCa management [177]. Several commercial screening panels are now available to assess main PCa risk
genes [178]. However, it remains unclear when germline testing should be considered and how this may impact
localised and metastatic disease management. Germline BRCA1 and BRCA2 mutations occur in approximately
0.2% to 0.3% of the general population [179]. It is important to understand the difference between somatic
testing, which is performed on the tumour, and germline testing, which is performed on blood or saliva and
identifies inherited mutations. Genetic counselling is required prior to and after undergoing germline testing.

Germline mutations can drive the development of aggressive PCa. Therefore, the consensus is the following
men, with a personal or family history of PCa or other cancer types arising from DNA repair gene mutations
should be considered for germline testing:
• Men with metastatic PCa;
• Men with high-risk PCa and a family member diagnosed with PCa at age < 60 years;
• Men with multiple family members diagnosed with csPCa at age < 60 years or a family member who died
from PCa cancer;
• Men with a family history of high-risk germline mutations or a family history of multiple cancers on the
same side of the family.

Further research in this field (including not so well-known germline mutations) is needed to develop screening,
early detection and treatment paradigms for mutation carriers and family members.

5.1.4 Guidelines for germline testing*

Recommendations Strength rating

Consider germline testing in men with metastatic PCa. Weak
Consider germline testing in men with high-risk PCa who have a family member diagnosed Weak
with PCa at age < 60 years.
Consider germline testing in men with multiple family members diagnosed with PCa at age Weak
< 60 years or a family member who died from PCa.
Consider germline testing in men with a family history of high-risk germline mutations or a Weak
family history of multiple cancers on the same side of the family.
*Genetic counselling is required prior to germline testing.

5.1.5 Guidelines for screening and individual early detection

Recommendations Strength rating

Do not subject men to prostate-specific antigen (PSA) testing without counselling them on Strong
the potential risks and benefits.
Offer an individualised risk-adapted strategy for early detection to a well-informed man with Weak
a life-expectancy of at least 10 to 15 years.
Offer early PSA testing to well-informed men at elevated risk of having PCa: Strong
• men from 50 years of age;
• men from 45 years of age and a family history of PCa;
• men of African descent from 45 years of age;
• men carrying BRCA2 mutations from 40 years of age.

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 27

Offer a risk-adapted strategy (based on initial PSA level), with follow-up intervals of 2 years Weak
for those initially at risk:
• men with a PSA level of > 1 ng/mL at 40 years of age;
• men with a PSA level of > 2 ng/mL at 60 years of age;
Postpone follow-up up to 8 years in those not at risk.
In asymptomatic men with a prostate-specific antigen (PSA) level between 3–10 ng/mL and Weak
a normal digital rectal examination (DRE), repeat the PSA test prior to further investigations.
In asymptomatic men with a PSA level between 3–10 ng/mL and a normal DRE, use one of Strong
the following tools for biopsy indication:
• risk-calculator, provided it is correctly calibrated to the population prevalence;
• magnetic resonance imaging of the prostate;
• an additional serum, urine biomarker test. Weak
Stop early diagnosis of PCa based on life expectancy and performance status; men who Strong
have a life-expectancy of < 15 years are unlikely to benefit.

5.2 Clinical diagnosis

Prostate cancer is usually suspected on the basis of DRE and/or PSA levels. Definitive diagnosis depends on
histopathological verification of adenocarcinoma in prostate biopsy cores.

5.2.1 Digital rectal examination

In ~18% of cases, PCa is detected by suspect DRE alone, irrespective of PSA level [180]. A suspect DRE in
patients with a PSA level < 2 ng/mL has a positive predictive value (PPV) of 5–30% [180]. In the ERSPC trial, an
abnormal DRE in conjunction with an elevated PSA more than doubled the risk of a positive biopsy (48.6% vs.
22.4%) [181]]. An abnormal DRE is associated with an increased risk of a higher ISUP grade, predicts csPCa in
men under AS [182] and is an indication for MRI and biopsy [181, 183]. cT staging is dependent on DRE and a
strong predictor of advanced PCa (OR: 11.12 for cT3 and OR: 5.28 for cT4) [184].

5.2.2 Prostate-specific antigen

The use of PSA as a serum marker has revolutionised PCa diagnosis [185]. Prostate-specific antigen is
organ- but not cancer specific; therefore, it may be elevated in benign prostatic hypertrophy (BPH), prostatitis
and other non-malignant conditions. However, PSA keeps its diagnostic value for cancer detection even in
symptomatic patients [186].
PSA value is also negatively impacted by hormonal treatments, even those given for benign
conditions such as finasteride or dutasteride [187]. In such cases, interpretation of PSA level should be
adapted as these treatments can frequently lower the PSA level by half.

There are no agreed standards for defining PSA thresholds [188]. It is a continuous parameter, with higher
levels indicating greater likelihood of PCa. Many men may harbour PCa despite having low serum PSA [189].
Table 5.2 demonstrates the occurrence of ISUP > grade 2 PCa in systematic biopsies at low PSA levels,
precluding an optimal PSA threshold for detecting non-palpable but csPCa. The use of nomograms and
biomarkers may help in predicting indolent PCa [154, 190, 191]. In case of an elevated PSA (up to 10 ng/mL), a
repeated test should be considered to confirm the increase before going to the next step.

5.2.2.1 Repeat PSA testing

A repeat PSA test before prostate biopsies in men with an initial PSA 3–10 ng/mL reduced the indication
for biopsies in 16.8% of men while missing 5.4% ISUP grade > 1 in the STHLM3 trial [192]. Similarly, in the
Prostate Testing for Cancer and Treatment (ProtecT) trial men with a more than 20% lower repeat-PSA analysis
within 7 weeks had a lower risk of PCa (OR: 0.43, 95% CI: 0.35–0.52) as well as a lower risk of ISUP grade
> 2 (OR: 0.29, 95% CI: 0.19–0.44) [193]. A study with a PSA interval of 4 weeks showed similar findings of a
reduced risk of PCa and ISUP grade > 1 [194]. These observations indicate that an early repeat-PSA prior to
the decision of prostate biopsies has prognostic information.

Table 5.2: Risk of PCa identified by systemic PCa biopsy in relation to low PSA values [173]

PSA level (ng/mL) Risk of PCa (%) Risk of ISUP grade > 2 PCa (%)
0.0–0.5 6.6 0.8
0.6–1.0 10.1 1.0
1.1–2.0 17.0 2.0
2.1–3.0 23.9 4.6
3.1–4.0 26.9 6.7

28 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

5.2.2.2 PSA density
Prostate-specific antigen density is the level of serum PSA divided by the prostate volume. The higher the PSA-D,
the more likely it is that the PCa is clinically significant; in particular in smaller prostates when a PSA-D cut-off of
0.15 ng/mL/cc was applied [195] (see Section 5.2.4.2.6.3). Several studies found a PSA-D over 0.1–0.15 ng/mL/cc
predictive of cancer [196, 197]. Patients with a PSA-D below 0.09 ng/mL/cc were found unlikely (4%) to be
diagnosed with csPCa [198]. A systematic review showed heterogeneity among studies using PSA-D to select
men with PI-RADS 3 category on MRI reading for biopsies but suggest a cut-off of 0.15 ng/mL/cc [196]. Others
found its added value to biparametric (bp) MRI-guided biopsies unclear with an area under the curve (AUC) of
0.87–0.95 for the direction of csPCa based on bpMRI and 0.91–0.95 for the combined test of bpMRI and PSA-D
[199].

5.2.2.3 Free/total PSA ratio

Free/total (f/t) PSA must be used cautiously because it may be adversely affected by several pre-analytical and
clinical factors (e.g., instability of free PSA at 4°C and room temperature, variable assay characteristics, and
concomitant BPH in large prostates) [200]. A systematic review including 14 studies found a pooled sensitivity
of 70% in men with a PSA of 4–10 ng/mL [201]. Free/total PSA is of no clinical use if the total serum PSA is
> 10 ng/mL or during follow-up of known PCa. The clinical value of f/t PSA is limited in light of the new
diagnostic pathways incorporating MRI.

5.2.3 Other blood and urine biomarkers

5.2.3.1 Blood based biomarkers: PHI/4K score/IsoPSA
Several assays measuring a panel of kallikreins in serum or plasma are now commercially available, including
the U.S. Food and Drug Administration (FDA) approved Prostate Health Index (PHI) test (combining free and
total PSA and the [-2]pro-PSA isoform [p2PSA]), and the four kallikrein (4K) score test (measuring free, intact
and total PSA and kallikrein-like peptidase 2 [hK2] in addition to age, DRE and prior biopsy status). Both tests
are intended to reduce the number of unnecessary prostate biopsies in PSA-tested men. A few prospective
multi-centre studies demonstrated that both the PHI and 4K score test out-performed f/t PSA PCa detection,
with an improved prediction of csPCa in men with a PSA between 2–10 ng/mL [202-205]. In a head-to-head
comparison both tests performed equally [206].
In contrast to the 4K score and PHI, which focus on the concentration of PSA isoforms, IsoPSA
utilises a novel technology which focuses on the structure of PSA [207]. Using an aqueous two-phase solution,
it partitions the isoforms of PSA and assesses for structural changes in PSA. In a multi-centre prospective
validation in 271 men the assay AUC was 0.784 for high-grade vs. low-grade cancer/benign histology, which
was superior to the AUCs of total PSA and percent free PSA [208]. In men with a negative mpMRI, PSA-D, 4K
score and family history predicted the risk of csPCa on biopsy and using a nomogram reduced the number of
negative biopsies and indolent cancers by 47% and 15%, respectively, while missing 10% of csPCas [209].
The Stockholm3 test is a prediction model that is based on several clinical variables (age, first-
degree family history of PCa, and previous biopsy), blood biomarkers (total PSA, free PSA, ratio of free PSA
to total PSA, human kallikrein 2, macrophage inhibitory cytokine-1, and microseminoprotein-β [MSMB]), and
a polygenic risk score for predicting the risk of PCa with ISUP > 2, and was shown to reduce the percent of
clinically insignificant cancers when used in combination with MRI in a PSA screening population [268].
The Proclarix® test is a blood-based test that estimates the likelihood of csPCa according to
measurement results for thrombospondin-1, cathepsin D, total PSA, percentage free PSA and patient age. This
test has been correlated with the detection of significant PCa, notably in case of equivocal MRI (PI-RADS 3
lesions) [210].

5.2.3.2 Urine biomarkers: PCA3/SelectMDX/Mi Prostate score (MiPS)/ExoDX

Prostate cancer gene 3 (PCA3) is an overexpressed long non-coding RNA (lncRNA) biomarker that is
detectable in urine sediments obtained after three strokes of prostatic massage during DRE. However, the
clinical utility of the commercially available Progensa urine test for PCA3 for biopsy decision-making remains
uncertain. However, combining MRI findings with the PCA3 score may improve risk stratification [211].

The SelectMDX test is similarly based on mRNA biomarker isolation from urine. The presence of HOXC6 and
DLX1 mRNA levels is assessed to provide an estimate of the risk of both presence of PCa on biopsy as well
as presence of high-risk cancer [212]. A multi-centre trial evaluated SelectMDX in men with a MRI PI-RADS
score < 4 or PI-RADS score < 3, and the percentage of missed csPCas was 6.5% and 3.2%, respectively,
whereas 45.8% and 40% of biopsies were avoided [213]. Hendriks et al., found more biopsies were avoided
and more high-grade PCas detected in a MRI-based biopsy strategy compared to a SelectMDX strategy. When
both tests were combined, more Gleason grade > 1 lesions were found, but the number of negative or low-
grade cancer biopsies more than doubled [191]. Combining SelectMDX and MRI in men with a PSA between

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 29

3–10 ng/mL had a negative predictive value (NPV) of 93% [214]. The clinically added value of SelectMDX in the
era of upfront MRI and targeted biopsies remains unclear [215].

TMPRSS2-ERG fusion, a fusion of the trans-membrane protease serine 2 (TMPRSS2) and the ERG gene
can be detected in 50% of PCas [216]. When detection of TMPRSS2-ERG in urine was added to PCA3
expression and serum PSA (Mi(chigan)Prostate Score [MiPS]), cancer prediction improved [217]. Exosomes
secreted by cancer cells may contain mRNA diagnostic for high-grade PCa [218, 219]. Use of the ExoDx
Prostate IntelliScore urine exosome assay resulted in avoiding 27% of unnecessary biopsies when compared
to standard of care (SOC). However, currently, both the MiPS-score and ExoDx assay are considered
investigational.

In the screening population of the ERSPC study the use of both PCA3 and 4K panel when added to the risk
calculator led to an improvement in AUC of less than 0.03 [220]. Based on the available evidence, some
biomarkers could help in discriminating between aggressive and non-aggressive tumours with an additional
value compared to the prognostic parameters currently used by clinicians [221]. However, upfront MRI is also
likely to affect the utility of above-mentioned biomarkers (see Section 5.2.3.2).

5.2.3.3 Biomarkers to select men for a repeat biopsy

In men with an elevated risk of PCa with a prior negative biopsy, the role of PHI, Progensa PCA3, and
SelectMDX in deciding whether to take a repeat biopsy in men who had a previous negative biopsy is uncertain
and probably not cost-effective [222]. The ConfirmMDx test is based on the concept that benign prostatic
tissue in the vicinity of a PCa focus shows distinct epigenetic alterations. In case PCa is missed at biopsy,
demonstration of epigenetic changes in the benign tissue would indicate the presence of carcinoma. The
ConfirmMDX test quantifies the methylation level of promoter regions of three genes (Methylated APC, RASSF1
and GSTP1) in benign prostatic tissue. A multicentre study found a NPV of 88% when methylation was absent
in all three markers, implying that a repeat biopsy could be avoided in these men [223]. Given the limited
available data and the fact that the role of MRI in tumour detection was not accounted for, no recommendation
can be made regarding the routine application of ConfirmMDX, in particular in the light of current use of MRI
before biopsy.

5.2.4 Imaging
5.2.4.1 Transrectal ultrasound and ultrasound-based techniques
Standard TRUS is not reliable at detecting PCa [224] and the diagnostic yield of additional biopsies
performed on hypoechoic lesions is negligible [124]. New sonographic modalities such as micro-Doppler,
sonoelastography or contrast-enhanced US provided promising preliminary findings, either alone, or combined
into the so-called ‘multiparametric US’ [225, 226]. In the multiparametric US vs. multiparametric MRI to
diagnose PCa (CADMUS) trial, 306 patients underwent both multiparametric MRI and multiparametric US
composed of B-mode, Colour Doppler, real-time elastography, and contrast-enhanced US. Patients with at
least one positive test underwent targeted biopsy. Multiparametric US detected 4.3% fewer csPCa while
submitting 11.1% more patients to biopsy than MRI [227].
High-resolution micro-US operates at 29 MHz instead of 8-12 MHz with conventional TRUS. As
high frequency ultrasonic waves are rapidly attenuated, micro-US is intrinsically limited for the exploration
of the anterior part of large prostates. Several studies combined into a meta-analysis [228] obtained similar
csPCa detection rates for micro-US-targeted and MRI-targeted biopsy. However, this conclusion is limited by
the retrospective non-randomized design of the included studies, and by the fact that the micro-US operator
was not blinded to MRI results in most of them. One prospective trial included 203 patients referred for biopsy
in three centers [229]. The biopsy operator was blinded to the MRI report until after the micro-US targets had
been assessed. After unblinding, micro-US and mpMRI targets were sampled, followed by systematic biopsy.
Micro-US and mpMRI detected respectively 58 (73%) and 60 (76%) of the 79 csPCas, while systematic
sampling detected 45/79 cases (57%). MRI-targeted biopsy detected 7 csPCas missed by micro-US; of these
three were anterior lesions. Micro-US-guided biopsy detected 5 csPCas missed by MRI; of these, three were
at the apex. Although these findings require further confirmation, they suggest that micro-US and MRI could
complement each other. Micro-US could also be an interesting alternative to MRI/US fusion since most MRI
lesions seem visible on micro-US [230]. Of note, evaluation of micro-US inter-operator variability is currently
lacking.

5.2.4.2 Magnetic resonance imaging

5.2.4.2.1 MRI diagnostic performance in detecting PCa
Correlation with RP specimens shows that MRI has good sensitivity for the detection and localisation of ISUP
grade > 2 cancers, especially when their diameter is larger than 10 mm [231-233]. This good sensitivity was

30 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

further confirmed in patients who underwent template biopsies. In a Cochrane meta-analysis which compared
MRI to template biopsies (> 20 cores) in biopsy-naive and repeat-biopsy settings, MRI had a pooled sensitivity
of 0.91 (95% CI: 0.83–0.95) and a pooled specificity of 0.37 (95% CI: 0.29–0.46) for ISUP grade > 2 cancers [168].
For ISUP grade > 3 cancers, MRI pooled sensitivity and specificity were 0.95 (95% CI: 0.87–0.99) and 0.35
(95% CI: 0.26–0.46), respectively. MRI is less sensitive in identifying ISUP grade 1 PCa. It identifies less than
30% of ISUP grade 1 cancers smaller than 0.5 cc identified on RP specimens by histopathology analysis [231].
In a meta-analysis of 17 studies involving men with suspected or biopsy-proven PCa, the average
PPVs for ISUP grade > 2 cancers of lesions with a PI-RADSv2.1 score of 3, 4 and 5 were 16% (7–27%), 59%
(39–78%), and 85% (73–94%), respectively, but with significant heterogeneity among studies [234].

5.2.4.2.2 Targetted biopsy improves the detection of ISUP grade > 2 cancer as compared to systemic biopsy.
In pooled data of 25 reports on agreement analysis (head-to-head comparisons) between systematic biopsy
(median number of cores: 8–15) and MRI-targeted biopsies (median number of cores: 2–7), the detection ratio
(i.e. the ratio of the detection rates obtained by MRI-targeted biopsy alone and by systematic biopsy alone)
was 1.12 (95% CI: 1.02–1.23) for ISUP grade > 2 cancers and 1.20 (95% CI: 1.06–1.36) for ISUP grade > 3
cancers, and therefore in favour of MRI-targeted biopsy [168].
Another meta-analysis of studies limited to biopsy-naive patients with a positive MRI found
that MRI-targeted biopsy detected significantly more ISUP grade > 2 cancers than systematic biopsy (risk
difference, -0.11 [95% CI: -0.2 to 0.0]; p = 0.05), in prospective cohort studies (risk difference, -0.18 [95%
CI: -0.24 to -0.11]; p < 0.00001), and in retrospective cohort studies (risk difference, -0.07 [95% CI: -0.12 to
-0.02]; p = 0.004) [235]. This data was confirmed in prospective multi-centre trials evaluated MRI-targeted
biopsy in biopsy-naive patients [123-125].
The Target Biopsy Techniques Based on Magnetic Resonance Imaging in the Diagnosis of Prostate
Cancer in Patients with Prior Negative Biopsies (FUTURE) randomised trial compared three techniques of
MRI-targeted biopsy in the repeat-biopsy setting [236]. In the subgroup of 152 patients who underwent both
MRI-targeted biopsy and systematic biopsy, MRI-targeted biopsy detected significantly more ISUP grade > 2
cancers than systematic biopsy (34% vs. 16%; p < 0.001, detection ratio of 2.1), which is a finding consistent
with the Cochrane agreement analysis (detection ratio: 1.44). An ISUP grade > 2 cancer would have been
missed in only 1.3% (2/152) of patients, had systematic biopsy been omitted [237]. These findings support that
MRI-targeted biopsy significantly out-performs systematic biopsy for the detection of ISUP grade > 2 in the
repeat-biopsy setting. In biopsy-naive patients, the difference appears to be less marked but remains in favour
of MRI-targeted biopsy.

5.2.4.2.3 Reduced detection of ISUP grade 1 cancers by MRI-targeted biopsy without systematic biopsy
In pooled data of 25 head-to-head comparisons between systematic biopsy and MRI-targeted biopsy, the
detection ratio for ISUP grade 1 cancers was 0.62 (95% CI: 0.44–0.88) in patients with prior negative biopsy
and 0.63 (95% CI: 0.54–0.74) in biopsy-naive patients [168]. In the PRECISION and 4M trials, the detection rate
of ISUP grade 1 patients was significantly lower in the MRI-targeted biopsy group as compared to systematic
biopsy (9% vs. 22%, p < 0.001, detection ratio of 0.41 for PRECISION; 14% vs. 25%, p < 0.001, detection ratio
of 0.56 for 4M) [123, 125]. In the MRI-FIRST trial, MRI-targeted biopsy detected significantly fewer patients with
clinically insignificant PCa (defined as ISUP grade 1 and maximum cancer core length < 6 mm) than systematic
biopsy (5.6% vs. 19.5%, p < 0.0001, detection ratio of 0.29) [124]. Consequently, MRI-targeted biopsy without
systematic biopsy significantly reduces over-diagnosis of low-risk disease, as compared to systematic biopsy.
This seems true even when systematic biopsies are indicated after after risk stratification with a US-based risk
calculator (i.e. Rotterdam Prostate Cancer Risk Calculator) [169].

5.2.4.2.4 Added value of systematic biopsy and targeted biopsy

MRI-targeted biopsies can be used in two different diagnostic pathways: 1) the ‘combined pathway’, in which
patients with a positive MRI undergo combined systematic and targeted biopsy, and patients with a negative
MRI undergo systematic biopsy; or 2) the ‘MRI pathway’, in which patients with a positive MRI undergo only
MRI-targeted biopsy, and patients with a negative MRI who are not biopsied at all. The first diagnostic pathway
focuses on maximizing the detection of significant cancers, also termed as the ‘rule-in’ ability. However, this
pathway has the disadvantage of leading to a greater detection of insignificant cancers and of referring all
patients with a clinical suspicion of cancer to biopsy. The second diagnostic pathway focuses on the ‘rule-out’
ability, and minimizes these disadvantages at the cost of missing a small proportion of significant cancers. Risk
profiling is necessary to balance the ‘rule-in’ or ‘rule-out’ ability on an individual basis, incorporating patient
and physician preference (i.e. biopsy averse/cancer averse), choosing for either adding or avoiding systematic
biopsies. Table 5.3 shows the added value of systematic and MRI-targeted biopsy for ISUP grade > 2 and > 3
cancer detection.

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 31

  bsolute added values of targeted and systematic biopsies for ISUP grade > 2 and > 3 Cancer
Table 5.3: A
Detection

ISUP > 2 ISUP > 3

ISUP grade Cochrane MRI-FIRST 4M trial Cochrane MRI-FIRST 4M trial
meta- trial* [124] [125] meta- trial* [124] [125]
analysis* analysis*
[168] [168]
Added value of 6.3% 7.6% 7.0% (ND) 4.7% 6.0% 3.2% (ND)
MRI-TBx (4.8–8.2) (4.6–11.6) (3.5–6.3) (3.4–9.7)
Added value 4.3% 5.2% 5.0% (ND) 2.8% 1.2% 4.1% (ND)
Biopsy-naïve of systematic (2.6–6.9) (2.8–8.7) (1.7–4.8) (0.2–3.5)
biopsy
Overall 27.7% 37.5% 30% (ND) 15.5% 21.1% 15% (ND)
prevalence (23.7–32.6) (31.4–43.8) (12.6–19.5) (16.2–26.7)
Added value of 9.6% - - 6.3% - -
MRI-TBx (7.7–11.8) (5.2–7.7)
Prior negative Added value of 2.3% - - 1.1% - -
biopsy systematic biopsy (1.2–4.5) (0.5–2.6)
Overall 22.8% - - 12.6% - -
prevalence (20.0–26.2) (10.5–15.6)
*Intervals in parenthesis are 95% CI.
The absolute added value of a given biopsy technique is defined by the percentage of patients of the entire
cohort diagnosed only by this biopsy technique.
ISUP = International Society of Urological Pathology (grade); MRI-TBx = magnetic resonance imaging-targeted
biopsies; ND = not defined.

In Table 5.3, the absolute added values refer to the percentage of patients in the entire cohort; if the cancer
prevalence is taken into account, the ‘relative’ percentage of additional detected PCa can be computed.
Adding MRI-targeted biopsy to systematic biopsy in biopsy-naive patients increases the number of detected
ISUP grade > 2 and grade > 3 PCa by approximately 20% and 30%, respectively. In the repeat-biopsy setting,
adding MRI-targeted biopsy increases detection of ISUP grade > 2 and grade > 3 PCa by approximately 40%
and 50%, respectively. Omitting systematic biopsy in biopsy-naive patients would miss approximately 16%
of all detected ISUP grade > 2 PCa and 18% of all ISUP grade > 3 PCa. In the repeat-biopsy setting, it would
miss approximately 10% of ISUP grade > 2 PCa and 9% of ISUP grade > 3 PCa.

In the GÖTEBORG-2 prospective trial, 37,887 men between 50 and 60 years of age were invited to undergo
regular PSA screening [238]. Participants with a PSA level above 3 ng/mL were randomly allocated to MRI and
combined systematic- and targeted biopsy (reference group) or to MRI and targeted biopsy only in case of
PI-RADS > 3 lesions (experimental group). In the experimental group, the detection rate of ISUP 1 cancers was
reduced by half (detection ratio: 0.46, 95% CI: 0.33–0.64, p < 0.001); that of ISUP > 2 cancers was lower but
not significantly (detection ratio: 0.81, 95% CI: 0.60 to 1.1). In the reference group, 10 of the 68 men with ISUP
> 2 cancer were diagnosed by systematic biopsy only. All these 10 patients were of intermediate risk. Thus, in
a screening setting, the ‘MRI pathway’ may reduce the risk of over-diagnosis by half, at the cost of delaying
detection of intermediate-risk tumours in a small percentage of patients. However, these good results were
obtained at a single academic centre with double reading of the MRI, which may limit their generalisability in
less experienced centers (see Sections 5.2.4.2.6.1 and 5.2.4.2.6.2).

5.2.4.2.5 Avoiding biopsies in the ‘MR pathway’

The diagnostic yield and number of biopsy procedures potentially avoided by the ‘MR pathway’ depends
on the Likert/PI-RADS threshold used to define a positive MRI. In pooled studies on biopsy-naive patients
and patients with prior negative biopsies, a Likert/PI-RADS threshold of > 3 would have avoided 30% (95%
CI: 23–38) of all biopsy procedures while missing 11% (95% CI: 6–18) of all detected ISUP grade > 2 cancers
(relative percentage) [168]. Increasing the threshold to > 4 would have avoided 59% (95% CI: 43–78) of all
biopsy procedures while missing 28% (95% CI: 14–48) of all detected ISUP grade > 2 cancers [168]. Of note,
the percentages of negative MRI (Likert/PI-RADS score < 2) in the MRI-FIRST, PRECISION and 4M trials
were 21.1%, 28.9% and 49%, with related ISUP grade > 2 cancer prevalences of 27.7% (23.7–32.6), 37.5%
(31.4–43.8), and 30% (ND) respectively [123-125].

32 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

5.2.4.2.6 Practical considerations
5.2.4.2.6.1 Prostate MRI reproducibility
Despite the use of the PI-RADSv2 scoring system [239], MRI inter-reader reproducibility remains moderate at
best which currently limits its broad use by non-dedicated radiologists [240]. However, significant improvement
in the accuracy of MRI and MRI-targeted biopsy can be observed over time, both in academic and community
hospitals, especially after implementation of PI-RADSv2 scoring and multidisciplinary meetings using
pathological correlation and feedback [241-244]. An updated version of the PI-RADS score (PI-RADSv2.1) has
been published to improve reader reproducibility, showing improved diagnostic performance [234] but it has
not yet been fully evaluated [245]. It is still too early to predict whether quantitative approaches and computer-
aided diagnostic systems will improve the characterisation of lesions seen at MRI [246]. Standardisation of MRI
interpretation and quality check of acquisition and of MRI-targeted biopsy technique is required to optimise the
‘MRI pathway’ in large-volume and small-volume (non-expert) centres [247-249].

5.2.4.2.6.2 Targeted biopsy accuracy and reproducibility

Clinically significant PCa not detected by the ‘MRI pathway’ can be missed because of MRI failure (invisible
cancer or reader’s misinterpretation) or because of targeting failure (target missed or under sampled by MRI-
targeted biopsy).
The accuracy of MRI-targeted biopsy is substantially impacted by the experience of the biopsy
operator [240], and two retrospective studies on patients with a unilateral lesion found that the added value of
systematic biopsy was higher in the MRI-positive lobe than in the MRI-negative lobe [250, 251]. This suggests
that a substantial part of the added value of systematic biopsies is due to mistargeting issues (i.e., the lesion
has been correctly identified by MRI but missed by MRI-targeted biopsy and detected by systematic sampling).
Increasing the number of cores taken per target may partially compensate for guiding imprecision,
and a minimum of 3 to 5 cores is required for proper sampling of the lesions [252-254]. Consequently, some
authors have suggested MRI-directed biopsy approaches using targeted biopsies combined with peri-lesional/
regional systematic biopsies, rather than standard sextant-based systematic biopsies. This could decrease the
number of cores taken (by avoiding systematic biopsies in MRI-negative lobes) and improve the detection of
csPCa (by improving the lesional and peri-lesional sampling). A recent meta-analysis of 8 retrospective studies
showed a nonsignificant difference in detection of ISUP grade > 2 PCa in the MRI-directed targeted- and
regional biopsy approach, compared to the recommended practice of MRI-directed targeted- and systematic
biopsy approach (RR: 0.95, 95% CI: 0.90–1.01; p = 0.09). However MRI-directed targeted- and regional biopsy
approach detected significantly more csPCa than MRI-targeted biopsy alone (RR: 1.18, 95% CI: 1.10–1.25;
p < 0.001) [255]. However, due to the heterogeneity of the retrospective studies, prospective clinical studies are
needed before the role of this biopsy approach can be assessed. The impact of per-lesional sampling on non-
significant (ISUP 1) cancer has not been fully assessed either.

5.2.4.2.6.3 Risk-stratification
Using risk-stratification to avoid biopsy procedures
Prostate-specific antigen density may help refine the risk of csPCa in patients undergoing MRI as PSA-D and
the PI-RADS score are significant independent predictors of csPCa at biopsy [256, 257]. In a meta-analysis
of 8 studies, pooled MRI NPV for ISUP grade > 2 cancer was 84.4% (95% CI: 81.3–87.2) in the whole cohort,
82.7% (95% CI: 80.5–84.7) in biopsy-naive men and 88.2% (95% CI: 85–91.1) in men with prior negative
biopsies. In the subgroup of patients with PSA-D < 0.15 ng/mL, NPV increased to respectively 90.4% (95%
CI: 86.8–93.4), 88.7% (95% CI: 83.1–93.3) and 94.1% (95% CI: 90.9–96.6) [258]. In contrast, the risk of csPCa
is as high as 27–40% in patients with negative MRI and PSA-D > 0.15–0.20 ng/mL/cc [125, 172, 257, 259-261].

Based on a meta-analysis of > 3,000 biopsy-naive men, a risk-adapted data table of csPCa was developed,
linking PI-RADS score (1-2, 3, and 4-5) to PSA-D categories (< 0.10, 0.10–0.15, 0.15–0.20 and > 0.20 ng/mL)
(Table 5.4) [170]. For example, the risk of having ISUP grade > 2 cancer in biopsy-naive men with a PI-RADS
1–2 assessment score and PSA-D below 0.10 is 3–4%, in a below-average-risk population of < 5% [170]. This
risk-adapted matrix table based on PSA-D and on MRI risk assessments may guide the decision to perform a
biopsy.

These data are applicable for a mean ISUP grade > 2 cancer prevalence of 35% (range 28–46%) in biopsy-naive
men, and would need to be adjusted to other populations’ prevalence. Awaiting validation of MRI-based
multivariate risk-prediction tools, corroboration linking MRI findings to PSA-D values for biopsy decisions is
beginning to emerge which may promote their routine use in clinical practice [20, 262]. It must be emphasised,
however, that the use of PSA-D remains currently limited due to the lack of standardisation of prostate volume
measurement (assessed by DRE or by imaging [TRUS or MRI using various techniques such as ellipsoid formula
or planimetry]). The impact of this lack of standardisation on the volume estimation remains underevaluated.

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 33

Table 5.4: R
 isk data table of clinically significant prostate cancer, related to PI-RADS score and PSA-D
categories in biopsy-naive men, clinically suspected of having significant disease [170]*

Detection of clinically significant prostate cancer (ISUP grade 2 and higher)

PSA-density risk groups
PI-RADS risk Prevalence ISUP Low Intermediate-low Intermediate-high High
categories > 2 PCa < 0.10 0.10–015 0.15–0.20 > 0.20
31% 28% 16% 25%
(678/2199) (612/2199) (360/2199) (553/2199)
Compiled totals
of csPCa risk
PI-RADS 1–2 6% 3% 7% 8% 18%
(48/839) (11/411) (17/256) (8/104) (12/68)
PI-RADS 3 16% 4% 13% 29% 29%
(41/254) (3/74) (11/88) (12/41) (15/51)
PI-RADS 4–5 62% 31% 54% 69% 77%
(687/1106) (59/189) (144/286) (148/215) (336/434)
All PI-RADS 35% 11% 28% 47% 66%
(776/2199) (73/674) (172/612) (168/360) (363/553)

Risk-adapted matrix table for biopsy decision management

PI-RADS 1–2 No biopsy No biopsy No biopsy Consider biopsy
PI-RADS 3 No biopsy Consider biopsy Highly consider Perform biopsy
biopsy
PI-RADS 4–5 Perform biopsy Perform biopsy Perform biopsy Perform biopsy

very low 0–5% csPCa (below population risk) #

low 5–10% csPCa (acceptable risk) ##
Intermediate-low 10–20% csPCa
Intermediate-high 20–30% csPCa
High 30–40% csPCa
Very high > 40% csPCa
#  hompson IM et al. N Engl J Med. 2004 May 27;350(22):2239-46. Prevalence of prostate cancer among men
T
with a prostate-specific antigen level < or = 4.0 ng/mL.
## 2019 EAU guidelines: csPCa 9% (95% CI: 6–14%).

Table adapted from: Schoots, IG and Padhani AR. BJU Int 2021 127(2):175. Risk-adapted biopsy decision
based on prostate magnetic resonance imaging and prostate-specific antigen density for enhanced biopsy
avoidance in first prostate cancer diagnostic evaluation, with permission from Wiley.

Several groups have developed comprehensive risk calculators which combine MRI findings with simple
clinical data as a tool to predict subsequent biopsy results [263]. At external validation, they tended to
outperform risk calculators not incorporating MRI findings (ERSPC and Prostate Cancer Prevention Trial) with
good discriminative power (as measured by the AUC). However, they also tended to be miscalibrated with
under- or over-prediction of the risk of ISUP grade > 2 cancer [264, 265]. In one study that externally assessed
four risk calculators combining MRI findings and clinical data, only two demonstrated a distinct net benefit
when a risk of false-negative prediction of 15% was accepted. The others were harmful for this risk level,
as compared to the ‘biopsy all’ strategy [264]. This illustrates the prevalence-dependence of risk models.
Recalibrations taking into account the local prevalence are possible, but this approach is difficult in routine
clinical practice as the local prevalence is difficult to estimate and may change over time.

Using risk-stratification to avoid MRI scans and biopsy procedures

A retrospective analysis including 200 men from a prospective database of patients who underwent MRI and
combined systematic and targeted biopsy showed that upfront use of the Rotterdam Prostate Cancer Risk
Calculator would have avoided MRI and biopsy in 73 men (37%). Of these 73 men, 10 had ISUP grade 1
cancer and 4 had ISUP grade > 2 cancer [266]. A prospective multi-centre study evaluated several diagnostic
pathways in 545 biopsy-naive men who underwent MRI and systematic and targeted biopsy. Using a PHI

34 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

threshold of > 30 to perform MRI and biopsy would have avoided MRI and biopsy in 25% of men at the cost
of missing 8% of the ISUP grade > 2 cancers [267]. Another prospective multi-centre trial including 532 men
(with or without history of prostate biopsy) showed that using a threshold of > 10% for the Stockholm3 test to
perform MRI and biopsy would have avoided MRI and biopsy in 38% of men at the cost of missing 8% of ISUP
grade > 2 cancers [268].

5.2.4.2.6.4 Potential cancer grade shift, induced by improved diagnosis by MRI and MRI-targeted biopsy
MRI findings are significant predictors of adverse pathology features on prostatectomy specimens, and of
survival-free BCR after RP or RT [105, 269-271]. In addition, tumours visible on MRI are enriched in molecular
hallmarks of aggressivity, as compared to invisible lesions [272]. Thus, MRI does identify aggressive tumours.
Nonetheless, as MRI-targeted biopsy is more sensitive than systematic biopsy in detecting areas
of high-grade cancer, ISUP grade > 2 cancers detected by MRI-targeted biopsy are, on average, of better
prognosis than those detected by the classical diagnostic pathway (Will Rogers phenomenon [107]). This
is illustrated in a retrospective series of 1,345 patients treated by RP which showed that, in all risk groups,
patients diagnosed by MRI-targeted biopsy had better BCR-free survival than those diagnosed by systematic
biopsy only [105]. To mitigate this grade shift, in case of targeted biopsies, the 2019 ISUP consensus
conference recommended using an aggregated ISUP grade summarizing the results of all biopsy cores from
the same MR lesion, rather than using the result from the core with the highest ISUP grade [110]. When long-
term follow-up of patients who underwent MRI-targeted biopsy is available, a revision of the risk-groups
definition will become necessary. In the meantime, results of MRI-targeted biopsy must be interpreted in the
context of this potential grade shift [273].

5.2.4.3 Guidelines for MRI imaging in biopsy decision

Recommendations for all patients Strength rating

Do not use magnetic resonance imaging (MRI) as an initial screening tool. Strong
Adhere to PI-RADS guidelines for MRI acquisition and interpretation and evaluate MRI Strong
results in multidisciplinary meetings with pathological feedback.

Recommendations in biopsy-naïve patients Strength rating

Perform MRI before prostate biopsy. Strong
When MRI is positive (i.e., PI-RADS > 3), combine targeted and systematic biopsy. Strong
When MRI is negative (i.e., PI-RADS < 2), and clinical suspicion of PCa is low (e.g., PSA Weak
density < 0.15 ng/mL), omit biopsy based on shared decision-making with the patient.

Recommendations in patients with prior negative biopsy Strength rating

Perform MRI before prostate biopsy. Strong
When MRI is positive (i.e., PI-RADS > 3), perform targeted biopsy only. Weak
When MRI is negative (i.e., PI-RADS < 2), and clinical suspicion of PCa is high, perform Strong
systematic biopsy based on shared decision-making with the patient.

5.2.5 Baseline biopsy decision

The need for prostate biopsy is based on PSA level, PSA density, other biomarkers and/or suspicious DRE
and/or imaging (see Section 5.2.4). Age, potential co-morbidity and therapeutic consequences should also
be considered and discussed beforehand [241]. Risk stratification is a potential tool for reducing unnecessary
biopsies [274].
Limited PSA elevation alone should not prompt immediate biopsy. Prostate-specific antigen
level should be verified after a few weeks, in the same laboratory using the same assay under standardised
conditions (i.e. no ejaculation, manipulations, and urinary tract infections [UTIs]) [275, 276]. Empiric use of
antibiotics in an asymptomatic patient in order to lower the PSA should not be undertaken [277].

Ultrasound (US)-guided and/or MRI-targeted biopsy is now the SOC. Prostate biopsy is performed by either
the recommended transperineal approach or the transrectal one. Cancer detection rates, when performed
without prior imaging with MRI, are comparable between the two approaches [246], however, evidence
suggests reduced infection risk with the transperineal route (see Section 5.2.8.1.1) [278, 279]. Transurethral
resection of the prostate (TURP) should not be used as a tool for cancer detection [280].

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 35

5.2.6 Repeat biopsy decision
5.2.6.1 Repeat biopsy after previously negative biopsy
Men with a previous negative systematic biopsy should be offered a prostate MRI and in case of PI-RADS > 3
findings, a repeat (targeted) biopsy should be done. Other indications for repeat biopsy should be discussed on
an individual basis taking into account PSA level and its evolution, DRE, PSA density and pathological findings
on the previous biopsy.

In a contemporary series of biopsies the likelihood of finding a csPCa after follow-up biopsy after a diagnosis
of atypical small acinar proliferation and high-grade prostatic intraepithelial neoplasia (PIN) was only 6-8%, not
significantly different from follow-up biopsies after a negative biopsy [281, 282].
The added value of other biomarkers remains unclear (see Sections 5.2.3.1 and 5.2.3.2).

5.2.6.2 Saturation biopsy

The incidence of PCa detected by saturation repeat biopsy (> 20 cores) is 30–43% and depends on the
number of cores sampled during earlier biopsies [283]. Saturation biopsy may be performed with the
transperineal technique, which detects an additional 38% of PCa. The rate of urinary retention varies
substantially from 1.2% to 10% [284-287].
However, given the very low risk of subsequent csPCa after a negative biopsy and/or in case of
negative MRI, the clinical utility of saturation biopsy in the repeat biopsy setting remains uncertain in the
current MRI-driven diagnostic pathway and such schemes should not be routinely used [288].

5.2.7 Prostate biopsy procedure

For systematic biopsies, where no prior imaging is used for targeting, the sample sites should be bilateral from
apex to base, as far posterior and lateral as possible in the peripheral gland regardless of the approach used.
A 2006 systematic review showed that 12 is the minimum number of cores for systematic biopsies, with > 12
cores not increasing cancer detection rate significantly [289].

Additional cores should be obtained from suspect areas identified by DRE or on pre-biopsy MRI; multiple cores
(3–5) should be taken from each MRI-visible lesion.

Where MRI has shown a suspicious lesion, MR-targeted biopsy can be obtained through cognitive guidance,
US/MR fusion software or direct in-bore guidance. Current literature, including systematic reviews and
meta-analyses, does not show a clear superiority of one image-guided technique over another [236, 290-293].
However, regarding approach, the only systematic review and meta-analysis comparing MRI-targeted
transrectal biopsy to MRI-targeted transperineal biopsy, analysing 8 studies, showed a higher sensitivity
for detection of csPCa when the transperineal approach was used (86% vs. 73%) [294]. This benefit was
especially pronounced for anterior tumours. Multiple cores (3–5) should be taken from each lesion (see Section
5.2.4.2.6.2).

As detailed in Section 5.2.4.2.6.2, the added value of systematic biopsy is partially explained by the fact
that they compensate for guiding imprecisions of targeted biopsy. Therefore, biopsy strategies with multiple
peri-lesional (regional) targeted cores obtained in addition of MRI-directed targeted cores are being
investigated [250, 251, 295-298]. Prospective clinical trials are needed to evaluate whether these strategies can
replace the combination of systematic and targeted biopsy currently recommended as the diagnostic work-up
in men with positive MRI scans.

5.2.8 Summary of evidence and guidelines for prostate biopsies

Summary of evidence LE
Literature review including multiple biopsy schemes suggests that a minimum 12-core scheme is 3
optimal in the majority of initial and repeat biopsy patients, dependent on prostate size. These biopsy
schemes should be heavily weighted towards the lateral aspect and the apex of the prostate to
maximize peripheral zone sampling [299].
Systematic review and meta-analysis comparing MRI-targeted transrectal biopsy to MRI-targeted 2
transperineal biopsy, analysing 8 studies, showed a higher sensitivity for detection of csPCa when the
transperineal approach was used (86% vs. 73%).
Current literature, including systematic reviews and meta-analyses, does not show a clear superiority 2
of one image-guided technique (cognitive guidance, US/MR fusion software or direct in-bore
guidance) over the other.

36 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

Recommendations Strength rating
When performing systematic biopsy only, at least 12 cores are recommended. Strong
Systematic transperineal biopsies are preferred over systematic transrectal biopsies for Strong
detection of clinically significant PCa.
Where magnetic resonance imaging (MRI) has shown a suspicious lesion, MR-targeted Weak
biopsy can be obtained through cognitive guidance, US/MR fusion software or direct
in-bore guidance.

5.2.8.1 Antibiotics prior to biopsy

5.2.8.1.1 Transperineal prostate biopsy
A total of eight randomised studies including 1,596 patients compared the impact of biopsy route on
infectious complications. Infectious complications were significantly higher following transrectal biopsy
(48 events among 789 men) compared to transperineal biopsy (22 events among 807 men) (RR: 95%
CI: 2.48 [1.47–4.2]) [300, 301]. In addition, a systematic review including 165 studies with 162,577 patients
described sepsis rates of 0.1% and 0.9% for transperineal and transrectal biopsies, respectively [302]. Finally,
a population-based study from the UK (n = 73,630) showed lower re-admission rates for sepsis in patients
who had transperineal vs. transrectal biopsies (1.0% vs. 1.4%, respectively) [303]. The available evidence
demonstrates that the transrectal approach should be abandoned in favour of the transperineal approach
despite any possible logistical challenges. A systematic review and meta-analysis of eight non-RCTs reported
no significant differences between patients receiving or not receiving antibiotic prophylaxis in terms of
post-biopsy infection (0,11% vs. 0.31%) and sepsis (0.13% vs. 0,09%), for the transperineal approach [304].
This is in line with another systematic review and meta-analysis of 112 individual patient cohorts which also
showed no significant difference in the number of patients experiencing post-transperineal-biopsy infection
1.35% of 29,880 patients receiving antibiotic prophylaxis and 1.22% of 4,772 men not receiving antibiotic
prophylaxis (p = 0.8) [305]. In addition, two recently published RCTs have reported comparably low post-biopsy
infection rates for transperineal biopsy regardless of whether antibiotic prophylaxis was administered or not
[306, 307].
There is a growing body of evidence to suggest that antibiotic prophylaxis may not be required for
transperineal biopsy; however the Panel has chosen to wait until a number of ongoing RCTs report their study
findings before making a recommendation on this.

5.2.8.1.2 Transrectal prostate biopsy

An updated meta-analysis of eleven RCTs including 2,237 men showed that use of a rectal povidone-iodine
preparation before biopsy, in addition to antimicrobial prophylaxis, resulted in a significantly lower rate of
infectious complications (RR: 95% CI: 0.47 [0.36–0.61]) [301, 308-310]. Single RCTs showed no evidence of
benefit for perineal skin disinfection [311], but reported an advantage for rectal povidone-iodine preparation
before biopsy compared to after biopsy [312].
A meta-analysis of four RCTs including 671 men evaluated the use of rectal preparation by enema
before transrectal biopsy. No significant advantage was found regarding infectious complications (RR: 95%
CI: 0.96 [0.64–1.54]) [301].
An updated meta-analysis of 28 RCTs with 4,027 patients found no evidence that use of peri-
prostatic injection of local anaesthesia resulted in more infectious complications than no injection (RR: 95%
CI: 1.08 [0.79–1.48]) [300, 301, 313]. A meta-analysis of 9 RCTs including 2,230 patients found that extended
biopsy templates showed comparable infectious complications to standard templates (RR: 95% CI: 0.80
[0.53–1.22]) [301]. Additional meta-analyses found no difference in infectious complications regarding needle
guide type (disposable vs. reusable), needle type (coaxial vs. non-coaxial), needle size (large vs. small), and
number of injections for peri-prostatic nerve block (standard vs. extended) [301].

A meta-analysis of eleven studies with 1,753 patients showed significantly reduced infections after transrectal
prostate biopsy when using antimicrobial prophylaxis as compared to placebo/control (RR: 95% CI: 0.56
[0.40–0.77]) [314].
Fluoroquinolones have been traditionally used for antibiotic prophylaxis in this setting; however,
overuse and misuse of fluoroquinolones has resulted in an increase in fluoroquinolone resistance. In
addition, the European Commission has implemented stringent regulatory conditions regarding the use of
fluoroquinolones resulting in the suspension of the indication for peri-operative antibiotic prophylaxis including
prostate biopsy [315].
A systematic review and meta-analysis on antibiotic prophylaxis for the prevention of infectious
complications following prostate biopsy concluded that in countries where fluoroquinolones are allowed
as antibiotic prophylaxis, a minimum of a full one-day administration, as well as targeted therapy in case
of fluoroquinolone resistance, or augmented prophylaxis (combination of two or more different classes of

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 37

antibiotics) is recommended [314]. In countries where use of fluoroquinolones are suspended, cephalosporins
or aminoglycosides can be used as individual agents with comparable infectious complications based on
meta-analysis of two RCTs [314]. A meta-analysis of three RCTs reported that fosfomycin trometamol was
superior to fluoroquinolones (RR: 95% CI: 0.49 [0.27–0.87]) [314], but routine general use should be critically
assessed due to the relevant infectious complications reported in non-randomised studies [316]. Of note the
indication of fosfomycin trometamol for prostate biopsy has been withdrawn in Germany as the manufacturers
did not submit the necessary pharmacokinetic data in support of this indication. Urologists are advised
to check their local guidance in relation to the use of fosfomycin trometamol for prostate biopsy. Another
possibility is the use of augmented prophylaxis without fluoroquinolones, although no standard combination
has been established to date. Finally, targeted prophylaxis based on rectal swap/stool culture is plausible, but
no RCTs are available on non-fluoroquinolones. See figure 5.1 for prostate biopsy workflow to reduce infections
complications.

5.2.8.2 Summary of evidence and recommendations for performing prostate biopsy

(in line with the EAU Urological Infections Guidelines Panel)

Summary of evidence LE
A meta-analysis of eight studies including 1,596 patients showed significantly reduced infectious 1a
complications in patients undergoing transperineal biopsy as compared to transrectal biopsy.
A meta-analysis of eight non-RCTS reported comparable rates of post-biopsy infections in patients 1a
undergoing transperineal biopsy irrespective if antibiotic prophylaxis was given or not.
A meta-analysis of eleven RCTs including 2,036 men showed that use of a rectal povidone-iodine 1a
preparation before transrectal biopsy, in addition to antimicrobial prophylaxis, resulted in a significantly
lower rate of infectious complications.
A meta-analysis on eleven studies with 1,753 patients showed significantly reduced infections after 1a
transrectal biopsy when using antimicrobial prophylaxis as compared to placebo/control.

Recommendations Strength rating*

Perform prostate biopsy using the transperineal approach due to the lower risk of infectious Strong
complications.
Use routine surgical disinfection of the perineal skin for transperineal biopsy. Strong
Use rectal cleansing with povidone-iodine prior to transrectal prostate biopsy. Strong
Do not use fluoroquinolones for prostate biopsy in line with the European Commission final Strong
decision on EMEA/H/A-31/1452.
Use either target prophylaxis based on rectal swab or stool culture; augmented prophylaxis Weak
(two or more different classes of antibiotics); or alternative antibiotics (e.g., fosfomycin
trometamol**, cephalosporin, aminoglycoside) for antibiotic prophylaxis for transrectal
biopsy.
Ensure that prostate core biopsies from different sites are submitted separately for Strong
processing and pathology reporting.
* Note on strength ratings:
The above strength ratings are explained here due to the major clinical implications of these recommendations.
Although data showing the lower risk of infection via the transperineal approach is low in certainty, its statistical
and clinical significance warrants its Strong rating. Strong ratings are also given for routine surgical disinfection
of skin in transperineal biopsy and povidone-iodine rectal cleansing in transrectal biopsy as, although quality
of data is low, the clinical benefit is high and practical application simple. A ‘Strong’ rating is given for avoiding
fluoroquinolones in prostate biopsy due to its legal implications in Europe.
** The indication of fosfomycin trometamol for prostate biopsy has been withdrawn in Germany as the
manufacturers did not submit the necessary pharmacokinetic data in support of this indication. Urologists are
advised to check their local guidance in relation to the use of fosfomycin trometamol for prostate biopsy.

38 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

Figure 5.1: Prostate biopsy workflow to reduce infectious complications*

Indicaon for prostate biopsy?

Transperineal biopsy feasible?

Yes No

Transperineal biopsy - 1st choice ( ) Transrectal biopsy – 2nd choice ( )

with: with:
• perineal cleansing1 • povidone-iodine rectal preparaon
• anbioc prophylaxis1 • anbioc prophylaxis2

Fluoroquinolones licensed?3

No Yes

1. Targeted prophylaxis1,7: based on rectal Duraon of anbioc prophylaxis ≥ 24 hrs

swab or stool cultures ( )

2. Augmented prophylaxis1,2,4: two or more 1. Targeted prophylaxis6,7 ( ): based

different classes of anbiocs on rectal swab or stool cultures
3. Alternave anbiocs5 ( ): 2. Augmented prophylaxis2,4,6,8 ( ):
• fosfomycin trometamol (e.g. 3 g before • Fluoroquinolone plus aminoglycoside
and 3 g 24-48 hrs aŽer biopsy)* • Fluoroquinolone plus cephalosporin
• cephalosporin (e.g. ceŽriaxone 1 g i.m.;
cefixime 400 mg p.o. for 3 days starng 3. Fluoroquinolone prophylaxis5
24 hrs before biopsy) ( ; )
• aminoglycoside (e.g. gentamicin 3 mg/kg
i.v.; amikacin 15 mg/kg i.m.)

Suggested workflow on how to reduce post biopsy infections.

1. T
 wo systematic reviews including non-RCTs and two RCTs describe comparable rates of post-transperineal
biopsy infection in patients with and without antibiotic prophylaxis.
2. Be informed about local antimicrobial resistance.
3. Banned by European Commission due to side effects.
4. Contradicts principles of Antimicrobial Stewardship.
5. Fosfomycin trometamol (3 RCTs), cephalosporins (2 RCTs), aminoglycosides (2 RCTs).
6. Only one RCT comparing targeted and augmented prophylaxis.
7. Originally introduced to use alternative antibiotics in case of fluoroquinolone resistance.
8. V
 arious schemes: fluoroquinolone plus aminoglycoside (3 RCTs); and fluoroquinolone plus
cephalosporin (1 RCT).

GRADE Working Group grades of evidence. High certainty: (⊕⊕⊕⊕) very confident that the true effect lies close
to that of the estimate of the effect. Moderate certainty: (⊕⊕⊕) moderately confident in the effect estimate:
the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially
different. Low certainty: (⊕⊕) confidence in the effect estimate is limited: the true effect may be substantially
different from the estimate of the effect. Very low certainty: (⊕) very little confidence in the effect estimate:
the true effect is likely to be substantially different from the estimate of effect. Figure adapted from Pilatz et al.,
[314] with permission from Elsevier.
*O f note: local guidance in relation to the use of fosfomycin trometamol for prostate biopsy needs to be
checked.

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 39

5.2.8.3 Local anaesthesia prior to biopsy
Ultrasound-guided peri-prostatic block is recommended [317]. Ten mL of 2% lidocaine is infiltrated bilaterally
along the apex to base. Intra-rectal instillation of local anaesthesia is inferior to peri-prostatic infiltration [318].
Local anaesthesia can also be used effectively for MRI-targeted and systematic transperineal biopsy [319].
Patients are placed in the lithotomy position. Twenty mL of 0.5% bupivacaine with adrenaline (1 in 200,000) is
injected into the perineal skin and subcutaneous tissues anterior to the anus, followed two minutes later by a
peri-prostatic block. A systematic review evaluating pain in 3 studies comparing transperineal vs. transrectal
biopsies found that the transperineal approach significantly increased patient pain (RR: 1.83 [1.27–2.65]) [320].
In a randomised comparison a combination of peri-prostatic and pudendal block anaesthesia reduced pain
during transperineal biopsies compared to peri-prostatic anaesthesia only [321]. Targeted biopsies can then
be taken via a brachytherapy grid or a freehand needle-guiding device under local infiltration anaesthesia
[319, 322, 323].

5.2.8.4 Complications
Complications of TRUS biopsy are listed in Table 5.5 [324]. Mortality after prostate biopsy is extremely rare and
most are consequences of sepsis [325]. Low-dose aspirin is no longer an absolute contra-indication [326]. A
systematic review found favourable infection rates for transperineal compared to TRUS biopsies with similar
rates of haematuria, haematospermia and urinary retention [327]. A meta-analysis of 4,280 men randomised
between transperineal vs. TRUS biopsies in 13 studies found no significant differences in complication rates,
however, data on sepsis compared only 497 men undergoing TRUS biopsy to 474 having transperineal biopsy.
The transperineal approach required more (local) anaesthesia [328].

Table 5.5: Adverse events of three groups of targeted biopsy [324]*

Overall Transrectal Transperineal Transrectal p value

(n = 234) MRI-TB (n = 77) FUS-TB (n = 79) COG-TB (n = 78)
Clavien-Dindo grade < 0.001
No adverse events 30.3 (71) 47.4 (36) 29.1 (23) 15.4 (12)
Grade 1 63.2 (148) 50.0 (38) 65.8 (52) 74.4 (58)
Grade 2 6.0 (14) 2.6 (2) 5.1 (4) 10.3 (8)
Grades 3, 4, 5 – – – –
Haematuria 53.4 (125) 35.5 (27) 50.6 (40) 74.4 (58) < 0.001
Haematospermia 37.2 (87) 26.3 (20) 35.4 (28) 50.0 (39) < 0.01
Rectal bleeding 3.4 (8) 2.6 (2) 2.5 (2) 5.1 (4) 0.59
UTI 3.4 (8) 2.6 (2) 1.3 (1) 6.4 (5) 0.21
Fever 3 (7) 1.3 (1) 2.5 (2) 5.1 (4) 0.46
Urinary retention 3 (7) – 3.8 (3) 5.1 (4) 0.15
Haematoma 1.3 (3) – 3.8 (3) – 0.29
Other 0.56
Lower back pain 0.9 (2) 1.3 (1) 1.3 (1) –
Atrial fibrillation 0.4 (1) – 1.3 (1) –
COG-TB = cognitive registration TRUS targeted biopsy; FUS-TB = MRI-TRUS fusion targeted biopsy;
MRI = magnetic resonance imaging; MRI-TB = in-bore MRI targeted biopsy; TB = targeted biopsy;
TRUS = transrectal ultrasound; UTI = urinary tract infection. Data are presented as % (n).
*With permission by Elsevier.

5.2.8.5 Seminal vesicle biopsy

Indications for SV (staging) biopsies are poorly defined. At a PSA of > 15 ng/mL, the odds of tumour
involvement are 20–25% [329]. A SV staging biopsy is only useful if it has a decisive impact on treatment, such
as ruling out radical tumour resection or for potential subsequent RT. Its added value compared with MRI is
questionable.

5.2.8.6 Transition zone biopsy

Transition zone sampling during baseline biopsies has a low detection rate and should be limited to MRI-
detected lesions or repeat template biopsies [330].

40 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

5.2.9 Pathology of prostate needle biopsies
5.2.9.1 Processing
Prostate core biopsies from different sites are processed separately, as delivered by the biopsy operator.
Before processing, the number and length of the cores are recorded. The length of biopsy tissue significantly
correlates with the PCa detection rate [331]. In case individual cores can clearly be identified in submitted jars,
a maximum of three cores should be embedded per tissue cassette, and sponges or paper should be used to
keep the cores stretched and flat to achieve optimal flattening and alignment [332-334]. To optimise detection
of small lesions and improve accuracy of grading, paraffin blocks should be cut at three levels and intervening
unstained sections may be kept for immunohistochemistry (IHC) [335].

5.2.9.2 Microscopy and reporting

Diagnosis of PCa is based on histology. The diagnostic criteria include features pathognomonic of cancer,
major and minor features favouring cancer and features against cancer. Ancillary staining and additional
(deeper) sections should be considered if a suspect lesion is identified [335]. Diagnostic uncertainty is resolved
by intradepartmental or external consultation [335]. Sections 5.2.9.2.1 and 5.2.9.2.2 list the recommended
terminology and item list for reporting prostate biopsies [332]. Type and subtype of PCa should be reported
such as for instance acinar adenocarcinoma, ductal adenocarcinoma and small or large cell neuroendocrine
carcinoma, even if representing a small proportion of the PCa. The distinct aggressive nature of small/large
cell neuroendocrine carcinoma should be commented upon in the pathology report [332]. Apart from grading
acinar and ductal adenocarcinoma, the percentage of Gleason grade 4 component should be reported in
Gleason score 7 (3+4 and 4+3) PCa biopsies. Percentage Gleason grade 4 has additional prognostic value
and is considered in some AS protocols [336-338]. Considerable evidence has been accumulated in recent
years supporting that among the Gleason grade 4 patterns, cribriform pattern carries an increased risk of
biochemical recurrence, metastatic disease and death of disease [339, 340]. Reporting of this sub-pattern
based on established criteria is recommended [110, 341]. Intraductal carcinoma, defined as an extension
of cancer cells into pre-existing prostatic ducts and acini, distending them, with preservation of basal cells
[110], should be distinguished from high-grade PIN [342] as it conveys unfavourable prognosis in terms of
biochemical recurrence and cancer-specific survival (CSS) [343, 344]. Its presence should be reported, whether
occurring in isolation or associated with adenocarcinoma [110].

5.2.9.2.1 Recommended terminology for reporting prostate biopsies [287]

Benign/negative for malignancy; if appropriate, include a description

Active inflammation
Granulomatous inflammation
High-grade prostatic intraepithelial neoplasia (PIN)
High-grade PIN with atypical glands, suspicious for adenocarcinoma
Focus of atypical glands/lesion suspicious for adenocarcinoma/atypical small acinar proliferation, suspicious
for cancer
Adenocarcinoma, provide type and subtype, and presence or absence of cribriform pattern
Intraductal carcinoma

Each biopsy site should be reported individually, including its location (in accordance with the sampling site)
and histopathological findings, which include the histological type and the ISUP 2019 grade [110, 345, 346].
For MRI targeted biopsies consisting of multiple cores per target the aggregated (or composite) ISUP grade
should be reported per targeted lesion [110]. If the targeted biopsies are negative, presence of specific benign
pathology should be mentioned, such as dense inflammation, fibromuscular hyperplasia or granulomatous
inflammation [110, 347]. A global ISUP grade comprising all systematic (non-targeted) and targeted biopsies is
also reported (see Section 4.2). The global ISUP grade takes into account all biopsies positive for carcinoma,
by estimating the total extent of each Gleason grade present. For instance, if three biopsy sites are entirely
composed of Gleason grade 3 and one biopsy site of Gleason grade 4 only, the global ISUP grade would be
2 (i.e. GS 7[3+4]) or 3 (i.e. GS 7[4+3]), dependent on whether the extent of Gleason grade 3 exceeds that of
Gleason grade 4, whereas the worst grade would be ISUP grade 4 (i.e. GS 8[4+4]). Neither global nor worst
ISUP grade is clearly superior over the other [348]. The majority of clinical studies have not specified whether
global or worst biopsy grade was taken into account. In addition to Gleason score/ISUP grade, the presence/
absence of intraductal/invasive cribriform pattern should be reported [110, 345, 346]. Furthermore, in biopsy
Gleason score 7 (ISUP grade 2 and 3) percentage Gleason grade 4 should be monitored at the case and/or
biopsy level [110, 346]. Lymphovascular invasion (LVI) and EPE must each be reported, if identified, since both
carry unfavourable prognostic information [349-351].

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 Recently, a series of studies have demonstrated that computer-assisted PCa grading artificial
intelligence algorithms can perform grading at the level of experienced genito-urinary pathologists. These
algorithms have potential in supporting grading of less experienced pathologist, by reducing inter-observer
variability, and in quantitative analyses. However, more extensive and prospective validation of these algorithms
is needed for implementation in daily clinical practise [110, 345, 346].
The proportion of systematic (non-targeted) carcinoma-positive cores as well as the extent of
tumour involvement per biopsy core correlate with the ISUP grade, tumour volume, surgical margins and
pathological stage in RP specimens and predict BCR, post-prostatectomy progression and radiotherapy (RT)
failure. These parameters are included in nomograms created to predict pathological stage and SV invasion
after RP and RT failure [352, 353]. A pathology report should therefore provide both the number of carcinoma-
positive cores and the extent of cancer involvement for each core. The length in mm and percentage of
carcinoma in the biopsy have equal prognostic impact [354]. An extent of > 50% of adenocarcinoma in a single
core is used in some AS protocols as a cut off [355] triggering immediate treatment vs. AS in patients with
ISUP grade 1 (see Section 6.1.1.1).

5.2.9.2.2 Recommended item list for reporting prostate cancer biopsies [110, 345, 346]

Type of carcinoma
Primary and secondary Gleason grade, per biopsy site and global
International Society of Urological Pathology (ISUP) grade
Percentage of global Gleason grade 4 in GS 7 biopsies
Presence/absence of intraductal/invasive cribriform carcinoma
Number of cancer-positive biopsy cores
Extent of cancer (in mm or percentage)
For MRI-targeted biopsies with multiple cores aggreggate (or composite) ISUP grade per lesion
For carcinoma-negative MRI-targeted biopy, specific benign pathology, e.g. fibrouscular hyperplasia or
granulamatous inflammation
If present, lymphovascular invasion, extra-prostatic extension and ejaculatory duct/seminal vesicle
involvement

5.2.9.3 Tissue-based prognostic biomarker testing

After a comprehensive literature review and several panel discussions an ASCO-EAU-AUA multidisciplinary
expert panel made recommendations regarding the use of tissue-based PCa biomarkers. The
recommendations were limited to 5 commercially available tests (Oncotype Dx®, Prolaris®, Decipher®,
Decipher PORTOS and ProMark®) with extensive validation in large retrospective studies and evidence that
their test results might actually impact clinical decision-taking [356]. The selected commercially available
tests significantly improved the prognostic accuracy of clinical multivariable models for identifying men who
would benefit of AS and those with csPCa requiring curative treatment, as well as for guidance of patient
management after RP. Few studies showed that tissue biomarker tests and MRI findings independently
improved the detection of csPCa in an AS setting, but it remains unclear which men would benefit of both
tests. Decipher® test outcome has been associated with presence of intraductal/invasive cribriform carcinoma,
but retains independent value in multivariable analysis [357-359]. Since the long-term impact of the use of
these commercially available tests on oncological outcome remains unproven and prospective trials are largely
lacking, the Panel concluded that these tests should not be offered routinely but only in subsets of patients
where the test result provides clinically actionable information, such as for instance in men with favourable
intermediate-risk PCa who might opt for AS or men with unfavourable intermediate-risk PCa scheduled for
radiotherapy (RT) to decide on treatment intensification with hormonal therapy (HT).

5.2.9.4 Histopathology of radical prostatectomy specimens

5.2.9.4.1 Processing of radical prostatectomy specimens
Histopathological examination of RP specimens describes the pathological stage, histopathological type,
grade and surgical margins of PCa. It is recommended that RP specimens are totally embedded to enable
assessment of cancer location, multifocality and heterogeneity. For cost-effectiveness, partial embedding may
also be considered, particularly for prostates > 60 g. The most widely accepted method includes complete
embedding of the posterior prostate and a single mid-anterior left and right section. Compared with total
embedding, partial embedding with this method missed 5% of positive margins and 7% of EPE [360].

The entire RP specimen should be inked upon receipt in the laboratory to demonstrate the surgical
margins. Specimens are fixed by immersion in buffered formalin for at least 24 hours, preferably before

42 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

slicing. After fixation, the apex and the base (bladder neck) are removed and cut into (para)sagittal or radial
sections; the shave method is not recommended [108]. The remainder of the specimen is cut in transverse,
3–4 mm sections, perpendicular to the long axis of the urethra. The resultant tissue slices can be embedded
and processed as whole-mounts or after quadrant sectioning. Whole-mounts provide better topographic
visualisation, faster histopathological examination and better correlation with pre-operative imaging, although
they are more time-consuming and require specialist handling. For routine sectioning, the advantages of whole
mounts do not outweigh their disadvantages.

5.2.9.4.2 Radical prostatectomy specimen report

The pathology report provides essential information on the prognostic characteristics relevant for clinical
decision-making (Table 5.6). As a result of the complex information to be provided for each RP specimen, the
use of synoptic(-like) or checklist reporting is recommended. Synoptic reporting results in more transparent and
complete pathology reporting [361].

Table 5.6: Mandatory elements provided by the pathology report

Histopathological (sub)type
Type of carcinoma, e.g., conventional acinar adenocarcinoma, (small cell) neuroendocrine cell carcinoma or
ductal carcinoma
Subtype and unusual variants, e.g., pleomorphic giant cell or mucinous
Histological grade
Primary (predominant) Gleason grade
Secondary Gleason grade
Tertiary Gleason grade (if applicable)
Global ISUP grade
Approximate percentage of Gleason grade 4 or 5
Tumour quantitation (optional)
Percentage of prostate involved
Size/volume of dominant tumour nodule
Pathological staging (pTNM)
If extraprostatic extension is present:
• indicate whether it is focal or extensive (see Section 5.2.9.4.4);
• specify sites;
• indicate whether there is seminal vesicle invasion.
If applicable, regional lymph nodes:
• location;
• number of nodes retrieved;
• number of nodes involved.
Surgical margins
If carcinoma is present at the margin:
• specify sites;
• extent: focal or extensive (see Section 5.2.9.4.6)
• (highest) grade at margin.
Other
Presence of lymphovascular/angio-invasion
Location of dominant tumour
Presence of intraductal carcinoma/cribriform architecture

5.2.9.4.3 ISUP grade in prostatectomy specimens

Grading of conventional prostatic adenocarcinoma using the Gleason system is the strongest prognostic
factor for clinical behaviour and treatment response [109]. The Gleason score is incorporated in nomograms
that predict disease-specific survival (DSS) after prostatectomy [362-364]. The ISUP grade in prostatectomy
specimens is determined mostly in a similar way as in biopsies, with a minor exception; i.e. the exclusion
of minor (< 5%) high-grade components from the ISUP grade. For instance, in a carcinoma almost entirely
composed of Gleason grade 3 the presence of a minor (< 5%) Gleason grade 4 or 5 component is not included
in the Gleason score (ISUP grade 1), but its presence is commented upon [110]. In case of multifocality the
ISUP grade of the index lesion i.e. the tumour having the highest grade, stage or volume, is given.

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5.2.9.4.4 Definition of extra-prostatic extension
Extra-prostatic extension is defined as carcinoma mixed with peri-prostatic adipose tissue, or tissue that
extends beyond the prostate gland boundaries (e.g., neurovascular bundle, anterior prostate). Microscopic
bladder neck invasion is considered EPE. It is useful to report the location and extent of EPE because the latter
is related to recurrence risk [365].
There are no internationally accepted definitions of focal or microscopic, vs. non-focal or extensive
EPE. Some describe focal as a few glands [366] or < 1 high-power field in one or at most two sections whereas
others measure the depth of extent in millimetres [366].
At the apex of the prostate, tumour mixed with skeletal muscle does not constitute EPE. In the
bladder neck, microscopic invasion of smooth muscle fibres is not equated to bladder wall invasion, i.e. not
as pT4, because it does not carry independent prognostic significance for PCa recurrence and should be
recorded as EPE (pT3a) [367, 368]. Stage pT4 is assigned when the tumour invades the bladder muscle wall as
determined macroscopically [103].

5.2.9.4.5 PCa volume

Although PCa volume at RP correlates with tumour grade, stage and surgical margin status, the independent
prognostic value of PCa volume has not been established [366, 369-372]. Improvement in prostatic radio-
imaging allows more accurate pre-operative measurement of cancer volume. Since the independent value of
pathological tumour volume at RP has not been established, reporting of the diameter/volume of the dominant
tumour nodule, or a rough estimate of the percentage of cancer tissue, is optional [373].

5.2.9.4.6 Surgical margin status

Surgical margin status is an independent risk factor for BCR. Margin status is positive if tumour cells are in
contact with the ink on the specimen surface. Margin status is negative if tumour cells are close to the inked
surface [370] or at the surface of the tissue lacking ink. In tissues that have severe crush artefacts, it may not
be possible to determine margin status [374].
Surgical margin is separate from pathological stage, and a positive margin is not evidence of EPE
[375]. There is evidence for a relationship between margin extent and recurrence risk [376, 377]. However,
some indication must be given of the multifocality and extent of margin positivity, such as the linear extent
in mm of involvement: focal, < 1 mm vs. extensive, > 1 mm [378], or number of blocks with positive margin
involvement. Gleason score at the positive margin was found to correlate independently with outcome, and
should be reported [361, 376, 379].

5.3 Diagnosis - Clinical Staging

5.3.1 T-staging
The cT category listed in Table 4.1 (TNM Classification) only relies on DRE findings. Imaging parameters and
biopsy results for local staging are, so far, not part of the risk category stratification [380].

5.3.1.1 US-based techniques and CT

Transrectal US has limited accuracy for PCa local staging [381]. More advanced US-based techniques have
not yet been tested in large-scale studies. In case of locally-advanced cancers, abdominopelvic US or CT may
show rectal or bladder invasion and dilatation of the upper collecting systems [381].

5.3.1.2 MRI
T2-weighted imaging remains the most useful method for local staging on MRI. Pooled data from a meta-
analysis showed a sensitivity and specificity of 0.57 (95% CI: 0.49–0.64) and 0.91 (95% CI: 0.88–0.93), 0.58
(95% CI: 0.47–0.68) and 0.96 (95% CI: 0.95–0.97), and 0.61 (95% CI: 0.54–0.67) and 0.88 (95% CI: 0.85–0.91),
for EPE, SVI, and overall stage T3 assessment, respectively [382].
Detection of EPE and SVI seems more accurate at high field strength (3 Tesla) [382], while the added
value of functional imaging remains debated [382, 383].

In 552 men treated by RP at seven different Dutch centres, MRI showed significantly higher sensitivity (51%
vs. 12%; p < 0.001), and lower specificity (82% vs. 97%; p < 0.001) than DRE for non-organ confined disease.
All risk groups redefined using MRI findings rather than DRE findings showed better BCR-free survival due to
improved discrimination and the Will Roger’s phenomenon [384].

Traditionally, EPE/SVI is assessed visually using qualitative signs (e.g., capsular disruption, visible tumour within
peri-prostatic fat). Inter-reader agreement with such subjective reading is moderate, with kappa (k) values
ranging from 0.41 to 0.68 [385]. The length of tumour capsule contact (LCC) is also a significant predictor of
EPE; it has the advantage of being quantitative, although the ideal cut-off value remains debated [386, 387].

44 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

Several grading systems combining subjective qualitative signs and/or LCC into a score have shown good
sensitivity for EPE (0.68–0.82) with substantial inter-reader agreement (κ = 0.63–0.74), but at the expense of
decreased specificity (0.71–0.77); none of these scores has shown definitive superiority over the others [388].

Magnetic resonance imaging findings can improve the prediction of the pathological stage when combined
with clinical and biopsy data. As a result, several groups developed multivariate risk calculators for predicting
EPE/SVI or positive surgical margins [389]. In external validation cohorts, these risk calculators showed
significantly better discrimination than nomograms without MRI-based features [390-392]. However, they
remain limited by substantial miscalibration and therefore their results must be interpreted with care.
Given its low sensitivity for focal (microscopic) EPE, MRI is not recommended for local staging in
low-risk patients. However, MRI can still be useful for treatment planning.

5.3.2 N-staging
5.3.2.1 Computed tomography and MRI
Abdominal CT and T1-T2-weighted MRI indirectly assess nodal invasion by using LN diameter and
morphology. However, the size of non-metastatic LNs varies widely and may overlap the size of LN metastases.
Usually, LNs with a short axis > 8 mm in the pelvis and > 10 mm outside the pelvis are considered malignant.
Decreasing these thresholds improves sensitivity but decreases specificity. As a result, the ideal size threshold
remains unclear [393, 394]. Computed tomography and MRI sensitivity is less than 40% [395, 396]. Detection
of microscopic LN invasion by CT is < 1% in patients with ISUP grade < 4 cancer, PSA < 20 ng/mL, or
localised disease [393, 397].
Diffusion-weighted MRI (DW-MRI) may detect metastases in normal-sized nodes, but a negative
DW-MRI cannot rule out the presence of LN metastases, and DW-MRI provides only modest improvement for
LN staging over conventional imaging [398].

5.3.2.2 Risk calculators incorporating MRI findings and clinical data

Because CT and MRI lack sensitivity for direct detection of positive LNs, nomograms combining clinical and
biopsy findings have been used to estimate the risk of patients harbouring positive LNs [399-401]. Although
these nomograms are associated with good performance, they have been developed using systematic biopsy
findings and may therefore not be appropriate for patients diagnosed with combined MRI-targeted biopsy and
systematic biopsy.
Two models incorporating MRI-targeted biopsy findings and MRI-derived findings recently
underwent external validation [364, 402]. One model was tested on an external cohort of 187 patients with a
prevalence of LN invasion of 13.9% (vs. 16.9% in the development cohort). The C-index was 0.73 (vs. 0.81
in the development cohort); at calibration analysis, the model tended to overpredict the actual risk [402]. The
other model was validated in an external multi-centre cohort of 487 patients with a prevalence of 8% of LN
invasion (vs. 12.5% in the development cohort). The AUC was 0.79 (vs. 0.81 in the development cohort). Using
a risk cut-off of 7% would have avoided LN dissection in 273 (56% of the cohort), while missing LN invasion
in 7 patients (2.6% of the patients below the 7% threshold; 18% of the 38 patients with LN invasion) [403].
Therefore, this nomogram and a 7% threshold should be used after MRI-targeted biopsy to identify candidates
for extended LN dissection (eLND).

5.3.2.3 Choline PET/CT

In a meta-analysis of 609 patients, pooled sensitivity and specificity of choline PET/CT for pelvic LN
metastases were 62% (95% CI: 51–66%) and 92% (95% CI: 89–94%), respectively [404]. In a prospective
trial of 75 patients at intermediate risk of nodal involvement (10–35%), the sensitivity was only 8.2% at
region-based analysis and 18.9% at patient-based analysis, which is too low to be of clinical value [405]. The
sensitivity of choline PET/CT increases to 50% in patients at high risk and to 71% in patients at very high risk [406].
Due of its low sensitivity, choline PET/CT does not reach clinically acceptable diagnostic accuracy
for detection of LN metastases, or to rule out a nodal dissection based on risk factors or nomograms (see
Section 6.3.4.1.2).

5.3.2.4 Prostate-specific membrane antigen-based PET/CT

Prostate-specific membrane antigen PET/CT uses several different radiopharmaceuticals; most published
studies used 68Ga-labelling for PSMA PET imaging, but some used 18F-labelling. PSMA is also an attractive
target because of its specificity for prostate tissue, even if the expression in other non-prostatic malignancies
or benign conditions may cause incidental false-positive findings [407-411].

A multi-centre prospective phase III imaging trial, investigating men with intermediate- and high-risk
PCa who underwent RP and PLND, showed a sensitivity and specificity of 68Ga-PSMA-11 PET of 0.40

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(95% CI: 0.34-0.46), and 0.95 (95% CI: 0.92-0.97), respectively [412]. This is line with previous results from
prospective, multi-centre studies addressing the accuracy of 68Ga-PSMA and 18F-DCFPyL PET/CT for LN
staging in patients with newly diagnosed PCa [413, 414]. Comparable results were also demonstrated in a
phase II/III prospective, multi-centre study (OSPREY) with a median specificity of 97.9% (95% CI: 94.5–99.4%)
and median sensitivity of 40.3% (28.1–52.5%) for pelvic nodal involvement [415]. This suggests that current
PSMA-based PET/CT imaging cannot yet replace diagnostic ePLND (see also Section 6.1.2.3.2).
Prostate-specific antigen may be a predictor of a positive PSMA PET/CT. In the primary staging
cohort from a meta-analysis, however, no robust estimates of positivity were found [416].

Comparison between PSMA PET/CT and MRI was performed in a systematic review and meta-analysis
including 13 studies (n = 1,597) [417]. 68Ga-PSMA was found to have a higher sensitivity and a comparable
specificity for staging pre-operative LN metastases in intermediate- and high-risk PCa [418].
PSMA PET/CT has a good sensitivity and specificity for LN involvement, possibly impacting clinical
decision-making. In a review and meta-analysis including 37 articles, a subgroup analysis was performed in
patients undergoing PSMA PET/CT for primary staging. On a per-patient-based analysis, the sensitivity and
specificity of 68Ga-PSMA PET were 77% and 97%, respectively, after eLND at the time of RP. On a per-lesion-
based analysis, sensitivity and specificity were 75% and 99%, respectively [416].

In summary, PSMA PET/CT is more sensitive in N-staging as compared to MRI, abdominal contrast-enhanced
CT or choline PET/CT; however, small LN metastases, under the spatial resolution of PET (~5 mm), may still be
missed.

5.3.2.5 Risk calculators incorporating MRI and PSMA findings

Recently, an international, multi-centre study incorporated PSMA PET into existing nomograms in order to
predict pelvic LN metastatic disease in PCa patients. Performance of 3 nomograms was assessed in 757
patients undergoing RARP and ePLND. Addition of PSMA PET to the nomograms substantially improved the
discriminative ability of the models yielding cross-validated AUCs of 0.76 (95% CI: 0.70–0.82), 0.77 (95% CI:
0.72–0.83), and 0.82 (95% CI: 0.76–0.87), respectively [419].

5.3.3 M-staging
5.3.3.1 Bone scan
99mTc-Bone scan is a highly sensitive conventional imaging technique, evaluating the distribution of active

bone formation in the skeleton related to malignant and benign disease. A meta-analysis showed combined
sensitivity and specificity of 79% (95% CI: 73–83%) and 82% (95% CI: 78–85%) at patient level [420]. Bone
scan diagnostic yield is significantly influenced by the PSA level, the clinical stage and the tumour ISUP
grade [393, 421]. A retrospective study investigated the association between age, PSA and GS in 703 newly
diagnosed PCa patients who were referred for bone scintigraphy. The incidence of bone metastases increased
substantially with rising PSA and upgrading GS [422]. In two studies, a dominant Gleason pattern of 4 was
found to be a significant predictor of positive bone scan [423, 424]. Bone scanning should be performed in
symptomatic patients, independent of PSA level, ISUP grade or clinical stage [393].

5.3.3.2 Fluoride PET/CT, choline PET/CT and MRI

18F-sodium fluoride (18F-NaF) PET or PET/CT, similarly to bone scintigraphy, only assesses the presence
of bone metastases. The tracer was reported to have similar specificity and superior sensitivity to bone
scintigraphy for detecting bone metastases in patients with newly diagnosed high-risk PCa [425, 426]. Inter-
observer agreement for the detection of bone metastases was excellent, demonstrating that 18F-NaF PET/CT is
a robust tool for the detection of osteoblastic lesions in patients with PCa [427].
It remains unclear whether choline PET/CT is more sensitive than bone scan but it has higher
specificity with fewer indeterminate bone lesions [428-430]. Choline PET/CT has also the advantage of
detecting visceral and nodal metastases.
Diffusion-weighted whole-body and axial skeleton MRI are more sensitive than bone scan and
targeted conventional radiography in detecting bone metastases in high-risk PCa. Whole-body MRI can also
detect visceral and nodal metastases; it was shown to be more sensitive and specific than combined bone
scan, targeted radiography and abdominopelvic CT [431]. A meta-analysis found that whole-body MRI is more
sensitive than choline PET/CT and bone scan for detecting bone metastases on a per-patient basis, although
choline PET/CT had the highest specificity [420].

5.3.3.3 PSMA PET/CT

A systematic review including 12 studies (n = 322) reported high variation in 68Ga-PSMA PET/CT sensitivity
for initial staging (range 33–99%; median sensitivity on per-lesion analysis 33–92%, and on per-patient

46 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

analysis 66–91%), with good specificity (per-lesion 82–100%, and per-patient 67–99%), with most studies
demonstrating increased detection rates with respect to conventional imaging modalities (bone scan and CT) [432].

In a prospective multi-centre study in patients with high-risk PCa before curative surgery or RT (proPSMA),
302 patients were randomly assigned to conventional imaging or 68Ga-PSMA-11 PET/CT [433]. The primary
outcome focused on the accuracy of first-line imaging for the identification of pelvic LN or distant metastases.
Accuracy of 68Ga-PSMA PET/CT was 27% (95% CI: 23–31) higher than that of CT and bone scintigraphy (92%
[95% CI: 88–95] vs. 65% [95% CI: 60–69]; p < 0.0001). Conventional imaging had a lower sensitivity (38%
[95% CI: 24–52] vs. 85% [95% CI: 74–96]) and specificity (91% [95% CI: 85–97] vs. 98% [95% CI: 95–100])
than PSMA PET/CT. Furthermore, 68Ga-PSMA PET/CT scan prompted management change more frequently
as compared to conventional imaging (41 [28%] men [95% CI: 21–36] vs. 23 [15%] men [95% CI: 10–22],
p = 0.08), with less equivocal findings (7% [95% CI: 4–13] vs. 23% [95% CI: 17–31]) and lower radiation
exposure (8.4 mSv vs. 19.2 mSv; p < 0.001) [433].The comparison of whole body MRI and PSMA PET/CT in
detecting bone metastases has led to inconclusive opposite results in two small cohorts [418, 434].

5.3.4 Summary of evidence and practical considerations on initial N/M staging

The field of non-invasive N- and M-staging of PCa patients is evolving very rapidly. Evidence shows that
choline PET/CT, PSMA PET/CT and whole-body MRI provide a more sensitive detection of LN- and bone
metastases than the classical work-up with bone scan and abdominopelvic CT. In view of the evidence offered
by the randomised, multi-centre proPSMA trial [433], replacing bone scan and abdominopelvic CT by more
sensitive imaging modalities may be a consideration in patients with high-risk PCa undergoing initial staging.
However, in absence of prospective studies demonstrating survival benefit, caution must be used when taking
therapeutic decisions [435]. The prognosis and ideal management of patients diagnosed as metastatic by
these more sensitive tests is unknown. In particular, it is unclear whether patients with metastases detectable
only with PET/CT or whole-body MRI should be managed using systemic therapies only, or whether they
should be subjected to aggressive local and metastases-directed therapies [436].
Results from RCTs evaluating the management and outcome of patients with (and without)
metastases detected by choline PET/CT, PSMA PET/CT and MRI are awaited before a recommendation can be
made to treat patients based on the results of these tests [437].

5.3.5 Summary of evidence and guidelines for staging of prostate cancer

Summary of evidence LE
PSMA PET/CT is more accurate for staging than CT and bone scan for high-risk disease but to date 1b
no outcome data exist to inform subsequent management.

Recommendations Strength rating

Any risk group staging
Use pre-biopsy MRI for local staging information. Weak
Treatment should not be changed based on PSMA PET/CT findings, in view of current Strong
available data.
Low-risk localised disease
Do not use additional imaging for staging purposes. Strong
Intermediate-risk disease
In ISUP grade 3, include at least cross-sectional abdominopelvic imaging and a bone-scan Weak
for metastatic screening.
High-risk localised disease/locally-advanced disease
Perform metastatic screening including at least cross-sectional abdominopelvic imaging Strong
and a bone-scan.
When using PSMA-PET or whole body MRI to increase sensitivity, be aware of the lack of Strong
outcome data of subsequent treatment changes.

5.4 Estimating life expectancy and health status

5.4.1 Introduction
Evaluation of life expectancy and health status is important in clinical decision-making for screening, diagnosis,
and treatment of PCa. Prostate cancer is common in older men (median age 68) and diagnoses in men > 65 will
result in a 70% increase in annual diagnosis by 2030 in Europe and the USA [438, 439].

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 47

 Active treatment mostly benefits patients with intermediate- or high-risk PCa and longest expected
survival. In localised disease, over 10 years life expectancy is considered mandatory for any benefit from local
treatment and an improvement in CSS may take longer to become apparent. Older age and worse baseline
health status have been associated with a smaller benefit in PCSM and life expectancy of surgery vs. AS [440].
Although in a RCT the benefit of surgery with respect to death from PCa was largest in men < 65 years of age
(RR: 0.45), RP was associated with a reduced risk of metastases and use of androgen deprivation therapy
(ADT) among older men (RR: 0.68 and 0.60, respectively) [441]. External beam RT shows similar cancer control
regardless of age, assuming a dose of > 72 Gy when using intensity-modulated or image-guided RT [442].
Older men have a higher incidence of PCa and may be under-treated despite the high overall
mortality rates [443, 444]. Of all PCa-related deaths 71% occur in men aged > 75 years [445], probably due
to the higher incidence of advanced disease and death from PCa despite higher death rates from competing
causes [446-448]. In the USA, only 41% of patients aged > 75 years with intermediate- and high-risk disease
received curative treatment compared to 88% aged 65–74 [449].

5.4.2 Life expectancy

Life expectancy tables for European men are available online: https://ec.europa.eu/eurostat/web/
productsdatasets/-/tps00205. Survival may be variable and therefore estimates of survival must be
individualised. Gait speed is a good single predictive method of life expectancy (from a standing start, at usual
pace, generally over 6 meters). For men at age 75, 10-year survival ranged from 19% < 0.4 m/s to 87%, for
> 1.4 m/s [450].

Figure 5.2: Predicted Median Life Expectancy by Age and Gait Speed for males* [450]

*Figure reproduced with permission of the publisher, from Studenski S, et al. JAMA 2011 305(1)50.

5.4.3 Health status screening

Heterogeneity increases with advancing age, so it is important to use measures other than just age or
performance status (PS) when considering treatment options. The International SIOG PCa Working Group
recommends that treatment for adults over 70 years of age should be based on a systematic evaluation of
health status using the G8 (Geriatric 8) screening tool (see Table 5.7) [159]. This tool helps to discriminate
between those who are fit and those with frailty, a syndrome of reduced ability to respond to stressors.
Patients with frailty have a higher risk of mortality and negative side effects of cancer treatment [451]. Healthy
patients with a G8 score > 14 or vulnerable patients with reversible impairment after resolution of their geriatric
problems should receive the same treatment as younger patients. Frail patients with irreversible impairment
should receive adapted treatment. Patients who are too ill should receive only palliative treatment (see
Figure 5.3) [159]. Patients with a G8 score < 14 should undergo a comprehensive geriatric assessment
(CGA) as this score is associated with 3-year mortality. A CGA is a multi-domain assessment that includes
co-morbidity, nutritional status, cognitive and physical function, and social supports to determine if

48 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

impairments are reversible [452]. A systematic review of the effect of geriatric evaluation for older cancer
patients showed improved treatment tolerance and completion [453].
The Clinical Frailty Scale (CFS) is another screening tool for frailty (see Figure 5.4) [454]. Although
not frequently used in the cancer setting, it is considered to be a common language for expressing degree of
frailty. The scale runs from 1 to 9, with higher scores indicating increasing frailty. Patients with a higher CFS
score have a higher 30-day mortality after surgery and are less likely to be discharged home [455].
It is important to use a validated tool to identify frailty, such as the G8 or CFS, as clinical judgement
has been shown to be poorly predictive of frailty in older patients with cancer [456].

5.4.3.1 Co-morbidity
Co-morbidity is a major predictor of non-cancer-specific death in localised PCa treated with RP and is more
important than age [457, 458]. Ten years after not receiving active treatment for PCa, most men with a high
co-morbidity score had died from competing causes, irrespective of age or tumour aggressiveness [457].
Measures for co-morbidity include: Cumulative Illness Score Rating-Geriatrics (CISR-G) [459, 460] (Table 5.8)
and Charlson Co-morbidity Index (CCI) [461].

5.4.3.2 Nutritional status

Malnutrition can be estimated from body weight during the previous 3 months (good nutritional status < 5%
weight loss; risk of malnutrition: 5–10% weight loss; severe malnutrition: > 10% weight loss) [462].

5.4.3.3 Cognitive function

Cognitive impairment can be screened for using the mini-COG (https://mini-cog.com/) which consists of
three-word recall and a clock-drawing test and can be completed within 5 minutes. A score of < 3/5 indicates
the need to refer the patient for full cognitive assessment. Patients with any form of cognitive impairment
(e.g., Alzheimer’s or vascular dementia) may need a capacity assessment of their ability to make an informed
decision, which is an increasingly important factor in health status assessment [463-465]. Cognitive impairment
also predicts risk of delirium, which is important for patients undergoing surgery [466].

5.4.3.4 Physical function

Measures for overall physical functioning include: Karnofsky score and ECOG scores [467]. Measures for
dependence in daily activities include: Activities of Daily Living (ADL; basic activities) and Instrumental Activities
of Daily Living (IADL; activities requiring higher cognition and judgement) [468-470].

5.4.3.5 Shared decision-making

The patient’s own values and preferences should be taken into account as well as the above factors. A shared
decision-making process also involves anticipated changes to QoL, functional ability, and a patient’s hopes,
worries and expectations about the future [471]. Particularly in older and frail patients, these aspects should
be given equal importance to disease characteristics during the decision-making process [472]. Older patients
may also wish to involve family members, and this is particularly important where cognitive impairment exists.

5.4.4 Conclusion
Individual life expectancy, health status, frailty, and co-morbidity, not only age, should be central in clinical
decisions on screening, diagnostics, and treatment for PCa. A life expectancy of 10 years is most commonly
used as a threshold for benefit of local treatment. Older men may be under-treated. Patients aged 70 years of
age or older who have frailty should receive a comprehensive geriatric assessment. Resolution of impairments
in vulnerable men allows a similar urological approach as in fit patients.

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 49

Table 5.7: G8 screening tool (adapted from [473])

Items Possible responses (score)

A Has food intake declined over the past 3 months 0 = severe decrease in food intake
due to loss of appetite, digestive problems, 1 = moderate decrease in food intake
chewing, or swallowing difficulties? 2 = no decrease in food intake
B Weight loss during the last 3 months? 0 = weight loss > 3 kg
1 = does not know
2 = weight loss between 1 and 3 kg
3 = no weight loss
C Mobility? 0 = bed or chair bound
1 = able to get out of bed/chair but does not go out
2 = goes out
D Neuropsychological problems? 0 = severe dementia or depression
1 = mild dementia
2 = no psychological problems
E BMI? (weight in kg)/(height in m2) 0 = BMI < 19
1 = BMI 19 to < 21
2 = BMI 21 to < 23
3 = BMI > 23
F Takes more than three prescription drugs per 0 = yes
day? 1 = no
G In comparison with other people of the same 0.0 = not as good
age, how does the patient consider his/her health 0.5 = does not know
status? 1.0 = as good
2.0 = better
H Age 0 = > 85
1 = 80-85
2 = < 80
Total score 0-7

Figure 5.3: Decision tree for health status screening (men > 70 years)** [159]

Screening by G8 and mini-COG

TM*

G8 score > 14/17

G8 score ≤ 14/17
no geriatric
a full geriatric evaluation is
evaluation is
mandatory
needed

- Abnormal ADL: 1 or 2 - Abnormal ADL: > 2

- Weight loss 5-10% - Weight loss > 10%
- Comorbidities CISR-G - Comorbidities CISR-G
grades 1-2 grades 3-4

Geriatric assessment
then geriatric intervention

Group 1 Group 2 Group 3

Fit Vulnerable Frail

Mini-COGTM = Mini-COGTM cognitive test; ADLs = activities of daily living; CIRS-G = Cumulative Illness

Rating Score - Geriatrics; CGA = comprehensive geriatric assessment.

50 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

*F or Mini-COGTM, a cut-off point of < 3/5 indicates a need to refer the patient for full evaluation of potential
dementia.
**Reproduced with permission of Elsevier, from Boyle H.J., et al. Eur J Cancer 2019:116; 116 [159].

Figure 5.4: The Clinical Frailty Scale version 2.0 [454]*

CLINICAL FRAILTY SCALE 6 LIVING

WITH
People who need help with all outside
activities and with keeping house.
MODERATE Inside, they often have problems with
stairs and need help with bathing and
1 VERY People who are robust, active, energetic
FIT and motivated. They tend to exercise
FRAILTY might need minimal assistance (cuing,
standby) with dressing.
regularly and are among the fittest for
their age.
7 LIVING
WITH
Completely dependent for personal
care, from whatever cause (physical or
2 FIT People who have no active disease
symptoms but are less fit than category
SEVERE
FRAILTY
cognitive). Even so, they seem stable
and not at high risk of dying (within ~6
1. Often, they exercise or are very active months).
occasionally, e.g., seasonally.
8 LIVING Completely dependent for personal care

3 MANAGING People whose medical problems are

WELL well controlled, even if occasionally
WITH VERY
SEVERE
and approaching end of life. Typically,
they could not recover even from a
symptomatic, but often are not FRAILTY minor illness.
regularly active beyond routine walking.
9 TERMINALLY Approaching the end of life. This
4 LIVING
WITH
Previously “vulnerable,” this category
marks early transition from complete
ILL category applies to people with a life
expectancy <6 months, who are not
VERY MILD independence. While not dependent on otherwise living with severe frailty.
(Many terminally ill people can still
FRAILTY others for daily help, often symptoms
exercise until very close to death.)
limit activities. A common complaint
is being “slowed up” and/or being tired
during the day. SCORING FRAILTY IN PEOPLE WITH DEMENTIA
The degree of frailty generally In moderate dementia, recent memory is
5 LIVING
WITH
People who often have more evident
slowing, and need help with high
corresponds to the degree of
dementia. Common symptoms in
very impaired, even though they seemingly
can remember their past life events well.
mild dementia include forgetting They can do personal care with prompting.
MILD order instrumental activities of daily
the details of a recent event, though In severe dementia, they cannot do
FRAILTY living (finances, transportation, heavy still remembering the event itself, personal care without help.
housework). Typically, mild frailty repeating the same question/story
In very severe dementia they are often
progressively impairs shopping and and social withdrawal.
bedfast. Many are virtually mute.
walking outside alone, meal preparation,
medications and begins to restrict light Clinical Frailty Scale ©2005–2020 Rockwood,
housework. Version 2.0 (EN). All rights reserved. For permission:
www.geriatricmedicineresearch.ca
Rockwood K et al. A global clinical measure of fitness
www.geriatricmedicineresearch.ca and frailty in elderly people. CMAJ 2005;173:489–495.

*Permission to reproduce the CFS was granted by the copyright holder.

Table 5.8: Cumulative Illness Score Rating-Geriatrics (CISR-G)

1 Cardiac (heart only)

2 Hypertension (rating is based on severity; affected systems are rated separately)
3 Vascular (blood, blood vessels and cells, marrow, spleen, lymphatics)
4 Respiratory (lungs, bronchi, trachea below the larynx)
5 ENT (eye, ear, nose, throat, larynx)
6 Upper GI (esophagus, stomach, duodenum. Biliar and parcreatic trees; do not include diabetes)
7 Lower GI (intestines, hernias)
8 Hepatic (liver only)
9 Renal (kidneys only)
10 Other GU (ureters, bladder, urethra, prostate, genitals)
11 Musculo-Skeletal-Integumentary (muscles, bone, skin)
12 Neurological (brain, spinal cord, nerves; do not include dementia)
13 Endocrine-Metabolic (includes diabetes, diffuse infections, infections, toxicity)
14 Psychiatric/Behavioural (includes dementia, depression, anxiety, agitation, psychosis)
All body systems are scores on a 0 - 4 scale.
- 0: No problem affecting that system.
- 1: Current mild problem or past significant problem.
- 2: Moderate disability or morbidity and/or requires first line therapy.
- 3: Severe problem and/or constant and significant disability and/or hard to control chronic problems.
- 4: E xtremely severe problem and/or immediate treatment required and/or organ failure and/or
severe functional impairment.
Total score 0-56

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 51

5.4.5 Guidelines for evaluating health status and life expectancy

Recommendations Strength rating

Use individual life expectancy, health status, and co-morbidity in PCa management. Strong
Use the Geriatric-8, mini-COG and Clinical Frailty Scale tools for health status screening. Strong
Perform a full specialist geriatric evaluation in patients with a G8 score < 14. Strong
Consider standard treatment in vulnerable patients with reversible impairments (after Weak
resolution of geriatric problems) similar to fit patients, if life expectancy is > 10 years.
Offer adapted treatment to patients with irreversible impairment. Weak
Offer symptom-directed therapy alone to frail patients. Strong

6. TREATMENT
This chapter reviews the available treatment modalities, followed by separate sections addressing treatment for
the various disease stages.

6.1 Treatment modalities

6.1.1 Deferred treatment (active surveillance/watchful waiting)
As PCa is such a common disease, and with the increased rate of early detection of small tumours after the
introduction of PSA, there is a distinct risk of over-diagnosis and subsequent over-treatment of the disease [474].
As all available curative treatment options for PCa carry a risk of significant side effects there is a need for
conservative treatment options for patients with low risk of dying from their PCa. Data from studies conducted
on patients who did not undergo local treatment with up to 25 years of follow-up, with endpoints of OS and CSS,
are available. Several series have shown a consistent CSS rate of 82–87% at 10 years [475-478], and 80–95% for
T1/T2 and ISUP grade < 2 PCas [479]. In three studies with data beyond 15 years, the CSS was 80%, 79% and
58% respectively [475, 477, 478], and two reported 20-year CSS rates of 57% and 32% [475, 477]. The observed
heterogeneity in outcomes is due to different inclusion criteria, with some older studies from the pre-PSA era
showing worse outcomes [477]. In addition, many patients classified as ISUP grade 1 would now be classified as
ISUP grade 2–3 based on the 2005 Gleason classification, suggesting that the above-mentioned results should
be considered as minimal. Patients with well-, moderately- and poorly-differentiated tumours had 10-year CSS
rates of 91%, 90% and 74%, respectively, correlating with data from a pooled analysis [479]. Observation is
most effective in men aged 65–75 years with low-risk PCa [480]. In screen-detected localised PCa there is also a
lead-time bias, resulting in a higher rate of early detected PCa, but also an even higher risk of detecting clinically
insignificant PCa that never would have caused any problems [474]. Cancer-specific survival from untreated
screen-detected PCa in patients with ISUP grade 1–2 is therefore likely to be even higher than for PCa detected
of other reasons. Consequently, a high proportion of men with PSA-detected PCa are suitable for conservative
treatment.

The high CSS rates of localised PCa leads to a life expectancy of at least 10 years to be considered mandatory
for any benefit from active treatment. Co-morbidity is as important as age in predicting life expectancy in
men with PCa. Increasing co-morbidity greatly increases the risk of dying from non-PCa-related causes. In an
analysis of 19,639 patients aged > 65 years who were not given curative treatment, most men with a CCI score
> 2 had died from competing causes at 10 years follow-up regardless of their age at time of diagnosis. Tumour
aggressiveness had little impact on OS suggesting that patients could have been spared biopsy and diagnosis
of cancer. Men with a CCI score < 1 had a low risk of death at 10 years, especially for well- or moderately-
differentiated lesions [457]. This highlights the importance of assessing co-morbidity even before considering a
biopsy, but also before advising a patient with a PCa diagnosis on the optimal treatment for him.

There are two distinct strategies for conservative management that aim to reduce over-treatment: AS and WW
(Table 6.1.1).

52 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

Table 6.1.1: Definitions of active surveillance and watchful waiting [481]

Active surveillance Watchful waiting

Treatment intent Curative Palliative
Follow-up Pre-defined schedule Patient-specific
Assessment/markers used DRE, PSA, MRI at recruitment, Not pre-defined, but dependent
re-biopsy on development of symptoms of
progression
Life expectancy > 10 years < 10 years
Aim Minimise treatment-related toxicity Minimise treatment-related toxicity
without compromising survival
Eligible patients Mostly low-risk patients Can apply to patients with all stages
DRE = digital rectal examination; PSA = prostate-specific antigen; MRI = magnetic resonance imaging.

6.1.1.1 Active surveillance

Active surveillance aims to avoid unnecessary treatment, and consequently unnescessary side effects, in
men with clinically localised PCa, and a life expectancy of 10 years or more, who do not require immediate
treatment, but at the same time achieve the correct timing for curative treatment in those who eventually do
[482]. Patients remain under close surveillance through structured surveillance programmes with regular follow-
up consisting of PSA testing, clinical examination, MRI imaging and repeat prostate biopsies, with curative
treatment being prompted by pre-defined thresholds indicative of potentially life-threatening disease, which is
still curable, while considering individual life expectancy.

No formal RCT is available comparing AS to curative treatment. Several cohorts have investigated AS in
organ-confined disease, the findings of which were summarised in a systematic review [483]. More recently,
the largest prospective series of men with low-risk PCa managed by AS was published [484]. Table 6.1.2
summarises the results of selective AS cohorts. It is clear that the long-term OS and CSS of patients on AS are
extremely good. However, more than one-third of patients are ‘reclassified’ during follow-up, most of whom
undergo curative treatment due to disease upgrading, increase in disease extent, disease stage, progression
or patient preference. There is considerable variation and heterogeneity between studies regarding patient
selection and eligibility, follow-up policies (including frequency and type of imaging such as MRI imaging,
type and frequency of repeat prostate biopsies, such as MRI-targeted biopsies or transperineal template
biopsies, use of PSA kinetics and density, and frequency of clinical follow-up), when active treatment should be
instigated (i.e., reclassification criteria) and which outcome measures should be prioritised [482]. For specific
guidelines on inclusion criteria and follow-up strategies for AS, see Sections 6.2.1.1, 6.2.1.3 and 6.2.2.1 and
6.2.2.5.

In the ProtecT-trial, a RCT, 1,643 patients were randomised into one of three arms: active treatment with
either RP or EBRT or active monitoring (AM) [485]. Even though the ProtecT trial is a RCT it does not
include a formal AS strategy as described above and in Sections 6.2.1.1.4 and 6.2.1.3, but rather AM, a
significantly less stringent surveillance strategy in terms of clinical follow-up, imaging and repeat biopsies.
Fifty-six percent of the patients had low-risk disease, with 90% having a PSA < 10 ng/mL, 77% ISUP grade 1
(20% ISUP grade 2–3), and 76% had T1c disease. The remaining patients had mainly intermediate-risk
disease. The key finding was that AM was as effective as active treatment at 10 years (CSS = 99% vs. 98.8%),
but at a cost of increased metastatic progression risk (2.6% vs. 6%). Metastases, although rare, were more
frequent than seen with comparable AS protocols [483]. Recently, a comprehensive characterisation of the
ProtecT study cohort was performed, stratifying patients at baseline according to risk of progression using
clinical stage, grade at diagnosis and PSA level [486]. Additionally, detailed clinico-pathological information
on participants who received RP were analysed. The authors aimed to test the hypothesis that the clinico-
pathological features of participants with disease progression differed from those with stable disease in
order to identify prognostic markers. The results showed that out of all patients who had been randomised
(n = 1,643), 34% (n = 505) had intermediate- or high-risk disease, and 66% (n = 973) had low-risk disease.
Of all patients who had received AM, RP or RT within 12 months of randomisation (n = 1,607), 12% (n =
198) developed progression at a median follow-up of 10 years, of which 72% (n = 142) had undergone AM.
Treatment received, age (65–69 vs. 50–64 years), PSA, ISUP grade at diagnosis, cT stage, risk group, number
of PCa-involved biopsy cores, maximum length of tumour (median 5.0 vs. 3.0 mm), aggregate length of tumour
(median 8.0 vs. 4.0 mm), and presence of perineural invasion were each associated with increased risk of
disease progression (p < 0.001 for each). However, these factors could not reliably predict progression in
individuals. Notably, 53% (n = 105) of patients who progressed had biopsy ISUP grade 1 disease, although,

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 53

conversely, none of the participants who received RP and subsequently progressed had pathological ISUP
grade 1 tumours. This discrepancy in progression and metastases rate between the AM arm of the ProtecT-
study and comparable AS protocols can, most likely, be explained by inadequate sampling by PSA testing and
10-core TRUS-guided biopsies and differences in intensity of surveillance.

It is important to note that the AM arm in ProtecT represented an intermediate approach between
contemporary AS protocols and WW in terms of a monitoring strategy based almost entirely on PSA
measurements alone; there was no use of MRI scan, either at recruitment or during the monitoring period,
nor were there any protocol-mandated repeat prostate biopsies at regular intervals. In addition, approximately
40% of randomised patients had intermediate-risk disease. Nevertheless, the ProtecT study has reinforced the
role of deferred active treatment (i.e., either AS or some form of initial AM) as a feasible alternative to active
curative interventions in patients with low-grade and low-stage disease. Beyond 10 years, no RCT-data is
available, as yet, although AS is likely to give more reassurance especially in younger men, based on more
accurate risk stratification at recruitment and more stringent criteria regarding follow-up, imaging, repeat biopsy
and reclassification. Individual life expectancy must continuously be evaluated before considering any active
treatment in low-risk patients and in those with up to 10 years’ individual life expectancy [486].

Table 6.1.2: A
 ctive surveillance in screening-detected prostate cancer
(large cohorts with longer-term follow-up)

Studies N Median FU (mo) pT3 in RP patients* 10-year 10-year

OS (%) CSS (%)
Van As, et al. 2008 [487] 326 22 8/18 (44%) 98 100
Carter, et al. 2007 [488] 407 41 10/49 (20%) 98 100
Adamy, et al. 2011 [489] 533-1,000 48 4/24 (17%) 90 99
Soloway, et al. 2010 [490] 99 45 0/2 100 100
Roemeling, et al. 2007 [491] 278 41 - 89 100
Godtman, et al. 2013 [492] 439 72 - 81 99.5
Klotz, et al. 2015 [493] 993 77 - 85 98.1
Tosoian, et al. 2020 [494] 1,818 60 - 93 99.9
Carlsson, et al. 2020 [495] 2,664 52 - 94 100
Total 7,557-8,024 50.8 - 92 99.6
* Patients receiving active therapy following initial active surveillance.
CSS = cancer-specific survival; FU = follow-up; mo = months; n = number of patients; n.r. = not reported;
OS = overall survival; RP = radical prostatectomy.

6.1.1.2 Watchful Waiting

Watchful waiting refers to conservative management for patients deemed unsuitable for curative treatment
from the outset, and patients are clinically ‘watched’ for the development of local or systemic progression
with (imminent) disease-related complaints, at which stage they are then treated palliatively according to their
symptoms in order to maintain QoL.

There are two RCTs and one Cochrane review comparing the outcomes of WW to RP. The SPCG-4 study
was a RCT from the pre-PSA era, randomising patients to either WW or RP [496]. The study found RP to
provide superior CSS, OS and PFS compared to WW at a median follow-up of 23.6 years (range 3 weeks–28
years). However, the benefit in favour of RP over WW was only apparent after 10 years. The PIVOT trial, a RCT
conducted in the early PSA era, made a similar comparison between RP vs. WW in 731 men (50% with non-
palpable disease) but in contrast to the SPCG-4, it found little, to no, benefit of RP (cumulative incidence of
all-cause death, RP vs. observation: 68% vs. 73%; RR: 0.92, 95% CI: 0.84–1.01) within a median follow-up
period of 18.6 years (interquartile range, 16.6 to 20 years) [497]. Exploratory subgroup analysis showed that
the borderline benefit from RP was most marked for intermediate-risk disease (RR: 0.84, 95% CI: 0.73–0.98)
but there was no benefit in patients with low- or high-risk disease. Overall, no adverse effects on health-
related QoL (HRQoL) and psychological well-being was apparent in the first 5 years [498]. However, one of the
criticisms of the PIVOT trial is the relatively high overall mortality rate in the WW group compared with more
contemporary series. A Cochrane review performed a pooled analysis of RCTs comparing RP vs. WW [499].
Three studies were included; the previously mentioned SPCG-4 [496] and PIVOT [497] and the Veteran’s
Administration Cooperative Urological Research Group (VACURG) study which was conducted in the
pre-PSA era [500]. The authors found that RP compared with WW reduced time to death by any cause
(HR: 0.79, 95% CI: 0.70–0.90), time to death by PCa (HR: 0.57, 95% CI: 0.44–0.73) and time to metastatic

54 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

progression (HR: 0.56, 95% CI: 0.46–0.70) at 29 years’ follow-up. However, RP was associated with higher
rates of urinary incontinence (RR: 3.97, 95% CI: 2.34–6.74) and erectile dysfunction (ED) (RR: 2.67, 95%
CI: 1.63–4.38).

The overall evidence indicates that for men with asymptomatic, clinically localised PCa, and with a life
expectancy of < 10 years based on co-morbidities and/or age, the oncological advantages of active treatment
over WW are unlikely to be relevant to them. Consequently, WW should be adopted for such patients. For
assistance in estimating life expectancy and health status see Section 5.4.

6.1.2 Radical prostatectomy

6.1.2.1 Introduction
The goal of RP by any approach is the eradication of cancer while, whenever possible, preserving pelvic
organ function [501]. The procedure involves removing the entire prostate with its capsule intact and SVs,
followed by vesico-urethral anastomosis. Surgical approaches have expanded from perineal and retropubic
open approaches to laparoscopic and robotic-assisted techniques; anastomoses have evolved from Vest
approximation sutures to continuous suture watertight anastomoses under direct vision and mapping of the
anatomy of the dorsal venous complex (DVC) and cavernous nerves has led to excellent visualisation and
potential for preservation of erectile function [502]. The main results from multi-centre RCTs involving RP are
summarised in Table 6.1.3.

Table 6.1.3: Oncological results of radical prostatectomy in organ-confined disease in RCTs

Study Acronym Population Treatment Median Risk category CSS (%)

period FU (mo)
Bill-Axelson, et al. SPCG-4 Pre-PSA era 1989-1999 283 Low risk and 80.4
2018 [496] intermediate risk (at 23 yr.)
Wilt, et al. PIVOT Early years of 1994-2002 152 Low risk and 95.9
2017 [503] PSA testing intermediate risk 91.5
(at 19.5 yr.)
Hamdy, et al. ProtecT Screened 1999-2009 120 Mainly low- and 99
2016 [485] population intermediate risk (at 10 yr.)
CSS = cancer-specific survival; FU = follow-up; mo = months; PSA = prostate-specific antigen; yr. = year.

6.1.2.2 Pre-operative preparation

6.1.2.2.1 Pre-operative patient education
As before any surgery appropriate education and patient consent is mandatory prior to RP. Peri-operative
education has been shown to improve long-term patient satisfaction following RP [504]. Augmentation of
standard verbal and written educational materials such as use of interactive multimedia tools [505, 506] and
pre-operative patient-specific 3D printed prostate models has been shown to improve patient understanding
and satisfaction and should be considered to optimise patient-centred care [507].

6.1.2.2.2 Pre-operative pelvic floor exercises

Although many patients who have undergone RP will experience a return to urinary continence [508], temporary
urinary incontinence is common early after surgery, reducing QoL. Pre-operative pelvic floor exercises (PFE)
with, or without, biofeedback have been used with the aim of reducing this early post-operative incontinence.
A systematic review and meta-analysis of the effect of pre-RP PFE on post-operative urinary incontinence
showed a significant improvement in incontinence rates at 3 months post-operatively with an OR of 0.64
(p = 0.005), but not at 1 month or 6 months [509]. Pre-operative PFE may therefore provide some benefit,
however the analysis was hampered by the variety of PFE regimens and a lack of consensus on the definition
of incontinence.

6.1.2.2.3 Prophylactic antibiotics

Prophylactic antibiotics should be used; however, no high-level evidence is available to recommend specific
prophylactic antibiotics prior to RP (See EAU Urological Infections Guidelines [510]). In addition, as the
susceptibility of bacterial pathogens and antibiotic availability varies worldwide, any use of prophylactic
antibiotics should adhere to local guidelines.

6.1.2.2.4 Neoadjuvant androgen deprivation therapy

Several RCTs have analysed the impact of neoadjuvant ADT before RP, most of these using a 3-month period.

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 55

The main findings were summarised in a 2006 Cochrane review [511]. Neoadjuvant ADT is associated with
a decreased rate of pT3 (downstaging), decreased positive margins, and a lower incidence of positive LNs.
These benefits are greater with increased treatment duration (up to 8 months). However, since neither the PSA
relapse-free survival nor CSS were shown to improve, neoadjuvant ADT should not be considered as standard
clinical practice. These findings were supported by a 2021 systematic review and meta-analysis [512]

One recent RCT compared neoadjuvant luteinising hormone-releasing hormone (LHRH) alone vs. LHRH plus
abiraterone acetate plus prednisone (AAP) prior to RP in 65 localised high-risk PCa patients [513]. Patients in
the combination arm were found to have both significantly lower tumour volume and significantly lower BCR at
> 4 years follow-up (p = 0.0014). A pooled analysis of 3 RCTs, including 117 patients and assessing the impact
of intense neoadjuvant deprivation therapy has reported a complete pathological response rate of 9.4%,
with improved BCR outcomes in complete responders [514]. Further supportive evidence is required before
recommending combination neoadjuvant therapy including abiraterone prior to RP. Another RCT (CALGB
90203), comparing RP alone to RP with neoadjuvant chemo-hormonal therapy (CHT) including docetaxel for
clinically high-risk localised PCa did not meet the study’s primary endpoint of biochemical PFS at 3 years post-
operatively, due to contamination with early salvage RT (SRT). As a result, CHT is not currently recommended
unless longer-term data show a survival benefit using clinical endpoints [515].

6.1.2.2.5 Timing of radical prostatectomy

The effect of the COVID-19 pandemic on healthcare prompted a systematic review of whether delayed surgery
for intermediate and high-risk localised PCa affected oncological outcomes [516]. Evidence in the 19 studies
included was hampered by variation in definitions of delay from diagnosis to surgery, but oncological
outcomes, including adverse pathology, BCR, additional treatment and survival, were no worse with delays of
up to 3 months. Heterogeneity of data prevented any meaningful analysis of delays beyond 3 months.

6.1.2.3 Surgical techniques

Prostatectomy can be performed by open-, laparoscopic- or robot-assisted (RARP) approaches. The initial
open technique of RP described by Young in 1904 was via the perineum [502] but suffered from a lack of
access to pelvic LNs. If lymphadenectomy is required during perineal RP it must be done via a separate open
retropubic (RRP) or laparoscopic approach. The open retropubic approach was popularised by Walsh in
1982 following his anatomical description of the DVC, enabling its early control, and of the cavernous nerves,
permitting a bilateral nerve-sparing procedure [517]. In 2002, RARP was introduced using the da Vinci Surgical
System® by Binder [518]. This technology combined the minimally-invasive advantages of laparoscopic RP
with improved surgeon ergonomics and greater technical ease of suture reconstruction of the vesicourethral
anastomosis and has now become the preferred minimally-invasive approach when available.

In a randomised phase III trial, RARP was shown to have reduced admission times and blood loss, but not
earlier (12 weeks) functional or oncological outcomes compared to open RP [519]. An updated analysis
with follow-up at 24 months did not reveal any significant differences in functional outcomes between the
approaches [520]. Increased surgical experience has lowered the complication rates of RP and improved
cancer cure [477-480]. Lower rates of positive surgical margins for high-volume surgeons suggest that
experience and careful attention to surgical details, can improve cancer control with RP [521-523]. There is a
lack of studies comparing the different surgical modalities for these longer-term outcomes [476, 498, 503, 524].
A 2016 systematic review and meta-analysis included two small RCTs comparing RARP vs. laparoscopic RP
(LRP) [525]. The results suggested higher rates of return of erectile function (RR: 1.51, 95% CI: 1.19–1.92) and
return to continence function (RR: 1.14, 95% CI: 1.04–1.24) in the RARP group. However, a Cochrane review
comparing either RARP or LRP vs. open RP included two RCTs and found no significant differences between
the comparisons for oncological-, urinary- and sexual function outcomes, although RARP and LRP both
resulted in statistically significant improvements in duration of hospital stay and blood transfusion rates over
open RP [526]. Therefore, no surgical approach can be recommended over another.

Outcome after prostatectomy has been shown to be dependent on both surgeon [527] as well as hospital
volume [528]. Although various volume criteria have been set worldwide, the level of evidence is insufficient to
pinpoint a specific lower volume limit.

6.1.2.3.1 Robotic anterior versus Retzius-sparing dissection

Robot-assisted RP has typically been performed via the anterior approach, first dropping the bladder to expose
the space of Retzius. However, the posterior approach (Retzius-sparing [RS-RARP]) has been used to minimise
injury to support structures surrounding the prostate.

56 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

 Galfano et al., first described RS-RARP in 2010 [529]. This approach commences dissection
posteriorly at the pouch of Douglas, first dissecting the SVs and progressing caudally behind the prostate. All
of the anterior support structures are avoided, giving rise to the hypothetical mechanism for improved early
post-operative continence. RS-RARP thus offers the same potential advantage as the open perineal approach,
but without disturbance of the perineal musculature.

Retzius-sparing-RARP has been recently investigated in RCTs leading to four systematic reviews and
meta-analyses [530-532] including a 2020 Cochrane systematic review [533] and a large propensity score
matched analysis [534]. The Cochrane review used the most rigorous methodology and analysed 5 RCTs with
502 patients. It found with moderate certainty that RS-RARP improved continence at 1 week post catheter
removal compared to standard RARP (RR: 1.74). Continence may also be improved at 3 months post-
operatively (RR: 1.33), but this was based on low-certainty data. Continence outcomes appeared to equalise
by 12 months (RR: 1.01). These findings matched those of the other systematic reviews. However, a significant
concern was that RS-RARP appears to increase the risk of positive margins (RR: 1.95) but this was also low-
certainty evidence. A single-surgeon propensity score matched analysis of 1,863 patients reached the same
conclusion as the systematic reviews regarding earlier return to continence but did not show data on margin
status [534].
Based on these data, recommendations cannot be made for one technique over another. However,
the trade-offs between the risks of a positive margin vs. earlier continence recovery should be discussed with
prospective patients. Furthermore, no high-level evidence is available on high-risk disease with some concerns
that RS-RARP may confer an increased positive margin rate based on pT3 results. In addition, RS-RARP may
be more technically challenging in various scenarios such as anterior tumours, post-TURP, a grossly enlarged
gland, or a bulky median lobe [535].

6.1.2.3.2 Pelvic lymph node dissection

A systematic review has demonstrated that performing PLND during RP failed to improve oncological
outcomes, including survival [536]. Moreover, two RCTs have failed to show a benefit of an extended approach
vs. a limited PLND on early oncologic outcomes [537, 538].

Extended PLND includes removal of the nodes overlying the external iliac artery and vein, the nodes within the
obturator fossa located cranially and caudally to the obturator nerve, and the nodes medial and lateral to the
internal iliac artery. With this template, 94% of patients are correctly staged [539] and as such, ePLND provides
the most accurate information for staging and prognosis [536].

The individual risk of patients harbouring positive LNs can be estimated based on validated nomograms. The
Briganti [400, 401], Partin and MSKCC nomograms [540] have shown similar diagnostic accuracy in predicting
LN invasion [541-543]. However, these nomograms were developed in the pre-MRI setting based on systematic
random biopsy.

An updated nomogram has been externally validated in men diagnosed based on MRI followed by MRI-
targeted biopsy [401]. Using this nomogram, patients could be spared an ePLND if their risk of nodal
involvement was less than 7%; which would result in missing only 1.5% of patients with nodal invasion
[401, 403]. However, 70% of patients would still undergo an unnecessary ePLND as they would have no LN
involvement [364]. This is problematic due to the risk of complications of PLND (see below) as well as the
additional operative time required.

A 2021 systematic review and meta-analysis of 27 studies showed that PSMA PET had a significantly higher
sensitivity (93% vs. 54%, p = 0.008) and NPV (96% vs. 83%, p = 0.044) for LN positivity in intermediate-risk vs.
high-risk groups [544]. This suggests that, given a lack of survival benefit of PLND, it might be safely omitted
in intermediate-risk patients whose staging PSMA PET is negative. However, only 1 of the 27 studies with only
42 patients had focused on intermediate-risk cancer, indicating a need for further data in this risk group. The
authors conclude that PLND should still be performed in high-risk patients with negative PSMA PET, however
this should also be balanced against the risk of morbidity of PLND (see Section 5.3.2.4). For patients with
positive pelvic LNs on PSMA PET only, evidence is currently unavailable on the best treatment strategy.

6.1.2.3.2.1 Early complications of extended pelvic lymph node dissection

Extended PLND increases morbidity in the treatment of PCa [536]. Overall complication rates of 19.8% vs.
8.2% were noted for ePLND vs. limited PLND, respectively, with lymphoceles (10.3% vs. 4.6%) being the
most common adverse event (AE). Other authors have reported lower complication rates [545]. Similar rates of
lymphoceles have been observed in RALP series; however, in one subgroup analysis lymphoceles were more

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 57

common with the extraperitoneal approach (19%) vs. the transperitoneal approach (0%) [546, 547]. Briganti
et al., [548] also showed more complications after extended compared to limited PLND. Twenty percent of
men suffer a complication of some sort after ePLND. Thromboembolic events occur in less than 1% of cases
overall, but the RR of DVT and PE associated with PLND has been found to be 7.8 and 6.3, respectively [549]
(See section 6.1.2.4.2)

6.1.2.3.2.2 Sentinel node biopsy analysis

The rationale for a sentinel node biopsy (SNB) is based on the concept that a sentinel node is the first to be
involved by migrating tumour cells. Therefore, when this node is negative it is possible to avoid an ePLND
[550]. Intraprostatic injections of indocyanine green (ICG) have been used to visualise prostate-related LNs
for SNB. In a randomised comparison, Harke et al, found more cancer-containing LNs in men who underwent
a PLND guided by ICG but no difference in BCR at 22.9-month follow-up [551]. A systematic review of
21 studies showed a sensitivity of 95.2% and NPV of 98.0% for SNB in detecting men with metastases at
ePLND [552]. However, this review was hampered by widespread heterogeneity of both definitions and how
SNB is performed. This prompted the development of an expert consensus report to guide further research [550].
There currently remains insufficient evidence supporting SNB for nodal staging.

6.1.2.3.3 Prostatic anterior fat pad dissection and histologic analysis

Several multi-centre and large single-centre series have shown the presence of lymphoid tissue within the
fat pad anterior to the endopelvic fascia; the prostatic anterior fat pad (PAFP) [553-559]. This lymphoid tissue
is present in 5.5–10.6% of cases and contains metastatic PCa in up to 1.3% of intermediate- and high-risk
patients.
When positive, the PAFP is often the only site of LN metastasis. The PAFP is therefore a rare but
recognised route of spread of disease. Unlike PLND, there is no morbidity associated with removal of the PAFP.
The PAFP is always removed at RP for exposure of the endopelvic fascia and should be sent for histologic
analysis as per all removed tissue.

6.1.2.3.4 Management of the dorsal venous complex

Since the description of the anatomical open RP by Walsh and Donker in the 1980s, various methods of
controlling bleeding from the DVC have been proposed to optimise visualisation [517]. In the open setting,
blood loss and transfusion rates have been found to be significantly reduced when ligating the DVC prior to
transection [560]. However, concerns have been raised regarding the effect of prior DVC ligation on apical
margin positivity and continence recovery due to the proximity of the DVC to both the prostatic apex and the
urethral sphincter muscle fibres. In the robotic-assisted laparoscopic technique, due to the increased pressure
of pneumoperitoneum, whether prior DVC ligation was used or not, blood loss was not found to be significantly
different in one study [561]. In another study, mean blood loss was significantly less with prior DVC ligation (184
vs. 176 mL, p = 0.033), however it is debatable whether this was clinically significant [562]. The positive apical
margin rate was not different, however, the latter study showed earlier return to full continence at 5 months
post-operatively in the no prior DVC ligation group (61% vs. 40%, p < 0.01).

Ligation of the DVC can be performed with standard suture or using a vascular stapler. One study found
significantly reduced blood loss (494 mL vs. 288 mL) and improved apical margin status (13% vs. 2%) when
using the stapler [563].
Given the relatively small differences in outcomes, the surgeon’s choice to ligate prior to transection
or not, or whether to use sutures or a stapler, will depend on their familiarity with the technique and the
equipment available.

6.1.2.3.5 Nerve-sparing surgery

During prostatectomy, preservation of the neurovascular bundles (NVB) with parasympathetic nerve branches
of the pelvic plexus can spare erectile function [564, 565].

Extra-, inter-, and intra-fascial dissection planes can be planned, with those closer to the prostate and
performed bilaterally associated with superior (early) functional outcomes [566-569]. Furthermore, many
different techniques are propagated such as retrograde approach after anterior release (vs. antegrade), and
athermal and traction-free handling of bundles [570-572]. Nerve-sparing (NS) surgery may be performed using
clips or low bipolar energy without clear benefit favouring one technique over another regarding functional
outcomes [573].

58 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

A 2021 large retrospective study of high-risk patients also found that NS did not affect BCR, risk of metastasis,
or of death [574]. Notably, clinical and pathological stage T3 and ISUP Grade 5 did not impact these
oncological outcomes. However, as a retrospective study, it was subject to selection bias, whereby patients
with unfavourable characteristics were more likely to have undergone non-nerve-sparing surgery.

A 2021 systematic review of 19 studies analysing the parameters used for selection of NS found that individual
clinical and radiological factors were poor at predicting EPE, and consequently, the appropriateness of NS.
However, nomograms that incorporated mpMRI performed better. As with all nomograms, the question remains
as to where to set the cut-off point [575].

A 2022 systematic review of 18 comparative studies (no RCTs) of NS vs. non-nerve-sparing RP showed a RR
of side-specific positive margins of 1.5, but none of them included patients with high-risk PCa [576]. There was
no effect seen of NS on BCR. However, follow-up was short and studies were subject to selection bias with
mainly low-risk patients. For those patients with high-risk PCa, side-specific NS was avoided if disease was
palpable or EPE was present on MRI. Indeed, a 2019 systematic review showed that MRI affected the decision
to perform NS or not in 35% of cases without any negative impact on surgical margin rate [577] (See Section
5.3.1.2).
Although age and pre-operative function may remain the most important predictors for post-
operative erectile function, NS has also been associated with improved continence outcomes and may
therefore still be relevant for men with poor erectile function [578, 579]. The association with continence may
be mainly due to the dissection technique used during NS surgery, and not due to the preservation of the NVB
themselves [578].

In summary, the quality of data is not adequate to permit a strong recommendation in favour of NS or non-
nerve-sparing, but pre-operative risk factors for side-specific EPE such as PSA, PSA density, clinical stage,
ISUP grade, and PI-RADS score, EPE and capsule contact length on MRI, should be taken into account.

6.1.2.3.6 Lymph-node-positive patients during radical prostatectomy

Although no RCTs are available, data from prospective cohort studies comparing survival of pN+ patients
(as defined following pathological examination after RP) support that RP may have a survival benefit over
abandonment of RP in node-positive cases [580]. As a consequence there is no role for performing frozen
section of suspicious LNs.

6.1.2.3.7 Removal of seminal vesicles

The more aggressive forms of PCa may spread directly into the SVs. For oncological clearance, the SVs have
traditionally been removed intact with the prostate specimen [581]. However, in some patients the tips of the
SVs can be challenging to dissect free. Furthermore, the cavernous nerves run past the SV tips such that
indiscriminate dissection of the SV tips could potentially lead to ED [582]. However, a RCT comparing nerve-
sparing RP with and without a SV-sparing approach found no difference in margin status, PSA recurrence,
continence or erectile function outcomes. Whilst complete SV removal should be the default, preservation of
the SV tips may be considered in cases of low risk of involvement.

6.1.2.3.8 Techniques of vesico-urethral anastomosis

Following prostate removal, the bladder neck is anastomosed to the membranous urethra. The objective is to
create a precisely aligned, watertight, tension-free, and stricture-free anastomosis that preserves the integrity
of the intrinsic sphincter mechanism. Several methods have been described, based on the direct or indirect
approach, the type of suture (i.e. barbed vs. non-barbed/monofilament), and variation in suturing technique
(e.g., continuous vs. interrupted, or single-needle vs. double-needle running suture). The direct vesico-urethral
anastomosis, which involves the construction of a primary end-to-end inter-mucosal anastomosis of the
bladder neck to the membranous urethra by using 6 interrupted sutures placed circumferentially, has become
the standard method of reconstruction for open RP [583].

The development of laparoscopic- and robotic-assisted techniques to perform RP have facilitated the
introduction of new suturing techniques for the anastomosis. A systematic review and meta-analysis compared
unidirectional barbed suture vs. conventional non-barbed suture for vesico-urethral anastomosis during
robotic-assisted laparoscopic prostatectomy (RALP) [584]. The review included 3 RCTs and found significantly
reduced anastomosis time, operative time and posterior reconstruction time in favour of the unidirectional
barbed suture technique, but there were no differences in post-operative leak rate, length of catheterisation
and continence rate. However, no definitive conclusions could be drawn due to the relatively low quality of
the data. In regard to suturing technique, a systematic review and meta-analysis compared continuous vs.

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 59

interrupted suturing for vesico-urethral anastomosis during RP [585]. The study included only one RCT with
60 patients [586]. Although the review found slight advantages for continuous suturing over interrupted suturing
in terms of catheterisation time, anastomosis time and rate of extravasation, the overall quality of evidence
was low and no clear recommendations were possible. A recent RCT [587] compared the technique of suturing
using a single absorbable running suture vs. a double-needle single-knot running suture (i.e. Van Velthoven
technique) in laparoscopic RP [588]. The study found slightly reduced anastomosis time with the single running
suture technique, but anastomotic leak, stricture, and continence rates were similar.

Overall, although there are a variety of approaches, methods and techniques for performing the vesico-urethral
anastomosis, no clear recommendations are possible due to the lack of high-certainty evidence. In practice,
the chosen method should be based on surgeon experience and individual preference [583-588].

6.1.2.3.9 Bladder neck management

Bladder neck mucosal eversion
Some surgeons perform mucosal eversion of the bladder neck as its own step in open RP with the aim of
securing a mucosa-to-mucosa vesico-urethral anastomosis and avoiding anastomotic stricture. Whilst bringing
bladder and urethral mucosa together by the everted bladder mucosa covering the bladder muscle layer, this
step may actually delay healing of the muscle layers. An alternative is to simply ensure bladder mucosa is
included in the full thickness anastomotic sutures. A non-randomised study of 211 patients with and without
bladder neck mucosal eversion showed no significant difference in anastomotic stricture rate [589]. The
strongest predictor of anastomotic stricture in RP is current cigarette smoking [590], but it is also 2.2 higher in
open RP than RARP [591].

Bladder neck preservation

Whilst the majority of urinary continence is maintained by the external urethral sphincter at the membranous
urethra (see below), a minor component is contributed by the internal lissosphincter at the bladder neck [592].
Preservation of the bladder neck has therefore been proposed to improve continence recovery post-RP. A RCT
assessing continence recovery at 12 months and 4 years showed improved objective and subjective urinary
continence in both the short- and long term without any adverse effect on oncological outcome [593]. These
findings were confirmed by a systematic review [594]. However, concern remains regarding margin status for
cancers located at the prostate base.
A systematic review addressing site-specific margin status found a mean base-specific positive
margin rate of 4.9% with bladder neck preservation vs. only 1.9% without [592]. This study was inconclusive,
but it would be sensible to exercise caution when considering bladder neck preservation if significant cancer is
known to be at the prostate base. Bladder neck preservation should be performed routinely when the cancer
is distant from the base. However, bladder neck preservation cannot be performed in the presence of a large
median lobe or a previous TURP.

6.1.2.3.10 Urethral length preservation

The membranous urethra sits immediately distal to the prostatic apex and is chiefly responsible, along with its
surrounding pelvic floor support structures, for urinary continence. It consists of the external rhabdosphincter
which surrounds an inner layer of smooth muscle. Using pre-operative MRI, the length of membranous urethra
has been shown to vary widely. Two systematic reviews and meta-analyses found that every extra millimetre
of membranous urethral length seen on MRI pre-operatively improves early return to continence post-RP [595,
596]. Therefore, it is likely that preservation of as much urethral length as possible during RP will maximise
the chance of early return to continence. It may also be useful to measure urethral length pre-operatively to
facilitate counselling of patients on their relative likelihood of early post-operative continence.

6.1.2.3.11 Cystography prior to catheter removal

Cystography may be used prior to catheter removal to check for a substantial anastomotic leak. If such a
leak is found, catheter removal may then be deferred to allow further healing and sealing of the anastomosis.
However, small comparative studies suggest that a cystogram to assess anastomotic leakage is not indicated
as SOC before catheter removal 8 to 10 days after surgery [597]. If a cystogram is used, men with LUTS, large
prostates, previous TURP or bladder neck reconstruction, may benefit as these factors have been associated
with leakage [598, 599]. Contrast-enhanced transrectal US is an alternative [600].

6.1.2.3.12 Urinary catheter

A urinary catheter is routinely placed during RP to enable bladder rest and drainage of urine while the
vesicourethral anastomosis heals. Compared to a traditional catheter duration of around 1 week, some centres
remove the transurethral catheter early (post-operative day 2–3), usually after thorough anastomosis with

60 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

posterior reconstruction or in patients selected peri-operatively on the basis of anastomosis quality [601-604].
No higher complication rates were found. Although shorter catheterisation has been associated with more
favourable short-term functional outcomes, no differences in long-term function were found [605]. One RCT has
shown no difference in rate of UTI following indwelling catheter (IDC) removal whether prophylactic ciprofloxacin
was given prior to IDC removal or not, suggesting antibiotics should not be given at catheter removal [606].
As an alternative to transurethral catheterisation, suprapubic catheter insertion during RP has been
suggested. Some reports suggest less bother regarding post-operative hygiene and pain [607-611], while others
did not find any differences [612, 613]. No impact on long-term functional outcomes were seen.

6.1.2.3.13 Use of a pelvic drain

A pelvic drain has traditionally been used in RP for potential drainage of urine leaking from the vesico-urethral
anastomosis, blood, or lymphatic fluid when a PLND has been performed. Two RCTs in the robotic-assisted
laparoscopic setting have been performed [614, 615]. Patients with urine leak at intra-operative anastomosis
watertight testing were excluded. Both trials showed non-inferiority in complication rates when no drain was
used. When the anastomosis is found to be watertight intra-operatively, it is reasonable to avoid inserting a
pelvic drain. There is no evidence to guide usage of a pelvic drain in PLND.

6.1.2.4 Acute and chronic complications of radical protatectomy

Post-operative incontinence and ED are common problems following surgery for PCa. A key consideration
is whether these problems are reduced by using newer techniques such as RALP. Systematic reviews have
documented complication rates after RALP [616-620], and can be compared with contemporaneous reports
after RRP [621]. A prospective controlled non-RCT of patients undergoing RP in 14 centres using RALP or RRP
showed that 12 months after RALP, 21.3% of patients were incontinent, as were 20.2% after RRP (adjusted
OR: 1.08, 95% CI: 0.87–1.34) [622]. Erectile dysfunction was observed in 70.4% after RALP and 74.7% after
RRP. The adjusted OR was 0.81 (95% CI: 0.66–0.98) [622].
A systematic review and meta-analysis of unplanned hospital visits and re-admissions post-RP
analysed 60 studies with over 400,000 patients over a 20-year period up to 2020. It found an emergency room
visit rate of 12% and a hospital re-admission rate of 4% at 30 days post-operatively [623].
A RCT comparing RALP and RRP reported outcomes at 12 weeks in 326 patients and functional
outcomes at 2 years [519]. Urinary function scores did not differ significantly between RRP vs. RALP at 6 and
12 weeks post-surgery (74–50 vs. 71–10, p = 0.09; 83–80 vs. 82–50, p = 0.48), with comparable outcomes
for sexual function scores (30–70 vs. 32–70, p = 0.45; 35–00 vs. 38–90, p = 0.18). In the RRP group 14
(9%) patients had post-operative complications vs. 6 (4%) in the RALP group. The intra- and peri-operative
complications of RRP and RALP are listed in Table 6.1.4. Table 6.1.5 lists the Clavien-Dindo definition of
surgical complications. The early use of phosphodiesterase-5 (PDE5) inhibitors in penile rehabilitation remains
controversial resulting in a lack of clear recommendations (see Section 8.3.2.1).

Table 6.1.4: Intra-and peri-operative complications of retropubic RP, laparoscopic RP and RALP
(Adapted from [555])

Predicted probability of event RALP (%) Laparoscopic RP (%) RRP (%)

Bladder neck contracture 1.0 2.1 4.9
Anastomotic leak 1.0 4.4 3.3
Infection 0.8 1.1 4.8
Organ injury 0.4 2.9 0.8
Ileus 1.1 2.4 0.3
Deep-vein thrombosis 0.6 0.2 1.4
Predicted rates of event RALP (%) Laparoscopic RP (%) RRP (%)
Clavien-Dindo I 2.1 4.1 4.2
Clavien-Dindo II 3.9 7.2 17.5
Clavien-Dindo IIIa 0.5 2.3 1.8
Clavien-Dindo IIIb 0.9 3.6 2.5
Clavien-Dindo IVa 0.6 0.8 2.1
Clavien-Dindo V < 0.1 0.2 0.2
RALP = robot-assisted laparoscopic prostatectomy; RP = radical prostatectomy; RRP = radical retropubic
prostatectomy.

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Table 6.1.5: C
 lavien-Dindo grading of surgical complications [624]

Grade Definition
I Any deviation from the normal post-operative course not requiring surgical, endoscopic or
radiological intervention. This includes the need for certain drugs (e.g., antiemetics, antipyretics,
analgesics, diuretics and electrolytes), treatment with physiotherapy and wound infections that are
opened at the bedside
II Complications requiring drug treatments other than those allowed for Grade I complications; this
includes blood transfusion and total parenteral nutrition (TPN)
IIIa Complications requiring surgical, endoscopic or radiological intervention
- intervention not under general anaesthetic
IIIb Complications requiring surgical, endoscopic or radiological intervention
- intervention under general anaesthetic
IVa Life-threatening complications; this includes CNS complications (e.g., brain haemorrhage,
ischaemic stroke, subarachnoid haemorrhage) which require intensive care, but excludes transient
ischaemic attacks (TIAs)
- single-organ dysfunction (including dialysis)
IVb Life-threatening complications; this includes CNS complications (e.g., brain haemorrhage,
ischaemic stroke, subarachnoid haemorrhage) which require intensive care, but excludes transient
ischaemic attacks (TIAs)
- multi-organ dysfunction
V Death of the patient

6.1.2.4.1 Effect of anterior and posterior reconstruction on continence

Preservation of integrity of the external urethral sphincter is critical for continence post-RP. Less clear is the
effect of reconstruction of surrounding support structures to return to continence. Several small RCTs have
been conducted, however, pooling analyses is hampered by variation in the definitions of incontinence and
surgical approach, such as open vs. robotic and intra-peritoneal vs. extra-peritoneal. In addition, techniques
used to perform both anterior suspension or reconstruction and posterior reconstruction are varied. For
example, anterior suspension is performed either through periosteum of the pubis or the combination of ligated
DVC and puboprostatic ligaments (PPL). Posterior reconstruction from rhabdosphincter is described to either
Denonvilliers fascia posterior to bladder or to posterior bladder wall itself.
Two trials assessing posterior reconstruction in RALRP found no significant improvement in return
to continence [625, 626]. A third trial using posterior bladder wall for reconstruction showed only an earlier
return to 1 pad per day (median 18 vs. 30 days, p = 0.024) [627]. When combining both anterior and posterior
reconstruction, where for anterior reconstruction the PPL were sutured to the anterior bladder neck, another
RCT found no improvement compared to a standard anastomosis with no reconstruction [628].

Four RCTs including anterior suspension have also shown conflicting results. Anterior suspension alone
through the pubic periosteum, in the setting of extra-peritoneal RALRP, showed no advantage [629]. However,
when combined with posterior reconstruction in RRP, one RCT showed significant improvement in return to
continence at one month (7.1% vs. 26.5%, p = 0.047) and 3 months (15.4% vs. 45.2%, p = 0.016), but not
at 6 months (57.9% vs. 65.4%, p = 0.609) [630]. Another anterior plus posterior reconstruction RCT using the
Advanced Reconstruction of VesicoUrethral Support (ARVUS) technique and the strict definition of continence
of ‘no pads‘, showed statistically significant improvement in continence at 2 weeks (43.8% vs. 11.8%), 4 weeks
(62.5% vs. 14.7%), 8 weeks (68.8% vs. 20.6%), 6 months (75% vs. 44.1%) and 12 months (86.7% vs. 61.3%),
when compared to standard posterior Rocco reconstruction [631]. Anterior suspension alone through the DVC
and PPL combined without posterior construction in the setting of RRP has shown improvement in continence
at one month (20% vs. 53%, p = 0.029), 3 months (47% vs. 73%, p = 0.034) and 6 months (83% vs. 100%,
p = 0.02), but not at 12 months (97% vs. 100%, p = 0.313) [632]. Together, these results suggest a possible
earlier return to continence, but no long-term difference.

As there is conflicting evidence on the effect of anterior and/or posterior reconstruction on return to continence
post-RP, no recommendations can be made. However, no studies showed an increase in adverse oncologic
outcome or complications with reconstruction.

6.1.2.4.2 Deep venous thrombosis prophylaxis

For EAU Guidelines recommendations on post-RP deep venous thrombosis prophylaxis, please see the
Thromboprophylaxis Guidelines Section 3.1.6 [633]. However, these recommendations should be adapted
based on national recommendations, when available.

62 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

6.1.3 Radiotherapy
Intensity-modulated RT (IMRT) or volumetric arc radiation therapy (VMAT) with image-guided RT (IGRT) is
currently widely recognised as the standard treatment approach for EBRT.

6.1.3.1 External beam radiation therapy

6.1.3.1.1 Technical aspects
Intensity-modulated RT and VMAT employ dynamic multileaf collimators, which automatically and continuously
adapt to the contours of the target volume seen by each beam. Viani et al., show significantly reduced acute
and late grade > 2 genito-urinary (GU) and gastro-intestinal (GI) toxicity in favour of IMRT, while BCR-free rates
did not differ significantly when comparing IMRT with three-dimensional conformal radiation therapy (3D-CRT)
in a RCT comprising 215 patients [634]. A meta-analysis by Yu et al., (23 studies, 9,556 patients) concluded
that IMRT significantly decreases the occurrence of grade 2–4 acute GI toxicity, late GI toxicity and late rectal
bleeding, and achieves better PSA relapse-free survival in comparison with 3D-CRT. Intensity-modulated EBRT
and 3D-CRT show comparable acute rectal toxicity, late GU toxicity and OS, while IMRT slightly increases the
morbidity of acute GU toxicity [635]. Zapatero et al., found, based on 733 consecutive patients (295 IMRT vs.
438 3D-CRT), that compared with 3D-CRT, high-dose IMRT/IGRT is associated with a lower rate of late urinary
complications despite a higher radiation dose [636]. In conclusion, IMRT plus IGRT remain the SOC for the
treatment of PCa.

The advantage of VMAT over IMRT is shorter treatment times, generally two to three minutes in total. Both
techniques allow for a more complex distribution of the dose to be delivered and provide concave isodose
curves, which are particularly useful as a means of sparing the rectum. Radiotherapy treatment planning
for IMRT and VMAT differs from that used in conventional EBRT, requiring a computer system capable of
‘inverse planning’ and the appropriate physics expertise. Treatment plans must conform to pre-specified dose
constraints to critical organs at risk of normal tissue damage and a formal quality assurance process should be
routine.

With dose escalation using IMRT/VMAT, organ movement becomes a critical issue in terms of both tumour
control and treatment toxicity. Techniques will therefore combine IMRT/VMAT with some form of IGRT (usually
gold marker or cone-beam CT), in which organ movement can be visualised and corrected for in real time,
although the optimum means (number of applications per week) of achieving this is still unclear [637, 638].
Tomotherapy is another technique for the delivery of IMRT, using a linear accelerator mounted on a ring gantry
that rotates as the patient is delivered through the centre of the ring, analogous to spiral CT scanning.

While image-guided radiotherapy (IGRT) for PCa has resulted in lower rates of toxicity, the use of MR-guided
adapted RT is still investigational [639]. Planning studies confirm that MR-based adaptive RT significantly
reduces doses to organs at risk (OAR) and this should translate into a meaningful clinical benefit in due course
[640]. Although the rates of acute GI- and GU toxicity appear low, mostly on the basis of patients treated with
stereotactic RT [641], follow-up is too short for definitive conclusions [639]. Of interest, in one series, 36%
of patients treated with SBRT needed a catheter insertion for acute grade 2 urinary retention [642]. Above
that, the daily fraction time of up to 45 minutes [639, 641], the heavy MR-workflow and the limited field size
(rendering most pelvic fields too large) make its implementation not yet a routine [639]. Results of prospective
RCTs such as the MIRAGE trial (CT-guided Stereotactic Body Radiation Therapy and MRI-guided Stereotactic
Body Radiation Therapy for Prostate Cancer) will have to be awaited [643].

6.1.3.1.2 Dose escalation

Local control is a critical issue for the outcome of RT of PCa. It has been shown that local failure due to
insufficient total dose is prognostic for death from PCa as a second wave of metastases is seen 5 to 10 years
later on [644]. Several RCTs have shown that dose escalation (range 74–80 Gy) has a significant impact on
10-year biochemical relapse as well as metastases and disease-specific mortality [645-652]. These trials have
generally included patients from several risk groups, and the use of neoadjuvant/adjuvant HT has varied (see
Table 6.1.6). The best evidence of an OS benefit in patients with intermediate- or high-risk PCa, but not with
low-risk PCa, derives from a non-randomised but well conducted propensity-matched retrospective analysis
of the U.S. National Cancer Database by Kalbasi et al., including a total of 42,481 patients [653]. The concept
of a focal boost to the dominant intraprostatic lesion visible on MRI has been successfully validated in a RCT
of 571 intermediate- and high-risk patients [654]. Patients were randomised between 77 Gy in 35 fractions of
2.2 Gy and the same dose plus a focal boost up to 18 Gy. Additional ADT was given to 65% of patients in both
arms. However, the duration of the ADT was not reported. With a median follow-up of 72 months there was
a moderate improvement of biochemical PFS (primary endpoint). In addition, focal boosting decreased local
failure (HR: 0.33) and increased the rate of regional + distant MFS (HR: 0.58) [655]. No significant difference

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 63

for late GU- or GI toxicity grade > 2 (23% and 12% vs. 28% and 13%) was documented. For grade > 3
GU-toxicity these numbers were 3.5% and 5.6% (p > 0.05). However, longer follow-up is needed to assess
late GU-toxicity [655]. Of note, there was a clear decrease in biochemical failure with increasing boost dose,
individually given up to 18 Gy. If IMRT/VMAT and IGRT are used for dose escalation, rates of severe late side
effects (> grade 3) for the rectum are 2–4% and for the GU tract 2–6% [647, 654]. These data do not apply to
focal boost therapy.

Table 6.1.6: Randomised trials of dose escalation in localised PCa

Trial n PCa condition Radiotherapy Follow-up Outcome Results

Dose (median)
MD Anderson 301 T1-T3, N0, M0, 70 vs.78 Gy 15 yr. DM, DSM, All patients:
study 2011 PSA < 10 ng/mL FFF 18.9% FFF at 70 Gy
[652] PSA 10-20 ng/mL 12% FFF at 78 Gy
PSA > 20 ng/mL (p = 0.042)
3.4% DM at 70 Gy
1.1% DM at 78 Gy
(p = 0.018)
6.2% DSM at 70 Gy
3.2% DSM at 78 Gy
(p = 0.043)
No difference in OS
(p > 0.05)
PROG 95-09 393 T1b-T2b 70.2 vs.79.2 Gy 8.9 yr. 10-yr. All patients:
2010 [646] PSA < 15 ng/mL including ASTRO BCF 32% BF at 70.2 Gy
75% low-risk pts. proton boost 17% BF at 79.2 Gy
Low-risk: T1-2a, 19.8 vs. 28.8 Gy (p < 0.0001)
PSA < 10 mg/mL, Low-risk patients:
GS < 6 28% BF at 70.2 Gy
Interm-risk: PSA 7% BF at 79.2 Gy
10-15 ng/mL or (p < 0.0001)
GS 7 or T2b
High-risk: GS
8-10
MRC RT01 843 T1b-T3a, N0, M0 64 vs. 74 Gy 10 yr. BFS, OS 43% BFS at 64 Gy
2014 [651] PSA < 50 ng/mL 55% BFS at 74 Gy
neoadjuvant HT (p = 0.0003)
71% OS both groups
(p = 0.96)
Dutch 664 T1b-T4 143 pts. 68 vs. 78 Gy 110 mo. Freedom 43% FFF at 68 Gy
randomised with (neo) biochemical 49% FFF at 78 Gy
phase III trial adjuvant HT (Phoenix) (p = 0.045)
2014 [650] and/or clinical
failure at
10 yr.
GETUG 06 306 T1b-T3a, N0, M0 70 vs. 80 Gy 61 mo. BCF (ASTRO) 39% BF at 70 Gy
2011 [649] PSA < 50 ng/mL 28% BF at 80 Gy
RTOG 0126 1,532 T1b-T2b 70.2 vs. 79.2 Gy 100 mo. OS, DM, BCF 75% OS at 70.2 Gy
2018 [645] ISUP grade 1 (ASTRO) 76% OS at 79.2 Gy
+ PSA 10-20 6% DM at 70.2 Gy
ng/mL or ISUP 4% DM at 79.2 Gy
grade 2/3 + (p = 0.05)
PSA < 15 ng/mL 47% BCF at 70.2 Gy
31% BCF at 79.2 Gy
(p < 0.001;
Phoenix, p < 0.001)

64 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

FLAME Trial 571 EAU risk 77 Gy (35 fx. 72 mo. BFS (5 yr.) BFS:
[654, 655] classification: 2.2 Gy) vs. (median) DSM (5 yr.) 92% at 77 Gy + boost
Intermediate risk 77 Gy (35 Fx.) 85% at 77 Gy
(15%) + focal boost (p < 0.001, HR: 0.45)
High risk (84%) (up to 18 Gy) DSM: p = 0.49
ADT (65% both Focal boost in favour
arms – duration of: Local control
unknown) (HR: 0.33)
Distant MFS
(HR: 0.58)
BF = biochemical failure; BFS = biochemical progression-free survival; DM = distant metastases; DSM = disease
specific mortality; FFF = freedom from biochemical or clinical failure; HT = hormone therapy; MFS = metastasis-
free survival; mo. = months; n = number of patients; OS = overall survival; PSA = prostate-specific antigen;
yr. = year.

6.1.3.1.3 Hypofractionation
Fractionated RT utilises differences in the DNA repair capacity of normal and tumour tissue and slowly
proliferating cells are very sensitive to an increased dose per fraction [656]. A meta-analysis of 25 studies
including > 14,000 patients concluded that since PCa has a slow proliferation rate, hypofractionated RT
could be more effective than conventional fractions of 1.8–2 Gy [657]. Hypofractionation (HFX) has the added
advantage of being more convenient for the patient at lower cost.
Moderate HFX is defined as RT with 2.5–3.4 Gy/fx. Several studies report on moderate HFX applied
in various techniques also including HT in part [658-665]. A systematic review concluded that studies on
moderate HFX (2.5–3.4 Gy/fx) delivered with conventional 3D-CRT/IMRT have sufficient follow-up to support
the safety of this therapy but long-term efficacy data are still lacking [664]. These results were confirmed by
a recent Cochrane review on moderate HFX for clinically localised PCa [666]. Eleven studies were included
(n = 8,278) with a median follow-up of 72 months showing little or no difference in PCa-specific survival
(HR: 1.00). Based on 4 studies (n = 3,848), HFX probably makes little or no difference to late radiation
GU toxicity (RR: 1.05) or GI toxicity (RR: 1.1), but this conclusion is based on relatively short follow-up, and
10 to 15-year data will be required to confirm these findings.

Moderate HFX should only be done by experienced teams using high-quality EBRT using IGRT and IMRT/
VMAT and published phase III protocols should be adhered to (Table 6.1.7).

Table 6.1.7: Major phase III randomised trials of moderate hypofractionation for primary treatment

Study/ n Risk, ISUP ADT RT Regimen BED, Gy Median Outcome

Author grade, or FU, mo
NCCN
Lee, et al. 550 low risk None 70 Gy/28 fx 80 70 5 yr. DFS 86.3%
2016 [660] 542 73.8 Gy/41 fx 69.6 (n.s.)
5 yr. DFS 85.3%
Dearnaley, 1,077/19 fx 15% low 3-6 mo. 57 Gy/19 fx 73.3 62 5 yr. BCDF
et al. CHHiP 1,074/20 fx 73% before 60 Gy/20 fx 77.1 85.9% (19 fx)
2016 [661] 1,065/37 fx intermediate and 74 Gy/37 fx 74 90.6% (20 fx)
12% high during 88.3% (37 fx)
EBRT
De Vries, 403 30% ISUP None 64.6 Gy/19 fx 90.4 89 8-yr. OS 80.8%
et al., 2020 392 grade 1 78 Gy/39 fx 78 vs. 77.6%
[667] 45% ISUP (p = 0.17)
grade 2-3,
25% ISUP 8 yr. TF 24.4%
grade 4-5 vs. 26.3%

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 65

Catton, et al. 608 intermediate None 60 Gy/20 fx 77.1 72 5 yr. BCDF both
2017 [663] risk arms 85%
53% T1c HR: 0.96 (n.s)
46% T2a-c
598 9% ISUP 78 Gy/39 fx 78
grade 1
63% ISUP
grade 2
28% ISUP
grade 3
ADT = androgen deprivation therapy; BCDF = biochemical or clinical disease failure; BED = biologically
equivalent dose, calculated to be equivalent in 2 Gy fractions using an α/ß of 1.5 Gy; DFS = disease-
free survival; EBRT = external beam radiotherapy; FU = follow-up; fx = fractions; HR = hazard ratio;
ISUP = International Society of Urological Pathology; mo. = month; n = number of patients; NCCN = National
Comprehensive Cancer Network; n.s. = not significant; TF = treatment failure; yr. = year.

Ultra-HFX has been defined as RT with > 3.4 Gy per fraction [665]. It requires IGRT and (ideally) stereotactic
body RT (SBRT). Table 6.1.8 provides an overview of selected studies. Short-term biochemical control (5-years)
is comparable to conventional fractionation. However, there are concerns about high-grade GU and rectal
toxicity and full long-term side effects may not yet be known [664, 668]. In the HYPO-RT-PC randomised trial
by Widmark et al., (n = 1,200), no difference in failure-free survival was seen for conventional or ultra-HFX but
acute grade > 2 GU toxicity was 23% vs. 28% (p = 0.057), favouring conventional fractionation. There were no
significant differences in long-term toxicity [668]. A systematic review by Jackson et al., included 38 studies
with 6,116 patients who received RT with < 10 fractions and > 5 Gy per fraction. Five and 7-year biochemical
recurrence-free survival (BRFS) rates were 95.3% and 93.7%, respectively, and estimated late grade > 3 GU
and GI toxicity rates were 2.0% and 1.1%, respectively [669]. The authors conclude that there is sufficient
evidence to support SBRT as a standard treatment option for localised PCa, even though the median follow-up
in this review was only 39 months and it included at least one trial (HYPO-RT-PC) which used 3D-CRT in 80%
and IMRT/VMAT in the remainder for ultra-HFX. In their review on SBRT, Cushman et al., evaluated 14 trials,
including 2,038 patients and concluded that despite a lack of long-term follow-up and the heterogeneity of the
available evidence, prostate SBRT affords appropriate biochemical control with few high-grade toxicities [670].
In the Intensity-modulated fractionated RT vs. stereotactic body RT for PCa (PACE-B) trial, acute grade > 2 GU or
GI toxicities did not differ significantly between conventional fractionation and ultra- HFX [671]. Adopting planning
dose constraints to the penile bulb might minimise ED, especially in younger patients (Table 6.1.8) [672].

First results of a small (n = 30) randomised phase-II trial in intermediate-risk PCa of ‘ultra-high single dose RT’
(SDRT) with 24 Gy compared with an ultra HFX stereotactic body RT regime with 5x9 Gy, have been published
recently [673].

Table 6.1.8: Selected trials on ultra-hypofractionation for intact localised PCa

Study n med FU Risk-Group Regimen (TD/fx) Outcome

(mo)
Widmark et al. 1,200 60 89% intermediate 78 Gy / 39 fx, 8 wk. FFS at 5 yr.
2019 11% high 42.7 Gy / 7 fx, 2.5 wk. 84% in both arms
HYPO-RT-PC No SBRT
[668]
Brand et al. 2019 847 variable 8% low 78 Gy / 39 fx, 8 wk. Grade > 2 acute GI
PACE-B [671] 92% intermediate 36.25 Gy / 5 fx, 1-2 wk. 12% vs. 10%, p = 0.38
SBRT Grade > 2 acute GU
27% vs. 23%, p = 0.16
FFS = failure-free survival; FU = follow-up; fx = number fractions; GI = gastro-intestinal toxicity; GU = genito-
urinary toxicity; mo. = months; n = number of patients; TD = total dose; SBRT = stereotactic body radiotherapy;
wk. = weeks; yr. = years.

6.1.3.1.4 Neoadjuvant or adjuvant hormone therapy plus radiotherapy

The combination of RT with LHRH ADT has definitively proven its superiority compared with RT alone followed
by deferred ADT on relapse, as shown by phase III RCTs [674-678] (Table 6.1.9). The main message is that
for all intermediate-risk disease a short duration of 4-6 months is optimal while a longer one, around 3 years,

66 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

is needed for high-risk patients. The OS impact of adding short-term ADT for favourable intermediate-risk
disease, however, remains a matter of debate [121].

Table 6.1.9: Selected studies of use and duration of ADT in combination with RT for PCa

Study TNM stage n Trial ADT RT Effect on OS

RTOG 85-31 T3 or N1 M0 977 EBRT ± ADT Orchiectomy or 65–70 Gy Significant benefit for
2005 [675] LHRH agonist combined treatment
15% RP (p = 0.002) seems to
be mostly caused by
patients with ISUP
grade 2-5
RTOG 94-13 T1c–4 N0–1 1,292 ADT timing 2 mo. Whole pelvic No significant
2007 [679] M0 comparison neoadjuvant RT vs. difference between
plus prostate neoadjuvant plus
concomitant vs. only; 70.2 Gy concomitant vs.
4 mo. adjuvant adjuvant androgen
suppression suppression therapy
groups (interaction
suspected)
RTOG 86-10 T2–4 N0–1 456 EBRT ± ADT Goserelin plus 65–70 Gy RT No significant
2008 [676] flutamide 2 mo. difference at 10 yr.
before, plus
concomitant
therapy
D’Amico AV, T2 N0 M0 206 EBRT ± ADT LHRH agonist 70 Gy Significant benefit that
et al. 2008 (localised plus flutamide 3D-CRT may pertain only to
[677] unfavourable for 6 mo. men with no or
risk) minimal co-morbidity
(HR: 0.55, 95% CI:
0.34–0.90, p = 0.01)
RTOG 92-02 T2c–4 N0–1 1554 Short vs. LHRH agonist 65–70 Gy p = 0.73,
2008 [680] M0 prolonged given for 2 yr. p = 0.36 overall;
ADT as adjuvant significant benefit
after 4 mo. as (p = 0.044) (p = 0.0061)
neoadjuvant in subset with ISUP
grade 4–5
EORTC T1c–2ab N1 970 Short vs. LHRH agonist 70 Gy Better result with 3 yr.
22961 2009 M0, T2c–4 prolonged for 6 mo. vs. 3D-CRT treatment than with
[681] N0–1 M0 ADT 3 yr. 6 mo. (3.8% improvement
in survival at 5 yr.)
EORTC T1–2 poorly 415 EBRT ± ADT LHRH agonist 70 Gy RT Significant benefit at
22863 2010 differentiated for 3 yr. 10 yr. for combined
[674] and M0, or (adjuvant) treatment (HR: 0.60,
T3–4 N0–1 M0 95% CI: 0.45–0.80,
p = 0.0004).
TROG T2b–4 N0 M0 802 Neoadjuvant Goserelin 66 Gy No significant difference
96-01 2011 ADT plus flutamide 3D-CRT in OS reported; benefit
[678] Duration 3 or 6 mo. in PCa-specific survival
before, plus (HR: 0.56, 95% CI:
concomitant 0.32–0.98, p = 0.04)
suppression (10 yr.: HR: 0.84,
0.65–1.08, p = 0.18)
RTOG 99-10 intermediate 1,579 Short vs. LHRH agonist 70.2 Gy 67 vs. 68%, p = 0.62,
2015 [682] risk prolonged 8 + 8 vs. 8 + 28 2D/3D confirms 8 + 8 wk.
94% T1–T2, ADT wk. LHRH as a standard
6% T3–4

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 67

PCSIII Intermediate 600 76 Gy alone LHRH + 70 vs. 76 Gy Significantly improved
2020 [683] risk vs. bicalutamide biochemical failure-
76 Gy + ADT 6 mo. free and PCa-specific
vs. 4 mo. prior to survival for ADT arms,
70 Gy + ADT RT with no difference in
OS.
ADT = androgen deprivation therapy; CI = confidence interval; EBRT = external beam radiotherapy in standard
fractionation; HR = hazard ratio; LHRH = luteinising hormone-releasing hormone; mo. = months; n = number of
patients; OS = overall survival; RP = radical prostatectomy; RT = radiotherapy; wk = week; yr. = year.

The question of the added value of EBRT combined with ADT has been clarified by 3 RCTs. All showed a clear
benefit of adding EBRT to long-term ADT (Table 6.1.10).

Table 6.1.10: Selected studies of ADT in combination with, or without, RT for PCa

Study TNM stage n Trial design ADT RT

Effect on OS
SPCG-7/ T1b–2 WHO 875 ADT ± EBRT LHRH agonist 34% (95% CI: 29–39%)
70 Gy
SFUO-3 Grade 1–3, for 3 mo. plus vs. 17% (95% CI: 13–22%
3D-CRT
2016 [684] T3 N0 M0 continuous CSM at 12 (15) yr. favouring
vs. no RT
flutamide combined treatment
(p < 0.0001 for 15-yr. results)
NCIC CTG PR.3/MRC
PRO7/NCIC T3–4 (88%), 1,205 ADT ± EBRT Continuous 65–70 Gy 10-yr. OS = 49% vs. 55%
2015 [685] PSA > 20 ng/mL LHRH agonist 3D-CRT favouring combined
(64%), ISUP vs. no RT treatment HR: 0.7,
grade 4–5 (36%) p < 0.001)
N0 M0
Sargos, et al. T3–4 N0 M0 273 ADT ± EBRT LHRH agonist 70 Gy Significant reduction of
2020 [686] for 3 yr. 3D-CRT clinical progression; 5-yr.
vs. no RT OS 71.4% vs. 71.5%
ADT = androgen deprivation therapy; CSM = cancer-specific mortality; EBRT = external beam radiotherapy;
HR = hazard ratio; LHRH = luteinising hormone-releasing hormone; mo. = months; n = number of patients;
OS = overall survival; RT = radiotherapy; 3D-CRT = three-dimensional conformal radiotherapy.

6.1.3.1.5 Combined dose-escalated radiotherapy and androgen-deprivation therapy

The combination of ADT with various forms of RT has been extensively studied, with extremely strong evidence
for the use of such combined modality therapy in several settings. The MARCAP (Individual Patient Data Meta-
Analysis of Randomized Trials in Cancer of the Prostate) consortium recently conducted a meta-analysis of
trials using individual patient data (IPD), and a primary endpoint of MFS, a validated surrogate for OS. Trials
were eligible if they studied the use or prolongation of ADT in patients receiving definitive RT, and included 12
trials with 10,853 patients. Median follow-up was over 11 years. The use of ADT was clearly associated with
significant improvements in BCR, metastatic recurrence, MFS, and OS. The benefits of ADT were independent
of RT dose, age, and risk groups comparing NCCN unfavourable intermediate-risk (see Sections 4.2 and
6.2.2.3), high-risk and locally-advanced disease. There were no demonstrable benefits from the extension of
duration of neoadjuvant ADT [687].

Three RCTs have shown that the benefits of ADT are independent of dose escalation, and that the use of ADT
would not compensate for a lower RT dose:
1. The GICOR study shows a better biochemical DFS in high-risk patients for 3D-CRT radiation dose > 72 Gy
when combined with long-term ADT [688].
2. DART01/05 GICOR shows improved OS in high-risk patients after ten years if 2 years of adjuvant ADT is
combined with high-dose RT [689].
3. EORTC trial 22991 shows that 6 months ADT improves biochemical and clinical DFS irrespective of the
dose (70, 74, 78 Gy) in intermediate-risk and low-volume high-risk localised PCa patients [690].

A meta-analysis based on IPD from two RCTs (RTOG 9413 and Ottawa 0101) has compared neoadjuvant/
concomitant vs. adjuvant ADT (without substratifying between favourable- and unfavourable intermediate-
risk disease) in conjunction with prostate RT and reported superior PFS with adjuvant ADT, but the data
heterogeneity means that this observation is hypothesis-generating only [691].

68 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

In addition, a Canadian two-arm dose-escalated (76 Gy) RCT compared neoadjuvant and concomitant with
adjuvant short-term ADT in 432 patients with intermediate-risk PCa. After 10 years no significant difference in
OS or RT-related grade > 3 GI or GU toxicity was seen [692]. Therefore both regimen in combination with dose
escalation are reasonable standards.

6.1.3.2 Proton beam therapy

In theory, proton beams are an attractive alternative to photon-beam RT for PCa, as they deposit almost all
their radiation dose at the end of the particle’s path in tissue (the Bragg peak), in contrast to photons which
deposit radiation along their path. There is also a very sharp fall-off for proton beams beyond their deposition
depth, meaning that critical normal tissues beyond this depth could be effectively spared. In contrast, photon
beams continue to deposit energy until they leave the body, including an exit dose.

One RCT on dose escalation (70.2 vs. 79.2 Gy) has incorporated protons for the boost doses of either
19.8 or 28.8 Gy. This trial shows improved outcome with the higher dose but it cannot be used as evidence
for the superiority of proton therapy [646]. Thus, unequivocal information showing an advantage of protons
over IMRT photon therapy is still not available. Studies from the SEER database and from Harvard describing
toxicity and patient-reported outcomes do not point to an inherent superiority of protons [693, 694]. In terms of
longer-term GI toxicity, proton therapy might even be inferior to IMRT [694].
A RCT comparing equivalent doses of proton-beam therapy with IMRT is underway. Meanwhile,
proton therapy must be regarded as an experimental alternative to photon-beam therapy.

6.1.3.3 Spacer during external beam radiation therapy

Biodegradable spacer insertion involves using a liquid gel or balloon to increase the distance between the
prostate and rectum and consequently reduce the amount of radiation reaching the rectum. Various materials
have been used with most evidence available for CE-marked hydrogel spacers [695]. A meta-analysis including
one RCT and six cohort studies using the hydrogel spacer demonstrated a 5–8% reduction in the rectal volume
receiving high-dose radiation, although heterogeneity between studies is found [696]. In the final analysis of
the RCT with a median follow-up of 37 months and with approximately two-thirds of patients evaluable, those
treated with spacer in situ had no deterioration from baseline bowel function whilst those treated without
spacer had a lower mean bowel summary score of 5.8 points which met the threshold for a minimally important
difference of 4–6 points [697].
This meta-analysis highlights inconsistent reporting of procedural complications. In addition, with
more widespread clinical use safety reports describe uncommon, but severe and life changing, complications
including prostatic abscess, fistulae and sepsis [698]. Implantation is associated with a learning curve and
should only be undertaken by teams with experience of TRUS and transperineal procedures with robust audit
reporting in place [699]. Its role in the context of moderate or extreme HFX is as yet unclear.

6.1.3.4 Brachytherapy
6.1.3.4.1 Low-dose rate brachytherapy
Low-dose rate (LDR) brachytherapy uses radioactive seeds permanently implanted into the prostate. In patients
declining or unsuitable for AS LDR monotherapy [700] can be offered to those with low-risk or NCCN favourable
intermediate-risk (see Section 4.2) and good urinary function defined as an International Prostatic Symptom Score
(IPSS) < 12 and maximum flow rate > 15 mL/min on urinary flow tests [701]. In addition, with due attention to
dose distribution, patients having had a previous TURP can undergo brachytherapy without an increase in risk
of urinary toxicity. A minimal channel TURP is recommended, leaving at least 1 cm rim of prostate tissue around
the post-TURP urethral defect at the postero-lateral sides of the prostate and there should be at least a 3-month
interval between TURP and brachytherapy to allow for adequate healing [702-705].

The only available RCT comparing RP and LDR brachytherapy as monotherapy was closed due to poor accrual
[706]. Outcome data are available from a number of large population cohorts with mature follow-up [707-711].
The biochemical DFS for ISUP grade 1 patients after 5 and 10 years has been reported to range from 71% to
93% and 65% to 85%, respectively [707-711]. A significant correlation has been shown between the implanted
dose and biochemical control [712]. A D90 (dose covering 90% of the prostate volume) of > 140 Gy leads to a
significantly higher biochemical control rate (PSA < 1.0 ng/mL) after 4 years (92 vs. 68%). There is no OS benefit
in adding neoadjuvant or adjuvant ADT to LDR monotherapy [713].

Low-dose rate brachytherapy can be combined with EBRT in NCCN unfavourable intermediate-risk PCa (see
Section 4.2) and high-risk patients. External beam RT (total dose of 78 Gy) has been compared with EBRT (total
dose 46 Gy) followed by LDR brachytherapy boost (prescribed dose 115 Gy) in intermediate-risk and high-risk
patients in the ASCENDE-RT randomised trial with 12 months of ADT in both arms [714]. The LDR boost resulted

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 69

in 5- and 7-year PSA PFS increase (89% and 86%, respectively, compared to 84% and 75%). This improvement
was achieved at a cost of increased late grade 3+ GU toxicity (18% compared to 8%) [715]. Toxicity resulted
mainly in the development of urethral strictures and incontinence and great care should be taken during treatment
planning.

6.1.3.4.2 High-dose rate brachytherapy

High-dose rate (HDR) brachytherapy uses a radioactive source temporarily introduced into the prostate to
deliver radiation. The technical differences are outlined in Table 6.1.11. The use of the GEC (Groupe Europeen
de Curietherapie)/ESTRO Guidelines is strongly recommended [716]. High-dose rate brachytherapy can be
delivered in single or multiple fractions and is often combined with EBRT of at least 45 Gy [717]. A systematic
review of non-RCTs and data from population studies suggest outcomes with EBRT plus HDR brachytherapy
are superior to EBRT alone [718, 719].

A single-centre RCT of EBRT (55 Gy in 20 fractions) vs. EBRT (35.75 Gy in 13 fractions), followed by HDR
brachytherapy (17 Gy in two fractions over 24 hours) has been reported [720]. In 218 patients with T1–3 N0M0
PCa the combination of EBRT and HDR brachytherapy showed a significant improvement in the biochemical
disease-free rate (p = 0.04) at 5 and 10 years (75% and 46% compared to 61% and 39%). However, an
unexpectedly high rate of early recurrences was observed in the EBRT arm alone, even after 2 years, possibly
due to a dose lower than the current standard used [720].

Supporting, but not definitive, evidence of the benefit of HDR boost is available from the TROG 03.04 RADAR
trial. This multi-centre study had upfront radiation dose escalation (non-randomised) with dosing options of 66,
70, or 74 Gy EBRT, or 46 Gy EBRT plus HDR brachytherapy boost and randomised men with locally-advanced
PCa to 6 or 18 months ADT. After a minimum follow-up of 10 years HDR boost significantly reduced distant
progression, the study primary endpoint (sub HR: 0.68, 95% CI: 0.57–0.80; p < 0.0001), when compared to
EBRT alone and, independent of duration of ADT, HDR boost was associated with increased IPSS of 3 points at
18 months post-treatment resolving by 3 years but decreased rectal symptoms when compared to EBRT [721].
Although radiation dose escalation using brachytherapy boost provides much higher biological doses, the
TROG 03.04 RADAR RCT and systematic reviews show ADT use independently predicts better outcomes
regardless of radiation dose intensification [713, 721, 722]. Omitting ADT may result in inferior OS and based
on current evidence ADT use and duration should be in line with that used when delivering EBRT alone.

Fractionated HDR brachytherapy as monotherapy can be offered to patients with low- and intermediate-risk
PCa, who should be informed that results are only available from limited series in very experienced centres.
Five-year PSA control rates of 97.5% and 93.5% for low- and intermediate-risk PCa, respectively, are
reported, with late grade 3+ GU toxicity rates < 5% and no, or very minimal, grade 3+ GI toxicity rates [723].
Single fraction HDR monotherapy should not be used as it has inferior biochemical control rates compared to
fractionated HDR monotherapy [724].

Table 6.1.11: Difference between LDR and HDR brachytherapy

Differences in prostate brachytherapy techniques

Low dose rate (LDR) • Permanent seeds implanted
• Uses Iodine-125 (I-125) (most common), Palladium-103 (103Pd-) or
Cesium-131 isotopes
• Radiation dose delivered over weeks and months
• Acute side effects resolve over months
• Radiation protection issues for patient and carers
High dose rate (HDR) • Temporary implantation
• Iridium-192 (IR-192) isotope introduced through implanted needles or
catheters
• Radiation dose delivered in minutes
• Acute side effects resolve over weeks
• No radiation protection issues for patient or carers

6.1.3.5 Acute side effects of external beam radiotherapy and brachytherapy

Gastro-intestinal and urinary side effects are common during and after EBRT. In the EORTC 22991 trial,
approximately 50% of patients reported acute GU toxicity of grade 1, 20% of grade 2, and 2% grade 3. In
the same trial, approximately 30% of patients reported acute grade 1 GI toxicity, 10% grade 2, and less than

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1% grade 3. Common toxicities included dysuria, urinary frequency, urinary retention, haematuria, diarrhoea,
rectal bleeding and proctitis [725]. In addition, general side effects such as fatigue are common. It should be
noted that the incidence of acute side effects is greater than that of late effects (see Section 8.2.2.1), implying
that most acute effects resolve. In a RCT of conventional dose EBRT vs. EBRT and LDR brachytherapy the
incidence of acute proctitis was reduced in the brachytherapy arm, but other acute toxicities were equivalent
[714]. Acute toxicity of HDR brachytherapy has not been documented in a RCT, but retrospective reports
confirm lower rates of GI toxicity compared with EBRT alone and grade 3 GU toxicity in 10%, or fewer,
patients, but a higher incidence of urinary retention [726]. Similar findings are reported using HFX; in a pooled
analysis of 864 patients treated using extreme HFX and stereotactic RT, declines in urinary and bowel domains
were noted at 3 months which returned to baseline, or better, by 6 months [727].

6.1.4 Hormonal therapy

6.1.4.1 Introduction
6.1.4.1.1 Different types of hormonal therapy
Androgen deprivation can be achieved by suppressing the secretion of testicular androgens in different ways.
This can be combined with inhibiting the action of circulating androgens at the level of their receptor which has
been known as complete (or maximal or total) androgen blockade (CAB) using the old-fashioned antiandrogens
[728].

6.1.4.1.1.1 Testosterone-lowering therapy (castration)

6.1.4.1.1.1.1 Castration level
The castration level of testosterone is < 50 ng/dL (1.7 nmol/L), which was defined more than 40 years
ago when testosterone testing was less sensitive. Current methods have shown that the mean value after
surgical castration is 15 ng/dL [729]. Therefore, a more appropriate level should be defined as < 20 ng/dL
(< 0.7 nmol/L). This definition is important as better results are repeatedly observed with lower testosterone
levels compared to 50 ng/dL [730-732]. However, the castrate level considered by the regulatory authorities
and in clinical trials addressing castration in PCa is still the historical < 50 ng/dL (1.7 nmol/L).

6.1.4.1.1.1.2 Bilateral orchiectomy

Bilateral orchiectomy or subcapsular pulpectomy is still considered the primary treatment modality for ADT.
It is a simple, cheap and virtually complication-free surgical procedure. It is easily performed under local
anaesthesia, and it is the quickest way to achieve a castration level which is usually reached within less than
twelve hours. It is irreversible and therefore does not allow for intermittent treatment [733].

6.1.4.1.1.1.3 Oestrogens
Treatment with oestrogens results in testosterone suppression and is not associated with bone loss [734].
Early studies tested oral diethylstilboestrol (DES) at several doses. Due to severe side effects, especially
thromboembolic complications, even at lower doses these drugs are not considered as standard first-line
treatment [735, 736]. Oestrogen patches are under investigation [737].

6.1.4.1.1.1.4 Luteinising-hormone-releasing hormone agonists

Long-acting LHRH agonists are currently the main forms of ADT. These synthetic analogues of LHRH are
delivered as depot injections on a 1-, 2-, 3-, 6-monthly, or yearly basis. The first injection induces a transient
rise in luteinising hormone (LH) and follicle-stimulating hormone (FSH) leading to the ‘testosterone surge’
or ‘flare-up’ phenomenon which starts two to three days after administration and lasts for about one week.
This may lead to detrimental clinical effects (the clinical flare) such as increased bone pain, acute bladder
outlet obstruction, obstructive renal failure, spinal cord compression, and cardiovascular death due to
hypercoagulation status [738]. Patients at risk are usually those with high-volume symptomatic bony disease.
Concomitant therapy with an anti-androgen decreases the incidence of clinical flare but does not completely
remove the risk. Anti-androgen therapy is usually continued for 4 weeks but neither the timing nor the duration
of anti-androgen therapy are based on strong evidence. In addition, the long-term impact of preventing ‘flare
up’ is unknown [739].
Chronic exposure to LHRH agonists results in the down-regulation of LHRH-receptors, suppressing
LH and FSH secretion and therefore testosterone production. A castration level is usually obtained within 2
to 4 weeks [740]. Although there is no formal direct comparison between the various compounds, they are
considered to be equally effective [741]. So far, no survival difference between LHRH agonists and orchiectomy
has been reported due to the lack of high-quality trials [742].
The different products have practical differences that need to be considered in everyday practice,
including the storage temperature, whether a drug is ready for immediate use or requires reconstitution, and
whether a drug is given by subcutaneous or intramuscular injection.

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6.1.4.1.1.1.5 Luteinising-hormone-releasing hormone antagonists
Luteinising-hormone-releasing hormone antagonists immediately bind to LHRH receptors, leading to a rapid
decrease in LH, FSH and testosterone levels without any flare. The practical shortcoming of these compounds
is the lack of a long-acting depot formulation with, so far, only monthly formulations being available. Degarelix
is a LHRH antagonist. The standard dosage is 240 mg in the first month followed by monthly injections of
80 mg. Most patients achieve a castrate level at day three [740]. A phase III RCT compared degarelix to
monthly leuprorelin following up patients for 12 months, suggesting a better PSA PFS for degarelix 240/80 mg
compared to monthly leuprorelin [743]. A systematic review did not show a major difference between agonists
and degarelix and highlighted the paucity of on-treatment data beyond 12 months as well as the lack of
survival data [744]. Its definitive superiority over the LHRH analogues remains to be proven. Short-term follow-
up data from a meta-analysis indicate that the use of LHRH antagonist is associated with significantly lower
overall mortality and cardiovascular events as compared with agonists. On the other hand, other adverse
effects such as decreased libido, hot flushes, ED, weight gain, and injection site reactions are seen less often
with the agonists [745, 746].

Relugolix is an oral LHRH antagonist. It was compared to the LHRH agonist leuprolide in a randomised phase
III trial [747]. The primary endpoint was sustained testosterone suppression to castrate levels through 48
weeks. There was a significant difference of 7.9 percentage points (95% CI: 4.1–11.8) showing non-inferiority
and superiority of relugolix. The incidence of major adverse cardiovascular events was significantly lower
with relugolix (prespecified safety analysis). Relugolix has been approved by the FDA [748] and EMA [749] for
hormone sensitive PCa.

6.1.4.1.1.1.6 Anti-androgens
These oral compounds are classified according to their chemical structure as:
• steroidal, e.g., cyproterone acetate (CPA), megestrol acetate and medroxyprogesterone acetate;
• non-steroidal or pure, e.g., nilutamide, flutamide and bicalutamide.

Both classes compete with androgens at the receptor level. This leads to an unchanged or slightly elevated
testosterone level. Conversely, steroidal anti-androgens have progestational properties leading to central
inhibition by crossing the blood-brain barrier.

6.1.4.1.1.1.6.1 Steroidal anti-androgens

These compounds are synthetic derivatives of hydroxyprogesterone. Their main pharmacological side effects
are secondary to castration (gynaecomastia is quite rare) whilst the non-pharmacological side effects are
cardiovascular toxicity (4–40% for CPA) and hepatotoxicity.

Cyproterone acetate was the first licensed anti-androgen but the least studied. Its most effective dose
as monotherapy is still unknown. Although CPA has a relatively long half-life (31–41 hours), it is usually
administered in two or three fractionated doses of 100 mg each. In one RCT CPA showed a poorer OS when
compared with LHRH analogues [750]. An underpowered RCT comparing CPA monotherapy with flutamide
in M1b PCa did not show any difference in DSS and OS at a median follow-up of 8.6 years [751]. Other CPA
monotherapy studies suffer from methodological limitations preventing firm conclusions.

6.1.4.1.1.1.6.2 Non-steroidal anti-androgens

Non-steroidal anti-androgen monotherapy with e.g., nilutamide, flutamide or bicalutamide does not suppress
testosterone secretion and it is claimed that libido, overall physical performance and bone mineral density
(BMD) are frequently preserved [752]. Non-androgen-related pharmacological side effects differ between
agents. Bicalutamide shows a more favourable safety and tolerability profile than flutamide and nilutamide
[753]. The dosage licensed for use in CAB is 50 mg/day, and 150 mg/day for monotherapy. The non-steroidal
anti-androgens pharmacological side effects are mainly gynaecomastia (70%) and breast pain (68%). However,
non-steroidal anti-androgen monotherapy offers clear bone protection compared with LHRH analogues and
probably LHRH antagonists [752, 754]. All three agents share the potential for liver toxicity (occasionally fatal),
requiring regular monitoring of patients’ liver enzymes.

6.1.4.1.1.2 New androgen receptor pathway inhibitors (ARPis)

Once on ADT the development of castration-resistance (CRPC) is only a matter of time. It is considered to be
mediated through two main overlapping mechanisms: androgen-receptor (AR)-independent and AR-dependent
mechanisms (see Section 6.5 - Castrate-resistant PCa). In CRPC, the intracellular androgen level is increased
compared to androgen sensitive cells and an over-expression of the AR has been observed, suggesting an
adaptive mechanism [755]. This has led to the development of several new compounds targeting the androgen

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axis. In mCRPC, abirateron acetate and enzalutamide have been approved. In addition to ADT (sustained
castration), abiraterone acetate, apalutamide and enzalutamide have been approved for the treatment of
metastatic hormone sensitive PCa (mHSPC) by the FDA and the EMA. For the updated approval status see
EMA and FDA websites [756-760]. Finally, apalutamide, darolutamide and enzalutamide have been approved
for non-metastatic CRPC (nmCRPC) at high risk of further metastases [761-765].

6.1.4.1.1.2.1 Abiraterone acetate

Abiraterone acetate is a CYP17 inhibitor (a combination of 17α-hydrolase and 17,20-lyase inhibition). By
blocking CYP17, abiraterone acetate significantly decreases the intracellular testosterone level by suppressing
its synthesis at the adrenal level and inside the cancer cells (intracrine mechanism). This compound must be
used together with prednisone/prednisolone to prevent drug-induced hyperaldosteronism [756, 759].

6.1.4.1.1.2.2 Apalutamide, darolutamide, enzalutamide (alphabetical order)

These agents are novel non-steroidal anti-androgens with a higher affinity for the AR receptor than
bicalutamide. While previous non-steroidal anti-androgens still allow transfer of ARs to the nucleus and would
act as partial agonists, all three agents also block AR transfer and therefore suppress any possible agonist-like
activity [760-762]. Darolutamide has structurally unique properties [761]. In particular, in preclinical studies, it
showed not to cross the blood-brain barrier [766, 767].

6.1.4.2 Non-hormonal non-cytotoxic drug treatments

6.1.4.2.1 PARP inhibitors
Poly (ADP-ribose) polymerase inhibitors (PARPi) block the enzyme poly ADP-ribose polymerase (PARP) and
were developed aiming to selectively target cancer cells harbouring BRCA mutations and other mutations
inducing homologous recombination deficiency and high level of replication pressure with a sensitivity to PARPi
treatment. Due to the oncogenic loss of some DNA repair effectors and incomplete DNA repair repertoire, some
cancer cells are addicted to certain DNA repair pathways such as Poly (ADP-ribose) polymerase (PARP)-related
single-strand break repair pathway. The interaction between BRCA and PARP is a form of synthetic lethal effect
which means the simultaneously functional loss of two genes leads to cell death, while a defect in any single gene
only has a limited effect on cell viability [768]. The therapeutic indication for PCa is discussed in Section 6.5.8.1.

6.1.4.2.2 Immune checkpoint inhibitors

Checkpoint inhibitors target the molecules CTLA4, programmed cell death protein 1 (PD-1), and programmed
death-ligand 1 (PD-L1). For advanced PCa patients that are microsatellite instability-high/deficient mismatch
repair (MSI-H/dMMR), the PD-1 inhibitor pembrolizumab has been approved by the FDA but not by the EMA.
The label is tumour agnostic [769, 770]. See also Section 6.5.2.1

AKT inhibitors are small molecules which are designed to target and bind to all three isoforms of AKT, which is
a key component of the PI3K/AKT pathway. In clinical trials, ipatasertib, an oral, highly specific, AKT inhibitor
was used and showed significant activity when combined with abiraterone acetate in patients with loss of the
tumour suppressor protein PTEN on immunohistochemistry within the tumour [771, 772]. Currently, there are no
approved AKT inhibitors.

6.1.4.3 Radiopharmaceutical therapy

Radiopharmaceutical therapy (RPT) is based on the delivery of radioactive atoms to tumour-associated
targets. The mechanism of action for RPT is radiation-induced killing of cells. Radionuclides with different
emission properties are used to deliver radiation. The most commonly used radionuclides are represented
by β-particles (e.g., 177Lu) or α-particles (e.g., 223Ra, 225Ac). 177Lu is increasingly used because of its optimal
imaging range (100–200 keV), favourable half time (6.6 days) and appropriate β-particle energy for therapy.
The short path of the α-particles (0.05–0.08 mm) results in minimal toxic effects in adjacent healthy tissue.
These properties enable such radionuclides to be used as theranostics (i.e., the same radionuclide may be
used for both diagnostic and therapeutic purposes). However , an essential requirement prior to any RPT is to
assess the targeting of the agent, mainly using PET techniques which show the tumour expression and the
extent of cancer [773].177Lu has been approved by the FDA for the treatment of adult patients with PSMA-
positive mCRPC who have been treated with ARPI and taxane-based chemotherapy [774]. Clinical details are
discussed in Section 6.5.6.

6.1.5 Investigational therapies

6.1.5.1 Background
Besides RP, EBRT and brachytherapy, other modalities have emerged as potential therapeutic options in
patients with clinically localised PCa [775-777]. These new modalities have been developed as minimally-

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invasive procedures with the aim of providing equivalent oncological safety, reduced toxicity, and improved
functional outcomes. In this section, both whole gland- and focal treatment [778, 779] will be considered,
looking particularly at high-intensity focused US (HIFU), cryotherapeutic ablation of the prostate (cryotherapy)
and focal photodynamic therapy (PDT), as sufficient data are available to form the basis of some initial
judgements. Other options such as radiofrequency ablation (RFA) and electroporation, among others, are
considered to be in the early phases of evaluation [778].

6.1.5.2 Whole-gland therapies

6.1.5.2.1 Cryotherapy for whole-gland treatment
Cryotherapy uses freezing techniques to induce cell death by dehydration resulting in protein denaturation,
direct rupture of cellular membranes by ice crystals and vascular stasis and microthrombi, resulting in
stagnation of the microcirculation with consecutive ischaemic apoptosis [775-777]. Freezing of the prostate is
ensured by the placement of 17 gauge cryo-needles under TRUS guidance, placement of thermosensors at
the level of the external sphincter and rectal wall, and insertion of a urethral warmer. Two freeze-thaw cycles
are used under TRUS guidance resulting in a temperature of -40°C in the mid-gland and at the neurovascular
bundle. Currently, third and fourth generation cryotherapy devices are mainly used. Since its inception,
cryotherapy has been used for whole-gland treatment in PCa either as a primary or salvage treatment option.

The main adverse effects of whole-gland cryosurgery are ED (18%), urinary incontinence (2–20%), urethral
sloughing (0–38%), rectal pain and bleeding (3%) and recto-urethral fistula formation (0–6%) [780]. There is a
lack of prospective comparative data regarding oncological outcomes of whole-gland cryosurgery as a curative
treatment option for men with localised PCa, with most studies being non-comparative single-arm case series
with short follow-up [780].

6.1.5.2.2 High-intensity focused ultrasound for whole-gland treatment

High-intensity focused US consists of focused US waves emitted from a transducer that cause tissue damage
by mechanical and thermal effects as well as by cavitation [781]. The goal of HIFU is to heat malignant tissue
above 65°C, so that it is destroyed by coagulative necrosis. High-intensity focused US is performed under
general or spinal anesthesia, with the patient lying in the lateral or supine position. High-intensity focused US
has previously been widely used for whole-gland therapy with the following adverse effects: acute urinary
retention (10%), ED (23%), urethral stricture (8%), rectal pain or bleeding (11%), recto-urethral fistula (0–5%)
and urinary incontinence (10%) [780].

Since the ultrasound energy is most often delivered from the rectal cavity, HIFU faces challenges in delivering
energy to the anterior part in large prostates.
Similar to cryosurgery, the lack of any long-term prospective comparative data on oncological
outcomes, without significant reduction of side effects, prevents whole-gland HIFU from being considered as a
reasonable alternative to the established curative treatment options [780].

6.1.5.3 Focal therapy for whole-gland treatment

During the past two decades, there has been a trend towards earlier diagnosis of PCa as a result of greater
public and professional awareness leading to the adoption of both formal and informal screening strategies.
The effect of this has been that men are identified at an earlier stage with smaller tumours, with a greater
propensity for unifocal disease potentially suitable for focal therapy [782-784]. There is also greater awareness
of the risks of over-treatment leading to attempts to ablate only a region of the prostate containing the
tumour thereby limiting toxicity by sparing the neurovascular bundles, sphincter and urethra [785-787]. Most
focal therapies to date have been achieved with ablative technologies: cryotherapy, HIFU, PDT, irreversible
electroporation (IRE), and focal RT.
Despite these therapies having less impact on urogenital function, AS should remain the primary
option for patient with low-risk PCa.

A recent systematic review included data from 5,827 patients across 72 studies and covered different energy
sources including HIFU, cryotherapy, PDT, laser interstitial thermotherapy, focal brachytherapy, IRE and
radiofrequency ablation (RFA) [788]. The review favours HIFU and PDT for their higher quality data, over 95% of
pad-free incontinence and 85–90% of patients without clinical significant cancer in short-term analysis.
This has to be critially analysed, because 45% of all patients with a focal approach included in
this systematic review had an ISUP 1 cancer. The overall quality of the evidence was low, due to the majority
of studies being single-centre, non-comparative and retrospective in design, heterogeneity of definitions
and approaches, follow-up strategies, outcomes, and duration of follow-up. Although the review finds high-

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quality evidence that focal therapy has favourable functional outcomes and minimises AEs, definitive proof of
oncological effectiveness of focal therapy compared to standard treatments remains unavailable.

The currently largest analysis on oncologic outcomes following focal HIFU includes 625 patients, with 70%
having ISUP 2/3 disease, followed for 5 years with an 88% failure-free survival (FFS), defined as the need for
salvage treatment or systemic therapy [789]. In this study one repeated focal HIFU session was allowed and
performed in 25% of all patients. Follow-up was driven by PSA and clinics, with re-biopsies performed only in
36% of patients after a significant PSA rise and suspicious MRI.

The guideline Panel acknowledges the challenges for interventional RCTs [790-792]. The interim analysis
and meeting reports demonstrate slow recruitment, patients declining consent and rejecting their treatment
allocation into the RP group.

Propensity-matched analysis using prospective multi-centre databases are available for comparison of focal
therapy vs. radical therapy [793, 794]. Oncological follow-up data up to 8 years can be used to counsel
patients in treatment decisions [793]. Patients were managed by focal therapy had a HIFU or cryotherapy, with
one retreatment, if needed. 17.1% of patients in the focal arm received a retreatment. The primary outcome
was FFS defined as “need for local or systemic salvage treatment or metastasis”. Both groups included 246
patients with an average PSA of 7.9 ng/mL and 60% ISUP 2/3 cancers. The cancer core length was 5–6 mm
with 45% having bilateral cancer. The authors report similar cancer control 8 years after therapy, with FFS
and BCR of 83% and 23.9% for focal therapy vs. 79% and 24.8% for RP, respectively. Similar results were
demonstrated in a cohort-based analysis with a follow-up of 6 years [794].
The use of different definitions for oncological failure in the two arms is a limitation of these studies.
While any recurrence after RP was seen as failure, a second HIFU was permitted in the focal group. The current
data from the HIFU Evaluation and Assessment of Treatment (HEAT) registry indicates that a repeat-HIFU does
not significantely decrease urinary or erectile function [795]. However, this change of failure definition will have
to be re-evaluated.
It is important to note, that these results were achieved in centres with a dedicated focal program
where all patients had a mpMRI with targeted and systematic biopsies or full template mapping biopsies.

The prospective HEAT registry recently analysed over 800 men undergoing focal HIFU for localised PCa [795].
The functional data indicate low treatment-related toxicity with less than 4% decrease in pad-free incontinence
and a reduction in IIEF of 0.4 points. The low percentage of side effects was also maintained if a second round
of focal therapy was needed.

One comparative RCT was conducted in a very-low risk population, for which there is currently a strong
movement away from any form of active treatment. This study was comparing padeliporfin-based vascular-
targeted PDT vs. AS and found at a median follow-up of 24 months that less patients progressed in the PDT
arm compared with the AS arm (adjusted HR: 0.34, 95% CI: 0.24–0.46), and needed less radical therapy
(6% vs. 29%, p < 0.0001). Updated results were published in 2018 showing that these benefits were
maintained after four years [796]. Nevertheless, limitations of the study include an unusually high observed rate
of disease progression in the AS arm (58% in two years) and more patients in the AS arm chose to undergo
radical therapy without a clinical indication which may have introduced confounding bias. Finally, the AS arm
did not undergo any confirmatory biopsy or any MRI scanning, which is not representative of contemporary
practice.

In order to update the evidence base, a systematic review incorporating a narrative synthesis was performed
by the Panel, including comparative studies assessing focal ablative therapy vs. radical treatment, AS or
alternative focal ablative therapy, published between 1st January 2000 and 12th June 2020 [797]. In brief, out of
1,119 articles identified, 4 primary studies (1 RCT and 3 retrospective cohort studies) [796, 798-801] recruiting
3,961 patients, and 10 systematic reviews were included [780]. Only qualitative synthesis was possible due
to clinical heterogeneity. Comparative effectiveness data regarding focal therapy were inconclusive. Data
quality and applicability were poor due to clinical heterogeneity, RoB and confounding, lack of long-term data,
inappropriate outcome measures and poor external validity.

The impact of salvage therapies after focal therapy was investigated in smaller series [802, 803]. If a salvage
RP is necessary, the reported functional and oncological outcomes are comparable to treatment-naïve patients
[802, 803].

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The available evidence indicates that focal therapy is associated with less AEs than whole gland or radical
treatments. Robust prospective trials reporting standardised 10-year oncological outcomes [804] are needed
before unrestricted recommendations in support of focal therapy for routine clinical practice can be made
[778, 789, 804]. Currently, focal therapy using HIFU or cryotherapy should be performed within the context
of a prospective registry. All other ablative modalites should only be offered in well-designed prospective trial
setting.

6.1.6 General guidelines for the treatment of prostate cancer*

Recommendations Strength rating

No active treatment modality has shown superiority over any other active management Strong
options or deferred active treatment in terms of overall- and PCa-specific survival for
clinically localised low/intermediate-risk disease.
Offer a watchful waiting policy to asymptomatic patients with clinically localised disease Strong
and with a life expectancy < 10 years (based on co-morbidities and age).
Inform patients that all local treatments have side effects. Strong
Surgical treatment
Radical prostatectomy (RP) can be safely delayed for at least 3 months from diagnosis in Weak
any risk category.
Inform patients that no surgical approach (open-, laparoscopic- or robotic RP) has clearly Weak
shown superiority in terms of functional or oncological results.
When a lymph node dissection (LND) is deemed necessary based on a nomogram, perform Strong
an extended LND template for optimal staging.
Consider avoiding nerve-sparing surgery when there is a risk of ipsilateral extra-capsular Weak
extension (based on cT stage, ISUP grade, magnetic resonance imaging, or with this
information combined in a nomogram).
Do not offer neoadjuvant androgen deprivation therapy before surgery. Strong
Radiotherapeutic treatment
Offer intensity-modulated radiation therapy (IMRT) or volumetric arc radiation therapy Strong
(VMAT) plus image-guided radiation therapy (IGRT) for definitive treatment of PCa by
external-beam radiation therapy.
Offer moderate hypofractionation (HFX) with IMRT/VMAT plus IGRT to the prostate to Strong
patients with localised disease (60 Gy/20 fractions in 4 weeks or 70 Gy/28 fractions in
6 weeks).
Offer low-dose rate (LDR) brachytherapy monotherapy to patients with good urinary Strong
function and low-risk or NCCN favourable intermediate-risk disease.
Offer LDR or high-dose rate (HDR) brachytherapy boost combined with IMRT/VMAT plus Weak
IGRT to patients with good urinary function and NCCN unfavourable intermediate-risk or
high-risk disease and/or locally-advanced disease.
Active therapeutic options outside surgery or radiotherapy
Offer whole-gland cryotherapy and high-intensity focused ultrasound within a clinical trial Strong
setting or well-designed prospective cohort study.
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR abdomen/pelvis.

6.2 Treatment by disease stages

6.2.1 Treatment of low-risk disease
6.2.1.1 Active surveillance
The main risk for men with low-risk disease is over-treatment (see Sections 6.1.1.2 and 6.1.1.4); AS should
therefore be considered as first treatment for all such patients.

6.2.1.1.1 Active surveillance - inclusion criteria

Guidance regarding selection criteria for AS is limited by the lack of data from prospective RCTs. As a
consequence, the Panel undertook an international collaborative study involving healthcare practitioners
and patients to develop consensus statements for deferred treatment with curative intent for localised PCa,
covering all domains of AS (DETECTIVE Study) [273], as well as a formal systematic review on the various
AS protocols [805]. The criteria most often published include: ISUP grade 1, clinical stage cT1c or cT2a, PSA
< 10 ng/mL and PSA-D < 0.15 ng/mL/cc, as based on systematic biopsy schemes [483, 806]. The latter
threshold remains controversial [806, 807]. These criteria were supported by the DETECTIVE study consensus.

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There was no agreement on the maximum number of systematic cores that can be involved with cancer or the
maximum percentage core involvement (CI), although there was recognition that extensive disease on MRI
should exclude men from AS, even though there is no firm definition on this, especially when targeted biopsies
confirm ISUP grade 1 [273]. A systematic review and meta-analysis found three clinico-pathological variables
which were significantly associated with reclassification, high PSA-D, > 2 positive cores (on systematic
biopsies) and African-American descent [808]. In addition, a previous pathology consensus group suggested
excluding men from AS when any of the following features were present: predominant ductal carcinoma
(including pure intraductal carcinoma), cribriform histology, sarcomatoid carcinoma, small cell carcinoma, EPE
or LVI in needle biopsy [809] and perineural invasion [810].
Recently, a multidisciplinary consensus conference on germline testing attempted to develop a
genetic implementation framework for the management of PCa [178]. Based on consensus, BRCA2-gene
testing was recommended for AS discussions and could be performed in men with family history of prostate,
breast or ovarian cancers. However, the nature of such discussions and how a positive result influences
management were beyond the scope of the project. Currently, BRCA2 mutation does not exclude a patient
from AS if tumour factors are otherwise favourable. Furthermore, if included in AS programmes, patients with
a known BRCA2 mutation should be cautiously monitored until such time that more robust data are available.

6.2.1.1.2 Tissue-based prognostic biomarker testing for selection for active surveillance
Biomarkers, including Oncotype Dx®, Prolaris®, Decipher®, PORTOS and ProMark® are promising (see Section
5.2.8.3). However, further data will be needed before such markers can be used in standard clinical practice [221].

6.2.1.1.3 Magnetic resonance imaging for selection for active surveillance

In men eligible for AS based upon systematic biopsy findings alone who did not have a pre-biopsy MRI, a
re-biopsy within 6–12 months (usually referred to as ‘confirmatory biopsy’) seems mandatory to exclude
sampling error. A large body of literature including two RCTs showed that adding MRI-targeted biopsy to
systematic sampling at confirmatory biopsy improved detection of ISUP grade > 2 cancers and thus, patient
selection for AS [123, 811-815]. Adding MRI-targeted biopsy to systematic sampling at confirmatory biopsy
improved upgrade detection by increments of 0-7.9 per 100 men depending on the series [813]. In a meta-
analysis of 6 studies, the rate of upgrading to ISUP grade > 2 cancer increased from 20% (95% CI: 16–25%)
to 27% (95% CI: 22–34%) when MRI-targeted biopsy was added to systematic biopsy [811]. The Active
Surveillance Magnetic Resonance Imaging Study (ASIST) randomised men on AS scheduled for confirmatory
biopsy to either 12-core systematic biopsy or to MRI with targeted biopsy (when indicated), combined with
systematic biopsy (up to 12 cores in total). After 2 years of follow-up, use of MRI before confirmatory biopsy
resulted in fewer failures of surveillance (19% vs. 35%, p = 0.017) and in fewer patients progressing to ISUP
grade > 2 cancer (9.9% vs. 23%, p = 0.048) [812]. However, systematic biopsy retains its additional value,
which argues for a combined biopsy approach [811, 813]. The DETECTIVE study agreed that men eligible for
AS after combined systematic- and MRI-targeted biopsy do not require a confirmatory biopsy [273].
If the PCa diagnosis is made on MRI-targeted biopsy alone (recommended in some countries
national guidelines, e.g., the Nordic countries [816] in order to lower the risk of over-detection of insignificant
tumours) a confirmative systematic biopsy should be performed before definite decision of AS to rule out more
widespread cancer growth in the prostate.

6.2.1.1.4 Follow-up during active surveillance

Based on the DETECTIVE consensus study, the follow-up strategy should be based on serial DRE (at least
once yearly), PSA (at least once, every 6 months) and repeated biopsy. It was also agreed that PSA progression
or change in PSA kinetics alone should lead to reclassification only if accompanied by changes in histology on
repeat biopsy [273].

Yerram et al., analysed a prospectively-maintained AS cohort of 369 patients (272 with ISUP grade 1 cancer
and 97 with ISUP grade 2 cancer) who had been selected for AS after combined systematic and MRI-targeted
sampling during confirmatory biopy. At two years, systematic biopsy, MRI-targeted biopsy and combined
biopsy detected grade progression in 44 patients (15.9%), 73 patients (26.4%) and 90 patients (32.5%),
respectively. This suggests that both biopsy approaches retain added value, not only for confirmatory biopsy,
but also during AS [817].

In 2016, the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) criteria
were established to standardise the assessment of tumour progression on serial MRI [818]. Progression
on MRI, or not, as defined by PRECISE criteria, is a strong predictor of histological upgrading [819, 820].
Two independent meta-analyses assessed the value of MRI progression criteria for predicting histological
progression (mostly defined as progression to ISUP grade > 2). The pooled histological progression rate was

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27% in both reviews. If biopsies were triggered only by MRI progression findings, approximately two thirds of
the biopsies would be avoided, at the cost of missing 40% of men with histological progression. In addition,
at least half of biopsied men would have had negative findings for histological progression and thus would
have undergone unnecessary biopsies. If histological progression was restricted to progression to ISUP grade
> 3, approximately 30% of histological progression would be missed and approximately 80% of the biopsies
performed would be unnecessary. The use of the PRECISE criteria did not seem to change these results [821,
822]. This supports maintaining protocol-mandated follow-up biopsies during the course of AS.
However, several factors have been found to be associated with low re-classification rates and long
PFS: negative baseline or follow-up MRI [823-830], low PSA-D [825, 826, 828, 829], low PSA velocity [831,
832] or negative biopsy (i.e., no cancer at all) at confirmatory or follow-up biopsy [833]. In patients with stable
(PRECISE 3) follow-up MRI, a low PSA-D may be associated with a low rate of progression [834]. Using these
criteria, it might be possible, in the future, to create risk-based personalised AS biopsy schedules.

A Panel systematic review incorporating 263 surveillance protocols showed that 78.7% of protocols mandated
per-protocol confirmatory biopsies within the first 2 years and that 57.7% of the protocols performed repeat
biopsy at least every 3 years for 10 years after the start of AS [805]. In another recent review it was concluded
that a negative follow-up biopsy was associated with a 50% decrease in the risk of future reclassification and
upgrading [835]. In a single-centre AS cohort of 514 patients who underwent at least three protocol-mandated
biopsies after diagnosis (the confirmatory biopsy and at least two additional surveillance biopsies), men with
one negative biopsy (i.e., no cancer at all) at confirmatory or second biopsy, or men with two consecutive
negative biopsies had a lower likelihood of a positive third biopsy and significantly better 10-year treatment-
free survival [833]. This suggests that men with repetitive negative biopsies may pursue AS with at least less
frequent untriggered biopsies.

6.2.1.1.5 Active Surveillance - change in treatment

Men may remain on AS whilst they continue to consent, have a life expectancy of > 10 years and the disease
remains indolent. Patient anxiety about continued surveillance occurs in around 10% of patients on AS [836]
and was recognised as a valid reason for active treatment [273]. A thorough discussion on pros/cons of AS
vs. active treatment already at the time of diagnosis is therefore of outmost importance. More common is the
development of other co-morbidities which may result in a decision to transfer to a WW strategy.
A PSA change alone (including PSA-DT < 3 years) should not change management based on its
weak link with grade progression [837, 838] but rather trigger further investigation. There was clear agreement
in the DETECTIVE consensus meeting that a change in PSA should lead to repeat-MRI and repeat-biopsy.
It was also agreed that changes on follow-up MRI needed a confirmatory biopsy before considering active
treatment [273].

However, the histopathology criteria required to trigger a change in management in the targeted biopsy era
remain debated. Magnetic resonance imaging-targeted biopsy induces a grade shift and ISUP 2–3 cancers
detected by MRI-targeted biopsy have, on average, a better prognosis than those detected by systematic
sampling (see Section 5.2.4.2.6.4). As an increasing number of men with favourable intermediate-risk disease
are managed with AS (see section 6.2.2.1), it seems illogical to use progression to ISUP grade 2 based on
targeted biopsies as the sole criterion for reclassification. In addition, as acknowledged in the DETECTIVE
consensus meeting, the number of positive cores is not an indicator of tumour volume anymore if targeted
biopsies are performed [273, 839]. No agreement could be reached on the pathological criteria required to
trigger a change in management during the DETECTIVE consensus meeting [273]. However, based on the
findings of a systematic review incorporating 271 reclassification protocols, patients with low-volume ISUP 2
disease at recruitment, and with increased systematic core positivity (> 3 cores involvement [> 50% per core])
on repeat systematic biopsies not using MRI, should be reclassified [805].

6.2.1.2 Alternatives to active surveillance

In terms of alternatives to AS in the management of patients with low-risk disease there is some data from
randomised studies. In the PIVOT trial (Section 6.1.1) which compared surgery vs. observation, only 42%
of patients had low-risk disease [497]. Sub-group analysis revealed that for low-risk disease there was no
statistically significant difference in all-cause mortality between surgery vs. observation (RR: 0.93, 95%
CI: 0.78–1.11). In the ProtecT study (Section 6.1.1) which compared the far less organised follow-up of active
monitoring (PSA follow-up only) vs. surgery vs. EBRT, 56% of patients had low-risk disease [485]. However, no
sub-group analysis on disease risk was performed on this population. The study found no difference between
the three arms in terms of OS and CSS, but AM had higher metastatic progression compared with surgery or
EBRT (6.0% vs. 2.6%). There are no robust data comparing contemporary AS protocols with either surgery or
EBRT in patients with low-risk disease. Active surveillance should be considered SOC in patients with low-risk

78 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

disease and a life expectancy > 10 years. Surgery and EBRT should only be considered as alternatives to AS in
patients suitable for such treatments after thorough information on pros and cons of AS and active treatment,
and who after such information refuse or for some other reason are deemed unfit for AS, and who accept a
trade-off between toxicity and prevention of disease progression.
Other treatments such as whole-gland ablative therapy (f.i., cryotherapy or HIFU) or focal ablative
therapy remain unproven in the setting of localised low-risk disease compared with AS or radical treatment
options and should not be used outside a trial setting or well-designed prospective cohort setting. These
treatments are discussed in detail in Section 6.1.5.

6.2.1.2.1 Androgen deprivation monotherapy

Data regarding the use of ADT monotherapy in men with low-risk localised disease may be inferred indirectly
from the Early Prostate Cancer (EPC) Trial Programme which published its findings in 2006 [840]. The EPC
programme comprises three large RCTs including 8,113 men with localised (cT1–2, N0/NxM0) or locally-
advanced (cT3–4, any N; or any T, N+, M0) PCa. The intervention was oral bicalutamide 150 mg monotherapy
vs. placebo following standard care (defined as RP, radical EBRT or WW). The primary endpoints were PFS and
OS. Patients were stratified according to clinical stage only; data regarding PSA and Gleason score were not
assessed. The authors found in patients with localised disease, ADT monotherapy did not improve PFS nor
OS in any of the subgroups, compared with placebo. Instead, there was a statistically insignificant numerical
trend towards worse OS with ADT in the WW sub-group (HR: 1.16, 95% CI: 0.99–1.37; p = 0.07). Although the
trial did not directly address men with low-risk disease, it offered some evidence suggesting that otherwise
asymptomatic men with localised disease should not receive ADT monotherapy. Currently, there is no evidence
supporting the use of ADT monotherapy in asymptomatic men with low-risk disease who are not eligible for
any local/radical treatment; these men should simply be offered WW alone.

Other treatments such as whole-gland ablative therapy (f.i., cryotherapy or HIFU) or focal ablative therapy
remain unproven in the setting of localised low-risk disease compared with AS or radical treatment options;
these have been discussed in detail in Section 6.1.5.

6.2.1.3 Summary of evidence and guidelines for follow-up during active surveillance

Summary of evidence LE
Serial magnetic resonance imaging can improve the detection of aggressive cancers during follow-up. 3
A progression on MRI mandates a repeat biopsy before a change in treatment strategy.
A stationary MRI does not make repeat biopsy superfluous.

Recommendations Strength rating

Base follow-up during active surveillance (AS) on a strict protocol including digital rectal Strong
examination (at least once yearly), prostate-specific antigen (PSA) (at least once every
6 months) and repeated biopsy every 2 to 3 years.
Perform magnetic resonance imaging (MRI) and repeat biopsy if PSA is rising (PSA-doubling Strong
time < 3 years).
Re-classify patients with low-volume ISUP grade group 2 disease included in AS protocols, Weak
if repeat non-MRI-based systematic biopsies performed during monitoring reveal > 3
positive cores or maximum CI > 50%/core of ISUP 2 disease.
Base change in treatment on biopsy progression, not on progression on MRI and/or PSA. Weak
Patients with a PI-RADS 1-2 findings on MRI and a low PSA density (< 0.15) may be Weak
excepted from repeat biopsy.

6.2.1.4 Summary of evidence and guidelines for the management of low-risk disease*

Summary of evidence LE
Active surveillance or WW is SOC, based on life expectancy. 2a
All active treatment options present a risk of over-treatment. 1a

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Recommendations Strength rating
Watchful Waiting
Manage patients with a life expectancy < 10 years by watchful waiting. Strong
Active surveillance (AS)
Manage patients with a life expectancy > 10 years and low-risk disease by AS. Strong
Selection of patients
Patients with intraductal histology on biopsy should be excluded from AS. Strong
Perform magnetic resonance imaging (MRI) before a confirmatory biopsy if no MRI has been Strong
performed before the initial biopsy.
Take both targeted biopsy (of any PI-RADS > 3 lesion) and systematic biopsy if a Strong
confirmatory biopsy is performed.
If MRI is not available, per-protocol confirmatory prostate biopsies should be performed. Weak
If a patient has had upfront MRI followed by systematic and targeted biopsies there is no Weak
need for confirmatory biopsies.
Follow-up of patients
Repeat biopsies should be performed at least once every 3 years for 10 years. Weak
In case of prostate-specific antigen progression or change in digital-rectal examination or Strong
MRI findings, do not progress to active treatment without a repeat biopsy.
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR abdomen/pelvis.

6.2.2 Treatment of intermediate-risk disease

When managed with non-curative intent, intermediate-risk PCa is associated with 10-year and 15-year PCSM
rates of 13.0% and 19.6%, respectively [841]. These estimates are based on systematic biopsies and may be
overestimated in the era of MRI-targeted biopsies.

6.2.2.1 Active Surveillance

In the ProtecT trial, where 34% of the randomised patients had intermediate- or high-risk disease, there was no
statistically significant difference in CSS at 10 years [485]. In the comprehensive characterisation of the patients in
the ProtecT trial, treatment received, PSA, ISUP grade at diagnosis, cT stage, risk group, number of PCa-involved
biopsy cores, maximum length of tumour (median 5.0 vs. 3.0 mm), aggregate length of tumour (median 8.0 vs.
4.0 mm), and presence of perineural invasion were each associated with increased risk of disease progression
(p < 0.001 for each). However, these factors could not reliably predict progression in individuals [483].
The outcomes of AS in intermediate-risk PCa has also been analysed in two recent systematic
reviews and meta-analyses, summarising available data on its oncological outcomes and comparing patients
with intermediate-risk PCa to patients with low-risk disease [842, 843]. The definition of AS was not strictly
defined in either of the reviews: instead the search strategies included ‘active surveillance’ as a search
term, and no a priori study protocol was available. The primary outcome was the proportion of patients who
remained on AS, whilst secondary outcomes included CSS, OS, and metastasis-free survival in both studies.
In the first review 17 studies were included, incorporating 6,591 patients with intermediate-
risk disease. Sixteen studies included patients with low- and intermediate-risk disease, hence enabling
comparative outcome assessment via pooled analysis. Only one study performed MRI at recruitment and
follow-up. There was significant clinical heterogeneity in terms of inclusion criteria for intermediate-risk
disease. The results showed the proportion of patients who remained on AS was comparable between the
low- and intermediate-risk groups after 10 and 15 years’ follow-up (OR: 0.97, 95% CI: 0.83–1.14; and OR:
0.86, 95% CI: 0.65–1.13, respectively). Cancer-specific survival was worse in the intermediate-risk group after
10 years (OR: 0.47, 95% CI: 0.31–0.69) and 15 years (OR: 0.34, 95% CI: 0.2–0.58). Overall survival was not
statistically significantly different at 5 years’ follow-up (OR: 0.84, 95% CI: 0.45–1.57) but was significantly worse
in the intermediate-risk group after 10 years (OR: 0.43, 95% CI: 0.35–0.53). Metastases-free survival did not
significantly differ after 5 years (OR: 0.55, 95% CI: 0.2–1.53) but was worse in the intermediate-risk group after
10 years (OR: 0.46, 95% CI: 0.28–0.77).
The slightly more recent review, including 25 studies and a total of 29,673 low- or intermediate-risk
patients, showed similar results in terms of treatment-free survival at 10 years (RR: 1.16, 95% CI: 0.99-1.36),
risk of developing metastases (RR: 5.79, 95% CI: 4.61-7.29), risk of dying from PCa (RR: 3.93, 95% CI: 2.93-
5.27) and risk of dying from any cause (RR: 1.44, 95% CI: 1.11-1.86).
In a subgroup analyses of four studies comparing outcomes of patients with intermediate- and
low-risk PCa of ISUP < 2 (n = 1,900) no statistically significant difference could be found in terms of treatment-
free survival or risk of developing metastases (RR: 1.03, 95% CI: 0.62-1.71 and RR: 2.09, 95% CI: 0.75-5.82,
respectively). Both reviews indicate that AS in unselected intermediate-risk patients implies a higher risk
of progression over time. It remains unclear whether this difference only reflects the inborne difference in
outcome, that can also be seen when comparing immediate treatment of low- and intermediate-risk PCa, or

80 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

if the delay in treatment caused any worsenening of the outcomes in the intermediate-risk group in any way.
Both reviews conclude that AS could be offered to patients with intermediate-risk disease, but they should be
informed of a higher risk of progression and the latter study suggests limiting the inclusion of intermediate-risk
patients to those with low-volume ISUP 2 disease.
A Canadian consensus group proposes that low volume ISUP grade 2 (< 10% Gleason pattern
4 on systematic biopsies) may also be considered for AS. These recommendations have been endorsed
by the American Society of Clinical Oncology (ASCO) [338] and the DETECTIVE study consensus [273] for
those patients with a PSA < 10 ng/mL and low core positivity. The DETECTIVE Study concluded that men
with favourable ISUP 2 cancer (PSA < 10 ng/mL, low density, clinical stage < cT2a and a low number of
positive systematic cores) should also be considered for deferred treatment [273]. In this setting, re-biopsy
within 6 to 12 months to exclude sampling error is even more relevant than in low-risk disease [806, 844]. The
DETECTIVE Study-related qualitative systematic review aimed to determine appropriate criteria for inclusion of
intermediate-risk disease into AS protocols [805]. Out of 371 AS protocols included in the review, more than
50% included patients with intermediate-risk disease on the basis of PSA up to 20 ng/mL (25.3%), ISUP 2 or 3
(27.7%), clinical stage cT2b/c (41.6%) and/or direct use of D’Amico risk grouping of intermediate risk or above
(51.1%). The DETECTIVE study reached consensus that patients with ISUP 3, or patients with intraductal or
cribriform histology, should not be considered for AS. The presence of any grade 4 pattern is associated with
a 3-fold increased risk of metastases compared to ISUP grade 1, while a PSA up to 20 ng/mL might be an
acceptable threshold [844-846], especially in the context of low PSA-D. In addition, it is likely that MRI and
targeted biopsies will detect small foci of Gleason grade 4 cancer that might have been missed with systematic
biopsy. Therefore, care must be taken when explaining this treatment strategy, especially to patients with the
longest life expectancy.
There are no clear concensus on how to interpret MRI and targeted biopsies for AS but the
DETECTIVE study concensus was that if targeted biopsies based upon mpMRI images are performed, the
number of positive cores of the targeted biopsies are not an indicator of the extent of disease or tumour
volume. Indicator of the tumour volume may be either the number of positive cores, and the length of cancer in
each core, based on systematic biopsies, or the volume of the dominant lesion seen on mpMRI [273].
In summary, AS can be considered in patients with low-volume ISUP 2 (defined as < 3 positive
systematic cores and < 50% core involvement) or another single element of intermediate-risk disease (i.e.
favourable intermediate-risk disease). Patients with ISUP 3 disease, or patients with intraductal or cribriform
histology, should be excluded. The monitoring schedule should be diligent, given the potential higher risk of
progression, development of regional or distant metastases and death of this group compared with patients
with low-risk disease. During monitoring, if repeat non-MRI-based systematic biopsies reveal > 3 positive cores
or maximum CI > 50%/core of ISUP 2 disease, patients should be reclassified (i.e., actively treated).

6.2.2.2 Radical prostatectomy

Patients with intermediate-risk PCa should be informed about the results of two RCTs (SPCG-4 and PIVOT)
comparing RRP vs. WW in localised PCa. In the SPCG-4 study, death from any cause (RR: 0.71, 95%
CI: 0.53–0.95), death from PCa (RR: 0.38, 95% CI: 0.23–0.62) and distant metastases (RR: 0.49, 95%
CI: 0.32–0.74) were significantly reduced in intermediate-risk PCa at 18 years. In the PIVOT trial, according
to a pre-planned subgroup analysis among men with intermediate-risk tumours, RP significantly reduced
all-cause mortality (HR: 0.69, 95% CI: 0.49–0.98), but not death from PCa (0.50, 95% CI: 0.21–1.21) at
10 years. A meta-analysis based on the findings of SPCG-4, PIVOT and ProtecT demonstrated a benefit
from RP over observation with a significantly decreased risk of death of 9% and of disease progression of
43% [847]. However, no stratification by disease stages was performed. The risk of having positive LNs in
intermediate-risk PCa is between 3.7–20.1% [848]. An ePLND should be considered in intermediate-risk
PCa if the estimated risk for pN+ exceeds 5% [400] or 7% if using the nomogram by Gandaglia et al., which
incorporates MRI-guided biopsies [364]. However, preliminary data show a high NPV (96%) for LN-positivity
when using PSMA PET for staging (See Section 6.1.2.3.2). In all other cases ePLND can be omitted, which
means accepting a low risk of missing positive nodes. Nerve sparing surgery is discussed in Section 6.1.2.3.5.

6.2.2.3 Radiation therapy

6.2.2.3.1 Recommended IMRT/VMAT for intermediate-risk PCa
Patients suitable for ADT can be given combined IMRT/VMAT with short-term ADT (4–6 months) [849-851]. For
adjuvant RT of the pelvic lymphatics (45-50 Gy) for NCCN unfavourable intermediate risk (cN0) see Section
6.2.3.2.1 - Radiotherapy for localised high-risk PCa. For patients unsuitable (e.g., due to co-morbidities) or
unwilling to accept ADT (e.g., to preserve their sexual health) the recommended treatment is IMRT/VMAT
(76–78 Gy or equivalent moderate HFX) or a combination of IMRT/VMAT and brachytherapy as described
below (see Section 6.2.2.3.2). A secondary analysis of the PCS III trial has suggested that patients with NCCN
favourable intermediate-risk disease (see Section 4.4) can safely omit ADT if their RT dose is 76 Gy, but this is
based on an unplanned subgroup analysis and only 138 patients had favourable intermediate-risk disease. An

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individual discussion between the physician and the patient of the possible benefits and harms of omitting ADT in
this group is essential [852]. In the absence of higher quality data, SOC will remain short-term ADT + IMRT/VMAT.

6.2.2.3.2 Brachytherapy for intermediate-risk PCa

Systematic review recommends LDR brachytherapy monotherapy can be offered to patients with NCCN
favourable intermediate-risk disease and good urinary function (see Section 4.4) [853]. Fractionated HDR
brachytherapy as monotherapy can be offered to selected patients with intermediate-risk PCa although they
should be informed that results are only available from small series in very experienced centres. Five-year
PSA control rates over 90% are reported, with late grade 3+ GU toxicity rates < 5% and no, or very minimal,
grade 3+ GI toxicity rates [723]. There are no direct data to inform on the use of ADT in this setting. Trimodality
therapy with IMRT plus brachytherapy boost and short-term ADT can be considered for NCCN unfavourable
intermediate-risk PCa (see Section 4.4) but patients should be made aware that the potential improvements in
biochemical control are accompanied with an increased risk of long-term urinary problems [714, 715, 719].

6.2.2.4 Other options for the primary treatment of intermediate-risk PCa (experimental therapies)
6.2.2.4.1 Focal therapy
A prospective study on focal therapy using HIFU in patients with localised intermediate-risk disease was
published but the data was derived from an uncontrolled single-arm case series [789]. There is a paucity of
high-certainty data for either whole-gland or focal ablative therapy in the setting of intermediate-risk disease.
Consequently, neither whole-gland ablative treatment nor focal treatment can be considered as standard
therapy for intermediate-risk patients and, if offered, it should only be in the setting of clinical trials or
prospective registries [778].

6.2.2.4.2 Androgen deprivation therapy monotherapy

Data regarding the use of ADT monotherapy for intermediate-risk disease have been inferred indirectly from
the EORTC 30891 trial, which was a RCT comparing deferred ADT vs. immediate ADT in 985 patients with
T0–4 N0–2 M0 disease [848]. The trial showed a small, but statistically significant, difference in OS in favour of
immediate ADT monotherapy but there was no significant difference in CSS, predominantly because the risk of
cancer-specific mortality was low in patients with PSA < 8 ng/mL. Consequently, the use of ADT monotherapy
for this group of patients is not considered as standard, even if they are not eligible for radical treatment.

6.2.2.5 Guidelines for the treatment of intermediate-risk disease*

Recommendations Strength rating

Watchful Waiting (WW)
Offer WW in asymptomatic patients with life expectancy < 10 years. Strong
Active surveillance (AS)
Offer AS to highly selected patients with ISUP grade group 2 disease (i.e. < 10% pattern Weak
4, PSA < 10 ng/mL, < cT2a, low disease extent on imaging and low biopsy extent [defined
as < 3 positive cores and cancer involvement < 50% core involvement [CI]/per core]), or
another single element of intermediate-risk disease with low disease extent on imaging and
low biopsy extent, accepting the potential increased risk of metastatic progression.
Patients with ISUP grade group 3 disease should be excluded from AS protocols. Strong
Re-classify patients with low-volume ISUP grade group 2 disease included in AS protocols, Weak
if repeat non-MRI-based systematic biopsies performed during monitoring reveal > 3
positive cores or maximum CI > 50%/core of ISUP 2 disease.
Radical prostatectomy (RP)
Offer RP to patients with a life expectancy of > 10 years. Strong
Radical prostatectomy can be safely delayed for at least 3 months. Weak
Offer nerve-sparing surgery to patients with a low risk of extra-capsular disease on that side. Strong
Extended pelvic lymph node dissection (ePLND)
Perform an ePLND based on predicted risk of lymph node invasion (validated nomogram, Weak
see Section 6.1.2.3.2.)
Radiotherapeutic treatment
Offer low-dose rate (LDR) brachytherapy to patients with good urinary function and NCCN Strong
favourable intermediate-risk disease.
Offer intensity-modulated radiotherapy (IMRT)/volumetric modulated arc therapy (VMAT) Strong
plus image-guided radiotherapy (IGRT), with a total dose of 76–78 Gy or moderate
hypofractionation (60 Gy/20 fx in 4 weeks or 70 Gy/28 fx in 6 weeks), in combination with
short-term androgen deprivation therapy (ADT) (4–6 months).

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Offer LDR brachytherapy boost combined with IMRT/VMAT plus IGRT to patients with good Weak
urinary function and NCCN unfavourable intermediate-risk disease, in combination with
short-term ADT (4–6 months).
Offer high-dose rate (HDR) brachytherapy boost combined with IMRT/VMAT plus IGRT to Weak
patients with good urinary function and NCCN unfavourable intermediate-risk disease, in
combination with short-term ADT (4–6 months).
Other therapeutic options
Only offer whole-gland ablative therapy (such as cryotherapy, high-intensity focused Strong
ultrasound, etc.) or focal ablative therapy within clinical trials or registries.
Do not offer ADT monotherapy to asymptomatic men not able to receive any local Weak
treatment.
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR abdomen/pelvis.

6.2.3 Treatment of high-risk localised disease

Patients with high-risk PCa are at an increased risk of PSA failure, need for secondary therapy, metastatic
progression and death from PCa. Nevertheless, not all high-risk PCa patients have a uniformly poor prognosis
after RP [854]. When managed with non-curative intent, high-risk PCa is associated with 10-year and 15-year
PCSM rates of 28.8 and 35.5%, respectively [855]. There is no consensus regarding the optimal treatment of
men with high-risk PCa.
Some evidence suggests that radical treatment for high-risk PCa can be delayed up to 3 months
after the diagnosis without any oncological consequences [516, 856]. Systematic reviews suggest that there
is a higher risk of biochemical recurrence and worse pathological outcomes when definitive treatment is given
beyond a 6 to 9 months delay. However, there is no conclusive data regarding stronger endpoints (CSS or OS).

6.2.3.1 Radical prostatectomy

Provided that the tumour is not fixed to the pelvic wall or there is no invasion of the urethral sphincter, RP is
a standard option in selected patients with a low tumour volume. Extended PLND should be performed in all
high-risk PCa cases [400, 401]. Patients should be aware pre-operatively that surgery may be part of multi-
modal treatment, with adjuvant or SRT or ADT. Neoadjuvant therapy using ADT with or without new generation
HT or docetaxel is not indicated. (See Section 6.1.2.2.4) [511, 513]. Nerve sparing management is discussed in
Section 6.1.2.3.5.

6.2.3.1.1 ISUP grade 4–5

The incidence of organ-confined disease is 26–31% in men with an ISUP grade > 4 on systematic biopsy. A
high rate of downgrading exists between the biopsy ISUP grade and the ISUP grade of the resected specimen
[855]. Several retrospective case series have demonstrated CSS rates over 60% at 15 years after RP in the
context of a multi-modal approach (adjuvant or salvage ADT and/or RT) in patients with a biopsy ISUP grade 5
[441, 519, 857, 858].

6.2.3.1.2 Prostate-specific antigen > 20 ng/mL

Reports in patients with a PSA > 20 ng/mL who underwent surgery as initial therapy within a multi-modal
approach demonstrated a CSS at 15 years of over 70% [441, 519, 525, 859-861].

6.2.3.1.3 Radical prostatectomy in cN0 patients with pathologically confirmed LN invasion (pN1)
At 15 years follow-up cN0 patients who undergo RP but who were found to have pN1 were reported to have
an overall CSS and OS of 45% and 42%, respectively [862-867]. A systematic review has reported 10-year
BCR-free, CSS, and OS rates ranging from 28% to 56%, 72% to 98%, and 60% to 87.6%, respectively, in pN1
patients [868]. These findings highlight that pN1 patients represent a very heterogeneous patient group and
further treatment must be individualised based on risk factors (see Sections 6.2.5.2 and 6.2.5.6).

6.2.3.2 External beam radiation therapy

For high-risk localised PCa, a combined modality approach should be used consisting of IMRT/VMAT plus
long-term ADT. The duration of ADT has to take into account PS, co-morbidities and the number of poor
prognostic factors. It is important to recognise that in several studies EBRT plus short-term ADT did not
improve OS in high-risk localised PCa and long-term ADT (at least 2 to 3 years) is currently recommended for
these patients [676, 677, 687]. Moderate HFX is an option in selected high-risk patients with localised disease.
The CHHiP study included 12% high-risk patients (n = 386) but limited entry to those with a PSA < 30 ng/mL
and a Roach formula risk of SV involvement < 30% [661]. Patients were ineligible if they had both T3a tumours
and ISUP grade 4 or higher.

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6.2.3.2.1 Lymph node irradiation in cN0
There is no clear evidence for prophylactic irradiation of the pelvic LNs in intermediate- and high-risk disease.
The long-term results of the NRG/RTOG 9413-trial which randomised intermediate-risk and high-risk localised
PCa patients (1,322 cN0 patients were enrolled), showed that neoadjuvant HT plus whole pelvic RT improved
PFS only compared with neoadjuvant ADT plus prostate RT and whole pelvic RT plus adjuvant ADT [869].
However, at the increased risk of > grade 3 GI-toxicity.
A well-conducted single-centre RCT randomised 224 patients comparing prostate-only RT (PORT)
vs. whole pelvic RT (WPRT) in localised high-risk- and locally-advanced tumours (cN0) with a risk of > 20% of
positive nodes (Roach formula). With a median follow-up of 68 months there was a significant improvement of
distant metastasis-free survival (95.9% vs. 89.2%, HR: 0.35, p = 0.01) and DFS (89.5% vs.77.2%, p = 0.02).
However, there was a significant higher rate of late GU > 2 effects (17.7% vs. 7.5%, p = 0.02), the trial was
relatively small in size with additional limitations and these findings are therefore insufficient to define a change
in practice [870, 871]. The benefits of pelvic nodal irradiation using IMRT/VMAT merit further investigation in
large scale RCTs as conducted by the RTOG or the UK National Cancer Research Institute (NCRI).

6.2.3.2.2 Brachytherapy boost

In men with NCCN unfavourable intermediate- or high-risk PCa, brachytherapy boost with supplemental EBRT
and HT may be considered. See Sections 6.1.3.4.1 and 6.1.3.4.2 for details on RCTs comparing EBRT alone
and EBRT with LDR or HDR boost, respectively.

6.2.3.3 Options other than surgery or radiotherapy for the primary treatment of localised PCa
Currently there is a lack of evidence supporting any other treatment option apart from RP and radical RT in
localised high-risk PCa. The use of ADT monotherapy was addressed by the EORTC 30891 trial [848] (see
Section 6.2.4.4.2). Immediate ADT may only benefit patients with a PSA-DT < 12 months, and either a PSA
> 50 ng/mL or a poorly-differentiated tumour [848, 872].

6.2.3.4 Guidelines for radical and palliative treatment of high-risk localised disease*

Recommendations Strength rating

Watchful Waiting (WW)
Offer WW to asymptomatic patients with life expectancy < 10 years. Strong
Radical prostatectomy (RP)
Radical prostatectomy can be safely delayed for at least 3 months. Weak
Offer RP to selected patients as part of potential multi-modal therapy. Strong
Extended pelvic lymph node dissection (ePLND)
Perform an ePLND in high-risk PCa. Strong
Do not perform a frozen section of nodes during RP to decide whether to proceed with, or Strong
abandon, the procedure (see Section 6.2.4.1).
Radiotherapeutic treatment
Offer patients intensity-modulated radiation therapy (IMRT)/volumetric modulated arc therapy Strong
(VMAT) plus image-guided radiation therapy (IGRT) with 76–78 Gy in combination with long-
term androgen deprivation therapy (ADT) (2 to 3 years).
Offer patients with good urinary function IMRT/VMAT plus IGRT with brachytherapy boost Weak
(either high-dose rate or low-dose rate), in combination with long-term ADT (2 to 3 years).
Therapeutic options outside surgery or radiotherapy
Do not offer either whole gland or focal therapy. Strong
Only offer ADT monotherapy to those patients unwilling or unable to receive any form of Strong
local treatment if they have a prostate-specific antigen (PSA)-doubling time < 12 months,
and either a PSA > 50 ng/mL or a poorly-differentiated tumour.
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR abdomen/pelvis.

6.2.4 Treatment of locally-advanced PCa

In the absence of high-level evidence, a recent systematic review could not define the most optimal treatment
option [873]. Randomised controlled trials are only available for EBRT. A local treatment combined with a
systemic treatment provides the best outcome, provided the patient is fit enough to receive both. The initial
results of the SCPG-15 trials suggested that randomisation between surgery and EBRT is feasible, but
oncologic outcomes are awaited [874].

84 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

6.2.4.1 Radical prostatectomy
Surgery for locally-advanced disease as part of a multi-modal therapy has been reported [855, 875, 876].
However, the comparative oncological effectiveness of RP as part of a multi-modal treatment strategy vs. upfront
EBRT with ADT for locally-advanced PCa remains unknown, although a prospective phase III RCT (SPCG-15)
comparing RP (with or without adjuvant or salvage EBRT) against primary EBRT and ADT among patients with
locally-advanced (T3) disease is currently recruiting [877]. Data from retrospective case series demonstrated over
60% CSS at 15 years and over 75% OS at 10 years [855, 875, 876, 878-881]. For cT3b–T4 disease, PCa cohort
studies showed 10-year CSS of over 87% and OS of 65% [882, 883]. The indication for RP in all previously
described stages assumes the absence of clinically detectable nodal involvement (cN0), based on conventional
imaging. In case of suspected positive LNs during RP (initially considered cN0) the procedure should not be
abandoned since RP may have a survival benefit in these patients. Intra-operative frozen section analysis is not
justified in this case [580]. An ePLND is considered standard if a RP is planned.

6.2.4.2 Radiotherapy for locally-advanced PCa

In locally-advanced disease RCTs have clearly established that the additional use of long-term ADT combined
with RT produces better OS than ADT or RT alone (see Section 6.1.3.1.4 and Tables 6.1.9 and 6.1.10) [873].
See Sections 6.1.3.4.1 and 6.1.3.4.2 for LDR and HDR brachytherapy boost in T3N0M0 PCa.

6.2.4.3 Treatment of cN1 M0 PCa

Lymph-node metastasised PCa is where options for local therapy and systemic therapies overlap.
Approximately 5% to 10% of newly diagnosed PCa patients have synchronous suspected pelvic nodal
metastases on conventional imaging (CT/bone scan) without bone or visceral metastases (cN1 M0 stage).
Meta-analyses have shown that PSMA-PET/CT prior to primary treatment in advanced PCa detected disease
outside the prostate in 32% of cases despite prior negative conventional imaging using bone scan and pelvic
CT/MRI [416]. A RCT assessing PSMA-PET/CT as staging tool in high-risk PCa confirmed these findings and
showed a 32% increase in accuracy compared with conventional imaging for the detection of pelvic nodal
metastases [433]. Notably, more sensitive imaging also causes a stage shift with more cases classified as cN1,
but with, on average, lower nodal disease burden.

The management of cN1M0 PCa is historically based on long-term ADT combined with a local treatment.
The benefit of adding local treatment has been assessed in various retrospective studies, summarised in one
systematic review [884] including 5 studies only [885-889]. The findings suggested an advantage in both OS
and CSS after local treatment (RT or RP) combined with ADT as compared to ADT alone. The main limitations
of this analysis were the lack of randomisation, of comparisons between RP and RT, as well as the value of the
extent of PLND and of RT fields. Only limited evidence exists supporting RP for cN1 patients. Moschini et al.,
compared the outcomes of 50 patients with cN+ with those of 252 patients with pN1, but cN0 at pre-operative
staging. cN+ was not a significant predictor of CSS [890].
Based on the consistent benefit seen in retrospective studies including cN1 patients, local therapy
is recommended in patients with cN1 disease at diagnosis in addition to long-term ADT (see Table 6.2.4.1).

The addition of a brachytherapy boost to ADT plus EBRT was not associated with improved OS in a
retrospective study of 1,650 cN1 patients after multivariable adjustment and propensity score matching [891].

The intensification of systemic treatment (abiraterone acetate, docetaxel, zoledronic acid) has been assessed
in unplanned sub-group analyses from the STAMPEDE multi-arm RCT by stratifying for cN1 and M1 status
[888, 892]. The analyses were balanced for nodal involvement and for planned RT use in STAMPEDE at
randomisation and at analysis. Abiraterone acetate was associated with a non-significant OS improvement
(HR: 0.75, 95% CI: 0.48–1.18) in non-metastatic patients (N0/N+M0), but OS data were still immature with a
low number of events. Furthermore, this was an underpowered subgroup analysis and hypothesis generating
at best. Moreover, subgroup analyses were performed according to the metastatic/non-metastatic status and
to the nodal status (any M) without specific data for the N1M0 population (n = 369; 20% of the overall cohort).
The same would apply for the docetaxel arm in the STAMPEDE trial for which no specific subgroup analysis
of newly diagnosed N1M0 PCa (n = 171, 14% of the overall cohort) was performed. However, the addition of
docetaxel, zoledronic acid, or their combination, did not provide any OS benefit when stratifying by M0 and N+
status.

In the AFU-GETUG 12 trial comparing the impact of docetaxel plus estramustine in addition to ADT, 29%
of included high-risk non-metastatic PCa patients had a nodal involvement (pN1) at randomisation [893]. A
non-significant trend towards better relapse-free survival rates was reported in the treatment arm (HR 0.66;

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 85

0.43–1.01) without OS benefit. A meta-analysis of docetaxel trials in N0/N1-M0 patients concluded to an 8%
4-year survival advantage for docetaxel compared with ADT alone in terms of failure-free survival without OS
benefit [894].

Two RCTs from the STAMPEDE platform protocol reported on men with de novo high-risk/locally-advanced
M0 disease, or relapse after primary curative therapy with high-risk features. Thirty-nine percent of patients
(n = 774) were N1 on conventional imaging [895]. Radiotherapy in addition to long-term ADT was administered
in 71% of these patients. Given the MFS and OS benefits observed in the overall population (see Section
6.2.4.2), combined ADT (for 3 years) and additional abiraterone (for 2 years) should be a SOC in cN1 patients in
addition to prostate- and whole pelvic RT.

Table 6.2.4.1: Selected studies assessing local treatment in (any cT) cN1 M0 prostate cancer patients

Study n Design Study period/ Treatment Effect on survival

follow-up arms
Bryant, et al. 648 Retrospective 2000-2015 ADT ± EBRT Significant benefit for
2018 [896] (National combined treatment only
Veterans Affairs) 61 mo. if PSA levels less than the
median (26 ng/mL)
All-cause mortality HR: 0.50
CSS, HR: 0.38
Sarkar, et al. 741 Retrospective 2000-2015 ADT ± local Significant benefit for RP
2019 [897] (National treatment All cause mortality HR 0.36
Veterans Affairs) 51 mo. (surgery or RT) CSS, HR: 0.32

No statistical difference for

RP vs. RT (p > 0.1)
All-cause mortality HR: 047
CSS, HR: 0.88
Lin, et al. 983 before Retrospective 2004-2006 ADT ± EBRT Significant benefit for
2015 [886] propensity (NCDB) combined treatment
score 48 mo. 5-yr OS: 73% vs. 52%
matching HR: 0.5
Tward, et al. 1,100 Retrospective 1988-2006 EBRT Significant benefit for EBRT
2013 [885] (SEER) (n = 397) vs. 5-yr CSS 78% vs. 71%
64 mo. no EBRT HR: 0.66
(n = 703) 5-yr. OS: 68% vs. 56%,
No information HR: 0.70
on ADT)
Rusthoven, 796 Retrospective 1995-2005 EBRT vs. no Significant benefit for EBRT
et al. 2014 [889] (SEER) EBRT (no 10-yr OS: 45% vs. 29%
61 mo. information on HR: 0.58
ADT)
Seisen, et al. 1,987 Retrospective 2003-2011 ADT ± local Significant benefit for
2018 [887] (NCDB) treatment combined treatment
50 mo. (surgery or RT) 5-yr OS: 78.8% vs. 49.2%
HR: 0.31
No difference between RP
and RT
James, et al. 177 Unplanned sub- 2005-2014 ADT ± EBRT Significant benefit for
2016 [888] group analysis combined treatment
RCT 17 mo. 5-yr OS: 93% vs. 71%
2-yr FFS: 81% vs 53%
FFS, HR: 0.48
ADT = androgen deprivation therapy; CSS = cancer-specific survival; EBRT = external beam radiotherapy;
FFS = failure-free survival; HR = hazard ratio; mo = months; n = number of patients; OS = overall survival;
RP = radical prostatectomy; RT = radiotherapy; yr = year.

86 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

6.2.4.4 Options other than surgery or radiotherapy for primary treatment
6.2.4.4.1 Investigational therapies
Currently cryotherapy, HIFU or focal therapies have no place in the management of locally-advanced PCa.

6.2.4.4.2 Androgen deprivation therapy monotherapy

The deferred use of ADT as single treatment modality has been answered by the EORTC 30891 trial [848].
Nine hundred and eighty-five patients with T0–4 N0–2 M0 PCa received ADT alone, either immediately or after
symptomatic progression or occurrence of serious complications. After a median follow-up of 12.8 years, the
OS favoured immediate treatment (HR: 1.21, 95% CI: 1.05–1.39). Surprisingly, no different disease-free or
symptom-free survival was observed, raising the question of survival benefit. In locally-advanced T3–T4 M0
HSPC unsuitable for surgery or RT, immediate ADT may only benefit patients with a PSA > 50 ng/mL and a
PSA-DT < 12 months or those that are symptomatic [848, 872]. The median time to start deferred treatment
was 7 years. In the deferred treatment arm 25.6% of patients died without needing treatment.

6.2.4.5 Guidelines for radical- and palliative treatment of locally-advanced disease*

Recommendations Strength rating

Radical prostatectomy (RP)
Offer RP to patients with cN0 disease as part of multi-modal therapy. Weak
Extended pelvic lymph node dissection (ePLND)
Perform an ePLND. Strong
Radiotherapeutic treatments
Offer patients with cN0 disease intensity-modulated radiation therapy (IMRT)/volumetric Strong
modulated arc therapy (VMAT) plus image-guide radiation therapy in combination with
long-term androgen deprivation therapy (ADT).
Offer patients with cN0 disease and good urinary function, IMRT/VMAT plus IGRT with Weak
brachytherapy boost (either high-dose rate or low-dose rate), in combination with long-term
ADT.
Offer long-term ADT for at least 2 years. Strong
Offer IMRT/VMAT plus IGRT to the prostate in combination with long-term ADT and 2 years Strong
of abiraterone to cN0M0 patients with > 2 high-risk factors (cT3-4, Gleason > 8 or PSA > 40
ng/mL).
Offer IMRT/VMAT plus IGRT to the prostate plus pelvis in combination with long-term ADT Strong
and 2 years of abiraterone to cN1M0 patients.
Offer patients with cN1 disease a local treatment (either RP or IMRT/VMAT plus IGRT) plus Strong
long-term ADT.
Therapeutic options outside surgery or radiotherapy
Do not offer whole gland treatment or focal treatment. Strong
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR abdomen/pelvis.

6.2.5 Adjuvant treatment after radical prostatectomy

6.2.5.1 Introduction
Adjuvant treatment is by definition additional to the primary or initial therapy with the aim of decreasing the risk
of relapse, despite the apparent full control following surgery. A post-operative detectable PSA is an indication
of persistent prostate cells (see Section 6.2.6). All information listed below refers to patients with a post-
operative undetectable PSA.

6.2.5.2 Risk factors for relapse

Patients with ISUP grade > 2 in combination with EPE (pT3a) and particularly those with SV invasion (pT3b)
and/or positive surgical margins are at high risk of progression, which can be as high as 50% after 5 years
[898]. Irrespective of the pT stage, the number of removed nodes [899-906], tumour volume within the LNs and
capsular perforation of the nodal metastases are predictors of early recurrence after RP for pN1 disease [907].
A LN density (defined as ‘the percentage of positive LNs in relation to the total number of analysed/removed
LNs’) of over 20% was found to be associated with poor prognosis [908]. The number of involved nodes seems
to be a major factor for predicting relapse [901, 902, 909]; the threshold considered is less than 3 positive
nodes from an ePLND [536, 901, 909]. However, prospective data are needed before defining a definitive
threshold value.

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6.2.5.2.1 Biomarker-based risk stratification after radical prostatectomy
The Decipher® gene signature consists of a 22-gene panel representing multiple biological pathways and was
developed to predict systemic progression after definitive treatment. A meta-analysis of five studies analysed
the performance of the Decipher® Genomic Classifier (GC) test on men post-RP. The authors showed in
multivariable analysis that Decipher® GC remained a statistically significant predictor of metastasis (HR: 1.30,
95% CI: 1.14–1.47, p < 0.001) per 0.1 unit increase in score and concluded that it can independently improve
prognostication of patients post-RP within nearly all clinicopathologic, demographic, and treatment subgroups
[910]. A systematic review of the evidence for the Decipher® GC has confirmed the clinical utility of this test in
post-RP decision-making [911]. Further studies are needed to establish how to best incorporate Decipher® GC
in clinical decision-making.

6.2.5.3 Immediate (adjuvant) post-operative external irradiation after RP (cN0 or pN0)

Four prospective RCTs have assessed the role of immediate post-operative RT (adjuvant RT [ART])
(undetectable PSA mostly defined as PSA < 0.1 ng/mL), demonstrating an advantage (endpoint, development
of BCR) in high-risk patients (e.g., pT2 with positive surgical margins and ISUP 3–5 or pT3/4 with- or without
positive surgical margins and ISUP 3–5) post-RP (Table 6.2.5.1). In the ARO 96-02 trial, 80% of the pT3/R1/GS
8–10 patients randomised to observation developed BCR within 10 years [912]. It must be emphasised that PSA
was undetectable at inclusion only in the ARO 96-02 trial which presents a major limitation interpreting these
findings as patients with a detectable PSA would now be considered for salvage therapy rather than ART [912].

Table 6.2.5.1: O
 verview of all four randomised trials for adjuvant surgical bed radiation therapy after RP*
(without ADT)

Study n Inclusion Randomisation Definition of Median Biochemical Overall

criteria BCR PSA (ng/ FU (mo) Progression- survival
mL) free survival
SWOG 8794 431 pT3 cN0 ± 60-64 Gy vs. > 0.4 152 10 yr.: 53% vs. 10 yr.:
2009 [913] involved SM observation 30% 74% vs.
(p < 0.05) 66%
Median
time:
15.2 vs.
13.3 yr.,
p = 0.023
EORTC 1,005 pT3 ± 60 Gy vs. > 0.2 127 10 yr.: 60.6% 81% vs.
22911 2012 involved SM observation vs. 41% 77% n.s.
[914] pN0 pT2 (p < 0.001)
involved SM
pN0
ARO 96-02 388 pT3 (± 60 Gy vs. > 0.05 + 112 10 yr.: 56% vs. 10 yr.:
2014 [912] involved SM) observation confirmation 35% 82% vs.
pN0 PSA (p = 0.0001) 86% n.s.
post-RP
undetectable
FinnProstate 250 pT2,R1/ 66.6 Gy vs. > 0.4 (in 2 112 vs. 10 yr.: 82% vs. 10 yr.:
Group 2019 pT3a observation successive 103 61% 92% vs.
[915] (+ SRT) measurements) (patients p < 0.001 87% n.s.
alive)
*See Section 6.3.5.1 for delayed (salvage) post-radical prostatectomy external irradiation.
BCR = biochemical recurrence; FU = follow-up; mo = months; n = number of patients; n.s. = not significant;
OS = overall survival; PSA = prostate-specific antigen; RP = radical prostatectomy; SM = surgical margin;
SRT = salvage radiotherapy.

6.2.5.4 Comparison of adjuvant- and salvage radiotherapy

Two retrospective matched studies (510 and 149 patients receiving ART) failed to show an advantage for
metastasis-free survival [916, 917]. However, both studies were underpowered for high-risk patients (pT3b/R1/ISUP
grade 4–5 PCa). In contrast to these studies, a propensity score-matched retrospective analysis of two cohorts of
366 pT3 and/or R1 patients found that compared to SRT at a PSA between 0.1 and 0.5 ng/mL, ART given at
an undetectable PSA (< 0.1 ng/mL) improved all three endpoints; BCR, metastasis-free survival, and OS [918].

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Both approaches (ART and early SRT) together with the efficacy of adjuvant ADT are compared in
three prospective RCTs: the Medical Research Council (MRC) Radiotherapy and Androgen Deprivation
In Combination After Local Surgery (RADICALS) trial [919], the Trans-Tasman Oncology Group (TROG)
Radiotherapy Adjuvant Versus Early Salvage (RAVES) trial [920], and the Groupe d’Etude des Tumeurs Uro-
Genitales (GETUG-AFU 17) trial [921]. In addition, a pre-planned meta-analysis of all three trials has been
published (Table 6.2.5.2) [922].

Two trials closed early after randomising 333/470 patients (RAVES) and 424/718 (GETUG-AFU-17) patients.
RADICALS-RT included 1,396 patients with the option of subsequent inclusion in RADICALS-HT; 154/649
(24%) of patients starting in the adjuvant RT group also received neoadjuvant or adjuvant HT; 90 patients
for 6 months/45 for 2 years/19 patients outside RADICALS-HT. From the SRT group, 61/228 (27%) received
neoadjuvant or adjuvant HT for 6 months (n = 33) and 2 years (n = 13). Fifteen of these patients were treated
outside the trial [919]. All men in the GETUG-AFU-17 trial (n = 424) received 6 months of HT. All together, 684
out of 2,153 patients received additional ADT for at least 6 months across both trials [922]. Radiotherapy to the
pelvic lymphatics was allowed in the GETUG-AFU and in the RADICALS-RT trials.
The primary endpoint for RAVES and GETUG-AFU 17 was biochemical PFS, and for RADICALS-
RT metastasis-free survival. So far only PFS data has been reported, and not metastasis-free survival- or OS
data. With a median follow-up between 4.9 years and 6.25 years there was no statistically significant difference
for biochemical PFS for both treatments in all three trials (see Table 6.2.5.2) indicating that in the majority of
patients adjuvant irradiation should be avoided. Additionally, there was a significant lower rate of grade > 2 GU
late side effects and grade 3–4 urethral strictures in favour of early SRT; which may also be caused by the low
number of patients with PSA-progression and subsequent need for early SRT at the time of analysis (40% of
patients).

It is important to note that the indication for ART changed over the last ten years with the introduction of
ultra-sensitive PSA-tests, favouring early SRT. Therefore many patients, randomised in these 3 trials (accruing
2006–2008) are not likely to benefit from ART as there is a low risk of biochemical progression (~20–30%) in,
for example, pT3R0 or pT2R1-tumours. The median pre-SRT PSA in all 3 trials was 0.24 ng/mL. Therefore,
patients with ‘low-risk factors’ of biochemical progression after RP should be closely followed up with ultra-
sensitive assays and SRT should be discussed, if needed, as soon as PSA starts to rise, which has to be
confirmed by a second PSA measurement (see Section 6.3). The proportion of patients with adverse pathology
at RP (ISUP grade group 4–5 and pT3 with or without positive margins) in all 3 trials was low (between 10–20%)
and therefore even the meta-analysis may be underpowered to show an outcome in favour of SRT [922]. In
addition, the side-effect profile may have been impacted with a larger proportion of ART patients receiving
treatment with older 3D-treatment planning techniques as compared to SRT patients (GETUG-AFU 17: ART,
69% 3D vs. 46% SRT) and patients treated more recently were more likely to undergo IMRT techniques with a
proven lower rate of late side effects [634].

For these reasons, 10-year OS and metastasis-free survival endpoints results should be awaited before
drawing final conclusions. Due to the small number of patients with adverse pathology (ISUP grade group
4–5 and pT3) included in these 3 trials (between 10–20%), ART remains a recommended treatment option in
highly selected patients with adverse pathology (‘high-risk patients’) i.e. ISUP grade group 4–5 and pT3 with
or without positive margins [923, 924]. This recommendation was supported by a published retrospective
multi-centre study comparing ART and SRT in patients with high-risk features (pN1 or ISUP 4–5 and pT3/4-
tumours) after RP [925]. After a median follow-up of 8.2 years of the 26,118 men included in the study, 2,104
patients died, 25.62% from PCa (n = 539) and 2,424 patients had adverse pathology compared with 23,694
who did not. After excluding men with persistent PSA after RP, ART when compared with early SRT showed a
significantly lower acute mortality risk (p = 0.02, HR: 0.33).

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Table 6.2.5.2: O
 verview of all three randomised trials and one meta-analysis for patients treated with
adjuvant vs. early salvage RT after RP

Study n Inclusion Randomisation Definition of Median BPFS OS Side effects

criteria BCR PSA FU (yr) or
(ng/mL) MFS
RAVES 333 pT3a/pT3b 64 Gy ART PSA: > 0.4 post 6.1 5 yr.: n.r. LT grade
TROG 08.03/ target any T - SM+ < 0.1 ng/mL vs. RT 86% vs. > GU:
ANZUP was PSA post- 64 Gy early SRT 87% 70% vs.
2020 [920] 470 RP: at PSA (p > 0.05) 54%
early < 0.1 ng/mL > 0.2 ng/mL (p = 0.002)
closed med. pre-SRT: n.r.
RADICALS- 1,396 pT3a/ 52.5 Gy (20 Fx) > 0.4 or 2 at 4.9 5 yr.: n.r. SR urinary
RT pT3b/pT4 or 66 Gy (33 Fx) any time 85% vs. incontinence
2020 [919] PSA ART 88% 1 yr: 4.8 vs.
> 10 ng/mL early SRT (p = 0.56) 4 (p = 0.023)
pre-RP identical urethral
any T, SM+ at PSA > 0.1 stricture
Gleason med.pre-SRT: grade 3/4
7-10 0.2 ng/mL 2 yr:
PSA post-RP: 6% vs. 4%
< 0.2 ng/mL (p = 0.02)
GETUG-AFU 424 pT3a/pT3b/ 66 Gy (ART) vs. > 0.4 6.25 5 yr: n.r. LT grade > 2
17 target pT4a and 66 Gy early SRT 92% vs. GU 27% vs.
2020 [921] was SM + PSA at PSA 0.1 90% 7%
718 post-RP: both groups: (p = 0.42) (p < 0.001)
early < 0.1 ng/mL 6 mo. LHRH-A ED: 28% vs.
closed med. pre-SRT 8%
0.24 (p < 0.001)
ARTISTIC- 2,153 see above see above see above 4.5 5 yr.: n.r. n.r.
Meta-analysis 89% vs.
2020 [922] 88%
p = 0.7
ART = adjuvant radiotherapy; BCR = biochemical recurrence; BPFS = biochemical progression-free survival;
ED = erectile dysfunction; FU = follow-up; Fx = fraction; GU = genito-urinary; LHRH = luteinising hormone-
releasing hormone; LT = late toxicity; mo = months; med = median; MFS = metastasis-free survival; n.r. = not
reported; OS = overall survival; PSA = prostate-specific antigen; RP = radical prostatectomy; RT = radiotherapy;
SR = self reported; SRT = salvage radiotherapy; + = positive; yr = year.

6.2.5.5 Adjuvant systemic therapy in N0 disease

Adjuvant androgen ablation with bicalutamide 150 mg daily did not improve PFS in localised disease while it
did for locally-advanced disease after RT. However, this never translated to an OS benefit [926]. A systematic
review showed a possible benefit for PFS but not OS for adjuvant androgen ablation [511].

The TAX3501 trial comparing the role of leuprolide (18 months) with and without docetaxel (6 cycles) ended
prematurely due to poor accrual. A phase III RCT comparing adjuvant docetaxel against surveillance after
RP for locally-advanced PCa showed that adjuvant docetaxel did not confer any oncological benefit [927].
Consequently, adjuvant chemotherapy after RP should only be considered in a clinical trial [928].

6.2.5.6 Adjuvant treatment in pN1 disease

6.2.5.6.1 Adjuvant androgen ablation alone
The combination of RP and early adjuvant HT in pN+ PCa has been shown to achieve a 10-year CSS rate of
80% and has been shown to significantly improve CSS and OS in prospective RCTs [929, 930]. However, these
trials included mostly patients with high-volume nodal disease and multiple adverse tumour characteristics and
these findings may not apply to men with less extensive nodal metastases.

6.2.5.6.2 Adjuvant radiotherapy combined with ADT in pN1 disease

In a retrospective multi-centre cohort study, maximal local control with RT to the prostatic fossa appeared to
be beneficial in PCa patients with pN1 after RP, treated ‘adjuvantly‘ with continuous ADT (within 6 months after

90 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

surgery irrespective of PSA). The beneficial impact of adjuvant RT on survival in patients with pN1 PCa was
highly influenced by tumour characteristics. Men with low-volume nodal disease (< 3 LNs), ISUP grade 2–5
and pT3–4 or R1, as well as men with 3 to 4 positive nodes were more likely to benefit from RT after surgery,
while the other subgroups did not [931]. In contrast, a recent retrospective multi-centre study including 1,614
patients and a median follow-up of 7,02 years assessed ART + ADT. Adjuvant RT compared to SRT was
associated with a decreased all-cause mortality and this reduction increased with each additional positive
pelvic LN, from the first one on and the highest effect was for more than 3 positive nodes [932]. These data are
in agreement with a US National Cancer Database analysis based on 5,498 patients [933]. Another US National
Cancer Database study including 8,074 pN1 patients reports improved OS after ADT plus EBRT (including
pelvic LNs) vs. observation and vs. ADT alone in all men with single or multiple adverse pathological features.
Men without any adverse pathological features did not benefit from immediate adjuvant therapy [934].
In a systematic review of the literature, RT with or without ADT was associated with improved
survival in men with locally-advanced disease and a higher number of positive nodes [868]. Radiotherapy to the
pelvic lymphatics and the prostate fossa plus long-term ADT can be offered to patients with pN1 disease [931,
935]. However, the optimal duration of ADT is still unkown.

6.2.5.6.3 Observation of pN1 patients after radical prostatectomy and extended lymph node dissection
Several retrospective studies and a systematic review addressed the management of patients with pN1 PCa
at RP [868, 909, 931, 935, 936]. A subset of patients with limited nodal disease (1–2 positive LNs) showed
favourable oncological outcomes and did not require additional treatment.

An analysis of 209 pN1 patients with one or two positive LNs at RP showed that 37% remained metastasis-
free without need of salvage treatment at a median follow-up of 60.2 months [936]. Touijer et al., reported
their results of 369 pN1-positive patients (40 with and 329 without adjuvant treatment) and showed that higher
pathologic grade group and > 3 positive LNs were significantly associated with an increased risk of BCR
on multivariable analysis [909]. Biochemical-free survival rates in pN1 patients without adjuvant treatment
ranged from 43% at 4 years to 28% at 10 years [868]. Reported CSS rates were 78% at 5 years and 72% at
10 years. The majority of these patients were managed with initial observation after surgery, had favourable
disease characteristics, and 63% had only one positive node [868]. Initial observation followed by early
salvage treatment at the time of recurrence may represent a safe option in selected patients with a low disease
burden [868].

6.2.5.7 Guidelines for adjuvant treatment for pN0 and pN1 disease after radical prostatectomy*

Recommendations Strength rating

Do not prescribe adjuvant androgen deprivation therapy (ADT) to pN0 patients. Strong
In pN0 patients with ISUP grade group 4–5 and pT3 ± positive margins, offer adjuvant Strong
intensity-modulated radiation therapy (IMRT)/volumetric modulated arc therapy (VMAT) plus
image-guided radiation therapy (IGRT).
In pN1 patients, after an extended lymph node dissection, discuss three management Weak
options, based on nodal involvement characteristics:
1. Offer adjuvant ADT;
2. Offer adjuvant ADT with additional IMRT/VMAT plus IGRT;
 ffer observation (expectant management) to a patient after eLND and < 2 nodes and a
3. O
PSA < 0.1 ng/mL.
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR abdomen/pelvis.

6.2.6 Persistent PSA after radical prostatectomy

Between 5 and 20% of men continue to have detectable or persistent PSA after RP (when defined in the
majority of studies as detectable post-RP PSA of > 0.1 ng/mL within 4 to 8 weeks of surgery) [937, 938]. It may
result from persistent local disease, pre-existing metastases or residual benign prostate tissue.

6.2.6.1 Natural history of persistently elevated PSA after RP

Several studies have shown that persistent PSA after RP is associated with more advanced disease (such as
positive surgical margins, pathologic stage > T3a, positive nodal status and/or pathologic ISUP grade > 3) and
poor prognosis. Initially defined as > 0.1 ng/mL, improvements in the sensitivity of PSA assays now allow for
the detection of PSA at much lower levels.
Moreira et al., demonstrated that failure to achieve a PSA of less than 0.03 ng/mL within 6 months
of surgery was associated with an increased risk of BCR and overall mortality [939, 940]. However, since the

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 91

majority of the published literature is based on the 0.1 ng/mL PSA cut-off, there is significantly more long-
term data for this definition. Predictors of PSA persistence were higher BMI, higher pre-operative PSA and
ISUP grade > 3 [940]. In patients with PSA persistence, one and 5-year BCR-free survival were 68% and 36%,
compared to 95% and 72%, respectively, in men without PSA persistence [939]. Ten-year OS in patients with
and without PSA persistence was 63% and 80%, respectively.
Spratt et al., confirmed that a persistently detectable PSA after RP represents one of the worst
prognostic factors associated with oncological outcome [941]. Of 150 patients with a persistent PSA, 95%
received RT before detectable metastasis. In a multivariable analysis the presence of a persistently detectable
PSA post-RP was associated with a 4-fold increase in the risk of developing metastasis. This was confirmed
by data from Preisser et al., who showed that persistent PSA is prognostic of an increased risk of metastasis
and death [942]. At 15 years after RP, metastasis-free survival rates, OS and CSS rates were 53.0 vs. 93.2%
(p < 0.001), 64.7 vs. 81.2% (p < 0.001) and 75.5 vs. 96.2% (p < 0.001) for persistent vs. undetectable PSA,
respectively. The median follow-up was 61.8 months for patients with undetectable PSA vs. 46.4 months
for patients with persistent PSA. In multivariable Cox regression models, persistent PSA represented an
independent predictor for metastasis (HR: 3.59, p < 0.001), death (HR: 1.86, p < 0.001) and cancer-specific
death (HR: 3.15, p < 0.001).
However, not all patients with persistent PSA after RP experience disease recurrence. Xiang et al.,
showed a 50% 5-year BCR-free survival in men who had a persistent PSA level > 0.1 but < 0.2 ng/mL at
6–8 weeks after RP [943].

Rogers et al., assessed the clinical outcome of 160 men with a persistently detectable PSA level after RP [944].
No patient received adjuvant therapy before documented metastasis. In their study, 38% of patients had no
evidence of metastases for > 7 years while 32% of the patients were reported to develop metastases within
3 years. Noteworthy is that a significant proportion of patients had low-risk disease. In multivariable analysis
the PSA slope after RP (as calculated using PSA levels 3 to 12 months after surgery) and pathological ISUP
grade were significantly associated with the development of distant metastases.

6.2.6.2 Imaging in patients with persistently elevated PSA after RP

Standard imaging with bone scan and MRI has a low detection rate in men with a PSA below 2 ng/mL.
However, PSMA PET/CT has been shown to identify residual cancer with positivity rates of 33%, 46%, 57%,
82%, and 97%, in men with post-RP PSA ranges of 0–0.19, 0.2–0.49, 0.5–0.99, 1–1.99, and > 2 ng/mL,
respectively [945-950] which can guide SRT planning [951]. Based on these post-RP PSA ranges, Schmidt-
Hegemann et al., studied 129 patients who had either persistent PSA (52%) or BCR (48%) after RP, showing
that men with a persistent PSA had significantly more pelvic nodal involvement on PSMA PET/CT than those
developing a detectable PSA [952]. In a multi-centre retrospective study including 191 patients, 68Ga-PSM
localised biochemical persistence after RP in more than two-thirds of patients with high-risk PCa features.
The obturator and presacral/mesorectal nodes were identified as high risk for residual disease [953]. Another
retrospective study included 150 patients with persistent PSA after RARP who were re-staged with both
68Ga-PSMA and 18F-DCFPyL PSMA. The authors found that in the presence of persistent PSA the majority of

patients already had metastatic pelvic LNs or distant metastases which would support a role of PSMA PET/
CT imaging in guiding (salvage) treatment strategies [954]. At present there is uncertainty regarding the best
treatment if PSMA PET/CT shows metastatic disease outside the pelvis.

6.2.6.3 Impact of post-operative RT and/or ADT in patients with persistent PSA

The benefit of SRT in patients with persistent PSA remains unclear due to a lack of RCTs, however, it would
appear that men with a persistent PSA do less well than men with BCR undergoing RT.

Preisser et al., compared oncological outcomes of patients with persistent PSA who received SRT vs. those
who did not [942]. In the subgroup of patients with persistent PSA, after 1:1 propensity score matching
between patients with SRT vs. no RT, OS rates at 10 years after RP were 86.6 vs. 72.6% in the entire cohort
(p < 0.01), 86.3 vs. 60.0% in patients with positive surgical margin (p = 0.02), 77.8 vs. 49.0% in pT3b disease
(p < 0.001), 79.3 vs. 55.8% in ISUP grade 1 disease (p < 0.01) and 87.4 vs. 50.5% in pN1 disease (p < 0.01),
respectively. Moreover, CSS rates at 10 years after RP were 93.7 vs. 81.6% in the entire cohort (p < 0.01), 90.8
vs. 69.7% in patients with positive surgical margin (p = 0.04), 82.7 vs. 55.3% in pT3b disease (p < 0.01), 85.4
vs. 69.7% in ISUP grade 1 disease (p < 0.01) and 96.2 vs. 55.8% in pN1 disease (p < 0.01), for SRT vs. no RT,
respectively. In multivariable models, after 1:1 propensity score matching, SRT was associated with lower risk
of death (HR: 0.42, p = 0.02) and lower cancer-specific death (HR: 0.29, p = 0.03). These survival outcomes in
patients with persistent PSA who underwent SRT suggest they benefit but outcomes are worse than for men
experiencing BCR [955].

92 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

It is clear from a number of studies that poor outcomes are driven by the level of pre-RT PSA, the presence of
ISUP grade > 4 in the RP histology and pT3b disease [956-961]. Fossati et al., suggested that only men with
a persistent PSA after RP and ISUP grade < 3 benefit significantly [962], although this is not supported by
Preisser et al. [942]. The current data do not allow making any clear treatment decisions.

Addition of ADT may improve PFS [957]. Choo et al., studied the addition of 2-year ADT to immediate RT to
the prostate bed in patients with pT3 and/or positive surgical margins after RP [957]. Twenty-nine of the 78
included patients had persistently detectable post-operative PSA. The relapse-free rate was 85% at 5 years
and 68% at 7 years, which was superior to the 5-year progression-free estimates of 74% and 61% in the
post-operative RT arms of the EORTC and the SWOG studies, respectively, which included patients with
undetectable PSA after RP [913, 914]. Patients with persistently detectable post-operative PSA comprised
approximately 50% and 12%, respectively, of the study cohorts in the EORTC and the SWOG studies.
In the ARO 96-02, a prospective RCT, 74 patients with PSA persistence (20%) received immediate
SRT only (66 Gy per protocol [arm C]). The 10-year clinical relapse-free survival was 63% [956]. The GETUG-22
trial comparing RT with RT plus short-term ADT for post-RP PSA persistence (0.2–2.0 ng/mL) reported good
tolerability of the combined treatment. The oncological endpoints are yet to be published [963].

Two systematic reviews addressing persistent PSA confirmed a strong correlation of PSA persistence with poor
oncologic outcomes [937, 938]. Ploussard et al., also reported that SRT was associated with improved survival
outcomes, although the available evidence is of low quality [938].

6.2.6.4 Conclusion
The available data suggest that patients with PSA persistence after RP may benefit from early aggressive
multimodality treatment, however, the lack of prospective RCTs makes firm recommendations difficult.

6.2.6.5 Recommendations for the management of persistent PSA after radical prostatectomy

Recommendations Strength rating

Offer a prostate-specific membrane antigen (PSMA) positron emission tomography/ Weak
computed tomography (PET/CT scan to men with a persistent prostate-specific antigen
> 0.2 ng/mL if the results will influence subsequent treatment decisions.
Treat men with no evidence of metastatic disease with salvage radiotherapy and additional Weak
hormonal therapy.

6.3 Management of PSA-only recurrence after treatment with curative intent

Follow-up will be addressed in Chapter 7 and is not discussed in this section.

6.3.1 Background
Between 27% and 53% of all patients undergoing RP or RT develop a rising PSA (PSA recurrence). Whilst
a rising PSA level universally precedes metastatic progression, physicians must inform the patient that the
natural history of PSA-only recurrence may be prolonged and that a measurable PSA may not necessarily
lead to clinically apparent metastatic disease. Physicians treating patients with PSA-only recurrence face a
difficult set of decisions in attempting to delay the onset of metastatic disease and death while avoiding over-
treating patients whose disease may never affect their OS or QoL. It should be emphasised that the treatment
recommendations for these patients should be given after discussion in a multidisciplinary team.

6.3.1.1 PSA velocity and doubling time

Various PSA kinetics definitions have been proposed with different methods of calculation (log transformed or
not) and eligible PSAs:
• PSA velocity (PSAV): absolute annual increase in serum PSA (ng/mL/year);
• PSA doubling time (PSA-DT): which measures the exponential increase in serum PSA over time.

Prostate-specific antigen velocity is more simple to calculate by subtracting the initial value from the final value,
dividing by time. However, by ignoring middle values, not all PSA values are accurately taken into account.

Prostate-specific antigen-DT is calculated assuming an exponential rise in serum PSA. The formula takes into
account the natural logarithm of 2 divided by the slope obtained from fitting a linear regression of the natural
log of PSA over time [964]. However, many different PSA-DT calculations have been assessed according to the
mathematical formula used and to the included PSA values (number, time period, intervals) [965]. For example,

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the ‘MSKCC’ method calculates a regression slope integrating all PSA values. Other methods transform
PSA before calculating the slope and do not include all PSA values (different time frames and minimal
intervals) [966]. O’Brien and colleagues identified more than 20 different definitions of PSAV and PSA-DT and
demonstrated that obtained values could vary widely between definitions [966].

However, some rules can be considered for PSA-DT calculation [964]:

• At least 3 PSA measurements are required;
• A minimum time period between measurements (4 weeks) is preferable due to potential statistical ‘noise’
when PSA values are obtained too close together (this statement can be reconsidered in case of very
active disease);
• All included PSA values should be obtained within the past 12 months at most, to reflect the current
disease activity;
• PSA-DT is often mentioned in months, or in weeks in very active disease.

These measurements do not provide additional information compared with PSA alone [966-969]. In the post-
local therapy relapse setting, PSA-DT has been correlated with distant progression and with poorer outcomes
after salvage treatments [970, 971]. Prostate-specific antigen-DT has been linked with metastasis-free- and OS
in non-metastatic CRPC (nmCRPC) and identifies patients with high-risk nmCRPC who benefit from intensified
therapy (PSA-DT threshold < 10 months) [972].

6.3.2 Controversies in the definitions of clinically relevant PSA relapse

The PSA level that defines treatment failure depends on the primary treatment. Patients with rising PSA
after RP or primary RT have different risks of subsequent symptomatic metastatic disease based on various
parameters, including the PSA level. Therefore, physicians should carefully interpret BCR endpoints when
comparing treatments. Clinicians should interpret a PSA rise in light of the EAU BCR risk groups (see Section
6.3.3).

After RP, the threshold that best predicts further metastases is a PSA > 0.4 ng/mL and rising [973-975].
However, with access to ultra-sensitive PSA testing, a rising PSA much below this level will be a cause for
concern for patients.
After primary RT, with or without short-term hormonal manipulation, the RTOG-ASTRO Phoenix
Consensus Conference definition of PSA failure (with an accuracy of > 80% for clinical failure) is ‘any PSA
increase > 2 ng/mL higher than the PSA nadir value, regardless of the serum concentration of the nadir’ [976].
After HIFU or cryotherapy no endpoints have been validated against clinical progression or
survival; therefore, it is not possible to give a firm recommendation of an acceptable PSA threshold after these
alternative local treatments [977].

6.3.3 Natural history of biochemical recurrence

Once a PSA recurrence has been diagnosed, it is important to determine whether the recurrence has
developed at local or distant sites. A systematic review and meta-analysis investigated the impact of BCR
on hard endpoints and concluded that patients experiencing BCR are at an increased risk of developing
distant metastases, PCa-specific and overall mortality [977]. However, the effect size of BCR as a risk factor
for mortality is highly variable. After primary RP its impact ranges from HR 1.03 (95% CI: 1.004–1.06) to HR
2.32 (95% CI: 1.45–3.71) [978, 979]. After primary RT, OS rates are approximately 20% lower at 8 to 10 years
follow-up even in men with minimal co-morbidity [980, 981]. Still, the variability in reported effect sizes of BCR
remains high and suggests that only certain patient subgroups with BCR might be at an increased risk of
mortality.
The risk of subsequent metastases, PCa-specific- and overall mortality may be predicted by the
initial clinical and pathologic factors (e.g., T-category, PSA, ISUP grade) and PSA kinetics (PSA-DT and interval
to PSA failure), which was further investigated by the systematic review [977].

For patients with BCR after RP, the following outcomes were found to be associated with significant prognostic
factors:
• distant metastatic recurrence: positive surgical margins, high RP specimen pathological ISUP grade, high
pT category, short PSA-DT, high pre-SRT PSA;
• prostate-cancer-specific mortality: high RP specimen pathological ISUP grade, short interval to
biochemical failure as defined by investigators, short PSA-DT;
• overall mortality: high RP specimen pathological ISUP grade, short interval to biochemical failure, high
PSA-DT.

94 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

For patients with BCR after RT, the corresponding outcomes are:
• distant metastatic recurrence: high biopsy ISUP grade, high cT category, short interval to biochemical
failure;
• prostate-cancer-specific mortality: short interval to biochemical failure;
• overall mortality: high age, high biopsy ISUP grade, short interval to biochemical failure, high initial (pre-
treatment) PSA.

Based on this meta-analysis, proposal is to stratify patients into two risk categories since not all patients with
BCR will have similar outcomes (see Table 6.3.1). The stratification into ‘EAU Low-Risk’ or ‘EAU High-Risk’
BCR has recently been validated in a European cohort [982].

Table 6.3.1: EAU risk categories for biochemical recurrence

EAU Low Risk EAU High Risk

After RP PSA-DT > 1 year PSA-DT < 1 year
AND OR
pathological ISUP grade < 4 pathological ISUP grade 4–5
After RT interval to biochemical failure > 18 months interval to biochemical failure < 18 months
AND OR
biopsy ISUP grade < 4 biopsy ISUP grade 4–5

6.3.4 The role of imaging in PSA-only recurrence

Imaging is only of value if it leads to a treatment change which results in an improved outcome. In practice,
however, there are very limited data available regarding the outcomes consequent on imaging at recurrence.

6.3.4.1 Assessment of metastases (including nodal)

6.3.4.1.1 Bone scan and abdominopelvic CT
Because BCR after RP or RT precedes clinical metastases by 7 to 8 years on average [903, 983], the diagnostic
yield of conventional imaging techniques (bone scan and abdominopelvic CT) is low in asymptomatic patients
[984]. In men with PSA-only recurrence after RP the probability of a positive bone scan is < 5%, when the
PSA level is < 7 ng/mL [985, 986]. Only 11–14% of patients with BCR after RP have a positive CT [985]. In a
series of 132 men with BCR after RP the mean PSA level and PSA velocity associated with a positive CT were
27.4 ng/mL and 1.8 ng/mL/month, respectively [987].

6.3.4.1.2 Choline PET/CT

In two different meta-analyses the combined sensitivities and specificities of choline PET/CT for all sites of
recurrence in patients with BCR were 86–89% and 89–93%, respectively [988, 989].
Choline PET/CT may detect multiple bone metastases in patients showing a single metastasis on
bone scan [990] and may be positive for bone metastases in up to 15% of patients with BCR after RP and
negative bone scan [991]. The specificity of choline PET/CT is also higher than bone scan, with fewer false-
positive and indeterminate findings [420]. Detection of LN metastases using choline PET/CT remains limited
by the relatively poor sensitivity of the technique (see Section 5.3.2.3). Choline PET/CT sensitivity is strongly
dependent on the PSA level and kinetics [429, 992, 993]. In patients with BCR after RP, PET/CT detection
rates are only 5–24% when the PSA level is < 1 ng/mL but rises to 67–100% when the PSA level is > 5 ng/mL.
Despite its limitations, choline PET/CT may change medical management in 18–48% of patients with BCR after
primary treatment [994-996].
Choline PET/CT should only be recommended in patients fit enough for curative loco-regional
salvage treatment.

6.3.4.1.3 Fluoride PET/CT

18F-NaF PET/CT has a higher sensitivity than bone scan in detecting bone metastases [997]. However,
18F -NaF PET/CT is limited by a relative lack of specificity and by the fact that it does not assess soft-tissue

metastases [998].

6.3.4.1.4 Fluciclovine PET/CT

18F-Fluciclovine PET/CT has been approved in the U.S. and Europe and it is therefore one of the PCa-specific
radiotracers widely commercially available [999-1001].
18F-Fluciclovine PET/CT has a slightly higher sensitivity than choline PET/CT in detecting the site of

relapse in BCR [1002]. In a multi-centre trial evaluating 596 patients with BCR in a mixed population fluciclovine

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 95

PET/CT showed an overall detection rate of 67.7%; lesions could be visualised either at local level (38.7%) or
in LNs and bones (9%) [1003]. As for choline PET/CT, fluciclovine PET/CT sensitivity is dependent on the PSA
level, with a sensitivity likely inferior to 50% at PSA < 1 ng/mL.
In a prospective RCT evaluating the impact of 18F-fluciclovine PET/CT on SRT management
decisions in patients with recurrence post-prostatectomy, in 28 of 79 (35.4%) patients overall radiotherapeutic
management changed following 18F-fluciclovine PET/CT [1004]. 18F-Fluciclovine PET/CT had a significantly
higher positivity rate than conventional imaging (abdominopelvic CT or MRI plus bone scan) for whole body
(79.7% vs. 13.9%, p < 0.001), prostate bed (69.6% vs. 5.1%, p < 0.001), and pelvic LNs (38.0% vs. 10.1%,
p < 0.001) [1004]. However, as yet, no data demonstrating that these changes translate into a survival benefit
are available.

6.3.4.1.5 Prostate-specific membrane antigen based PET/CT

PSMA PET/CT has shown good potential in patients with BCR, although most studies are limited by their
retrospective design. Reported predictors of 68Ga-PSMA PET in the recurrence setting were recently updated
based on a high-volume series (see Table 6.3.2) [945]. High sensitivity (75%) and specificity (99%) were
observed on per-lesion analysis.

Table 6.3.2: PSMA-positivity separated by PSA level category [945]

PSA (ng/mL) 68Ga-PMSA PET positivity

< 0.2 33% (CI: 16–51)
02–0.49 45% (CI: 39–52)
0.5–0.99 59% (CI: 50–68)
1.0–1.99 75% (CI: 66–84)
2.0+ 95% (CI: 92–97)
PSA = prostate-specific antigen; 68Ga-PSMA PET = Gallium-68 prostate-specific membrane antigen positron
emission tomography.

PSMA PET/CT seems substantially more sensitive than choline PET/CT, especially for PSA levels < 1 ng/mL
[1005, 1006]. In a study of 314 patients with BCR after treatment and a median PSA level of 0.83 ng/mL,
68Ga-PSMA PET/CT was positive in 197 patients (67%) [1007]. In another prospective multi-centre trial

including 635 patients with BCR after RP (41%), RT (27%), or both (32%), PPV for 68Ga-PSMA PET/CT was
0.84 (95% CI: 0.75–0.90) by histopathologic validation (primary endpoint, n = 87) and 0.92 (95% CI: 0.75–0.90)
by a composite reference standard. Detection rates significantly increased with PSA value [1008].

A prospective multi-centre, multi-reader, open-label, phase II/III trial (OSPREY) evaluated the diagnostic
performance of 18F-DCFPyL in patients with presumptive radiologic evidence of recurrent or metastatic PCa
on conventional imaging [415]. Median sensitivity and median PPV were 95.8% (95% CI: 87.8%–99.0%) and
81.9% (95% CI: 73.7%–90.2%), respectively.
Another prospective study evaluated the diagnostic performance of 18F-DCFPyL in 208 men with
BCR after RP or RT. The primary endpoint, the correct localisation rate was achieved, demonstrating positive
findings on 18F-DCFPyL PET/CT in the setting of negative standard imaging [1009]. At present there are no
conclusive data about comparison of such tracers [1010].

6.3.4.1.6 Whole-body and axial MRI

Whole body MRI has not been widely evaluated in BCR because of its limited value in the detection of early
metastatic involvement in normal-sized LNs [418, 431, 1011]. In a prospective series of 68 patients with
BCR, the diagnostic performance of DW-MRI was significantly lower than that of 68Ga-PSMA PET/CT and
18NaF PET/CT for diagnosing bone metastases [1012].

6.3.4.2 Assessment of local recurrences

6.3.4.2.1 Local recurrence after radical prostatectomy
Because the sensitivity of anastomotic biopsies is low, especially for PSA levels < 1 ng/mL [984], SRT is usually
decided on the basis of BCR without histological proof of local recurrence. The dose delivered to the prostatic
fossa tends to be uniform since it has not been demonstrated that a focal dose escalation at the site of
recurrence improves the outcome. Therefore, most patients undergo SRT without local imaging.

Magnetic resonance imaging can detect local recurrences in the prostatic bed. The PSA threshold for MRI
positivity seems between 0.3 and 0.5 ng/mL; PSA kinetics also influence the MRI positivity, even at low PSA

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values [1013]. Two single-centre studies found that a negative MRI was an independent predictor of failure of
SRT [1014, 1015].
Choline PET/CT is less sensitive for local relapse than MRI but detects more regional and distant
metastases [1016].
The detection rates of 68Ga-PSMA PET/CT in patients with BCR after RP increase with the PSA
level [1017]. PSMA PET/CT studies showed that a substantial part of recurrences after RP were located outside
the prostatic fossa, even at low PSA levels [946, 1018]. Combining 68Ga-PSMA PET and MRI may improve the
detection of local recurrences, as compared to 68Ga-PSMA PET/CT alone [1019-1021].

The EMPIRE-1, a single-centre, open-label, phase II/III RCT included 365 patients with detectable PSA after
RP, but negative results on conventional imaging. They were randomised to RT directed by conventional
imaging alone or to conventional imaging plus 18F-fluciclovine-PET/CT; patients with M1 disease in the PET/
CT group (n = 4) were excluded. Patients with cN1 were irradiated to the pelvic lymphatics but without a boost
to the metastasis. After a median follow-up of 3.5 years,the PET/CT group was significantly associated with
longer event-free survival (HR: 2.04, 95% CI: 1.06–3.93, p = 0.0327) [1022].

6.3.4.2.2 Local recurrence after radiation therapy

In patients with BCR after RT, biopsy status is a major predictor of outcome, provided the biopsies are
obtained 18–24 months after initial treatment. Given the morbidity of local salvage options it is necessary to
obtain histological proof of the local recurrence before treating the patient [984].
MRI has yielded excellent results in identifying local recurrence and can be used for biopsy targeting
and guiding local salvage treatment [984, 1023-1026], even if it slightly underestimates the volume of the local
recurrence [1027]. Prostate-specific membrane antigen PET/CT can also detect local recurrences after RT [945]
and concordance between PSMA PET/CT and MRI is highly suggestive of cancer recurrence [1028].

6.3.4.3 Summary of evidence of imaging in case of biochemical recurrence

In patients with BCR imaging can detect both local recurrences and distant metastases, however, the
sensitivity of detection depends on the PSA level. After RP, PSMA PET/CT seems to be the imaging modality
with the highest sensitivity at low PSA levels (< 0.5 ng/mL) and may help distinguishing patients with
recurrences confined to the prostatic fossa from those with distant metastases which may impact the design
and use of post-RP SRT. After RT, MRI has shown excellent results at detecting local recurrences and guiding
prostate biopsy. Given the substantial morbidity of post-RT local salvage treatments, distant metastases
must be ruled out in patients with local recurrences and who are fit for these salvage therapies. Choline-,
fluciclovine- or PSMA-PET/CT can be used to detect metastases in these patients but for this indication PSMA
PET/CT seems the most sensitive technique.

6.3.4.4 Summary of evidence and guidelines for imaging in patients with biochemical recurrence

Recommendations Strength rating

Prostate-specific antigen (PSA) recurrence after radical prostatectomy
Perform prostate-specific membrane antigen (PSMA) positron emission tomography/ Weak
computed tomography (PET/CT) if the PSA level is > 0.2 ng/mL and if the results will
influence subsequent treatment decisions.
In case PSMA PET/CT is not available, and the PSA level is > 1 ng/mL, perform fluciclovine Weak
PET/CT or choline PET/CT imaging if the results will influence subsequent treatment decisions.
PSA recurrence after radiotherapy
Perform prostate magnetic resonance imaging to localise abnormal areas and guide Weak
biopsies in patients fit for local salvage therapy.
Perform PSMA PET/CT (if available) or fluciclovine PET/CT or choline PET/CT in patients fit Strong
for curative salvage treatment.

6.3.5 Treatment of PSA-only recurrences

The timing and treatment modality for PSA-only recurrences after RP or RT remain a matter of controversy
based on the limited evidence.

6.3.5.1 Treatment of PSA-only recurrences after radical prostatectomy

6.3.5.1.1 Salvage radiotherapy for PSA-only recurrence after radical prostatectomy (cTxcN0M0, without PET/CT)
Early SRT provides the possibility of cure for patients with an increasing PSA after RP. Boorjian et al., reported
a 75% reduced risk of systemic progression with SRT when comparing 856 SRT patients with 1,801 non-SRT

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 97

patients [1029]. The RAVES and RADICAL trials assessing SRT in post-RP patients with PSA levels exceeding
0.1–0.2 ng/mL showed 5-year freedom from BCR and BCR-free survival rates of 88% [919, 1030].
The PSA level at BCR was shown to be prognostic [1029]. More than 60% of patients who
are treated before the PSA level rises to > 0.5 ng/mL will achieve an undetectable PSA level [1031-1034],
corresponding to a ~80% chance of being progression-free 5 years later [1035]. A retrospective analysis of
635 patients who were followed after RP and experienced BCR and/or local recurrence and either received
no salvage treatment (n = 397) or SRT alone (n = 160) within 2 years of BCR showed that SRT was associated
with a 3-fold increase in PCa-specific survival relative to those who received no salvage treatment (p < 0.001).
Salvage RT has been shown to be effective mainly in patients with a short PSA-DT [1036]. For an overview of
SRT see Table 6.3.3.
The EAU BCR definitions have been externally validated and may be helpful for individualised
treatment decisions [977, 982]. Despite the indication for SRT, a ‘wait and see‘ strategy remains an option for
the EAU BCR ‘Low-Risk’ group [977, 982].

Although biochemical progression is now widely accepted as a surrogate marker of PCa recurrence; metastatic
disease, disease-specific and OS are more meaningful endpoints to support clinical decision-making. A
systematic review and meta-analysis on the impact of BCR after RP reports SRT to be favourable for OS and
PCSM. In particular SRT should be initiated in patients with rapid PSA kinetics after RP and with a PSA cut-off
of 0.4 ng/mL [977]. An international multi-institutional analysis of pooled data from RCTs has suggested that
metastasis-free survival is the most valid surrogate endpoint with respect to impact on OS [1037, 1038]. Table
6.3.4 summarises results of recent studies on clinical endpoints after SRT.

Table 6.3.3: S
 elected studies of post-prostatectomy salvage radiotherapy, stratified by pre-salvage
radiotherapy PSA level* (cTxcN0M0, without PET/CT)

Study n Median FU pre-SRT RT dose bNED/PFS 5-yr. results

(mo) PSA (ng/mL) ADT (year)
median
Bartkowiak, 464 71 0.31 66.6 Gy 54% (5.9) 73% vs. 56%; PSA
et al. 2018 < 0.2 vs. > 0.2 ng/mL
[1039] p < 0.0001
Soto, et al. 441 36 < 1 (58%) 68 Gy 63/55% (3) 44/40% ADT/no ADT
2012 [1040] 24% ADT ADT/no ADT p < 0.16
Stish, et al. 1,106 107 0.6 68 Gy 50% (5) 44% vs. 58%; PSA
2016 [1031] 16% ADT 36% (10) < 0.5 vs. > 0.5 ng/mL
p < 0.001
Tendulkar, 2,460 60 0.5 66 Gy 56% (5) Pre-SRT PSA
et al. 2016 16% ADT 71% 0.01–0.2 ng/mL
[1041] 63% 0.21–0.5 ng/mL
54% 0.51–1.0 ng/mL
43% 1.01–2.0 ng/mL
37% > 2.0 ng/mL
p < 0.001
*Androgen deprivation therapy can influence the outcome ‘biochemically no evidence of disease (bNED)’ or
‘progression-free survival’. To facilitate comparisons, 5-year bNED/PFS read-outs from Kaplan-Meier plots are
included.
ADT = androgen deprivation therapy; bNED = biochemically no evidence of disease; FU = follow up;
mo = months; n = number of patients; PFS = progression-free survival; PSA = prostate-specific antigen;
SRT = salvage radiotherapy; yr = year.

Table 6.3.4: R
 ecent studies reporting clinical endpoints after SRT (cTxcN0M0, without PET/CT)
(the majority of included patients did not receive ADT)

Study n Median FU Regimen Outcome

(mo)
Bartkowiak, 464 71 66.6 (59.4-72) Gy 5.9 yr. OS
et al. 2018 no ADT post-SRT PSA < 0.1 ng/mL 98%
[1039] post-SRT PSA > 0.1 ng/mL 92%
p = 0.005

98 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

Jackson, 448 64 68.4 Gy no ADT 5 yr. DM
et al. 2014 post-SRT PSA < 0.1 ng/mL 5%
[1042] post-SRT PSA > 0.1 ng/mL 29%
p < 0.0001
5 yr. DSM
post-SRT PSA < 0.1 ng/mL 2%
post-SRT PSA > 0.1 ng/mL 7%
p < 0.0001
OS
post-SRT PSA < 0.1 ng/mL 97%
post-SRT PSA > 0.1 ng/mL 90%
p < 0.0001
Stish, 1,106 107 68 (64.8-70.2) Gy 5 and 8.9 yr. DM
et al. 2016 39% 2D treatment SRT: PSA < 0.5 ng/mL 7% and 12%
[1031] planning SRT: PSA > 0.5 ng/mL 14% and 23%
incl. 16% ADT p < 0.001
5 and 8.9 yr. DSM
SRT: PSA < 0.5 ng/mL < 1% and 6%
SRT: PSA > 0.5 ng/mL 5% and 10%
p = 0.02 5 and 8.9 yr. OS
SRT: PSA < 0.5 ng/mL 94% and 86%
SRT: PSA > 0.5 ng/mL 91% and 78%
p = 0.14
Tendulkar, 2,460 60 66 (64.8-68.4) Gy 10-yr. DM (19% all patients)
et al. 2016 incl. 16% ADT Pre-SRT PSA
[1041] 9% 0.01–0.2 ng/mL
15% 0.21–0.5 ng/mL
19% 0.51–1.0 ng/mL
20% 1.01–2.0 ng/mL
37% > 2.0 ng/mL
p < 0.001
ADT = androgen deprivation therapy; DM = distant metastasis; DSM = disease specific mortality;
FU = follow up; mo. = month; n = number of patients; OS = overall survival; PSA = prostate specific antigen;
SRT = salvage radiotherapy.

6.3.5.1.2 Salvage radiotherapy combined with androgen deprivation therapy (cTxcN0, without PET/CT)
Data from RTOG 9601 suggest both CSS and OS benefit when adding 2 years of bicalutamide (150 mg o.d.)
to SRT [1043]. According to GETUG-AFU 16 also 6-months treatment with a LHRH-analogue can significantly
improve 10-year BCR, biochemical PFS and, modestly, metastasis-free survival. However, SRT combined
with either goserelin or placebo showed similar DSS and OS rates [1044]. In addition, Pollack et al., reported
on the results of a randomised 3-arm phase III trial (NRG Oncology/RTOG 0534 SPPORT) adding six months
treatment with a LHRH-analogue to SRT of the prostate bed (PBRT) (group 2) compared with PBRT alone
(group 1) or the former combination with PBRT-RT and pelvic LN RT (PLNRT) (group 3) [1045]). The primary
endpoint was freedom from progression (FFP) after 5 years. However, using the phoenix-definition of
biochemical progression (nadir + 2 ng/mL used for definitive RT), and not the criterion of nadir + 0.2, as is used
commonly (but without clear evidence) will have resulted in a later diagnosis of progression in the SPPORT trial.
With a median follow-up of 8.2 years of the surviving patients FFP increased significant for group 3
(87.4%) compared with group 2 (81.3%) (p = 0.0027) and group 1 (70.9%) (p < 0.0001) The difference between
group 2 and group 1 was also significant (p < 0.0001). Distant metastasis incidence rates were lowest in group
3 and were lower compared with group 1 (PBRT only, HR: 0.52) similar to the rate of PCa deaths (HR: 0.51). No
significant difference was seen for OS. There was a significantly higher risk of both acute- and late side effects
in group 3. In conclusion, the role of additional PLNRT remains unclear and should be further proven in RCTs
including PSMA PET-CT [1046]. Table 6.3.5 provides an overview of these three RCTs.

These RCTs support adding ADT to SRT. However, when interpreting these data it has to be kept in mind that
RTOG 9601 used outdated radiation dosages (< 66 Gy) and technique. The question with respect to the patient
risk profile, whether to offer combination treatment or not, and the optimal combination (LHRH or bicalutamide)
remains, as yet, unsolved. The EAU BCR risk classification may offer guidance in this respect [977].
One of these RCTs reports improved OS (RTOG 96-01) and the other (GETUG-AFU 16) improved
metastasis-free survival but due to methodological discrepancies and also related to follow-up and risk

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patterns, it is, as yet, not evident which patients should receive ADT, which type of ADT, and for how long. Men
at high risk of further progression (e.g., with a PSA > 0.7 ng/mL and GS > 8) may benefit from SRT combined
with two years of ADT; for those at lower risk (e.g., PSA < 0.7 ng/mL and GS = 8) SRT combined with 6 months
of ADT may be sufficient. Men with a low-risk profile (PSA < 0.5 ng/mL and GS < 8) may receive SRT alone.
In a sub-analysis of men with a PSA of 0.61 to 1.5 (n = 253) there was an OS benefit associated with anti-
androgen assignment (HR: 0.61, 95% CI: 0.39–0.94) [1047]. In those receiving early SRT (PSA 0.6 ng/mL,
n = 389), there was no improvement in OS (HR: 1.16, 95% CI: 0.79–1.70), with increased other-cause mortality
(sub-distribution HR: 1.94, 95% CI: 1.17–3.20, p = 0.01) and increased odds of late grades 3–5 cardiac and
neurologic toxic side effects (OR: 3.57, 95% CI: 1.09–15.97, p = 0.05). These results suggest that pre-SRT PSA
level may be a prognostic biomarker for outcomes of anti-androgen treatment with SRT. In patients receiving
late SRT (PSA > 0.6 ng/mL), HT was associated with improved outcomes. In men receiving early SRT (PSA
< 0.6 ng/mL), long-term anti-androgen treatment was not associated with improved OS [1047].
A systematic review addressing the benefit from combining HT with SRT suggested risk
stratification of patients based on the pre-SRT PSA (< 0.5, 0.6–1, > 1 ng/mL), margin status and ISUP grade as
a framework to individualise treatment [1048].

Table 6.3.5: R
 andomised controlled trials comparing salvage radiotherapy combined with androgen
deprivation therapy vs. salvage radiotherapy alone

Study n Risk groups Median Regimen Outcome

FU (mo)
GETUG-AFU 16 369 RT + ADT ISUP grade 112 66 Gy PBRT + 6 mo. 10-yr.
2019 [1044] < 2/3 89% LHRH analogue PFS: RT + ADT, 64%
374 RT PFS: RT, 49%
ISUP grade 66 Gy BPRT p < 0.0001
> 4 11% MFS: RT + ADT, 75%
cN0 MFS: RT, 69%
p = 0.034
RTOG 9601 384 RT + ADT pT2 R1, pT3 156 64.8 Gy PBRT + 12-yr.
2017 [1043] cN0 bicalutamide 24 mo. cumulative DM
376 RT RT + ADT: 14%
64.8 Gy PBRT + RT + placebo: 23%
placebo p = 0.005
OS
RT + ADT: 76%
RT + placebo: 71%
p = 0.04
DSM
RT + ADT: 5.8%
RT + placebo: 13.4%
p < 0.001
NRG Oncology/ 574 SRT + pT2 or pT3 survivors: 64.8–0.2 Gy PBRT 5-yr. FFP (primary
RTOG 0534 PBRT + ADT ISUP < 5 8.2 years endpoint)
SPPORT [1045] Pre SRT 64.8–70.2 Gy PBRT 70.9% Group 1
578 SRT + PSA: 0.1-2.0 6 mo. LHRH analogue 81.3% Group 2
ADT 87.4% Group 3
64.8–70.2 Gy PBRT + Comparisons :
564 SRT 45 Gy PLNRT G 3 vs. G 1:
6 mo. LHRH analogue p < 0.0001
G 2 vs. G 1
p < 0.0001
G 3 vs. G 2
p < 0.0027
ADT = androgen deprivation therapy; DM = distant metastasis; DSM = disease specific mortality;
PFS = progression free survival; FFP = Freedom From Progression; FU = follow-up; LHRH = luteinising
hormone-releasing hormone; MFS = metastasis-free survival; OS = overall survival; PFS = progression-free
survival; mo = months; n = number of patients; RT = radiotherapy; yr = year, PBRT = prostate bed radiotherapy;
PLNRT = pelvic lymph node radiotherapy.

100 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

6.3.5.1.2.1 Target volume, dose, toxicity
There have been various attempts to define common outlines for ‘clinical target volumes‘ for pN0 PCa [1049-
1051] and for organs at risk of normal tissue complications [1050, 1051]. However, given the variations of
techniques and dose-constraints, a satisfactory consensus has not yet been achieved. A benefit in biochemical
PFS but not metastasis-free survival has been reported in patients receiving whole pelvis SRT (± ADT) but the
advantages must be weighed against possible side effects [1046]. This is supported by data from the SPPORT-
Trial (NRG Oncology/RTOG 0534 SPPORT) but it remains controversial [1045].

The optimal SRT dose has not been well defined. It should be at least 64 Gy to the prostatic fossa (± the base
of the SVs, depending on the pathological stage after RP) [924, 1032, 1052]. In a systematic review, the pre-
SRT PSA level and SRT dose both correlated with BCR, showing that relapse-free survival decreased by 2.4%
per 0.1 ng/mL PSA and improved by 2.6% per Gy, suggesting that the treatment dose above 70 Gy should be
administered at the lowest possible PSA level [1053]. The combination of pT stage, margin status and ISUP
grade and the PSA at SRT seems to define the risk of biochemical progression, metastasis and overall mortality
[916, 1054, 1055]. In a study on 894 node-negative PCa patients, doses ranging from 64 to > 74 Gy were
assigned to twelve risk groups defined by their pre-SRT PSA classes < 0.1, 0.1–0.2, 0.2–0.4, and > 0.4 ng/mL
and ISUP grade, < 1 vs. 2/3 vs. > 4 [1056]. The updated Stephenson nomograms incorporate the SRT and ADT
doses as predictive factors for biochemical failure and distant metastasis [1041].

Two RCT’s were recently published (Table 6.3.6). Intensity-modulated radiation therapy plus IGRT was used in
57% of the patients in the SAKK-trial [924] and in all patients of a Chinese trial [1057]. No patient had a PSMA
PET/CT before randomisation. The primary endpoint in both trials was ‘freedom from biochemical progression’,
which was not significantly improved with higher doses. However, in the Chinese trial a subgroup analysis
showed a significant improvement of this endpoint for patients with Gleason 8-10 tumours (79.7% vs. 55%,
p = 0.049). In this trial, patients were treated with ART or SRT and the number of patients was relatively small
(n = 144). At this time it seems difficult to draw final conclusions about the optimal total RT-dose and longer
follow-up should be awaited.

Table 6.3.6: R
 andomized trials investigating dose escalation for SRT without ADT and without PET-CT

Trial n PCa Radiotherapy Follow-up Outcome Results

condition Dose (median)
SAKK 09/10 350 pT2a-3b 64 Gy vs.70 Gy 6.2 yr. Primary 6 yr. FFBP:
trial, 2021 R0 – R1 endpoint: 62% vs. 61%
[924] pN0 or cN0 No ADT allowed FFBP OS: no difference
PSA post-op
undetectable VMAT + IGRT: Late side effects:
(< 0.1 ng/mL) 57% GI grade 2:
or persistent 3-D planning: 7.3% vs. 20%
(> 0.1 ng/mL 43% GI grade 3:
< 0.4 ng/mL) 4.2% vs. 2.3%
p for > grade 2/3:
0.009
Phase-III-Trial 144 pT2-4 66 Gy vs. 49 mo. Primary 4 yr. FFBP:
Qi X, et al., ART: 33% R0-R1 72 Gy endpoint: 75.9% vs. 82.6%
2020 [1057] SRT: 67% pN0 or cN0 All patients FFBP (p > 0.05)
Med. PSA VMAT + IGRT High risk (GS: 8–10):
pre-RT: No ADT allowed 55.7% vs. 79.7%
0.2 ng/mL p < 0.049)
High risk
(pT3–4, GS: 8–10, Late side effects:
PSA > 20 ng/mL): GI + GU grade 2
whole pelvis RT: p > 0.05
126 (87.5%) No grade 3
ADT = androgen deprivation therapy; ART = adjuvant radiotherapy; FFBP = freedom from biochemical failure;
GI = gastro-intestinal; GU = genito-urinary; Gy = Gray; IGRT = image guided radiotherapy; mo = month;
n = number of patients; PSA = prostate-specific antigen; RT = radiotherapy; SRT = y = year; vs. = versus;
VMAT = volumetric arc radiation therapy.

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Salvage RT is associated with toxicity. In one report on 464 SRT patients receiving median 66.6 (max. 72) Gy,
acute grade 2 toxicity was recorded in 4.7% for both the GI and GU tract. Two men had late grade 3 reactions
of the GI tract, but overall, severe GU tract toxicity was not observed. Late grade 2 complications occurred
in 4.7% (GI tract) and 4.1% (GU tract), respectively, and 4.5% of the patients developed moderate urethral
stricture [1039].

In a RCT on dose escalation for SRT (n = 350), acute grade 2 and 3 GU toxicity was observed in 13.0% and
0.6%, respectively, with 64 Gy and in 16.6% and 1.7%, respectively, with 70 Gy. Gastro-intestinal tract grades
2 and 3 toxicity occurred in 16.0% and 0.6%, respectively, with 64 Gy, and in 15.4% and 2.3%, respectively,
with 70 Gy. Late effects have yet to be reported [1058, 1059]. Late grade 2 and 3 GI toxicity was significantly
increased with higher doses but without significant differences in QoL. In this study, however, the rectal wall
dose constraints were rather permissive and in 44% of the patients outdated 3-D-techniques were used [924].

With dose escalation over 72 Gy and/or up to a median of 76 Gy, the rate of severe side effects, especially GU
symptoms, clearly increases, even with newer planning and treatment techniques [1060, 1061]. In particular,
when compared with 3D-CRT, IMRT was associated with a reduction in grade 2 GI toxicity from 10.2 to
1.9% (p = 0.02) but no effect on the relatively high level of GU toxicity was shown (5-year, 3D-CRT 15.8% vs.
IMRT 16.8%) [1060]. However, in a RCT comparing 66 Gy and 72 Gy with all patients having IMRT plus IGRT
(n = 144), no significant differences for GI and GU-toxicity was demonstrated [1057]. After a median salvage
IMRT dose of 76 Gy, however, the 5-year risk of grade 2–3 toxicity rose to 22% for GU and 8% for GI
symptoms, respectively [1061]. Doses of at least 64 Gy and up to 72 Gy in patients without PET/CT can be
recommended [1039, 1058].

6.3.5.1.2.2 Salvage radiotherapy with or without ADT (cTx cN0/1) with PET/CT
In a prospective multi-centre study of 323 patients with BCR, PSMA PET/CT changed the management intent
in 62% of patients as compared to conventional staging. This was due to a significant reduction in the number
of men in whom the site of disease recurrence was unknown (77% vs. 19%, p < 0.001) and a significant
increase in the number of men with metastatic disease (11% vs. 57%) [1062].
A prospective study in a subgroup of 119 BCR patients with low PSA (< 0.5 ng/mL) reported a change
in the intended treatment in 30.2% of patients [946]; however, no data exist on the impact on final outcome.
Another prospective study in 272 patients with early biochemical recurrent PCa after RP showed
that 68Ga-PSMA PET/CT may tailor further therapy decisions (e.g., local vs. systemic treatment) at low PSA
values (0.2–1 ng/mL) [948].

A single-centre study retrospectively assessed 164 men who underwent imaging with PSMA PET/CT for a
rising PSA after RP with PSA levels < 0.5 ng/mL. In men with a negative PSMA PET/CT who received SRT,
85% (23 out of 27) demonstrated a treatment response compared to a further PSA increase in 65% of those
not treated (22 out of 34). In the 36/99 men with disease confined to the prostate fossa on PSMA, 83% (29
out of 36) responded to SRT [1063]. Thus, PSMA PET/CT might stratify men into a group with high response
(negative findings or recurrence confined to the prostate) and poor response (positive nodes or distant disease)
to SRT.
A recent multi-centre retrospective study evaluated patients who underwent SRT for BCR after RP,
without any signs of distant metastatic disease on PET/CT. After case-controle matching, 2 cohorts (n = 108
patients each), with and without PSMA PET/CT prior to SRT were analysed. In the cohort without PSMA PET/
CT, 23 patients (21%) had BCR at 1 year after SRT vs. 9 patients (8%) who underwent restaging with PSMA
PET/C prior to SRT (p = 0.007). PSMA-PET/CT was found to be associated with an improved oncological
outcome in patients with BCR after RP, receiving SRT to the prostatic fossa [1064]. It is worth mentioning
that in this study the median biologically effective radiation dose administered in the PSMA-cohort was
significantly higher than in the historical cohort (70 Gy vs. 66 Gy, respectively, p < 0.001). However, another
publication showed that the biochemical progression rate after SRT between patients who underwent 64 Gy or
70 Gy to the prostate bed, without HT for BCR, did not differ significantly [1065]. Therefore, it is questionable
whether this difference in administered radiation dose influenced the outcome in both cohorts. As there are no
prospective phase III data (in particular not for PCa-specific survival or OS) these results have to be confirmed
before a recommendation can be provided.

A single-centre open-label, phase II/III RCT (EMPIRE-1) evaluated the role of 18F-fluciclovine-PET/CT compared
with conventional imaging for SRT. Three hundred and sixty five patients with detectable PSA after RP but
negative results on conventional imaging, were randomised to RT directed by conventional imaging alone or
to conventional imaging plus PET/CT; patients with M1 disease in the PET/CT group (n = 4) were excluded.
Patients with cN1 were irradiated to the pelvic lymphatics but without a boost to the metastasis. Median follow-

102 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

up was 3.5 years. In adjusted analyses, the study group was significantly associated with event-free survival
(HR: 2.04, 95% CI: 1.06–3.93, p = 0.0327) [1022].

6.3.5.1.2.3 Nodal-directed therapy for rcN1 (with PET/CT)

Radiolabelled PSMA PET/CT is increasingly used as a diagnostic tool to assess metastatic disease burden
in patients with BCR following prior definitive therapy. A review including 30 studies and 4,476 patients
showed overall estimates of positivity in a restaging setting of 38% in pelvic LNs and 13% in extra-pelvic LN
metastases [945]. The percentage positivity of PSMA PET/CT was proven to increase with higher PSA values
[945]. Results of this review demonstrated a high sensitivity and specificity of 68Ga-PSMA in advanced PCa,
with a per-lesion-analysed sensitivity and specificity of 75% and 99%, respectively.

A large retrospective international study included patients with LN-recurrent PCa (cN1 and M1a) and PSA
progression following multi-modality treatment (surgery and post-operative RT) [1066]. The aim of the study
was to compare standard of care (SOC) with nodal metastasis-directed therapy (MDT). The nodal MDT-group
showed significantly better CSS than the SOC control group (5-year survival 98.6% vs. 95.7%, p < 0.01,
respectively) [1066].
Another retrospective study compared SABR with elective nodal irradiation (ENRT) in nodal
oligo-recurrent PCa (n = 506 patients, 365 of which with N1 pelvic recurrence). With a median follow-up of
36 months, ENRT (n = 197) was associated with a significant reduction of nodal recurrences (p < 0.001),
compared with SABR (n = 309) of 2% vs. 18%, respectively. In a a multi-variable analysis, patients with one LN
at recurrence had longer adjusted MFS after ENRT (HR: 0.50, 95% CI: 0.30–0.85, p = 0.009). The tendency to
relapse was higher for pelvic- than extra-pelvic nodes (p < 0.001) [1067]. For patients presenting with two or
more (extra)pelvic LNs, adjusted MFS was not significantly different (HR: 0.92, 95% CI: 0.54– 1.59, p = 0.8). In
these situations, SABR should be used in highly selected patients in prospective cohorts or clinical trials only,
before any recommendations can be made. For MDT in M1 patients see Section 6.4.7.

6.3.5.1.3 Salvage lymph node dissection

The surgical management of recurrent nodal metastases in the pelvis has been the topic of several
retrospective analyses [1068-1070] and a systematic review [1071]. The reported 5-year BCR-free survival rates
ranged from 6% to 31%. Five-year OS was approximately 84% [1071]. Biochemical recurrence rates were
found to be dependent on PSA at salvage surgery and location and number of positive nodes [1072]. Addition
of RT to the lymphatic template after salvage LN dissection may improve the BCR rate [1073]. In a multi-centre
retrospective study long-term outcomes of 189 patients who underwent salvage LN dissection were reported
to be worse than previously described in studies with shorter follow-up [1074]. Biochemical recurrence (BCR)-
free survival at 10 years was 11%. Patients with a PSA response after salvage LN dissection and patients
receiving ADT within 6 months from salvage LN dissection had a lower risk of death from PCa [1074]. The
majority of the patients (81%) had received a choline PET and median PSA at salvage LN dissection was 2.5
ng/mL. In a cohort study including patients treated with salvage LN dissection via PSMA-radio-guided surgery
(PSMA-RGS), 2-year BCR-free survival rate was 32% [1075]. In multi-variable analyses, higher pre-operative
PSA, higher number of PSMA-avid lesions, multiple (pelvic plus retroperitoneal), and retroperitoneal localisation
of lesions at pre-operative imaging were independent predictors of BCR after PSMA-RGS. High-level evidence
for the oncological value of salvage LN dissection (including adjuvant RT of the LNs) is still lacking [1071].

6.3.5.2 Management of PSA failures after radiation therapy

Therapeutic options in these patients are ADT or salvage local procedures, as well as a ‘wait and see’
approach, based on EAU BCR risk categories at relapse. A systematic review and meta-analysis included
studies comparing the efficacy and toxicity of salvage RP, salvage HIFU, salvage cryotherapy, SBRT, salvage
LDR brachytherapy, and salvage HDR brachytherapy in the management of locally recurrent PCa after primary
radical EBRT [1076]. The outcomes were BCR-free survival at 2 and 5 years. No significant differences with
regards to recurrence-free survival (RFS) between these modalities was found. Five-year RFS ranged from
50% after cryotherapy to 60% after HDR brachytherapy and SBRT. The authors reported that severe GU
toxicity exceeded 21% for HIFU and RP, whereas it ranged from 4.2% to 8.1% with re-irradiation. Differences
in severe GI toxicity also appeared to favour re-irradiation, particularly HDR brachytherapy [1076]. Due to the
methodological limitations of this review (the majority of the included studies were uncontrolled single-arm case
series and there was considerable heterogeneity in the definitions of core outcomes) the available evidence
for these treatment options is of low quality and strong recommendations regarding the choice of any of these
techniques cannot be made. The following is an overview of the most important findings for each of these
techniques.

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6.3.5.2.1 Salvage radical prostatectomy
Salvage RP after RT is associated with a higher likelihood of AEs compared to primary surgery because of the
risk of fibrosis and poor wound healing due to radiation [1077].

6.3.5.2.1.1 Oncological outcomes

In a systematic review of the literature, Chade, et al., showed that SRP provided 5- and 10-year BCR-free
survival estimates ranging from 47–82% and from 28–53%, respectively. The 10-year CSS and OS rates
ranged from 70–83% and from 54–89%, respectively. The pre-SRP PSA value and prostate biopsy ISUP grade
were the strongest predictors of the presence of organ-confined disease, progression, and CSS [1078]. In a
multi-centre analysis including 414 patients, 5-year BCR-free survival, CSS and OS were 56.7%, 97.7% and
92.1%, respectively [1079]. Pathological T stage > T3b (OR: 2.348) and GS (up to OR 7.183 for GS > 8) were
independent predictors for BCR (see Table 6.3.7).

Table 6.3.7: O
 ncological results of selected salvage radical prostatectomy case series

Study n Median Pathologic PSM Lymph-node BCR-free CSS Time

FU Organ- (%) involvement probability (%) probability
(mo) confined (%) (%) (%)
Chade, et al. 2011 404 55 55 25 16 37 83 10 yr.
[1080]
Mandel, et al. 55 36 50 27 22 49 89 5 yr.
2016 [1081]
Ogaya-Pinies, 96 14 50 17 8 85* - 14 mo.
et al. 2018 [1082]
Marra, et al. 2021 414 36 46 30 16 57 98 5 yr.
[1079]
*Percentage of patients without BCR.
BCR = biochemical recurrence; CSS = cancer-specific survival; FU = follow-up; mo = months; n = number of
patients; PSM = positive surgical margin; yr. = year.

6.3.5.2.1.2 Morbidity
Compared to primary open RP, SRP is associated with a higher risk of later anastomotic stricture (47 vs. 5.8%),
urinary retention (25.3% vs. 3.5%), urinary fistula (4.1% vs. 0.06%), abscess (3.2% vs. 0.7%) and rectal injury
(9.2 vs. 0.6%) [1083]. In more recent series, these complications appear to be less common [1077, 1078, 1081].
Functional outcomes are also worse compared to primary surgery, with urinary incontinence ranging
from 21% to 90% and ED in nearly all patients [1078, 1081].

6.3.5.2.1.3 Summary of salvage radical prostatectomy

In general, SRP should be considered only in patients with low co-morbidity, a life expectancy of at least 10 years,
a pre-SRP PSA < 10 ng/mL and initial biopsy ISUP grade < 2/3, no LN involvement or evidence of distant
metastatic disease pre-SRP, and those whose initial clinical staging was T1 or T2 [1078].

6.3.5.2.2 Salvage cryoablation of the prostate

6.3.5.2.2.1 Oncological outcomes
Salvage cryoablation of the prostate (SCAP) has been proposed as an alternative to salvage RP, as it has a
potentially lower risk of morbidity and equal efficacy.
In a systematic review a total of 32 studies assessed SCAP, recruiting a total of 5,513 patients. The
overwhelming majority of patients (93%) received whole-gland SCAP. The adjusted pooled analysis for 2-year
BCR-free survival for SCAP was 67.49% (95% CI: 61.68–72.81%), and for 5-year BCR-free survival was 50.25%
(95% CI: 44.10–56.40%). However, the certainty of the evidence was low. Table 6.3.8 summarises the results of
a selection of the largest series on SCAP to date in relation to oncological outcomes (BCR only) [1076].

104 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

Table 6.3.8: O
 ncological results of selected salvage cryoablation of the prostate case series, including at
least 250 patients

Study n Median Time point BCR-free probability Definition of failure

FU (mo) of outcome
measurement
(yr)
Ginsburg, et al. 2017 [1084] 898 19.0 5 71.3% Phoenix criteria
Spiess, et al. 2010 [1085] 450 40.8 3.4 39.6% PSA > 0.5 ng/mL
Li, et al. 2015 [1086] 486 18.2 5 63.8% Phoenix criteria
Kovac, et al. 2016 [1087] 486 18.2 5 75.5% Phoenix criteria
(nadir PSA < 0.4 ng/mL);
22.1%
(nadir PSA > 0.4 ng/mL)
Ahmad, et al. 2013 [1088] 283 23.9 3 67.0% Phoenix criteria
(nadir PSA < 1 ng/mL);
14.0%
(nadir PSA > 1 ng/mL)
Pisters, et al. 2008 [1089] 279 21.6 5 58.9% (ASTRO) ASTRO and Phoenix
54.5% (Phoenix) criteria
ASTRO = American Society for Therapeutic Radiology and Oncology; BCR = biochemical recurrence;
FU = follow-up; mo. = months; n = number of patients; PSA = prostate-specific antigen; yr. = year.

6.3.5.2.3 Salvage re-irradiation

6.3.5.2.3.1 Salvage brachytherapy for radiotherapy failure
Carefully selected patients with a good PS, primary localised PCa, good urinary function and histologically
proven local recurrence are candidates for salvage brachytherapy using either HDR or LDR.
In a systematic review a total of 16 studies (4 prospective) and 32 studies (2 prospective)
assessed salvage HDR and LDR brachytherapy, respectively, with the majority (> 85%) receiving whole-gland
brachytherapy rather than focal treatment [1076]. The adjusted pooled analysis for 2-year BCR-free survival for
HDR was 77% (95% CI: 70–83%) and for LDR was 81% (95% CI:74–86%). The 5-year BCR-free survival for
HDR was 60% (95% CI: 52–67%) and for LDR was 56% (95% CI: 48–63%). As noted above, brachytherapy
techniques are associated with lower rates of severe GU toxicity when compared to RP or HIFU, at 8% for
HDR (95% CI: 5.1–11%) and 8.1% for LDR (95% CI: 4.3–13%). Rates of severe GI toxicity are reported to
be very low at 0% for HDR (95% CI: 0–0.2%) and 1.5% for LDR (95% CI: 0.2–3.4%). High-dose-rate or LDR
brachytherapy are effective treatment options with an acceptable toxicity profile. However, the published series
are small and likely under-report toxicity. Consequently, this treatment should be offered in experienced centres
ideally within randomised clinical trials or prospective registry studies (see Table 6.3.9).

Table 6.3.9: T
 reatment-related toxicity and BCR-free probability in selected salvage brachytherapy
studies including at least 100 patients.

Study Study design n and BT type Median FU Treatment toxicity BCR-free probability
(mo)
Lopez, et al. multi-centre 75 HDR 52 23.5% late G3+ GU 5 yr 71%
2019 [1090] retrospective 44 LDR (95% CI: 65.9-75.9%)
Crook, et al. multi-centre 100 LDR 54 14% late G3 n.r.
2019 [1091] prospective combined GI/GU
Smith, et al. single-centre 108 LDR 76 15.7%/2.8% late G3 5 yr. 63.1%
2020 [1092] retrospective GU/GI 10 yr. 52%
Lyczek, et al. single-centre 115 HDR n.r. 12.2%/0.9% 60% at 40 mo.
2009 [1093] retrospective late G3+ GU/GI
BT = brachytherapy; CI = confidence interval; G = grade; GI = gastro-intestinal; GU = genito-urinary; HDR = high-
dose rate; LDR = low-dose rate; mo = months; n = number of patients; n.r. = not reported; yr = year.

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6.3.5.2.3.2 Salvage stereotactic ablative body radiotherapy for radiotherapy failure
6.3.5.2.3.2.1 Oncological outcomes and morbidity
Stereotactic ablative body radiotherapy (CyberKnife® or linac-based treatment) is a potentially viable new
option to treat local recurrence after RT. Carefully selected patients with good IPSS-score, without obstruction,
good PS and histologically proven localised local recurrence are potential candidates for SABR. In a meta-
analysis and systematic review five mostly retrospective studies including 206 patients were treated with
CyberKnife® or linac-based treatment showing 2-year RFS estimates (61.6%, 95% CI: 52.6–69.9%) [1076]. In
a retrospective multi-centre study (n = 100) the median pre-salvage PSA was 4.3 ng/mL with 34% of patients
having received ADT for twelve months (median). All recurrences were biopsy proven. Patients were treated
with the CyberKnife® with a single dose of 6 Gy in six daily fractions (total dose 36 Gy). With a median follow-
up of 30 months the estimated 3-year second BCR-free survival was 55% [1094].
In a smaller retrospective series including 50 men with histologically proven local recurrence with
a median pre-salvage PSA of 3.9 ng/mL only 15% had received additional ADT. The estimated 5-year second
BCR-free survival was 60% (median follow-up of 44 months) which is an outcome comparable to series
treating patients with RP, HIFU or brachytherapy [1095]. Table 6.3.10 summarises the results of the two larger
SABR series addressing oncological outcomes and morbidity.

Table 6.3.10: T
 reatment-related toxicity and BCR-free survival in selected SABR studies

Study Study design n and Median Fractionation ADT Treatment BCR-free

RT-type FU (mo) (SD/TD) toxicity survival
Bergamin, single-centre 25 25 SD 6-6.2 0/25 2 yr. late 2 yr. 80%
et al. 2020 prospective LINAC TD 36-38 Gy G1 GI 8%
[1096] based G2 GU 4%
Fuller, et al. single-centre 50 44 SD 6.8 Gy 7/50 5 yr: 8% late 5 yr. 60%
2020 [1095] retrospective Cyber Knife TD 34 Gy G3+ GU
Pasquier, multi-centre 100 30 SD 6 Gy 34/100 3 yr. grade 2+ 3 yr. 55%
et al. 2020 retrospective Cyber Knife TD 36 Gy median GU 20.8%
[1094] 12 mo. GI 1%
BCR = biochemical recurrence; FU = follow-up; mo = months; n = number of patients; RT-type = type of radio-
therapy; SD = single dose; TD = total dose; yr = year.

6.3.5.2.3.2.2 Morbidity
In a retrospective single-centre study with 50 consecutive patients chronic significant toxicity was only seen
for the GU domain with 5-year grade 2+ and grade 3+ GU rates of 17% and 8%, respectively. No GI toxicity
> grade 1 was seen. Of note, of the fifteen patients who were sexually potent pre-salvage SBRT, twelve
subsequently lost potency [1095]. In a retrospective French (GETUG) multi-centre series (n = 100) the 3-year late
grade 2+ GU and GI toxicity was 20.8% (95% CI: 13–29%) and 1% (95% CI: 0.1–5.1%), respectively [1094].

6.3.5.2.3.2.3 Summary of salvage stereotactic ablative body radiotherapy

Despite the encouraging results so far the number of patients treated with SABR is relatively limited. In view of
the rates of higher grade 2+ GU side effects, SABR should only be offered to selected patients, in experienced
centres as part of a clinical trial or well-designed prospective study.

6.3.5.2.4 Salvage high-intensity focused ultrasound

6.3.5.2.4.1 Oncological outcomes
Salvage HIFU has emerged as an alternative thermal ablation option for radiation-recurrent PCa. Being
relatively newer than SCAP the data for salvage HIFU are even more limited. A systematic review and meta-
analysis included 20 studies (n = 1,783) assessing salvage HIFU [1076]. The overwhelming majority of patients
(86%) received whole-gland salvage HIFU. The adjusted pooled analysis for 2-year BCR-free survival for
salvage HIFU was 54.14% (95% CI: 47.77–60.38%) and for 5-year BCR-free survival 52.72% (95% CI: 42.66–
62.56%). However, the certainty of the evidence was low. Table 6.3.11 summarises the results of a selection of
the largest series on salvage HIFU to date in relation to oncological outcomes (BCR only).

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Table 6.3.11: O
 ncological results of selected salvage cryoablation of the prostate case series, including
at least 250 patients

Study n Median Time point BCR-free Definition of failure

FU (mo) of outcome probability
measurement
(yr)
Crouzet, et al. 418 39.6 5 49.0% Phoenix criteria
2017 [1097]
Murat, et al. 167 Mean 3 25.0% (high-risk) Phoenix criteria or positive
2009 [1098] 18.1 53.0% (low-risk)* biopsy or initiation of post-HIFU
salvage therapy
Kanthabalan, et al. 150 35.0 3 48.0% Phoenix criteria
2017 [1099]
Jones, et al. 100 12.0 1 50.0% Nadir PSA > 0.5 ng/mL or
2018 [1100] positive biopsy
*Results stratified by pre-EBRT D’Amico risk groups.
BCR = biochemical recurrence; FU = follow-up; mo = months; n = number of patients; yr = year.

6.3.5.2.4.2 Morbidity
The main adverse effects and complications relating to salvage HIFU include urinary incontinence, urinary
retention due to bladder outflow obstruction, rectourethral fistula and ED. The systematic review and meta-
analysis showed an adjusted pooled analysis for severe GU toxicity for salvage HIFU of 22.66% (95%
CI: 16.98–28.85%) [1076]. The certainty of the evidence was low. Table 6.3.12 summarises the results of a
selection of the largest series on salvage HIFU to date in relation to GU outcomes.

Table 6.3.12: P
 eri-operative morbidity, erectile function and urinary incontinence in selected salvage
HIFU case series, including at least 100 patients

Study n Time point Incontinence* Obstruction/ Rectourethral ED (%)

of outcome (%) retention (%) fistula (%)
measurement
(yr)
Crouzet, et al. 418 Median 39.6 42.3 18.0 2.3 n.r.
2017 [1097]
Murat, et al. 167 Median 18.1 49.5 7.8 3.0 n.r.
2009 [1098]
Kanthabalan, et al. 150 24 12.5 8.0 2.0 41.7
2017 [1099]
Jones, et al. 100 12 42.0 49.0 5.0 74.0
2018 [1100]
*Incontinence was heterogeneously defined; figures represent at least 1 pad usage.
ED = erectile dysfunction; n.r. = not reported; n = number of patients.

6.3.5.2.4.3 Summary of salvage high-intensity focused ultrasound

There is a lack of high-certainty data which prohibits any recommendations regarding the indications for
salvage HIFU in routine clinical practice. There is also a risk of significant morbidity associated with its use in
the salvage setting. Consequently, salvage HIFU should only be performed in selected patients in experienced
centres as part of a clinical trial or well-designed prospective cohort study.

6.3.6 Hormonal therapy for relapsing patients

The Panel conducted a systematic review including studies published from 2000 onwards [1101]. Conflicting
results were found on the clinical effectiveness of HT after previous curative therapy of the primary tumour.
Some studies reported a favourable effect of HT, including the only RCT addressing the research question
of this review (86% vs. 79% advantage in OS in the early HT group) [1102]. Other studies did not find any
differences between early vs. delayed, or no, HT. One study found an unfavourable effect of HT [1103]. This
may be the result of selecting clinically unfavourable cases for (early) HT and more intensive diagnostic workup
and follow-up in these patients.

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 The studied population is highly heterogeneous regarding their tumour biology and therefore clinical
course. Predictive factors for poor outcomes were; CRPC, distant metastases, CSS, OS, short PSA-DT, high
ISUP grade, high PSA, increased age and co-morbidities. In some studies, such as the Boorjian, et al., study
[1104], high-risk patients, mainly defined by a high ISUP grade and a short PSA-DT (most often less than
6 months) seem to benefit most from (early) HT, especially men with a long life expectancy.

No data were found on the effectiveness of different types of HT, although it is unlikely that this will have a
significant impact on survival outcomes in this setting. Non-steroidal anti-androgens have been claimed to be
inferior compared to castration, but this difference was not seen in M0 patients [1036]. One of the included
RCTs suggested that intermittent HT is not inferior to continuous HT in terms of OS and CSS [1105]. A small
advantage was found in some QoL domains but not overall QoL outcomes. An important limitation of this
RCT is the lack of any stratifying criteria such as PSA-DT or initial risk factors. Based on the lack of definitive
efficacy and the undoubtedly associated significant side effects, patients with recurrence after primary curative
therapy should not receive standard HT since only a minority of them will progress to metastases or PCa-
related death. The objective of HT should be to improve OS, postpone distant metastases, and improve QoL.
Biochemical response to only HT holds no clinical benefit for a patient. For older patients and those with
co-morbidities the side effects of HT may even decrease life expectancy; in particular cardiovascular risk
factors need to be considered [1106, 1107]. Early HT should be reserved for those at the highest risk of disease
progression defined mainly by a short PSA-DT at relapse (< 6–12 months) or a high initial ISUP grade (> 2/3)
and a long life expectancy.

6.3.7 Observation
In unselected relapsing patients the median actuarial time to the development of metastasis will be 8 years and
the median time from metastasis to death will be a further 5 years [903]. For patients with EAU Low-Risk BCR
features (see Section 6.3.3), unfit patients with a life expectancy of less than 10 years or patients unwilling to
undergo salvage treatment, active follow-up may represent a viable option.

6.3.8 Guidelines for second-line therapy after treatment with curative intent

Local salvage treatment Strength rating

Recommendations for biochemical recurrence (BCR) after radical prostatectomy
Offer monitoring, including prostate-specific antigen (PSA), to EAU Low-Risk BCR patients. Weak
Offer early salvage intensity-modulated radiotherapy/volumetric arc radiation therapy plus Strong
image-guided radiotherapy to men with two consecutive PSA rises.
A negative positron emission tomography/computed tomography (PET/CT) scan should not Strong
delay salvage radiotherapy (SRT), if otherwise indicated.
Do not wait for a PSA threshold before starting treatment. Once the decision for SRT has Strong
been made, SRT (at least 64 Gy) should be given as soon as possible.
Offer hormonal therapy in addition to SRT to men with BCR. Weak
Recommendations for BCR after radiotherapy
Offer monitoring, including PSA to EAU Low-Risk BCR patients. Weak
Only offer salvage radical prostatectomy (RP), brachytherapy, stereotactic body Strong
radiotherapy, high-intensity focused ultrasound, or cryosurgical ablation to highly selected
patients with biopsy-proven local recurrence within a clinical trial setting or well-designed
prospective cohort study undertaken in experienced centres.
Recommendations for systemic salvage treatment
Do not offer androgen deprivation therapy to M0 patients with a PSA-doubling time Strong
> 12 months.
Recommendations for follow-up after radical prostatectomy or radiotherapy
Routinely follow-up asymptomatic patients by obtaining at least a disease-specific history Strong
and serum prostate-specific antigen (PSA) measurement.
At recurrence, only perform imaging if the result will affect treatment planning. Strong

6.4 Treatment: Metastatic prostate cancer

6.4.1 Introduction
All prospective data available rely on the definition of M1 disease based on CT scan or MRI and bone
scintigraphy. The influence on treatment and outcome of newer, more accurate, imaging has not been
assessed yet.

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6.4.2 Prognostic factors
Median survival of patients with newly diagnosed metastases (synchronous mHSPC) is approximately
42 months with ADT alone, however, it is highly variable since the M1 population is heterogeneous [1108].
Several prognostic factors for survival have been suggested including the number and location of bone
metastases, presence of visceral metastases, ISUP grade, PS status and initial PSA and alkaline phosphatase
level, but only few have been validated [1109-1112].
‘Volume‘ of disease as a potential predictor was introduced by CHAARTED (Chemo-hormonal
Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) [1112-1114]
(see table 6.4.1) and subsequently, in STAMPEDE, was shown to be predictive in an adequately powered
subgroup analysis for benefit of addition of prostate RT to ADT in the subgroup of patients with low volume/
burden disease [1115] (See table 6.4.1).
‘Metachronous’ metastatic disease (after radical local treament of the primary tumour) vs.
synchronous (or de novo) metastatic disease has also been shown to have generally a better prognosis [1116].
Based on a large SWOG 9346 cohort, the PSA level after 7 months of ADT was used to create 3
prognostic groups (see Table 6.4.2) [1117]. A PSA < 0.2 ng/mL at 7 months has been confirmed as a prognostic
marker for men receiving ADT for metastatic disease in the CHAARTED study independent of the addition of
docetaxel [1118].

Table 6.4.1 D
 efinition of high- and low-volume in CHAARTED [1112-1114] and high- and low-risk in
LATITUDE [765]

High Low
CHAARTED > 4 Bone metastases including > 1 outside vertebral column or pelvis Not high
(volume) AND/OR
Visceral metastasis*
LATITUDE > 2 high-risk features of: Not high
(risk) • > 3 Bone metastasis
• Visceral metastasis
• > ISUP grade 4
*Lymph nodes are not considered as visceral metastases.

Table 6.4.2: Prognostic factors based on the SWOG 9346 study [1117]

PSA after 7 months after start of ADT Median survival on ADT monotherapy
< 0.2 ng/mL 75 months
0.2 < 4 ng/mL 44 months
> 4 ng/mL 13 months

6.4.3 First-line hormonal treatment

Primary ADT has been the SOC for over 50 years [728]. There is no high-level evidence in favour of a specific
type of ADT for oncological outcomes, neither for orchiectomy nor for a LHRH agonist or antagonist. The
level of testosterone is reduced much faster with orchiectomy and LHRH antagonist, therefore patients with
impending spinal cord compression or other potential impending complications from the cancer should be
treated with either a bilateral orchidectomy or LHRH antagonists as the preferred options.
There is a suggestion in some studies that cardiovascular side effects are less frequent in patients
treated with LHRH antagonists than patients treated with LHRH agonists [747, 1119, 1120]; therefore, patients
with pre-existing cardiovascular disease or other cardio-vascular risk factors might be considered to be treated
with antagonists if a chemical castration is chosen.

6.4.3.1 Non-steroidal anti-androgen monotherapy

Based on a Cochrane review comparing non-steroidal anti-androgen (NSAA) monotherapy to ADT (either
medical or surgical), NSAA was considered to be less effective in terms of OS, clinical progression, treatment
failure and treatment discontinuation due to AEs [1121] and is generally not recommended also because ADT-
based combination treatments have become SOC.

6.4.3.2 Intermittent versus continuous androgen deprivation therapy

Three independent reviews [1122-1124] and two meta-analyses [1125, 1126] looked at the clinical efficacy
of intermittent androgen deprivation (IAD) therapy. All of these reviews included 8 RCTs of which only 3 were

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 109

conducted in patients with exclusively M1 disease.
So far, the SWOG 9346 is the largest trial addressing IAD in M1b patients [1127]. Of 3,040 screened
patients, only 1,535 patients met the inclusion criteria. This highlights that only about 50% of M1b patients
can be expected to be candidates for IAD, i.e. the best PSA responders. This was a non-inferiority trial leading
to inconclusive results: the actual upper limit was above the pre-specified 90% upper limit of 1.2 (HR: 1.1,
CI: 0.99–1.23), the pre-specified non-inferiority limit was not achieved, and the results did not show a
significant inferiority for any treatment arm. However, based on this study inferior survival with IAD cannot be
completely ruled out even in this highly selected subgroup. The use of intermittent ADT has been superseeded
as continuous ADT has become SOC.

6.4.3.3 Early versus deferred androgen deprivation therapy

Early treatment before the onset of symptoms is recommended in the majority of patients with metastatic
hormone-sensitive disease despite lack of randomised phase III data in this specific setting and specifically not
with the combination therapies that are standard nowadays.

A Cochrane analysis from 2019 about the topic concluded that early ADT probably extends time to death
of any cause and time to death from PCa [1128]. Since the analysis included only a very limited number of
biochemical recurrence patients, the benefit of early ADT in this setting remains unproven. All of the trials
testing the combination therapies in the metastatic hormone-sensitive setting also included asymptomatic
patients.

The only candidates with metastatic disease who may possibly be considered for deferred treatment are
asymptomatic patients with a strong wish to avoid treatment-related side effects. The risk of developing
symptoms, and even dying from PCa, without receiving the benefit from HT with deferred treatment has been
highlighted [841, 1129], but in the era before next generation imaging was used.
Patients with deferred treatment for advanced PCa must be amenable to close follow-up. Another
potential exception are patients with recurrent oligometastatic disease who have a strong wish to postpone the
start of ADT (see Section 6.4.7).

6.4.4 Combination therapies

All of the following combination therapies have been studied with continuous ADT, not intermittent ADT.

6.4.4.1 ‘Combined’ androgen blockade with older generation NSAA (bicalutamide, flutamide, nilutamide)
Systematic reviews have shown that CAB using a NSAA appears to provide a small survival advantage
(< 5%) vs. monotherapy (surgical castration or LHRH agonists) [1130, 1131] but this minimal survival advantage
must be balanced against the increased side effects. In addition, the newer combination therapies (see
Tables 6.4.3, 6.4.4, 6.4.5) are more effective as shown specifically for enzalutamide which was tested against.
NSAA in a phase III trial [1132]. More recently another trial has demonstrated a significant OS benefit for the
addition of rezvilutamide vs. addition of bicalutamide to ADT in patients with high-volume mHSPC [1133].
Therefore, combination with NSAAs should only be considered if other combination therapies are not available.

6.4.4.2 Androgen deprivation combined with other agents

6.4.4.2.1 Androgen deprivation therapy combined with chemotherapy
Three large RCTs were conducted [849, 1112, 1134]. All trials compared ADT alone as the SOC with ADT
combined with immediate docetaxel (75 mg/sqm, every 3 weeks within 3 months of ADT initiation). The primary
objective in all three studies was to assess OS. The key findings are summarised in Table 6.4.3.

Table 6.4.3: Key findings - Hormonal treatment combined with chemotherapy

STAMPEDE [849, 1135] GETUG-AFU 15 [1134] CHAARTED [1112,1113]

ADT ADT + Docetaxel ADT ADT + Docetaxel ADT ADT + Docetaxel
(6 cycles) + P (9 cycles) (6 cycles)
N 1,184 592 193 192 393 397
Newly 58% 59% 75% 67% 73% 73%
diagnosed M+

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Key inclusion Patients scheduled for long- Metastatic disease Metastatic disease
criteria term ADT Karnofsky score > 70% ECOG PS 0, 1 or 2
- newly diagnosed M1 or N+
situations
- locally advanced (at least two
of cT3 cT4, ISUP grade > 4,
PSA > 40 ng/mL)
- relapsing locally treated
disease with a PSA > 4 ng/mL
and a PSA-DT < 6 mo.

or PSA > 20 ng/mL,

or nodal
or metastatic relapse
Primary OS OS OS
objective
Median follow 43; 78.2 (update M1) 50 54 (update)
up (mo)
HR (95% CI) 0.78 (0.66-0.93) 1.01 (0.75-1.36) 0.72 (0.59-0.89)
M1 only
N 1,086 - -
HR (95% CI) 0.81 (0.69-0.95) - -
ADT = androgen deprivation therapy; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group;
HR = hazard ratio; ISUP = International Society for Urological Pathology; mo = month; n = number of patients;
OS = overall survival; P = prednisone; PSA-DT = prostate-specific antigen-doubling time.

In the GETUG 15 trial, all patients had M1 PCa, either de novo or after a primary treatment [1134]. They were
stratified based on previous treatment and Glass risk factors [1109]. In the CHAARTED trial the same inclusion
criteria applied, and patients were stratified according to disease volume (see Table 6.4.1) [1112].

STAMPEDE is a multi-arm multi-stage trial in which the reference arm (ADT monotherapy) included 1,184
patients. One of the experimental arms was docetaxel combined with ADT (n = 593), another was docetaxel
combined with zoledronic acid (n = 593). Patients were included with either M1 or N1 or having two of the
following 3 criteria: T3/4, PSA > 40 ng/mL or ISUP grade 4–5. Also relapsed patients after local treatment were
included if they met one of the following criteria: PSA > 4 ng/mL with a PSA-DT < 6 months or a PSA > 20 ng/mL,
N1 or M1. No stratification was used regarding metastatic disease volume (high/low volume) [849]. In all 3 trials
toxicity was mainly haematological with around 12–15% grade 3–4 neutropenia, and 6–12% grade 3–4 febrile
neutropenia. The use of granulocyte colony-stimulating factor receptor (GCSF) was shown to be beneficial
in reducing febrile neutropenia. Primary or secondary prophylaxis with GCSF should be based on available
guidelines [1136, 1137].

Docetaxel in all three trials was used at the standard dose of 75 mg/sqm every 3 weeks, 6 cycles in
CHAARTED and STAMPEDE and up to 9 cycles in GETUG-AFU-15.

In subgroup analyses from GETUG-AFU 15 and CHAARTED the beneficial effect of the addition of docetaxel
to ADT was most evident in men with de novo metastatic high-volume disease [1113, 1114], while it was in
the same range whatever the volume in the post-hoc analysis from STAMPEDE [1135]. The effect of adding
docetaxel was less apparent in men who had prior local radical treatment although the numbers were small
and the event rates lower. A systematic review and meta-analysis which included these 3 trials showed that
the addition of docetaxel to SOC improved survival [1137]. The HR of 0.77 (95% CI: 0.68–0.87, p < 0.0001)
translates into an absolute improvement in 4-year survival of 9% (95% CI: 5–14).

Based on these data, upfront docetaxel combined with ADT was considered as a standard in men presenting
with metastases at first presentation, provided they are fit enough to receive docetaxel [1137]. More recently
two large Phase 3 studies have now shown an OS benefit by adding an ARPI to ADT and docetaxel. Therefore
adding docetaxel alone to ADT should only be considered if no ARPI is available or all available ones are
contra-indicated (see Section 6.4.4.2.3).

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 111

6.4.4.2.2 Combination with an ARPI alone (abiraterone, apalutamide, enzalutamide)
In two large RCTs (STAMPEDE, LATITUDE) the addition of abiraterone acetate (1000 mg daily) plus prednisone
(5 mg daily) to ADT in men with mHSPC was studied [765, 892, 1138] (see table 6.4.4). The primary objective
of both trials was an improvement in OS. Both trials showed a significant OS benefit. In LATITUDE with only
de novo high-risk metastatic patients included, the HR reached 0.62 (0.51–0.76) [765]. The HR in STAMPEDE
was very similar with 0.63 (0.52–0.76) in the total patient population (metastatic and non-metastatic) and a
HR of 0.61 in the subgroup of metastatic patients [892]. While only high-risk patients were included in the
LATITUDE trial a post-hoc analysis from STAMPEDE showed the same benefit whatever the risk or the volume
stratification [1139].

All secondary objectives such as PFS, time to radiographic progression, time to pain, or time to chemotherapy
were positive and in favour of the combination. No difference in treatment-related deaths was observed with
the combination of ADT plus AAP compared to ADT monotherapy (HR: 1.37 [0.82–2.29]). However, twice as
many patients discontinued treatment due to toxicity in the combination arms in STAMPEDE (20%) compared
to LATITUDE (12%) [1138]. Based on these data upfront AAP combined with ADT should be considered as a
standard in men presenting with metastases at first presentation, provided they are fit enough to receive the drug.

In three large RCTs (ENZAMET, ARCHES and TITAN) the addition of AR antagonists to ADT in men with
mHSPC was tested [763, 764, 1132]. In ARCHES the primary endpoint was radiographic PFS (rPFS). In the
primary analysis rPFS was significantly improved for the combination of enzalutamide and ADT with a HR
of 0.39 (0.3–0.5). Approximately 36% of the patients had low-volume disease; around 25% had prior local
therapy and 18% of the patients had received prior docetaxel. In the final prespecified analysis the key
secondary enpoint OS was significantly improved with a HR of 0.66 (0.53-0.81) and a significant benefit for
rPFS was maintained with a HR of 0.63 (0,52–0.76) [1140]. In ENZAMET the primary endpoint was OS. The
addition of enzalutamide to ADT in the first analysis improved OS with a HR of 0.67 (0.52–0.86) compared to
ADT plus a non-steroidal antiandrogen. Approximately half of the patients had concomitant docetaxel; about
40% had prior local therapy and about half of the patients had low-volume disease [764]. In the TITAN trial,
ADT plus apalutamide was used and rPFS and OS were co-primary endpoints. In the primary analysis rPFS
was significantly improved by the addition of apalutamide with a HR of 0.48 (0.39–0.6); OS at 24 months
was improved for the combination with a HR of 0.67 (0.51–0.89). In the final analysis the HR for OS was 0.65
(0.53–0.79) without adjustment for cross-over. In this trial 16% of patients had prior local therapy, 37% had
low-volume disease and 11% received prior docetaxel [763, 1141]. In the more recently published CHART trial,
ADT plus rezvilutamide was tested vs. ADT plus bicalutamide in patients with high-volume de novo metastatic
disease. Ninety percent of the patients were recruited in China. Overall survival and rPFS were co-primary
endpoints. At the pre-planned interim analysis rezvilutamide significantly improved rPFS compared with
bicalutamide with a HR of 0.44 (0.33–0.58) and OS with a HR of 0.58 (0.44–0.77) [1133].

In summary, the addition of the new AR antagonists significantly improves clinical outcomes with no convincing
evidence of differences between subgroups. The majority of patients had de novo metastatic disease and the
evidence is most compelling in this situation. In the trials with the new AR antagonists, a proportion of patients
had metachronous disease (see Table 6.4.5); in the subgroup analyses the effect seemed to be consistent and
therefore, a combination should also be offered for men progressing after radical local therapy [1142].

Table 6.4.4: Results from the STAMPEDE arm G and LATITUDE studies

STAMPEDE [892] LATITUDE [765]

ADT ADT + AA + P ADT + placebo ADT + AA + P
N 957 960 597 602
Newly diagnosed N+ 20% 19% 0 0
Newly diagnosed M+ 50% 48% 100% 100%
Key inclusion criteria Patients scheduled for long-term ADT Newly diagnosed M1 disease and 2 out
- newly diagnosed M1 or N+ situations of the 3 risk factors: ISUP grade > 4,
- locally advanced (at least two of cT3 cT4, > 3 bone lesions, measurable visceral
ISUP grade > 4, PSA > 40 ng/mL) metastasis
- relapsing locally treated disease with a
PSA > 4 ng/mL and a PSA-DT < 6 mo.

or PSA > 20 ng/mL

or nodal
or metastatic relapse

112 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

Primary objective OS OS
Radiographic PFS
Median follow up (mo) 40 30.4
3-yr. OS 83% (ADT + AA + P) 66% (ADT + AA + P)
76% (ADT) 49% (ADT + placebo)
HR (95% CI) 0.63 (0.52-0.76) 0.62 (0.51-0.76)
M1 only
N 1,002 1,199
3-yr. OS NA 66% (ADT + AA + P)
49% (ADT + placebo)
HR (95% CI) 0.61 (0.49-0.75) 0.62 (0.51-0.76)
HR FFS (biological, radiological, clinical or rPFS:
death): 0.29 (0.25-0.34) 0.49 (0.39-0.53)
AA = abiraterone acetate; ADT = androgen deprivation therapy; CI = confidence interval; FFS = failure-free
survival; HR = hazard ratio; ISUP = International Society of Urological Pathology; mo = month; n = number
of patients; NA = not available; OS = overall survival; P = prednisone; rPFS = radiographic progression-free
survival; PSA = prostate-specific antigen; yr. = year.

Table 6.4.5: Results from the ENZAMET and TITAN studies with OS as primary endpoint

ENZAMET [1132] TITAN [763, 1141]

ADT+ older ADT + enzalutamide ADT + placebo ADT +
antagonist ± docetaxel apalutamide
± docetaxel (SOC)
N 562 563 527 525
Newly diagnosed M+ 72.1% 72.5% 83.7% 78.3%
Low volume 47% 48% 36% 38%
Primary objective OS OS
rPFS
Median follow up (mo) 34 30.4
3-yr. OS 3-yr survival: 2-yr survival:
80% (ADT + enzalutamide) 84% (ADT + apalutamide)
72% (SOC) 74% (ADT + placebo)
HR (95% CI) for OS 0.67 (0.52-0.86) 0.67 (0.51-0.89)
ADT = androgen deprivation therapy; CI = confidence interval; HR = hazard ratio; mo = month; n = number of
patients; OS = overall survival; SOC = standard of care; rPFS = radiographic progression-free survival; yr = year.

Table 6.4.6: Results from the ARCHES and CHART studies [764, 1133, 1140]

ARCHES [764, 1140] CHART [1133]

ADT ± docetaxel ADT + enzalutamide ADT + ADT +
± docetaxel bicalutamide rezvilutamide
N 576 574 328 326
Newly diagnosed M+ 63% 70% 100% 100%
Low volume 35% 38% 0% 0%
Use of early docetaxel 18% (previous) 18% (previous) 0% 0%
Primary objective rPFS OS
rPFS
Median follow up (mo) 44.6 29.3
Median rPFS (mo.) 38.9 49.8 23.5 Not reached
HR (95% CI) for rPFS HR: 0.63 (0.52–0.76) HR: 0.46 (0.36–0.60)
Median OS Not reached Not reached Not reached Not reached
HR (95% CI) for OS 0.66 (0.53–0.81): Main secondary endpoint 0.58 (0.44–0.77)
HR = hazard ratio; mo = month; n = number of patients; OS = overall survival; rPFS = radiographic progression-
free survival; yr = year.

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6.4.4.2.3 Combination with docetaxel and an ARPI
The addition of abiraterone to ADT and docetaxel has been reported to have a benefit in rPFS and in OS in the
PEACE-1 trial [1143, 1144]. The trial has a 2x2 factorial design and participants with de novo (synchronous)
metastatic PCa were randomised to SOC; at the beginning of the trial ADT, later ADT plus docetaxel for 6
cycles if chemotherapy-fit) vs. SOC plus radiotherapy vs. SOC plus abiraterone vs. SOC plus radiotherapy plus
abiraterone. Co-primary endpoints were rPFS and OS, both were statistically significantly improved in the total
population. Also in the group of patients who received ADT plus docetaxel as SOC (n = 710) both rPFS and OS
were increased with a HR: 0.5 (0.34–0.71) and 0.75 (0.59–0.95), respectively. Of note; in this population about
35% had low-volume disease. Toxicity was modestly increased, mostly hypertension.
In the ARASENS Phase 3 trial all patients received ADT and docetaxel for 6 cycles as SOC plus
darolutamide or placebo [1145]. 1,306 metastatic patients were included, 14 % of them with relapsed disease
after radical local treatment (metachronous). Primary endpoint was OS and this was statistically significanty
increased by the addition of darolutamide with a HR of 0.68 (0.57–0.8).
Until now no subgroup analysis for high- and low-volume disease was reported. Interestingly, in
this trial the occurrence of AEs was similar in both arms. In both trials docetaxel and the ARPI have been given
concomitantly.
Also in ENZAMET, TITAN and ARCHES there were patients who received docetaxel as a part of
SOC, thus not all concommitantly, but the percentage of patients receiving docetaxel in these trials was much
lower [763, 764, 1132].

6.4.5 Treatment selection and patient selection

There have been several network meta-analyses of the published data concluding that combination therapy is
more efficient than ADT alone, but none of the combination therapies has been clearly proven to be superior
over another [1146, 1147]. As a consequence, patients should be offered combination treatment unless there
are clear contra-indications or they present with asymptomatic disease and a very short life expectancy (based
on non-cancer co-morbidities).

Since the data of the above mentioned Phase III trials of the triplet therapies have been reported, docetaxel
as sole addition to ADT is not longer a valid option in the majority of patients if an androgen receptor pathway
inhibitor (ARPI) is available and there are no contra-indiactions to use one. From subgroup analysis of all
the above-mentioned RCTs we know that probably all subgroups (high vs. low volume and synchronous
vs. metachronous) can profit from the addition of an ARPI to ADT. Therefore, in view of the current data
the recommendation is using ADT plus ARPI as the sole additional therapy or the triplet with an ARPI plus
docetaxel. Formally the question what the added value of adding docetaxel to ADT plus an ARPI has not
been evaluated, but since triplet therapy seems not to add a lot of unexpected overlapping toxicities, the data
should be discussed with patients who are fit for chemotherapy and an ARPI, realising that most of the toxicity
is caused by adding the chemotherapy. There is more evidence for using the triplet in synchronous disease
and the OS benefit in PEACE-1 seemed to be driven mostly by the high volume patients at the time point of
the analysis for the publication. In summary, the choice will most likely be driven by fitness for docetaxel, the
nature of the disease (low/high volume; synchronous/metachronous), patient preference, the specific side
effects, availability, logistics and cost.

6.4.6 Treatment of the primary tumour in newly diagnosed metastatic disease

The first reported trial evaluating prostate RT in men with metastatic castration-sensitive disease was the
HORRAD trial. Four hundred and thirty-two patients were randomised to ADT alone or ADT plus IMRT with
IGRT to the prostate. Overall survival was not significantly different (HR: 0.9 [0.7–1.14]), median time to PSA
progression was significantly improved in the RT arm (HR: 0.78 [0.63–0.97]) [1148]. The STAMPEDE trial
evaluated 2,061 men with metastatic castration-sensitive PCa (mCSPC) who were randomised to ADT alone
vs. ADT plus RT to the prostate. This trial confirmed that RT to the primary tumour did not improve OS in
unselected patients [1115]. However, following the results from CHAARTED and prior to analysing the data,
the original screening investigations were retrieved, and patients categorised as low- or high volume. In the
low-volume subgroup (n = 819) there was a significant OS benefit by the addition of prostate RT. This was
confirmed by the latest analysis of long-term follow-up (median follow-up of 61 months [HR: 0.64 for OS
benefit in the low-volume group]) [1149].
A secondary, not pre-planned, analysis of the STAMPEDE trial confirmed the benefit of prostate
RT in patients with < 3 bone metastases, but also showed a benefit in patients with M1a disease [1150]. No
evidence of difference in time to symptomatic local events was found with median follow-up of over 5 years
[1149]. The dose used in these indications should be equivalent of up to 72 Gy in 2 Gy fractions.
Therefore, RT of the prostate only in patients with low-volume metastatic disease should be
considered. Of note, only 18% of these patients had additional docetaxel and no patients had additional AAP,

114 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

so no clear recommendation can be made about triple combinations. In addition, it is not clear if these data
can be extrapolated to RP as local treatment as results of ongoing trials are awaited.
In a systematic review and meta-analysis including the above two RCTs, the authors found that,
overall, there was no evidence that the addition of prostate RT to ADT improved survival in unselected
patients (HR: 0.92, 95% CI: 0.81–1.04, p = 0.195) [1151]. However, there was a clear difference in the effect of
metastatic burden on survival with an absolute improvement of 7% in 3-year survival in men who had four or
fewer bone metastases.

6.4.7 Metastasis-directed therapy in M1-patients

In patients relapsing after a local treatment, a metastases-targeting therapy has been proposed, with the aim to
delay systemic treatment. There are two randomised phase II trials testing metastasis-directed therapy (MDT)
using surgery ± SABR vs. surveillance [1152] or SABR vs. surveillance in men with oligo-recurrent PCa [1153].
Oligo-recurrence was defined as < 3 lesions on choline-PET/CT only [1152] or conventional imaging with MRI/CT
and/or bone scan [1153]. The sample size was small with 62 and 54 patients, respectively, and a substantial
proportion of them had nodal disease only [1152]. Androgen deprivation therapy-free survival was the primary
endpoint in one study which was longer with MDT than with surveillance [1152]. The primary endpoint in the
ORIOLE trial was progression after 6 months which was significantly lower with SBRT than with surveillance
(19% vs. 61%, p = 0.005) [1153].
Recently the combined results of STOMP and ORIOLE confirmed the significant improvement in
PFS in favour of MDT (HR: 0.44, p < 0.001) [1154].

A phase II trial assessed the biochemical response after 18F-DCFPyL PET/MRI and subsequent MDT. Overall
biochemical response rate, defined as > 50% PSA decline, was 60%, including 22% of patients with complete
biochemical response [1155].

Currently there are no data to suggest an improvement in OS. Two comprehensive reviews highlighted MDT
(SABR) as a promising therapeutic approach that must still be considered as investigational until the results of
the ongoing RCT are available [1156, 1157]. Thus far, the toxicity of MDT appears to be low, but this also needs
to be confirmed [1158, 1159].

6.4.8 Guidelines for the first-line treatment of hormone-sensitive metastatic disease*

Recommendations Strength rating

Offer immediate systemic treatment with androgen deprivation therapy (ADT) to palliate Strong
symptoms and reduce the risk for potentially serious sequelae of advanced disease (spinal
cord compression, pathological fractures, ureteral obstruction) to M1 symptomatic patients.
At the start of ADT offer luteinising hormone-releasing hormone (LHRH) antagonists or Strong
orchiectomy to patients with impending clinical complications like spinal cord compression
or bladder outlet obstruction.
Offer early systemic treatment to M1 patients asymptomatic from their tumour. Strong
Offer short-term administration of an older generation androgen receptor (AR) antagonist to Weak
M1 patients starting LHRH agonist to reduce the risk of the ‘flare-up’ phenomenon.
Do not offer AR antagonist monotherapy to patients with M1 disease. Strong
Discuss combination therapy including ADT plus systemic therapy with all M1 patients. Strong
Do not offer ADT monotherapy to patients whose first presentation is M1 disease if they have Strong
no contra-indications for combination therapy and have a sufficient life expectancy to benefit
from combination therapy (> 1 year) and are willing to accept the increased risk of side effects.
Offer ADT combined with abiraterone acetate plus prednisone or apalutamide or Strong
enzalutamide to patients with M1 disease and who are fit for the regimen.
Offer docetaxel only in combination with ADT plus abiraterone or darolutamide to patients Strong
with M1 disease and who are fit for docetaxel.
Offer ADT combined with non-curative prostate radiotherapy (using doses up to the Strong
equivalent of 72 Gy in 2 Gy fractions) to patients whose first presentation is M1 disease and
who have low volume of disease by CHAARTED criteria/M1a disease.
Do not offer ADT combined with any local treatment (RT/surgery) to patients with high-volume Strong
(CHAARTED criteria) M1 disease outside of clinical trials (except for symptom control).
Do not offer ADT combined with surgery to M1 patients outside of clinical trials. Strong
Only offer metastasis-directed therapy to M1 patients within a clinical trial setting or well- Strong
designed prospective cohort study.
*All the following statements are based on metastatic disease defined by bone scintigraphy and CT scan/MRI.

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 115

6.5 Treatment: Castration-resistant PCa (CRPC)
6.5.1 Definition of CRPC
Castrate serum testosterone < 50 ng/dL or 1.7 nmol/L plus either:
a. Biochemical progression: Three consecutive rises in PSA at least one week apart resulting in two 50%
increases over the nadir, and a PSA > 2 ng/mL
or
b. Radiological progression: The appearance of new lesions: either two or more new bone lesions on
bone scan or a soft tissue lesion using RECIST (Response Evaluation Criteria in Solid Tumours) [1160].
Symptomatic progression alone must be questioned and subject to further investigation. It is not
sufficient to diagnose CRPC.

6.5.2 Management of mCRPC - general aspects

Selection of treatment for mCRPC is multifactorial and in general dependent on:
• previous treatment for mHSPC and for non-mHSPC;
• previous treatment for nmCRPC and mCRPC;
• quality of response and pace of progression on previous treatment;
• known cross resistance between androgen receptor pathway inhibitor (ARPI);
• co-medication and known drug interactions (see approved summary of product characteristics);
• known genetic alterations and microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR)
status;
• known histological variants and DNA repair deficiency (to consider platinum or targeted therapy like
PARPi);
• local approval status of drugs and reimbursement situation;
• available clinical trials;
• The patient and his co-morbidities.

6.5.2.1 Molecular diagnostics

All metastatic patients should be offered somatic genomic testing for homologous repair and MMR defects,
preferably on metastatic carcinoma tissue but testing on primary tumour may also be performed. Alternatively,
but still less common, genetic testing on circulating tumour DNA (ctDNA) is an option and has been used
in some trials. One test, the FoundationOne® Liquid CDx, has been FDA approved [1161]. Defective MMR
assessment can be performed by IHC for MMR proteins (MSH2, MSH6, MLH1 and PMS2) and/or by next-
generation sequencing (NGS) assays [1162]. Germline testing for BRCA1/2, ATM and MMR is recommended
for high-risk- and particularly for metastatic PCa if clinically indicated.
Molecular diagnostics should be performed by a certified (accredited) institution using a standard
NGS multiplication procedure (minimum depth of coverage of 200 X). The genes and respective exons should
be listed; not only DNA for mutations but RNA needs to be examined for fusions and protein expression to
obtain all clinically relevant information. A critical asset is the decision support helping to rate the mutations
according to their clinical relevance [1163, 1164].
Level 1 evidence for the use of PARP-inhibitors has been reported [1165-1167]. Microsatellite
instability (MSI)-high (or MMR deficiency) is rare in PCa, but for those patients, pembrolizumab has been
approved by the FDA and could be a valuable additional treatment option [770, 1168]. Germline molecular
testing is discussed in Section 5.1.3 - Genetic testing for inherited PCa. Recommendations for germline testing
are provided in Section 5.1.4.

6.5.3 Treatment decisions and sequence of available options

Approved agents for the treatment of mCRPC in Europe are docetaxel, abiraterone/prednisolone,
enzalutamide, cabazitaxel, olaparib and radium-223. In general, sequencing of ARPIs like abiraterone and
enzalutamide is not recommended particularly if the time of response to ADT and to the first ARPI was short
(< 12 months) and high-risk features of rapid progression are present (see detailed discussion in Section 6.5.7)
[1169, 1170].
The use of chemotherapy with docetaxel and subsequent cabazitaxel in the treatment sequence
is recommended and should be applied early enough when the patient is still fit for chemotherapy. This is
supported by high-level evidence [1169].

6.5.4 Non-metastatic CRPC

Frequent PSA testing in men treated with ADT has resulted in earlier detection of biochemical progression. Of
these men approximately one-third will develop bone metastases within two years, detected by conventional
imaging [972].
In men with CRPC and no detectable clinical metastases using bone scan and CT-scan, baseline

116 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

PSA level, PSA velocity and PSA-DT have been associated with time to first bone metastasis, bone
metastasis-free survival and OS [972, 1171]. These factors may be used when deciding which patients
should be evaluated for metastatic disease. A consensus statement by the PCa Radiographic Assessments
for Detection of Advanced Recurrence (RADAR) group suggested a bone scan and a CT scan when the PSA
reached 2 ng/mL and if this was negative, it should be repeated when the PSA reached 5 ng/mL, and again
after every doubling of the PSA based on PSA testing every three months in asymptomatic men [1172].
Symptomatic patients should undergo relevant investigations regardless of PSA level. With more sensitive
imaging techniques like PSMA PET/CT or whole-body MRI, more patients are diagnosed with early mCRPC
[1173]. It remains unclear if the use of PSMA PET/CT in this setting improves outcome.

Three large phase III RCTs, PROSPER [1174], SPARTAN [1175] and ARAMIS [1176], evaluated metastasis-free
survival as the primary endpoint in patients with nmCRPC (M0 CRPC) treated with enzalutamide (PROSPER)
vs. placebo or apalutamide (SPARTAN) vs. placebo or darolutamide vs. placebo (ARAMIS), respectively
(see Table 6.5.1). The M0 status was established by CT and bone scans. Only patients at high risk for the
development of metastasis with a short PSA-DT of < 10 months were included. Patient characteristics in trials
revealed that about two-thirds of participants had a PSA-DT of < 6 months. All trials showed a significant
metastasis-free survival benefit. All three trials showed a survival benefit after a follow-up of more than 30
months. In view of the long-term treatment with these AR targeting agents in asymptomatic patients, potential
AEs need to be taken into consideration and the patient informed accordingly.

Table 6.5.1: R
 andomised phase III controlled trials – nmCRPC

Study Intervention Comparison Selection criteria Main outcomes

ARAMIS ADT + darolutamide ADT + placebo nmCRPC; 59% reduction of distant
2019, 2020 baseline progression or death
[1176, 1177] PSA > 2 ng/mL Median MFS: darolutamide
PSA-DT < 10 mo. 40.4 vs placebo 18.4 mo;
31% reduction in risk of death
HR = 0.69 (95% CI: 0.53–0.88)
p = 0.003
PROSPER ADT + enzalutamide ADT + placebo nmCRPC; 71% reduction of distant
2018, 2020 baseline progression or death
[1174, 1178] PSA > 2 ng/mL Median MFS: enzalutamide
PSA-DT < 10 mo. 36.6 vs placebo 14.7 months;
27% reduction in risk of death
HR = 0.73 (95% CI: 0.61–0.89)
p = 0.001
SPARTAN ADT + apalutamide ADT + placebo nmCRPC; 72% reduction of distant
2018, 2021 baseline progression or death
[1175, 1179] PSA > 2 ng/mL Median MFS: apalutamide
PSA-DT < 10 mo. 40.5 vs placebo 16.2 months;
22% reduction in risk of death
HR = 0.78 (95% CI: 0.64–0.96)
p = 0.0161
ADT = androgen-deprivation therapy; CI = confidence interval; HR = hazard ratio; MFS = metastasis-free
survival; nmCRPC = non-metastatic castrate-resistent prostate cancer; PSA-DT = prostate-specific antigen
doubling time.

6.5.5 Metastatic CRPC

The remainder of this section focuses on the management of men with proven mCRPC on conventional
imaging.

6.5.5.1 Conventional androgen deprivation in CRPC

Eventually men with PCa will show evidence of disease progression despite castration. Two trials have
shown only a marginal survival benefit for patients remaining on LHRH analogues during second- and third-
line therapies [1180, 1181]. However, in the absence of prospective data, the modest potential benefits of
continuing castration outweigh the minimal risk of treatment. In addition, all subsequent treatments have been
studied in men with ongoing androgen suppression, therefore, it should be continued in these patients.

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6.5.6 First-line treatment of metastatic CRPC
6.5.6.1 Abiraterone
Abiraterone was evaluated in 1,088 chemo-naive, asymptomatic or mildly symptomatic mCRPC patients in the
phase III COU-AA-302 trial. Patients were randomised to abiraterone acetate or placebo, both combined with
prednisone [1182]. Patients with visceral metastases were excluded. The main stratification factors were ECOG
PS 0 or 1 and asymptomatic or mildly symptomatic disease. Overall survival and rPFS were the co-primary
endpoints. After a median follow-up of 22.2 months there was significant improvement of rPFS (median 16.5
vs. 8.2 months, HR: 0.52, p < 0.001) and the trial was unblinded. At the final analysis with a median follow-up
of 49.2 months, the OS endpoint was significantly positive (34.7 vs. 30.3 months, HR: 0.81, 95% CI: 0.70–0.93,
p = 0.0033) [1183]. Adverse events related to mineralocorticoid excess and liver function abnormalities were
more frequent with abiraterone, but mostly grade 1–2. Subset analysis of this trial showed the drug to be
equally effective in an elderly population (> 75 years) [1184].

6.5.6.2 Enzalutamide
A randomised phase III trial (PREVAIL) included a similar patient population and compared enzalutamide
and placebo [1185]. Men with visceral metastases were eligible but the numbers included were small.
Corticosteroids were allowed but not mandatory. PREVAIL was conducted in a chemo-naive mCRPC
population of 1,717 men and showed a significant improvement in both co-primary endpoints, rPFS (HR: 0.186,
CI: 0.15–0.23, p < 0.0001), and OS (HR: 0.706, CI: 0.6–0.84, p < 0.001). A > 50% decrease in PSA was seen
in 78% of patients. The most common clinically relevant AEs were fatigue and hypertension. Enzalutamide
was equally effective and well tolerated in men > 75 years [1186] as well as in those with or without visceral
metastases [1187]. However, for men with liver metastases, there seemed to be no discernible benefit [1187,
1188].
Enzalutamide has also been compared with bicalutamide 50 mg/day in a randomised double-blind
phase II study (TERRAIN) showing a significant improvement in PFS (15.7 months vs. 5.8 months, HR: 0.44,
p < 0.0001) in favour of enzalutamide [1188]. With extended follow-up and final analysis the benefit in OS and
rPFS were confirmed [1189].

6.5.6.3 Docetaxel
A statistically significant improvement in median survival of 2.0–2.9 months has been shown with docetaxel-
based chemotherapy compared to mitoxantrone plus prednisone [1190, 1191]. The standard first-line
chemotherapy is docetaxel 75 mg/m2, 3-weekly doses combined with prednisone 5 mg twice a day (BID), up
to 10 cycles. Prednisone can be omitted if there are contra-indications or no major symptoms. The following
independent prognostic factors: visceral metastases, pain, anaemia (Hb < 13 g/dL), bone scan progression,
and prior estramustine may help stratify the response to docetaxel. Patients can be categorised into three
risk groups: low risk (0 or 1 factor), intermediate (2 factors) and high risk (3 or 4 factors), and show three
significantly different median OS estimates of 25.7, 18.7 and 12.8 months, respectively [1192].
Age by itself is not a contra-indication to docetaxel [1193] but attention must be paid to careful
monitoring and co-morbidities as discussed in Section 5.4 - Estimating life expectancy and health status
[1194]. In men with mCRPC who are thought to be unable to tolerate the standard dose and schedule,
docetaxel 50 mg/m2 every two weeks seems to be well tolerated with less grade 3–4 AEs and a prolonged time
to treatment failure [1195].

6.5.6.4 Sipuleucel-T
In 2010 a phase III trial of sipuleucel-T showed a survival benefit in 512 asymptomatic or minimally
symptomatic mCRPC patients [1196]. After a median follow-up of 34 months, the median survival was
25.8 months in the sipuleucel-T group compared to 21.7 months in the placebo group, with a HR of 0.78
(p = 0.03). No PSA decline was observed and PFS was similar in both arms. The overall tolerance was very
good, with more cytokine-related AEs grade 1–2 in the sipuleucel-T group, but the same grade 3–4 AEs in both
arms. Sipuleucel-T is not available in Europe.

6.5.6.5 Ipatasertib
The AKT inhibitor ipatasertib in combination with AAP was studied in asymptomatic or mildly symptomatic
patients with and without PTEN loss by IHC and previously untreated for mCRPC. The randomised phase III
trial (IPAtential) showed a significant benefit for the first endpoint rPFS in the PTEN loss (IHC) 18.5 vs. 16.5 mo;
p = 0.0335, HR: 0.77, 95% CI: 0.61–0,98) but not in the intention to treat (ITT) population. The OS results are
still pending. Side effects of the AKT inhibitor ipatasertib include rash and diarrhoea [771]. Grade 3 or higher
AEs occurred nearly double as often in the combination group and the discontinuation rate due to AEs was
4 times higher. This combination is still investigational [1197].

118 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

6.5.6.6 Combinations
Based on the suggestion that there is a synergistic antitumour effect when combining abiraterone with a PARP
inhibitor, several such combination trials were conducted with conflicting results.

Abiraterone/prednisone plus olaparib

A randomised double-blind, phase 3 trial (PROpel) of abiraterone (1000 mg once daily) plus prednisone 5 mg/
twice daily (AAP) and olaparib (300 mg twice/daily) or placebo in patients with mCRPC in the first-line setting
was conducted [1198]. Of note, 796 patients met the eligibility criteria and were randomly assigned 1:1 to
study treatment regardless of homologous recombination repair gene mutation (HRRm) status which was
retrospectively evaluated and determined by tumour tissue and circulating tumour DNA tests. The primary
end point was imaging-based PFS (ibPFS) by investigator assessment. The result was significantly positive
in favour of the combination with ibPFS of 24.8 vs. 16.6 mo (HR 0.66; 95% CI: 0.54 to 0.81; p = 0.001). The
subgroup of patients with positive HRRm status showed a HR of 0.50 (CI: 0.34 to 0.73) which seems to be
a major driver of the overall result. Survival data are still immature. The most common side effects with the
combination were anaemia, fatigue/asthenia, and nausea.

Abiraterone/prednisone plus niraparib

At ASCO 2022, a randomised, double-blind, phase 3 trial (MAGNITUDE) evaluating abiraterone (1,000 mg once
daily) plus prednisone 5 mg twice/daily plus niraparib 200 mg once/daily or placebo, was presented [1199]. The
final paper has not yet been published.

Table 6.5.2: Randomised phase III controlled trials - first-line treatment of mCRPC

Study Intervention Comparison Selection criteria Main outcomes

DOCETAXEL
SWOG 99-16 docetaxel/EMP, mitoxantrone, OS: 17.52 vs. 15.6 mo.
2004 [1200] every 3 weeks, every 3 weeks, (p = 0.02, HR: 0.80;
60 mg/m2, EMP 12 mg/m2 95% CI: 0.67-0.97)
3 x 280 mg/day prednisone 5 mg PFS: 6.3 vs. 3.2 mo.
BID (p < 0.001)
TAX 327 docetaxel, every mitoxantrone, OS: 19.2 for 3 weekly
2004, 2008 3 weeks, 75 mg/m2 every 3 weeks, vs. 17.8 mo. 4-weekly
[1190,1201] prednisone 5 mg 12 mg/m2, and 16.3 in the control
BID Prednisone 5 mg group.
or BID (p = 0.004, HR: 0.79,
docetaxel, weekly, 95% CI: 0.67-0.93)
30 mg/m2
prednisone 5 mg
BID
ABIRATERONE
COU-AA-302 abiraterone + placebo + - No previous docetaxel. OS: 34.7 vs. 30.3 mo.
2013, 2014, 2015 prednisone prednisone - ECOG 0-1. (HR: 0.81, p = 0.0033).
[1182, 1183, 1202] - PSA or radiographic FU: 49.2 mo. rPFS:
progression. 16.5 vs. 8.3 mo.
- No or mild symptoms. (p < 0.0001)
- No visceral metastases.
ENZALUTAMIDE
PREVAIL enzalutamide placebo - No previous docetaxel. OS: 32.4 vs. 30.2 mo.
2014 [1185] - ECOG 0-1. (p < 0.001). FU: 22 mo.
- PSA or radiographic (p < 0.001 HR: 0.71,
progression. 95% CI: 0.60-0.84)
- No or mild symptoms. rPFS: 20.0 mo. vs.
- 10% had visceral mets. 5.4 mo. HR: 0.186
(95% CI: 0.15-0.23)
p < 0.0001)

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SIPULEUCEL-T
IMPACT2010 sipuleucel-T placebo - Some with previous OS: 25.8 vs. 21.7 mo.
[1196] docetaxel. (p = 0.03 HR: 0.78,
- ECOG 0-1. 95% CI: 0.61-0.98).
- Asymptomatic or FU: 34.1 mo. PFS:
minimally symptomatic. 3.7 vs. 3.6 mo. (no
difference)
2006 [1203] sipuleucel-T placebo - ECOG 0-1. OS: 25.9 vs. 21.4 mo.
- No visceral met. (p = 0.1). FU: 36 mo.
- No corticosteroids. PFS: 11.7 vs. 10.0 wk.
IPATASERTIB
IPAtential150 ipatasertib abiraterone + Previously untreated for rPFS in PTEN loss
2021 [1197] (400 mg/d) + prednisolone + mCRPC, asymptomatic/ (IHC) population:
abiraterone placebo mildly symptomatic, with 18.5 vs. 16.5 mo.
(1000 mg/d) + and without PTEN loss (p = 0.0335, HR: 0.77
prednisone by IHC 95% CI: 0.61-0.98)
(5 mg bid)
PROpel [1198] olaparib placebo + - ECOG 0-1. HR: 0.66; 95%
(300mg BID) + abiraterone + - regardless of HRRm CI: 0.54–0.81;
abiraterone prednisone (retrospective testing). (p = 0.001)
(1000 mg/d) + - prior taxane for
prednisone mHSPC allowed.
(5 mg BID)
BID = twice a day; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; EMP = 
estramustine; FU = follow-up; HR = hazard ratio; mets. = metastases; mo = month; ib (imaging based);
(r)PFS = (radiographic) progression-free survival; OS = overall survival; IHC = immunohistochemistry ;
HRRm = homologour recombination repair genes mutation; ITT = intention to treat; BICR = blinded
independent central review.

6.5.7 Second-line treatment for mCRPC and sequence

All patients who receive treatment for mCRPC will eventually progress. All treatment options in this setting are
presented in Table 6.5.3. High-level evidence exists for second-line treatments after first-line treatment with
docetaxel and for third-line therapy.

6.5.7.1 Cabazitaxel
Cabazitaxel is a novel taxane with activity in docetaxel-resistant cancers. It was studied in a large prospective,
randomised, phase III trial (TROPIC) comparing cabazitaxel plus prednisone vs. mitoxantrone plus prednisone
in 755 patients with mCRPC, who had progressed after or during docetaxel-based chemotherapy [1204].
Patients received a maximum of ten cycles of cabazitaxel (25 mg/m2) or mitoxantrone (12 mg/m2) plus
prednisone (10 mg/day). Overall survival was the primary endpoint which was significantly longer with
cabazitaxel (median: 15.1 vs. 12.7 months, p < 0.0001). There was also a significant improvement in PFS
(median: 2.8 vs. 1.4 months, p < 0.0001), objective RECIST response (14.4% vs. 4.4%, p < 0.005), and
PSA response rate (39.2% vs. 17.8%, p < 0.0002). Treatment-associated WHO grade 3–4 AEs developed
significantly more often in the cabazitaxel arm, particularly haematological (68.2% vs. 47.3%, p < 0.0002) but
also non-haematological (57.4 vs. 39.8%, p < 0.0002) toxicity. In two post-marketing randomised phase III
trials, cabazitaxel was shown not to be superior to docetaxel in the first-line setting; in the second-line setting
in terms of OS, 20 mg/m2 cabazitaxel was not inferior to 25 mg/m2, but less toxic. Therefore, the lower dose
should be preferred [1205, 1206]. Cabazitaxel should preferably be given with prophylactic granulocyte colony-
stimulating factor (G-CSF) and should be administered by physicians with expertise in handling neutropenia
and sepsis [1207].

6.5.7.2 Abiraterone acetate after docetaxel

Positive results of the large phase III trial (COU-AA-301) were reported after a median follow-up of 12.8 months
[1208] and confirmed by the final analysis [1209]. A total of 1,195 patients with mCRPC were randomised
2:1 to AAP or placebo plus prednisone. All patients had progressive disease based on the Prostate Cancer
Clinical Trials Working Group 2 (PCWG2) criteria after docetaxel therapy (with a maximum of two previous
chemotherapeutic regimens). The primary endpoint was OS, with a planned HR of 0.8 in favour of AAP. After
a median follow-up of 20.2 months, the median survival in the AAP group was 15.8 months compared to
11.2 months in the placebo arm (HR: 0.74, p < 0.0001). The benefit was observed in all subgroups and all
the secondary objectives were in favour of AAP (PSA, radiologic tissue response, time to PSA or objective

120 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

progression). The incidence of the most common grade 3–4 AEs did not differ significantly between arms, but
mineralocorticoid-related side effects were more frequent in the AAP group, mainly grade 1–2 (fluid retention,
oedema and hypokalaemia).

6.5.7.3 Enzalutamide after docetaxel

The planned interim analysis of the AFFIRM study was published in 2012 [1210]. This trial randomised
1,199 patients with mCRPC in a 2:1 fashion to enzalutamide or placebo. The patients had progressed after
docetaxel treatment, according to the PCWG2 criteria. Corticosteroids were not mandatory, but could be
prescribed, and were received by about 30% of the patients. The primary endpoint was OS, with an expected
HR benefit of 0.76 in favour of enzalutamide. After a median follow-up of 14.4 months, the median survival in
the enzalutamide group was 18.4 months compared to 13.6 months in the placebo arm (HR: 0.63, p < 0.001).
This led to the recommendation to halt and unblind the study. The benefit was observed irrespective of age,
baseline pain intensity, and type of progression. In the final analysis with longer follow-up the OS results were
confirmed despite crossover and extensive post-progression therapies [1189]. Enzalutamide was active also in
patients with visceral metastases.
All the secondary objectives were in favour of enzalutamide (PSA, soft tissue response, QoL, time
to PSA, or objective progression). No difference in terms of side effects was observed in the two groups, with
a lower incidence of grade 3–4 AEs in the enzalutamide arm. There was a 0.6% incidence of seizures in the
enzalutamide group compared to none in the placebo arm.

6.5.7.4 Radium-223
The only bone-specific drug that is associated with a survival benefit is the α-emitter radium-223. In a large
phase III trial (ALSYMPCA) 921 patients with symptomatic mCRPC, who failed or were unfit for docetaxel,
were randomised to six injections of 50 kBq/kg radium-223 or placebo plus SOC. The primary endpoint
was OS. Radium-223 significantly improved median OS by 3.6 months (HR: 0.70, p < 0.001) and was also
associated with prolonged time to first skeletal event, improvement in pain scores and improvement in QoL
[1211]. The associated toxicity was mild and, apart from slightly more haematologic toxicity and diarrhoea with
radium-223, which did not differ significantly from that in the placebo arm [1211]. Radium-223 was effective
and safe whether or not patients were docetaxel pre-treated [1212]. Due to safety concerns, use of radium-223
was recently restricted to after docetaxel and at least one AR targeted agent [1213]. In particular, the use of
radium-223 in combination with AAP showed significant safety risks related to fractures and more deaths. This
was most striking in patients without the concurrent use of bone health agents [1214].

6.5.8 Treatment after docetaxel and one line of hormonal treatment for mCRPC
6.5.8.1 Hormonal treatment
For men progressing quickly on AR targeted therapy (< 12 months) it is now clear that cabazitaxel is the
treatment supported by the best data. The CARD trial, an open label randomised phase III trial, evaluated
cabazitaxel after docetaxel and one line of ARPI (either AAP or enzalutamide) [1169]. It included patients
progressing in less than 12 months on previous abiraterone or enzalutamide for mCRPC. Cabazitaxel more
than doubled rPFS vs. another ARPI and reduced the risk of death by 36% vs. ARPI. The rPFS with cabazitaxel
remained superior regardless of the ARPI sequence and if docetaxel was given before, or after, the first ARPI.
The choice of further treatment after docetaxel and one line of HT for mCRPC is open for patients
who have a > 12 months response to first-line abiraterone or enzalutamide for mCRPC [1215]. Either
radium-223 or second-line chemotherapy (cabazitaxel) are reasonable options. In general, subsequent
treatments in unselected patients are expected to have less benefit than with earlier use [1216, 1217] and there
is evidence of cross-resistance between enzalutamide and abiraterone [1218, 1219].
In this context, radioligand therapy has been discussed for many years. In pre-treated and
highly selected patients, based on PSMA- and FDG PET scan results, 117Lu-PSMA-617 was compared with
cabazitaxel in a randomised phase II trial. The primary endpoint PSA reduction > 50% was in favour of the
radioligand therapy [1220]. Pivotal phase III data for 117Lu-PSMA-617 are discussed in Section 6.5.8.2.2.
Poly (ADP-ribose) polymerase inhibitors have shown high rates of response in men with somatic
homologous recombination repair (HRR) deficiency in initial studies. Men previously treated with both docetaxel
and at least one ARPI and whose tumours demonstrated homozygous deletions or deleterious mutations
in DNA-repair genes showed an 88% response rate to olaparib [1221] and in another confirmatory trial a
confirmed composite response of 54.3% (95% CI: 39.0–69.1) in the 400 mg cohort and in 18 of 46 (39.1%;
25.1–54.6) evaluable patients in the 300 mg cohort [1222]. See also section ‘Second-line management’).

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6.5.8.2 Radiopharmaceuticals
6.5.8.2.1 Introduction
Historically, several radiopharmaceuticals including phosphorous-32, strontium-89, yttrium-90, samarium-153,
and rhenium-186 were developed for the treatment of bone pain secondary to metastasis from PCa [1223].
They proved effective in a palliation setting, by relieving pain and improving QoL, especially in the setting
of diffuse bone metastases. However, they never gained widespread adoption. The first radioisotope to
demonstrate a survival benefit was radium-223 (see Section 6.5.7.4).

6.5.8.2.2 PSMA-based therapy

The increasing use of PSMA PET as a diagnostic tracer and the realisation that this allowed identification
of a greater number of metastatic deposits led to attempts to treat cancer by replacing the imaging isotope
with a therapeutic isotope which accumulates where the tumour is demonstrated (theranostics) [1224].
Therefore, after identification of the target, usually with diagnostic 68Gallium-labelled PSMA, therapeutic
radiopharmaceuticals labelled with β(lutetium-177 or yttrium-90) or α(actinium-225)-emitting isotopes could be
used to treat metastatic PCa.

The PSMA therapeutic radiopharmaceutical supported by the most robust data is 177Lu-PSMA-617. The
first patient was treated in 2014 and early clinical studies evaluating the safety and efficacy of 177Lu-PSMA
therapy have demonstrated promising results, despite the fact that a significant proportion of men had already
progressed on multiple therapies [1225]. The early data were based on single-centre experience [1226]. Data
from uncontrolled prospective phase II trials reported high response rates with low toxic effects [1227, 1228].
Positive signals are also coming from a randomised trial (TheraP) [1220].

In TheraP, a randomised phase II trial, patients for whom cabazitaxel was considered the next appropriate
standard treatment after docetaxel and who were highly selected by 68Ga-PSMA-11 and 18FDG PET-CT scans,
were randomised to receive 177Lu-PSMA-617 (6.0–8.5 GBq intravenously every 6 weeks for up to 6 cycles) or
cabazitaxel (20 mg/m2 for up to ten cycles). The primary endpoint was a reduction of at least 50% in PSA. The
first endpoint was met (66% vs. 37% for 177Lu–PSMA-617 vs. cabazitaxel, respectively, by ITT; difference 29%
(95% CI: 16–42; p < 0.0001; and 66% vs. 44% by treatment received; difference 23% [9–37]; p = 0.0016) [1220].

An open-label phase III trial (VISION) compared 177Lu–PSMA-617 radioligand therapy with protocol-permitted
SOC (i.e., excluded chemotherapy, immunotherapy, radium-223 and investigational drugs) in mCRPC patients,
with PSMA expressing metastases on PET/CT, previously treated with at least one ARPI and one (around 53%)
or two taxanes. Imaging-based PFS and OS were the alternate primary endpoints. More than 800 patients
were randomised. 177Lu-PSMA-617 plus SOC significantly prolonged both imaging-based PFS and OS, as
compared with SOC alone (see Table 6.5.3). Grade 3 or above AEs were higher with 177Lu-PSMA-617 than
without (52.7% vs. 38.0%), but QoL was not adversely affected. 177Lu–PSMA-617 has shown to be a valuable
additional treatment option in this mCRPC population [1229].

Recently, a systematic review and meta-analysis was updated, investigating the proportion of patients with
any or more than 50% PSA decrease, and OS. The review, including 69 articles and a total of 4,157 patients,
showed that patients treated with 177Lu–PSMA 617 had a significantly higher response to therapy compared to
controls, based on > 50% PSA decrease (OR = 5.33, 95% CI: 1.24–22.90, p < 0.05). Meta-analysis revealed an
OS of 0.26 according to pooled HRs for any PSA decline, which was significant after 177Lu–PSMA-617 therapy
(95% CI: 0.18–0.37, p < 0.00001) and an OS of 0.52 for > 50% PSA decrease, also significant after radioligand
(RLT) (95% CI: 0.40–0.67, p < 0.00001) [1230].

Currently, an increased interest for PSMA-targeted alpha therapy (225Ac-PSMA) is observed, due to the ability
to deliver potent higher local radiation more selectively to cancer cells than PSMA-targeted beta therapy, while
minimising unwanted damage to the surrounding normal tissues. Additionally, the intensive radiation to cancer
cells results in more effective DNA strand breakage and reduces the development of treatment resistance. A
meta-analysis, including 9 studies with 263 patients, investigated the therapeutic effects of 225Ac-PSMA RLT
in patients with metastatic CRPC, pre-treated with chemotherapy, 177Lu-PSMA and/or radium-223. The pooled
proportions of patients with more than 50% PSA decline and any PSA decline were 60.99% (95% CI: 54.92%–
66.83%) and 83.57% (95% CI: 78.62%–87.77%), respectively. The estimated mean PFS and mean OS were
9.15 months (95% CI: 6.69–11.03 months) and 11.77 months (95% CI: 9.51–13.49 months), respectively. These
findings suggests that 225Ac-PSMA RLT may be an effective treatment option for patients with mCRPC [1231].
Despite the encouraging therapeutic response and survival of patients who received 225Ac-PSMA RLT, major
AEs like xerostomia and severe haematotoxicity have to be considered as possible reasons for dose reduction
or discontinuation of the therapy.

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6.5.8.3 PARP inhibitors for mCRPC
So far, two PARP inhibitors, olaparib and rucaparib, are licenced by the FDA (EMA only approved olaparib) and
several other PARP inhibitors are under investigation (e.g., talazoparib, niraparib).

A randomised phase III trial (PROfound) compared the PARP inhibitor olaparib to an alternative ARPI in
mCRPC with alterations in > 1 of any qualifying gene with a role in HRR and progression on an ARPI. Most
patients were heavily pre-treated with 1–2 chemotherapies and up to 2 ARPIs [1166, 1167]. Radiographic
PFS by blinded independent central review in the BRCA1/2 or ATM mutated population (Cohort A) was
the first endpoint and significantly favoured olaparib (HR: 0.49, 95% CI: 0.38–0.63). The final results for OS
demonstrated a significant improvement among men with BRCA1/2 or ATM mutations (Cohort A) (p = 0.0175;
HR: 0.69, 95% CI: 0.50– 0.97). This was not significant in men with any (other) HRR alteration (Cohort B) (HR:
0.96, 95% CI: 0.63–1.49). Of note, patients in the physician’s choice of enzalutamide/abiraterone-arm who
progressed, 66% (n = 86/131) crossed over to olaparib.
The most common AEs were anaemia (46.1% vs. 15.4%), nausea (41.4% vs. 19.2%), decreased
appetite (30.1% vs. 17.7%) and fatigue (26.2% vs. 20.8%) for olaparib vs. enzalutamide/abiraterone. Among
patients receiving olaparib 16.4% discontinued treatment secondary to an AEs, compared to 8.5% of
patients receiving enzalutamide/abiraterone. Interestingly, 4.3% of patients receiving olaparib had a pulmonary
embolism, compared to 0.8% among those receiving enzalutamide/abiraterone, none of which were fatal.
There were no reports of myelodysplastic syndrome or acute myeloid leukaemia. This is the first trial to show a
benefit for genetic testing and precision medicine in mCRPC.

The olaparib approval by the FDA is for patients with deleterious or suspected deleterious germline- or somatic
HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone.
The EMA approved olaparib for patients with BRCA1 and BRCA2 alterations [1232]. The recommended
olaparib dose is 600 mg daily (300 mg taken orally twice daily), with or without food.

Rucaparib has been approved by the FDA for patients with deleterious BRCA mutations (germline and/
or somatic) who have been treated with ARPI and a taxane-based chemotherapy [1233]. Approval was not
based on OS data but on the results of the single-arm TRITON2 trial (NCT02952534). The confirmed ORR per
independent radiology review in 62 patients with deleterious BRCA mutations was 43.5% (95% CI: 31–57)
[1234].

6.5.8.4 Sequencing treatment

6.5.8.4.1 ARPI -> ARPI (chemotherapy-naive patients)
The use of sequential ARPIs in mCRPC showed limited benefit in retrospective series as well as in one
prospective trial [1235-1242]. In particular in patients who had a short response to the first ARPI for mCRPC
(< 12 months), this sequence should be avoided because of known cross resistance and the availability of
chemotherapy and PARP inhibitors (if a relevant mutation is present).
In highly selected patients treated for more than 24 weeks with AAP, the sequence with
enzalutamide showed some activity with a median rPFS of 8.1 months (95% CI: 6.1–8.3) and an unconfirmed
PSA response rate of 27% [1243]. In case the patient is unfit for chemotherapy and a PARP inhibitor, best
supportive care should be considered in case no other appropriate treatment option is available (clinical trial
or immunotherapy if MSI-high). An ARPI-ARPI sequence should never be the preferred option but might
be considered in such patients if the PS still allows for active treatment and the potential side effects seem
manageable.
First prospective cross-over data on an ARPI-ARPI sequence [1235] and a systematic review and
meta-analysis suggest that for the endpoints PFS and PSA PFS, but not for OS, abiraterone followed by
enzalutamide is the preferred choice [1244].

6.5.8.4.2 ARPI -> PARP inhibitor/olaparib

This sequence in patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated
mCRPC is supported by data from the randomised phase III PROfound trial [1167]. A subgroup of patients in
this trial was pre-treated with one or two ARPIs and no chemotherapy (35%). The ARPI – docetaxel - PARP
inhibitor vs. ARPI – PARP inhibitor - docetaxel sequences are still under investigation.

6.5.8.4.3 Docetaxel for mHSPC -> docetaxel rechallenge

There is limited evidence for second- or third-line use of docetaxel after treatment with docetaxel for mHSPC.
Docetaxel seems to be less active than ARPI at progression to mCRPC following docetaxel for mHSPC [1245].

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6.5.8.4.4 ARPI -> docetaxel or docetaxel -> ARPI followed by PARP inhibitor
Both olaparib and rucaparib are active in biomarker-selected mCRPC patients after ARPI and docetaxel in
either sequence [1167, 1233].

6.5.8.4.5 ARPI before or after docetaxel

There is level 1 evidence for both sequences (see Table 6.5.3).

6.5.8.4.6 ARPI –> docetaxel -> cabazitaxel or docetaxel –> ARPI -> cabazitaxel
Both third-line treatment sequences are supported by level 1 evidence. Of note, there is high-level evidence
favouring cabazitaxel vs. a second ARPI after docetaxel and one ARPI. CARD is the first prospective
randomised phase III trial addressing this question (see Table 6.5.3) [1169].

Table 6.5.3: Randomised controlled phase II/III - second-line/third-line trials in mCRPC

Study Intervention Comparison Selection criteria Main outcomes

ABIRATERONE
COU-AA-301 abiraterone + placebo + Previous docetaxel. OS: 15.8 vs. 11.2 mo.
2012 [1209] prednisone HR prednisone ECOG 0-2. (p < 0.0001, HR: 0.74, 95%
PSA or radiographic CI: 0.64–0.86; p < 0.0001).
progression. FU: 20.2 mo.
rPFS: no change
COU-AA-301 OS: 14.8 vs. 10.9 mo.
2011 [1208] (p < 0.001 HR: 0.65; 95%
CI: 0.54–0.77).
FU: 12.8 mo.
rPFS: 5.6 vs. 3.6 mo.
Radium-223
ALSYMPCA radium-223 placebo Previous or no OS: 14.9 vs. 11.3 mo.
2013 [1211] previous docetaxel. (p = 0.002, HR: 0.61; 95%
ECOG 0-2. Two or CI: 0.46–0.81).
more symptomatic All secondary endpoints show a
bone metastases. No benefit over best SOC.
visceral metastases.
CABAZITAXEL
TROPIC cabazitaxel + mitoxantrone + Previous docetaxel. OS: 318/378 vs. 346/377 events
2013 [1246] prednisone prednisone ECOG 0-2. (OR: 2.11; 95% CI: 1.33–3.33).
FU: 25.5 months OS > 2 yr 27%
vs. 16% PFS: -
TROPIC OS: 15.1 vs. 12.7 mo.
2010 [1204] (p < 0.0001, HR: 0.70;
95% CI: 0.59–0.83). FU: 12.8 mo.
PFS: 2.8 vs. 1.4 mo.
(p < 0.0001, HR: 0.74,
95% CI: 0.64-0.86)
CARD cabazitaxel ARTA: Previous docetaxel. Med OS 13.6 vs. 11.0 mo.
2019 [1169] (25 mg/m2 Q3W) abiraterone + Progression < 12 mo. (p = 0.008, HR: 0.64, 95%
+ prednisone prednisone on prior alternative CI: 0.46–0.89).
+ G-CSF OR ARTA (either before rPFS 8.0 vs. 3.7 mo.
enzalutamide or after docetaxel) (p < 0.001, HR: 0.54,
95% CI: 0.40–0.73).
FU: 9.2 mo.
ENZALUTAMIDE
AFFIRM enzalutamide placebo Previous docetaxel. OS: 18.4 vs. 13.6 mo.
2012 [1210] ECOG 0-2. (p < 0.001, HR: 0.63; 95%
CI: 0.53–0.75).
FU: 14.4 mo.
rPFS: 8.3 vs. 2.9 mo.
(HR: 0.40; 95% CI: 0.35–0.47,
p < 0.0001).

124 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

PARP inhibitor
PROfound olaparib abiraterone + Previous ARPI, rPFS: 7.39 vs. 3.55 mo.
2020 [1166, prednisolone or alterations in HRR (p < 0.0001, HR: 0.34; 95%
1167, 1247] enzalutamide; mutated genes CI: 0.25–0.47), conf. ORR
cross-over 33.3% vs. 2.3% (OR 20.86, 95%
allowed at CI: 4.18–379.18).
progression OS: 19.1 mo vs. 14.7 mo.
(in pts with BRCA1/2, ATM
alterations)
(p = 0.0175; HR 0.69, 95%
CI: 0.5–0.97).
Radioligand therapy
VISION 177Lu-PSMA-617 SOC alone Previous at least Imaging-based PFS:
2021 [1229] SOC 1 ARPI and one or 8.7 vs. 3.4 mo.
two taxane regimens; (p < 0.001; HR 0.40; 99.2%
Mandatory: PSMA- CI: 0.29–0.57)
positive gallium-68 OS: 15.3 vs. 11.3 mo.
(68Ga)–labeled (p < 0.001; HR 0.62; 95%
PSMA-PET scan CI: 0.5–0.74)
TheraP 177Lu-PSMA-617 177Lu-PSMA-617 mCRPC post PSA reduction of > 50%:
2021 [1220, (8.5 GBq 1:1 docetaxel, suitable 66 vs. 37 PSA responses; 66%
1248] i.v.q 6-weekly, randomisation for cabaziaxel vs. 37% by ITT; difference 29%
decreasing cabazitaxel (95% CI: 16–42; p < 0.0001;
0.5 GBq/cycle; (20 mg/m2 and 66% vs. 44% by treatment
up to 6 cycles) i.v.q 3-weekly, received; difference 23% [9–37];
up to 10 cycles) p = 0.0016).
*Only studies reporting survival outcomes as primary endpoints have been included.
ARPI = androgen receptor pathway inhibitor; CI = confidence interval; ECOG = Eastern Cooperative Oncology
Group; FU = follow-up; GBq = gigabecquerel; HR = hazard ratio; Lu = lutetium; mo = months OS = overall
survival; OR = odds ratio; ORR = objective response rate; PSA = prostate-specific antigen; PSMA = prostate-
specific membrane antigen; (r)PFS = (radiographic) progression-free survival; SOC = standard of care; yr = year;
HRR= homologous recombination repair.

6.5.8.5 Platinum chemotherapy

Cisplatin or carboplatin as monotherapy or combinations have shown limited activity in unselected patients in
the pre-docetaxel era [1249]. More recently, the combination of cabazitaxel and carboplatin was evaluated in
pre-treated mCRPC patients in a randomised phase I/II trial. The combination improved the median PFS from
4.5 months (95% CI: 3.5–5.7) to 7.3 months (95% CI: 5.5–8.2; HR: 0.69, 95% CI: 0.50–0.95, p = 0.018) and the
combination was well tolerated [1250]. On a histopathological and molecular level, there is preliminary evidence
that platinum adds efficacy in patients with aggressive variant PCa molecular signatures including TP53, RB1,
and PTEN [1251].

Patients with mCRPC and alterations in DDR genes are more sensitive to platinum chemotherapy than
unselected patients [1252], also after progression on PARP inhibitors. Interestingly, in contemporary
retrospective series, unselected patients as well as patients without DDR gene alterations also showed a
50% PSA decline in up to 36% of patients [1253]. In view of the excellent tolerability of e.g., carboplatin
monotherapy, platinum could be offered to patients with far advanced mCRPC harbouring DDR gene
aberrations after having progressed on standard treatment options. Prospective controlled trials are ongoing.

6.5.9 Monitoring of treatment

Baseline examinations should include a medical history, clinical examination as well as baseline blood
tests (PSA, total testosterone level, full blood count, renal function, baseline liver function tests, alkaline
phosphatase), bone scan and CT of chest, abdomen and pelvis [1254, 1255]. The use of choline or PSMA
PET/CT scans for progressing CRPC is unclear and most likely not as beneficial as for patients with BCR or
hormone-naive disease. Flares, PSMA upregulation and discordant results compared with PSA response or
progression on ARPI have been described [1256]. Prostate-specific antigen alone is not reliable enough [1257]
for monitoring disease activity in advanced CRPC since visceral metastases may develop in men without
rising PSA [1258]. Instead, the PCWG2 recommends a combination of bone scintigraphy and CT scans, PSA
measurements and clinical benefit in assessing men with CRPC [1191]. A majority of experts at the 2015
Advanced Prostate Cancer Consensus Conference (APCCC) suggested regular review and repeating blood

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 125

profile every two to three months with bone scintigraphy and CT scans at least every six months, even in the
absence of a clinical indication [1254]. This reflects that the agents with a proven OS benefit all have potential
toxicity and considerable cost and patients with no objective benefit should have their treatment modified. The
APCCC participants stressed that such treatments should not be stopped for PSA progression alone. Instead,
at least two of the three criteria (PSA progression, radiographic progression and clinical deterioration) should
be fulfilled to stop treatment. For trial purposes, the updated PCWG3 put more weight on the importance of
documenting progression in existing lesions and introduced the concept of no longer ‘clinically benefiting‘ to
underscore the distinction between first evidence of progression and the clinical need to terminate or change
treatment [1259]. These recommendations also seem valid for clinical practice outside trials.

6.5.10 When to change treatment

The timing of mCRPC treatment change remains a matter of debate in mCRPC although it is clearly advisable
to start or change treatment immediately in men with symptomatic progressing metastatic disease. Preferably,
any treatment change should precede development of de novo symptoms or worsening of existing symptoms.
Although, the number of effective treatments is increasing, head-to-head comparisons are still rare, as are
prospective data assessing the sequencing of available agents. Therefore it is not clear how to select the
most appropriate ‘second-line‘ treatment, in particular in patients without HRR alterations or other biomarkers.
A positive example, however, is the CARD trial which clearly established cabazitaxel as the better third-line
treatment in docetaxel pre-treated patients after one ARPI compared to the use of a second ARPI [1169].
The ECOG PS has been used to stratify patients. Generally men with a PS of 0–1 are likely to
tolerate treatments and those with a PS of > 2 are less likely to benefit. However, it is important that treatment
decisions are individualised, in particular when symptoms related to disease progression are impacting on
PS. In such cases, a trial of active life-prolonging agents to establish if a given treatment will improve the PS
may be appropriate. Sequencing of treatment is discussed in a summary paper published following the 2019
APCCC Conference [1260].

6.5.11 Symptomatic management in metastatic CRPC

Castration-resistant PCa is usually a debilitating disease often affecting the elderly male. A multidisciplinary
approach is required with input from urologists, medical oncologists, radiation oncologists, nurses,
psychologists and social workers [1260, 1261]. Critical issues of palliation must be addressed when
considering additional systemic treatment, including management of pain, constipation, anorexia, nausea,
fatigue and depression.

6.5.11.1 Common complications due to bone metastases

Most patients with CRPC have painful bone metastases. External beam RT is highly effective, even as a single
fraction [1262, 1263]. A single infusion of a third generation bisphosphonate could be considered when RT is
not available [1264]. Common complications due to bone metastases include vertebral collapse or deformity,
pathological fractures and spinal cord compression. Cementation can be an effective treatment for painful
spinal fracture whatever its origin, clearly improving both pain and QoL [1265]. It is important to offer standard
palliative surgery, which can be effective for managing osteoblastic metastases [1266, 1267]. Impending spinal
cord compression is an emergency. It must be recognised early and patients should be educated to recognise
the warning signs. Once suspected, high-dose corticosteroids must be given and MRI performed as soon
as possible. A systematic neurosurgery or orthopaedic surgeon consultation should be planned to discuss a
possible decompression, followed by EBRT [1268]. Otherwise, EBRT with, or without, systemic therapy, is the
treatment of choice.

6.5.11.2 Preventing skeletal-related events

6.5.11.2.1 Bisphosphonates
Zoledronic acid has been evaluated in mCRPC to reduce skeletal-related events (SRE). This study was
conducted when no active anti-cancer treatments, but for docetaxel, were available. Six hundred and forty
three patients who had CRPC with bone metastases were randomised to receive zoledronic acid, 4 or 8 mg
every three weeks for 15 consecutive months, or placebo [1269]. The 8 mg dose was poorly tolerated and
reduced to 4 mg but did not show a significant benefit. However, at 15 and 24 months of follow-up, patients
treated with 4 mg zoledronic acid had fewer SREs compared to the placebo group (44 vs. 33%, p = 0.021)
and in particular fewer pathological fractures (13.1 vs. 22.1%, p = 0.015). Furthermore, the time to first SRE
was longer in the zoledronic acid group. No survival benefit has been seen in any prospective trial with
bisphosphonates.

126 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

6.5.11.2.2 RANK ligand inhibitors
Denosumab is a fully human monoclonal antibody directed against RANKL (receptor activator of nuclear
factor κ-B ligand), a key mediator of osteoclast formation, function, and survival. In M0 CRPC, denosumab
has been associated with increased bone-metastasis-free survival compared to placebo (median benefit:
4.2 months, HR: 0.85, p = 0.028) [1262]. This benefit did not translate into a survival difference (43.9 compared
to 44.8 months, respectively) and neither the FDA or the EMA have approved denosumab for this indication [1270].
The efficacy and safety of denosumab (n = 950) compared with zoledronic acid (n = 951) in
patients with mCRPC was assessed in a phase III trial. Denosumab was superior to zoledronic acid in delaying
or preventing SREs as shown by time to first on-study SRE (pathological fracture, radiation or surgery to
bone, or spinal cord compression) of 20.7 vs. 17.1 months, respectively (HR: 0.82, p = 0.008). Both urinary
N-telopeptide and bone-specific alkaline phosphatase were significantly suppressed in the denosumab arm
compared with the zoledronic acid arm (p < 0.0001 for both). However, these findings were not associated with
any survival benefit and in a post-hoc re-evaluation of endpoints, denosumab showed identical results when
comparing SREs and symptomatic skeletal events [1271].

The potential toxicity (e.g., osteonecrosis of the jaw, hypocalcaemia) of these drugs must always be kept
in mind (5–8.2% in M0 CRPC and mCRPC, respectively) [1272, 1273]]. Patients should have a dental
examination before starting therapy as the risk of jaw necrosis is increased by several risk factors including
a history of trauma, dental surgery or dental infection [1274]. Also, the risk for osteonecrosis of the jaw
increased numerically with the duration of use in a pivotal trial [1275] (one year vs. two years with denosumab),
but this was not statistically significant when compared to zoledronic acid [1270]. According to the EMA,
hypocalcaemia is a concern in patients treated with denosumab and zoledronic acid. Hypocalcaemia must be
corrected by adequate intake of calcium and vitamin D before initiating therapy [1276]. Hypocalcaemia should
be identified and prevented during treatment with bone protective agents (risk of severe hypocalcaemia is 8%
and 5% for denosumab and zoledronic acid, respectively) [1273]. Serum calcium should be measured in patients
starting therapy and monitored during treatment, especially during the first weeks and in patients with risk factors
for hypocalcaemia or on other medication affecting serum calcium. Daily calcium (> 500 mg) and vitamin D (> 400
IU equivalent) are recommended in all patients, unless in case of hypercalcaemia [1273, 1277, 1278].

6.5.12 Summary of evidence and guidelines for life-prolonging treatments of castrate-resistant

disease

Summary of evidence LE
First-line treatment for mCRPC will be influenced by which treatments were used when metastatic 4
cancer was first discovered.
No clear-cut recommendation can be made for the most effective drug for first-line CRPC treatment 3
(i.e., hormone therapy, chemotherapy or radium-223) as no validated predictive factors exist.

Recommendations Strength rating

Ensure that testosterone levels are confirmed to be < 50 ng/dL before diagnosing castrate- Strong
resistant PCa (CRPC).
Counsel, manage and treat patients with metastatic CRPC (mCRPC) in a multidisciplinary Strong
team.
Treat patients with mCRPC with life-prolonging agents. Strong
Offer mCRPC patients somatic and/or germline molecular testing as well as testing for Strong
mismatch repair deficiencies or microsatellite instability.

6.5.13 Guidelines for systematic treatments of castrate-resistant disease

Recommendations Strength rating

Base the choice of treatment on the performance status (PS), symptoms, co-morbidities, Strong
location and extent of disease, genomic profile, patient preference, and on previous
treatment for hormone-sensitive metastatic PCa (mHSPC) (alphabetical order: abiraterone,
cabazitaxel, docetaxel, enzalutamide, olaparib, radium-223, sipuleucel-T).
Offer patients with mCRPC who are candidates for cytotoxic therapy and are chemotherapy Strong
naiive docetaxel with 75 mg/m2 every 3 weeks.

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 127

Offer patients with mCRPC and progression following docetaxel chemotherapy further Strong
life-prolonging treatment options, which include abiraterone, cabazitaxel, enzalutamide,
radium-223 and olaparib in case of DNA homologous recombination repair (HRR) alterations.
Base further treatment decisions of mCRPC on PS, previous treatments, symptoms, Strong
co-morbidities, genomic profile, extent of disease and patient preference.
Offer abiraterone or enzalutamide to patients previously treated with one or two lines of Strong
chemotherapy.
Avoid sequencing of androgen receptor targeted agents. Weak
Offer chemotherapy to patients previously treated with abiraterone or enzalutamide. Strong
Offer cabazitaxel to patients previously treated with docetaxel. Strong
Offer cabazitaxel to patients previously treated with docetaxel and progressing within 12 Strong
months of treatment with abiraterone or enzalutamide.
Novel agents
Offer poly(ADP-ribose) polymerase (PARP) inhibitors to pre-treated mCRPC patients with Strong
relevant DNA repair gene mutations.
Offer 177Lu-PSMA-617 to pre-treated mCRPC patients with one or more metastatic lesions, Strong
highly expressing PSMA (exceeding the uptake in the liver) on the diagnostic radiolabelled
PSMA PET/CT scan.

6.5.14 Guideline for non-metastatic castrate-resistant disease

Recommendation Strength rating

Offer apalutamide, darolutamide or enzalutamide to patients with M0 CRPC and a high risk Strong
of developing metastasis (PSA-DT < 10 months) to prolong time to metastases and overall
survival.

6.5.15 Guidelines for supportive care of castrate-resistant disease

These recommendations are in addition to appropriate systemic therapy.

Recommendations Strength rating

Offer bone protective agents to patients with mCRPC and skeletal metastases to prevent Strong
osseous complications.
Monitor serum calcium and offer calcium and vitamin D supplementation when prescribing Strong
either denosumab or bisphosphonates.
Treat painful bone metastases early on with palliative measures such as intensity-modulated Strong
radiation therapy/volumetric arc radiation therapy plus image-guided radiation therapy and
adequate use of analgesics.
In patients with spinal cord compression start immediate high-dose corticosteroids and Strong
assess for spinal surgery followed by irradiation. Offer radiation therapy alone if surgery is
not appropriate.

6.6 Summary of guidelines for the treatment of prostate cancer

Table 6.6.1: E
 AU risk groups for biochemical recurrence of localised and locally-advanced prostate
Cancer

Definition
Low-risk Intermediate-risk High-risk
PSA < 10 ng/mL PSA 10–20 ng/mL PSA > 20 ng/mL any PSA
and GS < 7 (ISUP grade 1) or GS 7 (ISUP grade 2/3) Or GS > 7 (ISUP grade 4/5) any GS (any ISUP grade)*
and cT1-2a* or cT2b* or cT2c* cT3-4* or cN+**
Localised Locally advanced
GS = Gleason score; ISUP = International Society for Urological Pathology; PSA = prostate-specific antigen.
* Based on digital rectal examination.
** Based on CT/bone scan.

128 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

6.6.1 General guidelines recommendations for the treatment of prostate cancer

Recommendations Strength rating

No active treatment modality has shown superiority over any other active management Strong
options or deferred active treatment in terms of overall- and PCa-specific survival for
clinically localised low/intermediate-risk disease.
Offer a watchful waiting policy to asymptomatic patients with clinically localised disease Strong
and with a life expectancy < 10 years (based on co-morbidities and age).
Inform patients that all local treatments have side effects. Strong
Surgical treatment
Radical prostatectomy can be safely delayed for at least 3 months from diagnosis in any Weak
risk category.
Inform patients that no surgical approach (open-, laparoscopic- or robotic radical Weak
prostatectomy) has clearly shown superiority in terms of functional or oncological results.
When a lymph node dissection (LND) is deemed necessary based on a nomogram, perform an Strong
extended LND template for optimal staging.
Consider avoiding nerve-sparing surgery when there is a risk of ipsilateral extra-capsular Weak
extension (based on cT stage, ISUP grade, magnetic resonance imaging, or with this
information combined in a nomogram).
Do not offer neoadjuvant androgen deprivation therapy before surgery. Strong
Radiotherapeutic treatment
Offer intensity-modulated radiation therapy (IMRT) or volumetric arc radiation therapy Strong
(VMAT) plus image-guided radiation therapy (IGRT) for definitive treatment of PCa by
external-beam radiation therapy.
Offer moderate hypofractionation (HFX) with IMRT/VMAT plus IGRT to the prostate to Strong
patients with localised disease (60 Gy/20 fractions in 4 weeks or 70 Gy/28 fractions in
6 weeks).
Offer low-dose rate (LDR) brachytherapy monotherapy to patients with good urinary Strong
function and low-risk or NCCN favourable intermediate-risk disease.
Offer LDR or high-dose rate (HDR) brachytherapy boost combined with IMRT/VMAT plus Weak
IGRT to patients with good urinary function and NCCN unfavourable intermediate-risk or
high-risk disease and/or locally-advanced disease.
Active therapeutic options outside surgery or radiotherapy
Only offer focal therapy with high-intensity focused ultrasound or cryotherapy within a Strong
clinical trial or prospective registry.

6.6.2 Guidelines recommendations for fist-line treatment of various disease stages*

Recommendations Strength rating

Low-risk disease
Watchful Waiting Offer WW to patients with a life expectancy < 10 years. Strong
(WW)
Active Manage patients with a life expectancy > 10 years and low-risk Strong
surveillance (AS) disease by AS.
Selection of patients
Patients with intraductal histology on biopsy should be excluded from Strong
AS.
Perform magnetic resonance imaging (MRI) before a confirmatory Strong
biopsy if no MRI has been performed before the initial biopsy.
Take both targeted biopsy (of any PI-RADS > 3 lesion) and systematic Weak
biopsy if a confirmatory biopsy is performed.
If MRI is not available, per-protocol confirmatory prostate biopsies Weak
should be performed.
If a patient has had upfront MRI followed by systematic and targeted Weak
biopsies there is no need for confirmatory biopsies.

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 129

 Follow-up of patients
Repeat biopsies should be performed at least once every 3 years for Weak
10 years.
In case of prostate-specific antigen progression or change in digital- Strong
rectal examination or MRI findings, do not progress to active treatment
without a repeat biopsy.
Intermediate-risk disease
WW Offer WW to asymptomatic patients with a life expectancy < 10 years. Strong
AS Offer AS to highly selected patients with ISUP grade group 2 disease Weak
(i.e. < 10% pattern 4, PSA < 10 ng/mL, < cT2a, low disease extent
on imaging and low biopsy extent [defined as < 3 positive cores and
cancer involvement < 50% core involvement [CI]/per core), or another
single element of intermediate-risk disease with low disease extent on
imaging and low biopsy extent, accepting the potential increased risk
of metastatic progression.
Patients with ISUP grade group 3 disease should be excluded from Strong
AS protocols.
Re-classify patients with low-volume ISUP grade group 2 disease Weak
included in AS protocols, if repeat non-MRI-based systematic
biopsies performed during monitoring reveal > 3 positive cores or
maximum CI > 50%/core of ISUP 2 disease.
Radical Offer RP to patients with a life expectancy of > 10 years. Strong
Prostatectomy Radical prostatectomy can be safely delayed for at least 3 months. Weak
(RP) Offer nerve-sparing surgery to patients with a low risk of extracapsular Strong
disease on that side.
Extended pelvic Perform an ePLND based on predicted risk of lymph node (LN) Weak
lymph node invasion (validated nomogram, see Section 6.1.2.3.2.)
dissection (ePLND)
Radiotherapeutic Offer low-dose rate (LDR) brachytherapy to patients with good urinary Strong
treatment function and NCCN favourable intermediate-risk disease.
Offer intensity-modulated radiotherapy (IMRT)/volumetric modulated Strong
arc therapy (VMAT) plus image-guided radiotherapy (IGRT), with a
total dose of 76–78 Gy or moderate hypofractionation (60 Gy/20 fx in
4 weeks or 70 Gy/28 fx in 6 weeks), in combination with short-term
androgen deprivation therapy (ADT) (4–6 months).
Offer LDR brachytherapy boost combined with IMRT/VMAT plus Weak
IGRT to patients with good urinary function and NCCN unfavourable
intermediate-risk disease, in combination with short-term ADT
(4–6 months).
Offer high-dose rate (HDR) brachytherapy boost combined with IMRT/ Weak
VMAT plus IGRT to patients with good urinary function and NCCN
unfavourable intermediate-risk disease, in combination with short-
term ADT (4–6 months).
Other therapeutic Only offer whole-gland ablative therapy (such as cryotherapy, high- Strong
options intensity focused ultrasound, etc.) or focal ablative therapy within
clinical trials or registries.
Do not offer ADT monotherapy to asymptomatic men not able to Weak
receive any local treatment.
High-risk localised disease
WW Offer WW to asymptomatic patients with a life expectancy < 10 years. Strong
RP Radical prostatectomy can be safely delayed for at least 3 months. Weak
Offer RP to selected patients as part of potential multi-modal therapy. Strong
ePLND Perform an ePLND in high-risk PCa. Strong
Do not perform a frozen section of nodes during RP to decide whether Strong
to proceed with, or abandon, the procedure (see Section 6.2.4.1).

130 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

Radiotherapeutic Offer patients IMRT)/VMAT plus IGRT with 76–78 Gy in combination Strong
treatments with long-term ADT (2 to 3 years).
Offer patients with good urinary function IMRT/VMAT plus IGRT with Weak
brachytherapy boost (either HDR or LDR), in combination with long-
term ADT (2 to 3 years).
Therapeutic Do not offer either whole gland or focal therapy. Strong
options outside Only offer ADT monotherapy to those patients unwilling or unable to Strong
surgery or receive any form of local treatment if they have a PSA-doubling time
radiotherapy < 12 months, and either a PSA > 50 ng/mL or a poorly-differentiated
tumour.
Locally-advanced disease
RP Offer RP to patients with cN0 disease as part of multi-modal therapy. Weak
ePLND Perform an ePLND. Strong
Radiotherapeutic Offer patients with cN0 disease IMRT/VMAT plus IGRT in combination Strong
treatments with long-term ADT.
Offer patients with cN0 disease and good urinary function, IMRT/ Weak
VMAT plus IGRT with brachytherapy boost (either HDR or LDR), in
combination with long-term ADT.
Offer long-term ADT for at least two years. Strong
Offer IMRT/VMAT plus IGRT to the prostate in combination with Strong
long-term ADT and 2 years of abiraterone to cN0M0 patients with > 2
high-risk factors (cT3-4, Gleason > 8 or PSA > 40 ng/mL).
Offer IMRT/VMAT plus IGRT to the prostate plus pelvis in combination Strong
with long-term ADT and 2 years of abiraterone to cN1M0 patients.
Offer patients with cN1 disease a local treatment (either RP or IMRT/ Strong
VMAT plus IGRT) plus long-term ADT.
Therapeutic Do not offer whole gland treatment or focal treatment. Strong
options outside
surgery or
radiotherapy
Adjuvant treatment for pN0 and pN1 disease after radical prostatectomy
pN0 & pN1 Do not prescribe adjuvant ADT to pN0 patients. Strong
disease In pN0 patients with ISUP grade group 4–5 and pT3 ± positive Strong
margins, offer adjuvant IMRT/VMAT plus IGRT.
In pN1 patients, after an eLND, discuss three management options, Weak
based on nodal involvement characteristics:
1. Offer adjuvant ADT;
2. Offer adjuvant ADT with additional IMRT/VMAT plus IGRT;
3. Offer observation (expectant management) to a patient after
eLND and < 2 nodes and a PSA < 0.1 ng/mL.
Non-curative or palliative treatments in a first-line setting
Persistent PSA after radical prostatectomy
Offer a prostate-specific membrane antigen positron-emission Weak
tomography (PSMA PET) scan to men with a persistent PSA > 0.2 ng/
mL if the results will influence subsequent treatment decisions
Treat men with no evidence of metastatic disease with SRT and Weak
additional hormonal therapy.
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR abdomen/pelvis.

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 131

6.6.3 Guidelines for metastatic disease, second-line and palliative treatments

Recommendations Strength rating

Metastatic disease in a first-line setting
M1 patients* Offer immediate systemic treatment with androgen deprivation therapy Strong
All statements (ADT) to palliate symptoms and reduce the risk for potentially serious
are based on sequelae of advanced disease (spinal cord compression, pathological
metastatic disease fractures, ureteral obstruction) to M1 symptomatic patients.
defined by bone At the start of ADT offer luteinising hormone-releasing hormone Strong
scintigraphy and (LHRH) antagonists or orchiectomy to patients with impending clinical
CT scan/MRI. complications like spinal cord compression or bladder outlet obstruction.
Offer early systemic treatment to M1 patients asymptomatic from their Strong
tumour.
Offer short-term administration of an older generation androgen Weak
receptor (AR) antagonist to M1 patients starting LHRH agonist to
reduce the risk of the ‘flare-up’ phenomenon.
Do not offer AR antagonist monotherapy to patients with M1 disease. Strong
Discuss combination therapy including ADT plus systemic therapy Strong
with all M1 patients.
Do not offer ADT monotherapy to patients whose first presentation is Strong
M1 disease if they have no contra-indications for combination therapy
and have a sufficient life expectancy to benefit from combination therapy
(> 1 year) and are willing to accept the increased risk of side effects.
Offer ADT combined with abiraterone acetate plus prednisone or Strong
apalutamide or enzalutamide to patients with M1 disease and who are
fit for the regimen.
Offer docetaxel only in combination with ADT plus abiraterone or Strong
darolutamide to patients with M1 disease and who are fit for docetaxel.
Offer ADT combined with non-curative prostate radiotherapy (using Strong
doses up to the equivalent of 72 Gy in 2 Gy fractions) to patients
whose first presentation is M1 disease and who have low volume of
disease by CHAARTED criteria/M1a disease.
Do not offer ADT combined with any local treatment (RT/surgery) to Strong
patients with high-volume (CHAARTED criteria) M1 disease outside of
clinical trials (except for symptom control).
Do not offer ADT combined with surgery to M1 patients outside of Strong
clinical trials.
Only offer metastasis-directed therapy to M1 patients within a clinical Strong
trial setting or well-designed prospective cohort study.
Biochemical recurrence after treatment with curative intent
Biochemical Offer monitoring, including PSA, to EAU Low-Risk BCR patients. Weak
recurrence (BCR) Offer early salvage intensity-modulated radiotherapy (IMRT)/volumetric Strong
after radical arc radiation therapy (VMAT) plus image-guided radiotherapy (IGRT) to
prostatectomy men with two consecutive PSA rises.
(RP) A negative positron emission tomography/computed tomography Strong
(PET/CT) scan should not delay salvage radiotherapy (SRT), if
otherwise indicated.
Do not wait for a PSA threshold before starting treatment. Once the Strong
decision for SRT has been made, SRT (at least 64 Gy) should be given
as soon as possible.
Offer hormonal therapy in addition to SRT to men with BCR. Weak
BCR after Offer monitoring, including PSA, to EAU Low-Risk BCR patients. Weak
RT Only offer salvage radical prostatectomy (SRP), brachytherapy, Strong
stereotactic body RT, high-intensity focused ultrasound, or
cryosurgical ablation to highly selected patients with biopsy-proven
local recurrence within a clinical trial setting or well-designed
prospective cohort study undertaken in experienced centres.
Systemic salvage Do not offer ADT to M0 patients with a PSA-doubling time (DT) > 12 Strong
treatment months.

132 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

Recommendations for follow-up after radical prostatectomy or radiotherapy
Routinely follow-up asymptomatic patients by obtaining at least a Strong
disease-specific history andserum prostate-specific antigen (PSA)
measurement.
At recurrence, only perform imaging if the result will affect treatment Strong
planning.
Life-prolonging treatments of castration-resistant disease
Ensure that testosterone levels are confirmed to be < 50 ng/dL, before Strong
diagnosing castration-resistant PCa (CRPC).
Counsel, manage and treat patients with metastatic CRPC (mCRPC) Strong
in a multidisciplinary team.
Treat patients with mCRPC with life-prolonging agents. Strong
Offer mCRPC patients somatic and/or germline molecular testing Strong
as well as testing for mismatch repair deficiencies or microsatellite
instability.
Systemic treatments of castrate-resistant disease
Base the choice of treatment on the performance status (PS), symptoms, Strong
co-morbidities, location and extent of disease, genomic profile, patient
preference, and on previous treatment for hormone-sensitive metastatic
PCa (mHSPC) (alphabetical order: abiraterone, cabazitaxel, docetaxel,
enzalutamide, olaparib, radium-223, sipuleucel-T).
Offer patients with mCRPC who are candidates for cytotoxic therapy Strong
and are chemotherapy naive docetaxel with 75 mg/m2 every 3 weeks.
Offer patients with mCRPC and progression following docetaxel Strong
chemotherapy further life-prolonging treatment options, which include
abiraterone, cabazitaxel, enzalutamide, radium-223 and olaparib in
case of DNA homologous recombination repair (HRR) alterations.
Base further treatment decisions of mCRPC on PS, previous Strong
treatments, symptoms, co-morbidities, genomic profile, extent of
disease and patient preference.
Offer abiraterone or enzalutamide to patients previously treated with Strong
one or two lines of chemotherapy.
Avoid sequencing of androgen receptor targeted agents. Weak
Offer chemotherapy to patients previously treated with abiraterone or Strong
enzalutamide.
Offer cabazitaxel to patients previously treated with docetaxel. Strong
Offer cabazitaxel to patients previously treated with docetaxel and Strong
progressing within 12 months of treatment with abiraterone or
enzalutamide.
Novel agents
Offer poly(ADP-ribose) polymerase (PARP) inhibitors to pre-treated Strong
mCRPC patients with relevant DNA repair gene mutations.
Offer 177Lu-PSMA-617 to pre-treated mCRPC patients with one or Strong
more metastatic lesions, highly expressing PSMA (exceeding the
uptake in the liver) on the diagnostic radiolabelled PSMA PET/CT scan.
Supportive care of castration-resistant disease
Offer bone protective agents to patients with mCRPC and skeletal Strong
metastases to prevent osseous complications.
Monitor serum calcium and offer calcium and vitamin D supplementation Strong
when prescribing either denosumab or bisphosphonates.
Treat painful bone metastases early on with palliative measures such Strong
as IMRT/VMAT plus IGRT and adequate use of analgesics.
In patients with spinal cord compression start immediate high-dose Strong
corticosteroids and assess for spinal surgery followed by irradiation.
Offer radiation therapy alone if surgery is not appropriate.
Non-metastatic castrate-resistant disease
Offer apalutamide, darolutamide or enzalutamide to patients with M0 Strong
CRPC and a high risk of developing metastasis (PSA-DT < 10 months)
to prolong time to metastases and overall survival.

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 133

Figure 6.1: Treatment non-metastasized (M0) – asymptomatic disease#

Eligible for ac
ve Radical prostatectomy +/- ePLND
surveillance? (ePLND based on nomogram risk)
Prostate cancer - All low-risk
adenocarcinoma Candidate for disease. EBRT1 + ADT (4–6 mo)
cura
ve yes no Intermediate
- non- - Selected pts with (76–78 Gy, moderate hypofraconaon (3 Gy – 60 Gy or 2.5 Gy – 70
treatment? ≤ 1 element of int risk
metastasized (PSA 10–20 or Gy)
(life expectancy risk disease (if GG2
(M0) GG 2–3 or Favourable LDR brachytherapy
based on age and in system. cores:
- asymptoma
c comorbidity*) < 10% paern 4, cT2b**) **** (consider urinary funcon and prostate volume)
disease ≤ 3 pos; no GG3,
no IDC / cribriform Unfavourable LDR or HDR brachytherapy boost + EBRT 1 + ADT (4–6 mo)
growth) **** (consider urinary funcon and prostate volume)

no yes
Radical prostatectomy + ePLND
Watchful Acƒve (risk for needing mulmodal treatment)
waiƒng surveillance
High risk EBRT1 + ADT (2–3 yrs)
localised (76–78 Gy)
(PSA >20 or
GG >3 or
LDR or HDR brachytherapy boost + EBRT 1 + ADT (2–3 yrs)
cT2c**)
(consider urinary funcon and prostate volume)

Two of: cT3–4**, EBRT 1 + ADT (3 years) + abiraterone (2 yrs)

GG 4, PSA 40 (consider urinary funcon)

Radical prostatectomy + ePLND

(high risk for needing mulmodal treatment)
Locally
advanced
(cT 3–4 cN0 EBRT1 + ADT (2–3 yrs)
**) (76–78 Gy)

LDR or HDR brachytherapy boost + EBRT 1 + ADT (2–3 yrs)

(consider urinary funcon and prostate volume)

Radical prostatectomy + ePLND

(high risk for needing mulmodal treatment)
cN1***
EBRT1 including pelvis + ADT (3 years) + abiraterone (2 yrs)
(consider urinary funcon)

* Rule of thumb: Life expectancy 10 years.

** Recommendation based on clinical staging using digital rectal examination, not imaging.
*** Recommendation based on staging using combination of bone scan and CT.
**** See text, dependent on GG and (biopsy) volume.
1EBRT: IMRT/VMAT + IGRT of the prostate.

= weak recommendation.
ADT = androgen deprivation therapy; EBRT =external beam radiotherapy; ECE = extracapsular extension;
ePLND = extended pelvic lymph node dissection; GG = grade group; HDR = high-dose rate; IDC = intraducal
carcinoma; IGRT = image-guided radiotherapy; IMRT = intensity-modulated radiotherapy; LDR = low-dose rate;
VMAT = volumetric modulated arc therapy.

Figure 6.2: Treatment of metastasized (M1*) – disease, M+HSPC

Prostate Upfront EBRT1

yes
adenocarcinoma Connuous Adequate life of the primary tumour
metastasized castraon expectancy (If no previous local therapy)
(M1*)
Low volume
(not fulfilling high
volume criteria)
no

No upfront Upfront double combinaon

combinaon systemic therapy: connuous
therapy castraon +**:
Eligible for - abiraterone / prednisone
docetaxel ? - apalutamide
- enzalutamide

High volume
(≥ 4 bone mets
including ≥ 1 outside
vertebral column or Upfront triple combinaon
pelvis OR visceral systemic therapy: connuous
mets) castraon + **:
- docetaxel 6 x +
abiraterone / pred
- docetaxel 6 x + darolutamide

* Based on staging using combination of bone scan and CT.

** Alphabetical order.
1EBRT: IMRT/VMAT + IGRT of the prostate (equivalent of up to 72 Gy in 2 Gy fractions).

= weak recommendation.
EBRT = external beam radiotherapy; IGRT = image-guided radiotherapy; IMRT = intensity-modulated radio-
therapy.

#Note:Please be aware that the various options in the following flowcharts present a generalised approach
only, and cannot take the management of individual patients into account, nor the availability of resources.

134 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

7. FOLLOW-UP
The rationale for following up patients is to assess immediate- and long-term oncological results, ensure
treatment compliance and allow initiation of further therapy, when appropriate. In addition, follow-up allows
monitoring of side effects or complications of therapy, functional outcomes and an opportunity to provide
psychological support to PCa survivors, all of which is covered in Chapter 8.
For patients the most critical aspect of PCa is the diagnosis, the ensuing treatment and follow-
up. These must be discussed between the patient and the clinician for co-decision on the treatment and the
planned follow-up, including modalities, periodicity and how this will be communicated to the patient. The
patient must be prepared for different potential outcomes of the follow-up, e.g., PSA levels, and what to expect
from these. Otherwise, f.i., even a very small increase in PSA levels can cause unnecessary fear, even panic.

7.1 Follow-up: After local treatment

7.1.1 Definition
Local treatment is defined as RP or RT, either by IMRT plus IGRT or LDR- or HDR-brachytherapy, or any
combination of these, including neoadjuvant and adjuvant therapy. Unestablished alternative treatments
such as HIFU, cryosurgery and focal therapy options do not have a well-defined, validated, PSA cut-off to
define BCR but follow the general principles as presented in this section. In general, a confirmed rising PSA is
considered a sign of disease recurrence.

7.1.2 Why follow-up?

The first post-treatment clinic visit focuses on detecting treatment-related complications and assist patients
in coping with their new situation apart from providing information on the pathological analysis. Men with PCa
are at increased risk of depression and attention for mental health status is required [1279, 1280]. Tumour or
patient characteristics may prompt changing the follow-up schedule. Follow-up of men diagnosed with PCa
may allow early treatment of disease and treatment-related problems. The use of salvage treatment should be
considered in light of the expected life-expectancy, especially when below 10 years in asymptomatic patients.

7.1.3 How to follow-up?

The procedures indicated at follow-up visits vary according to the clinical situation. A disease-specific history
is mandatory at every follow-up visit and includes psychological aspects, signs of disease progression, and
treatment-related complications. Evaluation of treatment-related complications in the post-treatment period
is highlighted in Sections 6.1.2.4 and 8.2. The examinations used for cancer-related follow-up after curative
surgery or RT are discussed below.

7.1.3.1 Prostate-specific antigen monitoring

Measurement of PSA is the cornerstone of follow-up after local treatment. While PSA thresholds depend on the
local treatment used, PSA recurrence almost always precedes clinical recurrence [975, 1281]. The key question
is to establish when a PSA rise is clinically significant since not all PSA increases have the same clinical value
(see Section 6.3) [977]. No prospective studies are available on the optimal timing for PSA testing.

7.1.3.1.1 Active surveillance follow-up

Patients included in an AS programme should be monitored according to the recommendations presented in
Section 6.2.1.3.

7.1.3.1.2 Prostate-specific antigen monitoring after radical prostatectomy

Following RP, the PSA level is expected to be undetectable. Biochemical recurrence is any rising PSA after
prostatectomy as defined in Section 6.3. Prostate-specific antigen level is expected to be undetectable
2 months after a successful RP [1282]. Prostate-specific antigen is generally determined every 6 months until
3 years and yearly thereafter but the evidence for a specific interval is low [485] and mainly based on the
observation that early recurrences are more likely to be associated with more rapid progression [977, 1283, 1284].
A rising PSA may occur after longer intervals up to 20 years after treatment and depends on the initial risk
group [898]. A yearly PSA after 3 years is considered adequate considering the fact that a longer interval to
BCR is correlated with a lower EAU-BCR risk score but around 50% of recurrence should be expected beyond
3 years. As mentioned in Section 6.3.2 no definitive threshold can be given for relapse after RP. Persistently
measurable PSA in patients treated with RP is discussed in Section 6.2.6.

Ultrasensitive PSA assays remain controversial for routine follow-up after RP. Men with a PSA nadir < 0.01 ng/mL
have a high (96%) likelihood of remaining relapse-free within 2 years [1285]. In addition, post-RP PSA levels
> 0.01 ng/mL in combination with clinical characteristics such as ISUP grade and surgical margin status may

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 135

predict PSA progression and can be useful to establish follow-up intervals [1284]. However, up to 86% of men
were reported to have PSA values below 0.2 ng/mL at 5 years after an initial PSA nadir below 0.1 ng/mL within
6 months after surgery [1286]. Lastly, PSA and associated PSA-DT [1287] calculated prior to 0.2 ng/mL may
help identify suitable candidates for early intervention [1288]. Prostate-specific antigen monitoring after SRT to
the prostatic fossa is done at similar intervals and an early and rapid PSA rise predicts more rapid progression
[1283] and is correlated to metastases-free and PCa-specific survival [1289].

7.1.3.1.3 Prostate-specific antigen monitoring after radiotherapy

Following RT, PSA drops more slowly as compared to post RP. A nadir < 0.5 ng/mL is associated with a
favourable outcome after RT although the optimal cut-off value remains controversial [1290]. The interval
before reaching the nadir can be up to 3 years, or more. At the 2006 RTOG-ASTRO Consensus Conference
the Phoenix definition of radiation failure was proposed to establish a better correlation between definition
and clinical outcome (mainly metastases), namely, an increase of 2 ng/mL above the post-treatment PSA nadir
[976]. This definition also applies to patients who received HT [976].

7.1.3.2 Digital rectal examination

Local recurrence after curative treatment is possible without a concomitant rise in PSA level although very
rarely [1291]. This has only been proven in patients with unfavourable undifferentiated tumours. Prostate-
specific antigen and DRE comprise the most useful combination for first-line examination in follow-up after RT
but the role of DRE was questioned since it failed to detect any local recurrence in the absence of a rising PSA
in a series of 899 patients [1292]. In a series of 1,118 prostatectomy patients, no local histologically proven
recurrence was found by DRE alone and PSA measurement may be the only test needed after RP [1293, 1294].

7.1.3.3 Transrectal ultrasound, bone scintigraphy, CT, MRI and PET/CT

Imaging techniques have no place in routine follow-up of localised PCa as long as the PSA is not rising.
Imaging is only justified in patients for whom the findings will affect treatment decisions, either in case of BCR
or in patients with symptoms (see Section 6.3.4 for a more detailed discussion).

7.1.3.4 Functional follow-up

All local treatments for PCa may cause short- and long-term side effect of various degree that will affect
the patients’ QoL. For quality control, and in order to help the patient in choosing the optimal treatment
for him, it is essential that the functional outcomes of any treatment given is measured and registered by
validated and reproducable methods. In order to adress side effects and their impact of QoL specific tools or
‘patient-reported outcome measures’ (PROMs) have been developed and validated for men with PCa. These
questionnaires assess common issues after PCa diagnosis and treatment and generate scores which reflect
the impact on perceptions of HRQoL. For further discussion on this see Section 8.3.

7.1.4 How long to follow-up?

Most patients who fail treatment for PCa do so within 7 years after local therapy [503]. Patients should be
followed more closely during the initial post-treatment period when risk of failure is highest. PSA measurement,
disease-specific history and DRE (if considered) are recommended every 6 months until 3 years and then
annually. Whether follow-up should be stopped if PSA remains undetectable (after RP) or stable (after RT)
remains an unanswered question, but it seems fair that follow-up is only done to the point that if a recurrence is
found the patient is fit enough for salvage therapy.
Risk assessment to predict metastases-free and PCa-specific survival after recurrence after primary
treatment may guide individual decisions on a need for longer follow-up [903, 977, 1295]. Even in men with
a PSA-DT less than 10 months after RP who choose to defer treatment, a median metastasis-free survival of
192 months and OS of 204 months from RP was observed, indicating the relatively long disease-free intervals
observed in men with a rising PSA after local treatment [1296].
Symptomatic recurrence without a PSA rise is extremely rare, however, the symptoms typical for
recurrent disease may vary and are poorly defined by published data. In case of the following symptoms PSA
testing should be performed to exclude a possible cancer recurrence in particular in men not followed up
by regular testing of their PSA levels: skeletal pain, haematuria, progressive voiding complaints, progressive
lower body oedema, progressive bowel complaints or complaints of fatigue, sarcopenia or unexplained weight
loss [1297].

136 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

7.1.5 Summary of evidence and guidelines for follow-up after treatment with curative intent

Summary of evidence LE
A detectable PSA, indicating a relaps of the disease, must be differentiated from a clinically meaningful 3
relapse. The PSA threshold that best predicts further metastases after RP is > 0.4 ng/mL and > NADIR
+ 2 ng/mL after IMRT/VMAT plus IGRT (± ADT].

Recommendations Strength rating

Routinely follow-up asymptomatic patients by obtaining at least a disease-specific history Strong
and a prostate-specific antigen measurement.
At recurrence, only perform imaging if the result will affect treatment planning. Strong

7.2 Follow-up: During first line hormonal treatment (androgen sensitive period)
7.2.1 Introduction
Androgen deprivation therapy is used in various situations: combined with RT for localised or locally-advanced
disease, as monotherapy for a relapse after a local treatment, or in the presence of metastatic disease often in
combination with other treatments. All these situations are based on the benefits of testosterone suppression
either by drugs (LHRH agonists or antagonists) or orchidectomy. Inevitably, the disease will become castrate-
resistant, although ADT will be maintained.
This section addresses the general principles of follow-up of patients on ADT alone. Section 6.5.7
includes further information on other drug treatments. Furthermore the specific follow-up needed for every
single drug is outside the scope of this text, as is follow-up after chemotherapy.
To detect disease- and treatment-related complaints, regular clinical follow-up is mandatory and
cannot be replaced by imaging or laboratory tests alone. Complementary investigations must be restricted to
those that are clinically helpful to avoid unnecessary examinations and costs.

7.2.2 Purpose of follow-up

The main objectives of follow-up in patients receiving ADT are to ensure treatment compliance, to monitor
treatment response, to detect side effects early, and to guide treatment at the time point of clinical progression.
After the initiation of ADT, it is recommended that patients are evaluated every 3 to 6 months. This must be
individualised and each patient should be advised to contact his physician in the event of troublesome symptoms.
This is even more important for patients who receive a combination of ADT and other potent medication, e.g.,
ARPI, for their disease.

7.2.3 General follow-up of men on ADT

Patients under ADT require regular follow-up, including monitoring of serum testosterone, creatinine, liver
function and metabolic parameters at 3 to 6 month intervals. Men on ADT can experience toxicity independent
of their disease stage. Androgen deprivation therapy reduces bone density gradually, increasing the risk of
fractures [1298]. It is therefore essential to asses bone density before and during treatment with ADT with or
without a combination with other drugs.
As the consequenses of ADT are so varying, a structured follow-up including lab results, radiology
and QoL, may be of value both for the patient and for the treating physician [1299].

7.2.3.1 Testosterone monitoring

Testosterone monitoring should be considered standard clinical practice in men on ADT. Many men receiving
medical castration will achieve a castrate testosterone level (< 20 ng/dL), and most a testosterone level
< 50 ng/dL. However, approximately 13–38% of patients fail to achieve these levels and up to 24% of
men may experience temporary testosterone surges (testosterone > 50 ng/dL) during long-term treatment
[1282] referred to as ‘acute on-chronic effect’ or ‘breakthrough response’ [1300]. Breakthrough rates for the
< 20 ng/dL threshold were found to be more frequent (41.3%) and an association with worse clinical outcomes
was suggested [1300].
The timing of measurements is not clearly defined. A 3 to 6-month testosterone level assessment
has been suggested to ensure castration is achieved (especially during medical castration) and maintained.
In case a castrate testosterone level is not reached, switching to another agonist or antagonist or to an
orchiectomy should be considered. In patients with a confirmed rising PSA and/or clinical progression,
serum testosterone must be evaluated in all cases to confirm a castration-resistant state. Ideally, suboptimal
testosterone castrate levels should be confirmed with an appropriate assay [1301, 1302]. After ADT cessation
(intermittent treatment or temporary ADT use as with EBRT) testosterone recovery is dependent on patient’ age
and the duration of ADT [1303, 1304].

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 137

7.2.3.2 Liver function monitoring
Liver function tests will detect treatment toxicity (especially applicable for NSAA), but rarely indicate disease
progression. Men on combined ADT should have their transaminase levels checked at least yearly but in
particular in the first 6 months of treatment initiation since liver function disorders were observed relatively
early in the majority of patients in larger trials [1305]. In view of potential liver toxicity a more frequent check is
needed with some drugs (including abiraterone acetate) [1306]. Alkaline phosphatase may increase secondary
to bone metastases and androgen-induced osteoporosis, therefore it may be helpful to determine bone-
specific isoenzymes as none are directly influenced by ADT [1307].

7.2.3.3 Serum creatinine and haematological parameters

Estimated glomerular filtration rate monitoring is good clinical practice as an increase may be linked to ureteral
obstruction or bladder retention. A decline in haemoglobin is a known side effect of ADT. A significant decline
after 3 months of ADT is independently associated with shorter progression-free and OS rates and might
explain significant fatigue although other causes should be considered [1308]. Anaemia is often multi-factorial
and other possible aetiologies should be excluded. An early decrease in haemoglobin 3 months after ADT
initiation predicted better survival whereas a decrease beyond 6 months was associated with poor outcome
in the SPCG-5 population [1309]. Radiotherapy to more extensive bone metastases locations may result in
myelosuppression and haematological toxicity [1310, 1311].

7.2.3.4 Monitoring of metabolic complications

The most severe complications of androgen suppression are metabolic syndrome, cardiovascular morbidity,
mental health problems, and bone resorption (see Section 8.2.4.5).

All patients should be screened for diabetes by checking fasting glucose and HbA1c (at baseline and routinely)
in addition to checking blood lipid levels. Men with impaired glucose tolerance and/or diabetes should be
referred for an endocrine consultation. Prior to starting ADT a cardiology consultation should be considered in
men with a history of cardiovascular disease and in men older than 65 years. Men on ADT are at increased risk
of cardiovascular problems and hypertension and regular checks are required [1312]. More profound androgen
ablation resulted in a higher cardiovascular toxicity [1313] and cardio-respiratory fitness decreased even after
6 months of ADT [1314]. Although LHRH antagonists have been suggested to provide a more favourable
cardiovascular toxicity profile compared to LHRH agonists, the prematurely closed PRONOUNCE study
found no difference at 12 months in major adverse cardiovascular events between men receiving degarelix or
leuprolide [1315].

7.2.3.5 Monitoring bone problems

Androgen deprivation therapy increases the risk of osteoporosis. A combination of ADT with apalutamide,
darolutamide, enzalutamide, abiraterone plus prednisone or docetaxel increases the fracture risk even more
[1141, 1316, 1317]. Administration of ADT for more than a year, as compared to less than one year, showed
a higher risk of osteoporosis (HR: 1.77 and 1.38, respectively) [1318]. Several scores (e.g., Fracture Risk
Assessment Tool [FRAX score], Osteoporosis Self-Assessment Tool [OST], Osteoporosis Risk Assessment
Instrument [ORAI], Osteoporosis Index of Risk [OSIRIS], Osteoporosis Risk Estimation [SCORE]) can help
identify men at risk of osteoporotic complications but validation of these scores in the ADT setting is required
(see Section 8.3.2.2) [1319-1321].
Routine bone monitoring for osteoporosis should be performed using dual emission X-ray
absorptiometry (DEXA) scan [1322-1324]. Presence of osteoporosis should prompt the use of bone protective
agents. The criteria for initiation of bone protective agents are mentioned in Section 8.3.2.2. If no bone
protective agents are given, a DEXA scan should be done regularly, at least every 2 years [1325].
A review summarising the incidence of bone fractures showed an almost doubling of the risk of
fractures when using ADT depending on patients’ age and duration and type of ADT with the highest incidence in
older men and men on additional novel ARPI medication across the entire spectrum of disease [1326]. In case of
an osteoporotic fracture a bone protective agent is mandatory. Vitamin D and calcium levels should be regularly
monitored when patients receive ADT and patients should be supplemented if needed (see Section 8.3.2.2).

7.2.3.6 Monitoring lifestyle, cognition, fatigue and sexual function

Lifestyle (e.g., diet, exercise, smoking status, etc.) affects QoL and potentially outcome [1307]. During
follow-up men should be counselled on the beneficial effects of exercise to avoid ADT-related toxicity [1327].
Androgen deprivation therapy may affect mental and cognitive health and men on ADT are three times more
likely to report depression [1328]. Attention to mental health should therefore be an integral part of the follow-
up scheme. Men on ADT may experience complaints of fatigue possibly related to systemic inflammation
[1329]. Reduced cognitive performance and fatigue may arise within 6 months after initiation of ADT but can

138 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

improve over time [1330]. Another apect of starting ADT is that it leads to sexual dysfunction, causing > 80%
of couples to cease sexual activity completely. This aspect affects patients as well as their partners and couple
counselling should be considered [1331].

7.2.4 Methods of follow-up in men on ADT without metastases

7.2.4.1 Prostate-specific antigen monitoring
Prostate-specific antigen is a key marker for following the course of androgen-sensitive non-metastasised PCa.
Imaging should be considered when PSA is rising > 2 ng/mL or in case of symptoms suggestive of metastasis.

7.2.4.2 Imaging
In general, asymptomatic patients with a stable PSA level do not require further imaging, although care
needs to be taken in patients with aggressive variants when PSA levels may not reflect tumour progression
[1332]. New bone pain requires at least targeted imaging and potentially a bone scan. When PSA progression
suggests CRPC status and treatment modification is considered, imaging, by means of a bone and CT scan, is
recommended for restaging. Detection of metastases greatly depends on imaging (see Section 6.3.4).

7.2.5 Methods of follow-up in men under ADT for hormone-sensitive metastatic PCa
In metastatic patients it is of the utmost importance to counsel about early signs of spinal cord compression,
urinary tract complications (ureteral obstruction, bladder outlet obstruction) or bone lesions that are at an
increased fracture risk. The intervals for follow-up in M1 patients should be guided by patients’ complaints
and can vary. Since most men will receive another anti-cancer therapy combined with ADT such as ARPI,
chemotherapy or local RT, follow-up frequency should also be dependent on the treatment modality. The
specific points related to follow-up during the castrate-resistant situation are detailed in Section 6.5.12.

7.2.5.1 PSA monitoring

In men on ADT alone, a PSA decline to < 4 ng/mL suggests a likely prolonged response and follow-up visits
may be scheduled every 3 to 6 months provided the patient is asymptomatic or clinically improving. This
applied to men on ADT monotherapy as well as after ADT plus docetaxel [1118]. Depending on symptoms
and risk assessment, more frequent visits may be indicated. Treatment response may be evaluated based
on a change in serum PSA level [1117, 1118] and bone- and CT scan although there is no consensus about
how frequently these should be performed [1260]. A rise in PSA level usually precedes the onset of clinical
symptoms by several months. A rising PSA should prompt assessment of testosterone level, which is
mandatory to define CRPC status, as well as restaging using imaging. However, it is now recognised that a
stable PSA during ADT is not enough to characterise a non-progressive situation [1333].

7.2.5.2 Imaging as a marker of response in metastatic PCa

Treatment response in soft-tissue metastases can be assessed by morphological imaging methods using the
Response Evaluation Criteria in Solid Tumours (RECIST) criteria. However, these criteria cannot be used in
bone where response assessment is difficult [1334, 1335].
When bone scan is used to follow bone metastases, a quantitative estimation of tracer uptake at
bone scan can be obtained through automated methods such as the Bone Scan Index [1336]. Nonetheless,
bone scan is limited by the so-called ‘flare’ phenomenon which is defined by the development of new images
induced by treatment on a first follow-up scan which, after longer observation, actually represent a favourable
response. Flare is observed within 8 to 12 weeks of treatment initiation and can lead to a false-positive
diagnosis of disease progression. Computed tomography cannot be used to monitor sclerotic bone lesions
because bone sclerosis can occur under effective treatment and reflects bone healing. Magnetic resonance
imaging can directly assess the bone marrow and demonstrate progression based on morphologic criteria or
changes in apparent diffusion coefficient. A standardisation for reporting is available [1337]. The ability of PET/
CT to assess response has been evaluated in a few studies. Until further data are available, MRI and PET/CT
should not be used outside trials for treatment monitoring in metastatic patients [1338].
Men with metastasised PCa on ADT should also in the absence of a PSA rise be followed up with
regular imaging since twenty-five percent of men with, or without, docetaxel in the CHAARTED trial developed
clinical progression without a PSA rise [1333]. One in eight men with a PSA < 2 ng/mL showed clinical
progression [1333]. The addition of docetaxel to ADT in the CHAARTED trial population did not reduce the
incidence of clinical progression at low PSA values and this rate was similar for both low- and high-volume
disease as per CHAARTED criteria [1333]. However, the optimal timing and image modality to be used remain
unclear, as is the real clinical value of any findings.

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7.2.6 Guidelines for follow-up during hormonal treatment

Recommendations Strength rating

The follow-up strategy must be individualised based on stage of disease, prior symptoms, Strong
prognostic factors and the treatment given.
In patients with stage M0 disease, schedule follow-up at least every 6 months. As a Strong
minimum requirement, include a disease-specific history, serum prostate-specific antigen
(PSA) determination, as well as liver and renal function in the diagnostic work-up.
In M1 patients, schedule follow-up at least every 3–6 months. Strong
In patients on long-term androgen deprivation therapy (ADT), measure initial bone mineral Strong
density to assess fracture risk.
During follow-up of patients receiving ADT, check PSA and testosterone levels and monitor Strong
patients for symptoms associated with metabolic syndrome as a side effect of ADT.
As a minimum requirement, include a disease-specific history, haemoglobin, serum Strong
creatinine, alkaline phosphatase, lipid profiles and HbA1c level measurements.
Counsel patients (especially with M1b status) about the clinical signs suggestive of spinal Strong
cord compression.
When disease progression is suspected, restaging is needed and the subsequent follow-up Strong
adapted/individualised.
In patients with suspected progression, assess the testosterone level. By definition, Strong
castration-resistant PCa requires a testosterone level < 50 ng/dL (< 1.7 nmol/L).

8. QUALITY OF LIFE OUTCOMES IN PROSTATE

CANCER
This chapter is presented in two parts. The first (Section 8.2) will summarise long-term consequences
(> 12 months) of therapies for PCa. Based on two systematic reviews, the second (Section 8.3) provides
evidence-based recommendations for supporting patients when selecting primary treatment options for
localised disease and also supportive interventions aimed at improving disease-specific QoL across all stages
of disease.

8.1 Introduction
Quality of life and personalised care go hand in hand. Treating PCa can affect an individual both physically
and mentally, as well as close relations and work or vocation. These multifaceted issues all have a bearing
on an individual‘s perception of QoL [1339, 1340]. Approaching care from a holistic point of view requires
the intervention of a multi-disciplinary team including urologists, medical oncologists, radiation oncologists,
oncology nurses, behavioural practitioners and many others including fellow patients. Attention to the
psychosocial concerns of people with PCa is integral to quality clinical care, and this can include the needs of
carers and partners [1341]. Prostate cancer care should not be reduced to focusing on the organ in isolation:
side effects or late adverse effects of treatment can manifest systemically and have a major influence on the
patient’s QoL. Psychological distress can be caused by the cancer diagnosis itself, cancer symptoms and/or
treatment side effects [1342]. Taking QoL into consideration relies on understanding the patient’s values and
preferences so that optimal treatment proposals can be formulated and discussed. Cross-sectional patient-
reported outcomes studies in general PCa populations show the impact of treatment on global and disease-
specific QoL is greater than that described in clinical trial populations who often have less co-morbidity and
belong to higher socio-economic groups. Individuals undergoing two or more treatments have more symptoms
and greater impact on QoL [1343, 1344]. Subgroups of people including those with poor general health, being
unmarried, older age and/or pre-exisitng depressive symptoms are more at risk of long-term mental health
issues following treatment for PCa [1345].

8.2 Adverse effects of PCa therapies

8.2.1 Surgery
A lack of clear consensus in reporting surgical complications following RP, specifically urinary incontinence
and stricture rates, and the introduction of different techniques has resulted in a wide variation in the types of
complications reported, as well as variation in the overall incidence of complications [1346-1349]. The most

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common post-operative complication is ED but other related issues to consider include dry ejaculation, which
occurs with removal of the prostate, change in the quality of orgasm and occasional pain on orgasm. Men
also complain of loss of penile length (3.73%, 19/510 men) [1350]. The second most commonly occurring
complication is long-term incontinence [1346-1349] but voiding difficulties may also occur associated with
bladder neck contracture (e.g., 1.1% after RALP) [1351].
For those undergoing minimally-invasive procedures port site hernia has been reported in 0.66%
after inserting 12 mm bladeless trocar and can occur more rarely with 8 mm and 5 mm trocars [1352]. A key
consideration is whether long-term consequences of surgery are reduced by using newer techniques such as
RALP. Systematic reviews have documented complication rates after RALP [616-620], and can be compared
with contemporaneous reports after RRP [621]. From these reports, the mean continence rates at 12 months
were 89–100% for patients treated with RALP and 80–97% for patients treated with RRP. A prospective
controlled non-randomised trial of patients undergoing RP in 14 centres using RALP or RRP demonstrated
that at 12 months after RALP, 21.3% were incontinent, as were 20.2% after RRP. The unadjusted OR was
1.08 (95% CI: 0.87–1.34). Erectile dysfunction was observed in 70.4% after RALP and 74.7% after RRP. The
unadjusted OR was 0.81 (95% CI: 0.66–0.98) [622, 1353]. Further follow-up demonstrates similar functional
outcomes with both techniques at 24 months [1353, 1354]. A single-centre randomised phase III study
comparing RALP and RRP (n = 326) also demonstrates similar functional outcomes with both techniques at
24 months [520]. Prostatectomy was found to increase the risk of complaints from an inguinal hernia, in
particular after an open procedure when compared to minimally-invasive approaches [1355, 1356].

8.2.2 Radiotherapy
8.2.2.1 Side effects of external beam radiotherapy
Analysis of the toxicity outcomes of the ProtecT trial shows that patients treated with EBRT and 6 months of
ADT report bowel toxicity including persistent diarrhoea, bowel urgency and/or incontinence and rectal bleeding
(described in detail in Section 8.3.1.1 below) [1357]. Participants in the ProtecT study were treated with 3D-CRT
and more recent studies using IMRT demonstrate less bowel toxicity than noted previously with 3D-CRT [1358].
A systematic review and meta-analysis of observational studies comparing patients exposed or
unexposed to RT in the course of treatment for PCa demonstrates an increased risk of developing second
cancers for bladder (OR: 1.39), colorectal (OR: 1.68) and rectum (OR: 1.62) with similar risks over lag times of
5 and 10 years. Absolute excess risks over 10 years are small (1–4%) but should be discussed with younger
patients in particular [1359].

8.2.2.2 Side effects from brachytherapy

Some patients experience significant urinary complications following implantation such as urinary retention
(1.5-22%), with post-implantation TURP reported as being required in up to 8.7% of cases, and incontinence
(0–19%) [1360]. Chronic urinary morbidity is more common with combined EBRT and brachytherapy and can
occur in up to 20% of patients, depending on the severity of the symptoms before brachytherapy. Urethral
strictures account for at least 50% of urinary complications and can be resolved with dilation in the majority
[715, 721]. Prevention of morbidity depends on careful patient selection and IPSS score, backed up by
urodynamic studies.

8.2.3 Local primary whole-gland treatments other than surgery or radiotherapy

8.2.3.1 Cryosurgery
In a systematic review and meta-analysis there was evidence that the rate of urinary incontinence at one year
was lower for cryotherapy than for RP, but the size of the difference decreased with longer follow-up [780].
There was no significant difference between cryotherapy vs. EBRT in terms of urinary incontinence at one year
(< 1%); cryotherapy had a similar ED rate (range 0–40%) to RP at one year. There were insufficient data to
compare cryotherapy vs. EBRT in terms of ED.

8.2.3.2 High-intensity focused ultrasound

In terms of toxicity there are insufficient data on urinary incontinence, ED or bowel dysfunction to draw any
conclusions, although at one year HIFU had lower incontinence rates than RP (OR: 0.06, 95% CI: 0.01–0.48) [780].

8.2.4 Hormonal therapy

A summary of psychological impacts due to the use of ADT such as sexual function, mood, depression,
cognitive function and impact on partners can be found in two clinical reviews [1361, 1362].
A small RCT evaluated the QoL at one-year follow-up in patients with non-localised PCa, between
various ADT regimens, or no treatment. Patients treated by ADT reported a significant decline in spatial
reasoning, spatial abilities and working memory as well as increased depression, tension, anxiety, fatigue and
irritability during treatment [1363]. Conversely, a prospective observational study with follow-up to 3 years

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failed to demonstrate an association with cognitive decline in men on ADT when compared to men with PCa
not treated with ADT and healthy controls [1364]. A prospective observational study of non-metastatic PCa
found that immediate ADT was associated with a lower overall QoL compared to deferred treatment [1365].
Another retrospective non-randomised study suggested that men receiving LHRH agonists reported more
worry and physical discomfort and poorer overall health, and were less likely to believe themselves free of
cancer than patients undergoing orchiectomy. The stage at diagnosis had no effect on health outcomes [1366].

8.2.4.1 Sexual function

Cessation of sexual activity is very common in people undergoing ADT, affecting up to 93% [1367]. Androgen
deprivation therapy reduces both libido and the ability to gain and maintain erections. The management of
acquired ED is mostly non-specific [1368].

Using a specific non-validated questionnaire, bicalutamide monotherapy showed a significant advantage

over castration in the domains of physical capacity and sexual interest (not sexual function) at
12 months [1369]. A post-hoc analysis, including only patients with sexual interest suggested that bicalutamide
was associated with better sexual preservation, including maintained sexual interest, feeling sexually attractive
[1370], preserved libido and erectile function [1371]. Intermittent androgen deprivation has been discussed
elsewhere (see Section 6.4.3.2).

8.2.4.2 Hot flushes

Hot flushes are a common side effect of ADT (prevalence estimated between 44–80% of men on ADT) [1367].
They appear 3 months after starting ADT, usually persist long-term and have a significant impact on QoL.

Serotonin re-uptake inhibitors (e.g., venlafaxine or sertraline) also appear to be effective in men but
less than hormone therapies based on a prospective RCT comparing venlafaxine, 75 mg daily, with
medroxyprogesterone, 20 mg daily, or cyproterone acetate, 100 mg daily [1372]. After 6 months of LHRH
(n = 919), 311 men had significant hot flushes and were randomised to one of the treatments. Based on median
daily hot-flush score, venlafaxine was inferior -47.2% (interquartile range -74.3 to -2.5) compared to -94.5%
(-100.0 to -74.5) in the cyproterone group, and -83.7% (-98.9 to -64.3) in the medroxyprogesterone group.

With a placebo effect influencing up to 30% of patients [1373], the efficacy of clonidine, veralipride,
gabapentine [1374] and acupuncture [1375] need to be compared in prospective RCTs.

8.2.4.3 Non-metastatic bone fractures

Due to increased bone turnover and decreased BMD in a time-dependent manner, ADT use is linked to an
increased risk of fracture (up to 45% RR with long-term ADT) [1376]. Severe fractures in men are associated
with a significant risk of death [1377]. A precise evaluation of BMD should be performed by DEXA, ideally
before or shortly after starting long-term ADT. An initial low BMD (T-score < -2.5 or < -1, with other risk factors)
indicates a high risk of subsequent non-metastatic fracture and causes should be investigated. Other risk
factors include increasing age, BMI of 19 or less, history of previous fracture or parent with fractured hip,
current smoking, use of glucocorticoids, rheumatoid arthritis, alcohol consumption > 2 units per day, history
of falls and a number of other chronic medical conditions [1378]. Fracture risk algorithms which combine BMD
and clinical risk factors such as FRAX score can be used to guide treatment decisions but uncertainty exists
regarding the optimal intervention threshold, therefore no specific risk algorithm can be recommended for men
on ADT for PCa. Obesity (increase in body fat mass by up to 10% and/or BMI > 30) and sarcopenia (decrease
in lean tissue mass by up to 3%) as well as weight loss are common and occur during the first year of ADT
[1379]. These changes increase the fracture risk [1380].

Bicalutamide monotherapy may have less impact on BMD but is limited by its suboptimal efficacy for M1
disease [1381, 1382]. The intermittent LHRH-agonist modality might be associated with less bone impact
[1383].

8.2.4.4 Metabolic effects

Lipid alterations are common and may occur as early as the first 3 months of treatment [1379]. Androgen
deprivation therapy also decreases insulin sensitivity and increases fasting plasma insulin levels, which is a
marker of insulin resistance. In diabetic patients, metformin appears to be an attractive option for protection
against metabolic effects based on retrospective analysis [1384], but there is insufficient data to recommend its
use in non-diabetic patients.

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Metabolic syndrome is an association of independent cardiovascular disease risk factors, often associated with
insulin resistance. The definition requires at least three of the following criteria [1385]:
• waist circumference > 102 cm;
• serum triglyceride > 1.7 mmol/L;
• blood pressure > 130/80 mmHg or use of medication for hypertension;
• high-density lipoprotein (HDL) cholesterol < 1 mmol/L;
• glycaemia > 5.6 mmol/L or the use of medication for hyperglycaemia.

The prevalence of a metabolic-like syndrome is higher during ADT compared with men not receiving ADT [1386].
Skeletal muscle mass heavily influences basal metabolic rate and is in turn heavily influenced by endocrine
pathways [1387]. Androgen deprivation therapy-induced hypogonadism results in negative effects on skeletal
muscle health. A prospective longitudinal study involving 252 men on ADT for a median of 20.4 months reported
lean body mass decreases progressively over 3 years; 1.0% at one year, 2.1% at 2 years, and 2.4% at 3 years
which appears more pronounced in men at > 70 years of age [1388].

8.2.4.5 Cardiovascular morbidity

Cardiovascular mortality is a common cause of death in PCa patients [1107, 1389, 1390]. Several
studies showed that ADT after only 6 months was associated with an increased risk of diabetes mellitus,
cardiovascular disease, and myocardial infarction [1391]. The RTOG 92-02 [1392] and 94-08 [1393] trials
confirmed an increased cardiovascular risk, unrelated to the duration of ADT and not accompanied by an
overall increased cardiovascular mortality. No increase in cardiovascular mortality has been reported in both a
secondary analysis of PLCO trial, even among subgroups with pre-existing cardiovascular disease [1394] and a
systematic meta-analysis of trials RTOG 8531, 8610, 9202, EORTC 30891 and EORTC 22863 [1395]. However,
serious concerns about the conclusions of this meta-analysis have been raised due to poor consideration
of bias in the included studies [1396, 1397]. A meta-analysis of observational data reports consistent links
between ADT and the risk of cardiovascular disease patients treated for PCa, e.g., the associations between
LHRH agonists and nonfatal or fatal myocardial infarction or stroke RR: 1.57 (95% CI: 1.26–1.94) and RR: 1.51
(95% CI: 1.24–1.84), respectively [1398]. An increase in cardiovascular mortality has been reported in patients
suffering from previous congestive heart failure or myocardial infarction in a retrospective database analysis
[1399] or presenting with a metabolic syndrome [1400]. It has been suggested that antagonists might be
associated with less cardiovascular morbidity compared to agonists, but, as yet, there is no definite evidence
[1315, 1401]. In a phase III RCT the use of relugolix, an oral LHRH antagonist, was associated with a reduced
risk of major adverse cardiovascular events when compared to leuprolide, an injectable LHRH agonists, at
2.9% vs. 6.2%, respectively, over a follow-up time of 48 weeks (HR 0.46, 95% CI: 0.24–0.88) [747].
Concerns about LHRH agonists resulted in an FDA warning and consensus paper from the
American Heart, Cancer Society and Urological Associations [1106]. Preventive advice includes non-specific
measures such as loss of weight, increased exercise, minimising alcohol intake, improved nutrition and
smoking cessation [92, 1402].

8.2.4.6 Fatigue
Fatigue often develops as a side effect of ADT. Regular exercise appears to be the best protective measure.
Reporting clinically significant fatigue is associated with severe psychological distress and should prompt
screening for anxiety and/or depression [1403]. Anaemia may be a cause of fatigue [1367, 1404]. Anaemia
requires an aetiological diagnosis (medullar invasion, renal insufficiency, iron deficiency, chronic bleeding) and
individualised treatment. Regular blood transfusions may be required in patients with severe anaemia.

8.2.4.7 Neurological side effects

Castration seems also to be associated with an increased risk of stroke [1405], and is suspected to be
associated with an increased risk for depression and cognitive decline such as Alzheimer disease [1406].

8.3 Overall quality of life in men with PCa

Living longer with PCa does not necessarily equate to living well [1339, 1341]. There is clear evidence of
unmet needs and ongoing support requirements for some individuals after diagnosis and treatment for PCa
[1407]. Fear of cancer recurrence and PSA anxiety has a prevalence of 16% and 22%, respectively, across
studies [1408]. Combined cognitive- and education-based psychological interventions improve depression,
anxiety and distress [1409]. Cancer impacts on the wider family and cognitive behavioural therapy can
help reduce depression, anxiety and stress in caregivers [1410]. Radical treatment for PCa can negatively
impact long-term QoL (e.g., sexual, urinary and bowel dysfunction) as can ADT used in short- or long-term
treatment, e.g., sexual problems, fatigue, psychological morbidity, adverse metabolic sequelae and increased
cardiovascular and bone fracture risk [1361, 1411]. Direct symptoms from advanced or metastatic cancer, e.g.,

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pain, hypercalcaemia, spinal cord compression and pathological fractures, also adversely affect health [1412,
1413]. Patients’ QoL including domains such as sexual function, urinary function and bowel function is worse
after treatment for PCa compared to non-cancer controls [1414, 1415]. A PCa diagnosis commonly results in
financial strain both for the individual and their families. This financial toxicity is associated with younger age
at diagnosis, black race, low socio-economic status, low educational attainment and living in a rural area.
Clinicians should discuss financial strains and signpost to support services so that quality of life and adherence
to treatment can be maintained [1416].

As QoL is subjective and can mean different things to different people it can be difficult to measure and
compare. Nevertheless, there are some generally common features across virtually all patients. Drawing from
these common features, specific tools or PROMs have been developed and validated for men with PCa.
These questionnaires assess common issues after PCa diagnosis and treatment and generate scores which
reflect the impact on perceptions of HRQoL. During the process of undertaking two dedicated systematic
reviews around cancer-specific QoL outcomes in patients with PCa as the foundation for our guideline
recommendations, the following validated PROMs were found in our searches (see Table 8.3.1).

The tools with the best evidence for psychometric properties and feasibility for use in routine practice and
research settings to assess PROMs in patients with localised PCa were EORTC QLQ-C30 and QLQ-PR25.
Since EORTC QLQ-C30 is a general module that does not directly assess PCa-specific issues, it should be
adopted in conjunction with the QLQ-PR25 module [1417].

Table 8.3.1: PROMs assessing cancer specific quality of life [1417]

Questionnaire Domains/items
European Organisation for Research and Treatment of Five functional scales (physical, role, cognitive,
Cancer QLQ-C30 (EORTC QLQ-C30) [1418] emotional, and social); three symptom scales
(fatigue, pain, and nausea and vomiting); global
health status/QoL scale; and a number of single
items assessing additional symptoms commonly
reported by cancer patients (dyspnoea, loss of
appetite, insomnia, constipation and diarrhoea)
and perceived financial impact of the disease.
European Organisation for Research and Treatment of Urinary, bowel and treatment-related symptoms,
Cancer QLQ-PR 25 (EORTC QLQ-PR 25) [1419] as well as sexual activity and sexual function.
Functional Assessment of Cancer Therapy-General Physical well-being, social/family well-being,
(FACT-G) [1420] emotional well-being, and functional well-being.
Functional Assessment of Cancer Therapy-Prostate 12 cancer site specific items to assess for
(FACT-P) [1421] prostate-related symptoms. Can be combined with
FACT-G or reported separately.
Expanded prostate cancer index composite (EPIC) [1422] Urinary, bowel, sexual, and hormonal symptoms.
Expanded prostate cancer index composite short form Urinary, sexual, bowel, and hormonal domains.
26 (EPIC 26) [1423]
UCLA Prostate Cancer Index (UCLA PCI) [1424] Urinary, bowel, and sexual domains.
Prostate Cancer Quality of Life Instrument (PCQoL) [1425] Urinary, sexual, and bowel domains, supplemented
by a scale assessing anxiety.
Prostate Cancer Outcome Study Instrument [1415] Urinary, bowel, and sexual domains.

8.3.1 Long-term (> 12 months) quality of life outcomes in men with localised disease
8.3.1.1 Men undergoing local treatments
The results of the ProtecT trial (n = 1,643 men) reported no difference in EORTC QLQ-C30 assessed global
QoL, up to 5 years of follow-up in men aged 50–69 years with T1–T2 disease randomised for treatment with
AM, RP or RT with 6 months of ADT [1357]. However, EPIC urinary summary scores (at 6 years) were worse in
men treated with RP compared to AM or RT (88.7 vs. 89.0 vs. 91.4, respectively) as were urinary incontinence
(80.9 vs. 85.8 vs. 89.4, respectively) and sexual summary, function and bother scores (32.3 vs. 40.6 vs. 41.3
for sexual summary, 23.7 vs. 32.5 vs. 32.7 for sexual function and 51.4 vs. 57.9 vs. 60.1 for sexual bother,
respectively) at 6 years of follow-up. Minimal clinically important differences for the 50 item EPIC questionnaire
are not available. For men receiving RT with 6 months of ADT, EPIC bowel scores were poorer compared to AM
and RP in all domains: function (90.8 vs. 92.3 vs. 92.3, respectively), bother (91.7 vs. 94.2 vs. 93.7, respectively)

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and summary (91.2 vs. 93.2 vs. 93.0, respectively) at 6 years of follow-up in the ProtecT trial.

The findings regarding RP and RT are supported by other observational studies [503, 668, 1349, 1426-1429].
The Prostate Cancer Outcomes Study (PCOS) studied a cohort of 1,655 men, of whom 1,164 had undergone
RP and 491 RT [1349]. The study reported that at 5 years of follow-up, men who underwent RP had a higher
prevalence of urinary incontinence and ED, while men treated with RT had a higher prevalence of bowel
dysfunction. However, despite these differences detected at 5 years, there were no significant differences
in the adjusted odds of urinary incontinence, bowel dysfunction or ED between RP and RT at 15 years.
Investigators have reported that although EBRT was associated with a negative effect in bowel function, the
difference in bowel domain score was below the threshold for clinical significance 12 months after treatment
[1358]. As 81% of patients in the EBRT arm of the study received IMRT, these data suggest that the risk
of side effects is reduced with IMRT compared to older 3D-CRT techniques. This is supported by 5-year
prospective, population-based cohort study where PROMs were compared in men with favourable- and
unfavourable-risk localised disease [1426]. In the 1,386 men with favourable risk, comparison between AS
and nerve-sparing prostatectomy, EBRT or LDR brachytherapy demonstrates that surgery is associated with
worse urinary incontinence at 5 years and sexual dysfunction at 3 years when compared to AS. External beam
RT is associated with changes not clinically different from AS, and LDR brachytherapy is associated with
worse irritative urinary-, bowel- and sexual symptoms at one year. In 619 men with unfavourable-risk disease,
comparison between non-nerve sparing RP and EBRT with ADT demonstrates that surgery is associated with
worse urinary incontinence and sexual function through 5 years. Systematic review demonstrates that the risk
of post-radiotherapy ED has reduced to a median of 25% at 2 years with utilisation of IMRT and is now similar
to that noted after LDR brachytherapy [1430].

A few prospective studies have reported specific long-term urinary functional outcomes after RP and RT even
if the studies are not comparative between the two treatment modalities. Considering incontinence and ED
after RP the prospective randomised PIVOT trial, comparing RP to observation, reported that 40% of men wore
pads, of which 20% wore more than > 1 pad/day, and an increased rate of ED in the RP group as compared to
observation from 70% to approximately 87%, after a median follow-up of 12.7 years [503]. The corresponding
figures from the prospective non-randomised LAPPRO-trial, comparing open- to robot-assisted RP, were
27–29% of the patients reporting urinary incontinence of some degree after 8 years and 66–70% reporting ED
[1427]. Data on urinary, sexual and bowel function after RT has been reported from the HYPO-RT-PC-trial, a
prospective randomised non-inferiority trial comparing ultra-HFX to conventional fractionation RT. In this trial
52–55% of the patients reported urinary problems (RTOG toxicity grade > 1) at five years, of which 4.2–4.7%
reported a RTOG grade > 3 urinary morbidity and 7–8% reported moderate-to-severe incontinence at 6 years.
Bowel toxicity of any level (RTOG toxicity grade > 1) was reported in 53–54% of the patients at five years, of
which 1.5–1.9% reported a RTOG grade > 3 bowel morbidity, and 66–71% reported to have little or no erection
without aids after six years follow-up [668, 1428].

With respect to brachytherapy cancer-specific QoL outcomes, one small RCT (n = 200) evaluated bilateral
nerve-sparing RP and brachytherapy in men with localised disease (up to T2a), which reported worsening of
physical functioning as well as irritative urinary symptomatology in 20% of brachytherapy patients at one year
of follow-up. However, there were no significant differences in EORTC QLQ-C30/PR-25 scores at 5 years of
follow-up when compared to pre-treatment values [1431]. It should be noted of this trial, within group tests
only were reported. In a subsequent study by the same group comparing bilateral nerve-sparing RARP and
brachytherapy (n = 165), improved continence was noted with brachytherapy in the first 6 months but lower
potency rates up to 2 years [1432]. These data and a synthesis of 18 randomised and non-randomised studies
in a systematic review involving 13,604 patients are the foundation of the following recommendations [1433].

8.3.1.2 Guidelines for quality of life in men undergoing local treatments

Recommendations Strength rating

Advise eligible patients for active surveillance that global quality of life is equivalent for up to Strong
5 years compared to radical prostatectomy or external beam radiotherapy (RT).
Discuss the negative impact of surgery on urinary and sexual function, as well as the Strong
negative impact of RT on bowel function with patients.
Advise patients treated with brachytherapy of the negative impact on irritative urinary Weak
symptomatology at one year but not after 5 years.

8.3.2 Improving quality of life in men who have been diagnosed with PCa

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8.3.2.1 Men undergoing local treatments
In men with localised disease, nurse-led multi-disciplinary rehabilitation (addressing sexual functioning, cancer
worry, relationship issues, depression, managing bowel and urinary function problems) provided positive short-
term effects (4 months) on sexual function (effect size 0.45) and long-term (12 months) positive effects on
sexual limitation (effect size 0.5) and cancer worry (effect size 0.51) [1434].
Exercise programs during RT combined with ADT result in consistent benefits for cardiovascular
fitness (standardised mean difference [SMD], 0.83; 95% CI: 0.31–1.36; p < 0.01) and muscle function (SMD,
1.30; 95% CI: 0.53–2.07; p < 0.01) with a reduction in urinary toxicity (SMD, -0.71; 95% CI: -1.25 to -0.18;
p < 0.01) [1435]. In men undergoing AS, 12 weeks of high-intensity interval training may improve cardiovascular
fitness and suppress PSA progression [1436].

Systematic review and meta-analysis of randomised trials show that exercise interventions for patients on ADT
result in higher lean body mass (mean difference: 0.88, 95% CI 0.4 to 1.36, p < 0.01), a lower body fat mass
(mean difference: -0.93, 95% CI: -1.10 to -0.10, p < 0.05), and a lower body fat rate (mean difference:-0.93,
95% CI: -1.39 to -0.47, p < 0.01). Greater efficacy was noted for exercise duration of > 6 months (vs. < 6 months)
and exercise immediately after starting ADT (vs. delayed exercise) [1437].

In men with post-surgical urinary incontinence, conservative management options include pelvic floor muscle
training with or without biofeedback, electrical stimulation, extra-corporeal magnetic innervation (ExMI),
compression devices (penile clamps), lifestyle changes, or a combination of methods. Uncertainty around the
effectiveness and value of these conservative interventions remains [1438]. Surgical interventions including
sling and artificial urinary sphincter (AUS) significantly decrease the number of pads used per day and increase
the QoL compared with before intervention. The overall cure rate is around 60% and results in improvement in
incontinence by about 25% [1439]. Other alternatives, such as the he Adjustable Transobturator Male System
(ATOMS) and the Adjustable Continence Therapy (proACT) may be an option but seems less efficacious than
AUS [1440]. For a more detailed overview of management of urinary incontinence in these men see Chapter 5.6
in the EAU Guidelines for Management of Non-neurogenic Male LUTS [1441].

The use of PDE5 inhibitors in penile rehabilitation has been subject to some debate. A single-centre, double-
blind RCT of 100 men undergoing nerve-sparing surgery reported no benefit of nightly sildenafil (50 mg)
compared to on-demand use [1442]. However, a multi-centre double-blind RCT (n = 423) in men aged
< 68 years, with normal pre-treatment erectile function undergoing either open, conventional or robot-assisted
laparoscopic nerve-sparing RP, tadalafil (5 mg) once per day improved participants EPIC sexual domain-scores
(least squares mean difference +9.6, 95% CI: 3.1–16.0) when compared to 20 mg ‘on demand’ or placebo at
9 months of follow-up, even though the difference vanished after the end of study [1443]. Therefore, based
on discordant results, no clear recommendation is possible, even if a trend exists for early use of PDE5
inhibitors after RP for penile rehabilitation [1444]. A detailed discussion can be found in the EAU Sexual and
Reproductive Health Guidelines [1445].

8.3.2.2 Men undergoing systemic treatments

Similar to men treated with a radical approach (see above), in men with T1-T3 disease undergoing RT and
ADT, a combined nurse-led psychological support and physiotherapist-led multi-disciplinary rehabilitation has
reported improvements in QoL. Specifically this intervention involved action planning around patients’ needs
related to lifestyle changes, weight control, toilet habits, sexuality, and psychological problems. This was
complemented with pelvic floor muscle therapy. Improvements in urinary (adjusted mean 4.5, 95% CI: 0.6–8.4),
irritative (adjusted mean 5.8, 95% CI: 1.4–10.3) and hormonal (adjusted mean 4.8, 95% CI: 0.8–8.8) EPIC
domains were found up to 22 weeks of follow-up [1446]. In a 3-year follow-up with 92% response rate from the
initial study, fewer participants had moderate-severe bowel problems in the intervention (n = 2; 3%) vs. control
group (n = 10; 14%) (p = 0.016) but the benefits in terms of urinary function were maintained only in those
participants with moderate-severe urinary problems at baseline [1447].
Providing supervised aerobic and resistance exercise training of a moderate intensity improves
EORTC QLQ-C30 role (adjusted mean 15.8, 95% CI: 6.6–24.9) and cognitive domain outcomes (adjusted
mean 11.4, 95% CI: 3.3–19.6) as well as symptom scales for fatigue (adjusted mean 11.0, 95% CI: 20.2–1.7),
nausea (adjusted mean 4.0, 95% CI: 7.4–0.25), and dyspnoea (adjusted mean 12.4, 95% CI: 22.5–2.3) up to 3
months in men treated with ADT [1448]. Such interventions have also reported clinically relevant improvements
in FACT-P (mean difference 8.9, 95% CI: 3.7–14.2) in men on long-term ADT [1449, 1450]. These findings are
supported by a systematic review which reported improvements up to 12 weeks in cancer-specific QoL in a
meta-analysis of high quality trials (SMD 0.33, 95%, CI: 0.08–0.58) [1404]. Supervised exercise interventions
delivered over 12 months are effective in reducing psychological distress; particularly in those men with highest
levels of baseline anxiety and depression [1451]. In untrained older men, systematic review suggests lower

146 PROSTATE CANCER - LIMITED UPDATE MARCH 2023

volume exercise programs at moderate-to-high intensity are as effective as higher volume resistance training
for enhancing body composition, functional capacity and muscle strength and may reduce barriers to exercise
and enhance adherence [1452].
If dietary intake is not adequate, vitamin D and calcium supplementation should be offered, as there
is evidence that vitamin D and calcium have modest effects on bone in men on ADT [1442]. Online tools are
available to calculate daily calcium intake for individual patients. For vitamin D deficiency a dose of at least 800
IU/day colecalciferol can be recommended. Use of a 25(OH) assay may be helpful to measure vitamin D levels
[1453, 1454].
Anti-resorptive therapy is recommended for men on ADT for > 6 months with either a BMD T-score
of < -2.5 or with an additional risk factor for osteoporosis or annual bone loss confirmed to exceed 5%, or
in cases of severe fracture. Referral to a bone specialist should be considered in complex cases with severe
fracture and/or multiple risk factors. Alendronate, risedronate, zoledronate and denosumab have all been
shown to prevent bone loss in men with hormone-sensitive locally-advanced and metastatic PCa on ADT
[1455-1458]. Patients should be warned about the < 5% risk of osteonecrosis of the jaw and/or atypical
femoral fractures associated with these drugs. Bisphosphonates increase BMD in the hip and spine by up to
7% in one year [1457, 1459]. The optimal regimen for zoledronic acid for men on ADT with hormone-sensitive
locally-advanced and metastatic PCa remains unclear: quarterly [1460] or yearly [1461] injections. The question
is relevant as the risk of jaw necrosis is both dose- and time-related [1462]. A quarterly regimen should be
considered for a BMD < 2.5 as a yearly injection is unlikely to provide sufficient protection [1463, 1464]. Care
should be taken when discontinuing treatment as rebound increased bone resorption can occur.

In M0 patients, denosumab has been shown to increase the lumbar BMD by 5.6% compared to a 1% decrease
in the placebo arm after 2 years, using a 60 mg subcutaneous regimen every 6 months [1465]. This was
associated with a significant decrease in vertebral fracture risk (1.5% vs. 3.9%, p = 0.006). The benefits were
similar whatever the age (< or > 70 years), the duration or type of ADT, the initial BMD, the patient’s weight or
the initial BMI. This benefit was not associated with any significant toxicity, e.g., jaw osteonecrosis or delayed
healing in vertebral fractures. In M0 patients, with the use of a higher dosage (120 mg every 4 weeks), a delay
in bone metastases of 4.2 months has been shown [1271] without any impact on OS, but with an increase in
side effects. Therefore, this later regimen cannot be recommended.

8.3.2.3 Decision regret

Several treatments with curative intent for localised PCa are available all with comparable 10-year OS [485].
They vary in terms of the incidence of major side effects, including urinary symptoms, bowel symptoms and
compromised sexual functioning [1357, 1358, 1466]. For this reason, patients’ treatment preferences, in which
they weigh expected benefits against likely side effects, are a central consideration in shared decision-making
and in making informed treatment decisions [1467-1469].
It remains challenging, however, to evaluate whether the decision-making process can be viewed
as successful; that is, whether the choice of treatment best reflects the patient’s preferences and expectations
[1470, 1471]. According to Decision Justification Theory (DJT), it is the more specific information on which
treatment experiences lead to regret that decision regret needs to be better understood and to minimise it in
future patients [1472]. About 25% of men with PCa undergoing either single or combined modality treatments
report experiencing worse side effects than expected [1473]. Urinary incontinence most strongly correlates with
regret after prostatectomy [1474].
Unmet expectations are comparable among the treatment groups, except for fatigue. Fatigue is
less frequently reported as worse than expected by patients who received brachytherapy when compared
to patients who received RP or EBRT. This could be explained by the less invasive treatment course of
brachytherapy in comparison to EBRT with or without ADT and RP [1475]. Unmet expectations were more
frequently reported by patients with positive surgical margins following surgery; having had a passive role in
the decision-making process; and who had higher scores on the decisional conflict scale (i.e., more uncertainty
about the treatment decision). Interestingly, positive surgical margins are not directly associated with an
increased risk of PC-related mortality [1036]. Active participation and support in the process of forming a
preference increases the chance of choosing a treatment that is in line with patients’ expectations [1469, 1476-
1478].
While it may seem desirable to tailor the patients’ role in decision-making to their initial preference,
and particularly to a preference for deferring to the advice of the clinician, this does not result in less decisional
conflict or regret. Increasing patients’ knowledge regardless of initial preference may actually be preferable [1474].

8.3.2.4 Decision aids in prostate cancer

Shared decision-making can increase patients’ comfort when confronted with management decisions but has
been shown to improve health outcome [1479] and more training seems needed for health care professionals

PROSTATE CANCER - LIMITED UPDATE MARCH 2023 147

guiding patients [1480]. Patient education decreased PSA testing [1481] and increased adherence to AS
protocols [1482, 1483]. Autonomous active decision-making by patients was associated with less regret after
prostatectomy regardless of the method chosen and decision aids reduce decisional conflict [1484]. Still,
guidance is needed to optimise patients’ understanding of the options [1485]. Patients prioritised effectiveness
and pain control over mode of administration and risk of fatigue when confronted with treatment choice in
metastasised PCa [1486]. When implementing decision aids clinical validity and utility should be carefully
evaluated and distinguished [1487]. A decision aid should educate as well as promote shared decision-making
to optimise efficacy [1488] and pay attention to communicative aspects [1489].

8.3.2.5 Guidelines for quality of life in men undergoing systemic treatments

Recommendations Strength rating

Offer men on androgen deprivation therapy (ADT), 12 weeks of supervised (by trained Strong
exercise specialists) combined aerobic and resistance exercise.
Advise men on ADT to maintain a healthy weight and diet, to stop smoking, reduce alcohol Strong
to < 2 units daily and have yearly screening for diabetes and hypercholesterolemia. Ensure
that calcium and vitamin D meet recommended levels.
Offer men with T1-T3 disease specialist nurse-led, multi-disciplinary rehabilitation based Strong
on the patients’ personal goals addressing incontinence, sexuality, depression and fear of
recurrence, social support and positive lifestyle changes after any radical treatment.
Offer men starting on long-term ADT dual emission X-ray absorptiometry (DEXA) scanning Strong
to assess bone mineral density.
Offer anti-resorptive therapy to men on long term ADT with either a BMD T-score of < -2.5 Strong
or with an additional clinical risk factor for fracture or annual bone loss on ADT is confirmed
to exceed 5%.

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1471. Ramsey, S.D., et al. Unanticipated and underappreciated outcomes during management of local
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10. CONFLICT OF INTEREST

All members of the EAU-EANM-ESTRO-ESUR-ISUP-SIOG Prostate Cancer Guidelines Panel have provided
disclosure statements of all relationships that they have that might be perceived as a potential source of
a conflict of interest. This information is publicly accessible through the European Association of Urology
website: https://uroweb.org/guideline/prostate-cancer/.
This guidelines document was developed with the financial support of the European Association of
Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation
and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other
reimbursements have been provided.

11. CITATION INFORMATION

The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the
citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location,
or an ISBN number may vary.

The compilation of the complete Guidelines should be referenced as:

EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2023. ISBN 978-94-92671-19-6.

If a publisher and/or location is required, include:

EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/

References to individual guidelines should be structured in the following way:

Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.

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