EAU Guidelines on Prostate Cancer

EAU Guidelines on Prostate Cancer

A. Heidenreich (chairman), P.J. Bastian, J. Bellmunt, M. Bolla, S. Joniau, M.D. Mason, V. Matveev, N. Mottet, T.H. van der Kwast, T. Wiegel, F. Zattoni © European Association of Urology 2012

TABLE OF CONTENTS PAGE

1. INTRODUCTION 8
1.1 Introduction 8
1.2 Data identification and evidence sources 8
1.3 Level of evidence and grade of recommendation 8
1.4 Publication history 9
1.5 Potential conflict of interest statement 10
1.6 References 10

2. BACKGROUND 10
2.1 References 11

3. CLASSIFICATION 11
3.1 Gleason score 12
3.2 References 12

4. RISK FACTORS 13
4.1 References 13

5. SCREENING AND EARLY DETECTION 14
5.1 References 15

6. DIAGNOSIS 16
6.1 Digital rectal examination (DRE) 16
6.2 Prostate-specific antigen (PSA) 16
6.2.1 Free/total PSA ratio (f/t PSA) 17
6.2.2 PSA velocity (PSAV), PSA doubling time (PSADT) 17
6.2.3 PCA3 marker 17
6.3 Transrectal ultrasonography (TRUS) 17
6.4 Prostate biopsy 17
6.4.1 Baseline biopsy 17
6.4.2 Repeat biopsy 18
6.4.3 Saturation biopsy 18
6.4.4 Sampling sites and number of cores 18
6.4.5 Diagnostic transurethral resection of the prostate (TURP) 18
6.4.6 Seminal vesicle biopsy 18
6.4.7 Transition zone biopsy 18
6.4.8 Antibiotics prior to biopsy 18
6.4.9 Local anaesthesia prior to biopsy 18
6.4.10 Fine-needle aspiration biopsy 18
6.4.11 Complications 18
6.5 Pathology of prostate needle biopsies 19
6.5.1 Grossing and processing 19
6.5.2 Microscopy and reporting 19
6.6 Pathohistology of radical prostatectomy (RP) specimens 20
6.6.1 Processing of the RP specimen 20
6.6.1.1 Recommendations for processing a prostatectomy specimen 20
6.6.2 RP specimen report 20
6.6.2.1 Gleason score 21
6.6.2.2 Interpreting the Gleason score 21
6.6.2.3 Definition of extraprostatic extension 22
6.6.3 Prostate cancer volume 22
6.6.4 Surgical margin status 22
6.6.5 Other factors 22
6.7 References 22

7. CLINICAL STAGING 28
7.1 T-staging 28
7.2 N-staging 29
7.3 M-staging 30
7.4 Guidelines for the diagnosis and staging of PCa 31
7.5 References 32

8. TREATMENT: DEFERRED TREATMENT (WATCHFUL WAITING/ACTIVE MONITORING) 35
8.1 Introduction 35
8.1.1 Definition 36
8.1.1.1 Watchful waiting (WW) 36
8.1.1.2 Active surveillance (AS) 36
8.2 Deferred treatment of localised PCa (stage T1-T2, Nx-N0, M0) 36
8.2.1 Watchful waiting (WW) 36
8.2.2 Active surveillance 38
8.3 Deferred treatment for locally advanced PCa (stage T3-T4, Nx-N0, M0) 40
8.4 Deferred treatment for metastatic PCa (stage M1) 41
8.5 Summary of deferred treatment for prostate cancer 41
8.5.1 Indications 41
8.5.2 Options 41
8.6 References 41

9. TREATMENT: RADICAL PROSTATECTOMY 44
9.1 Introduction 44
9.2 Low-risk, localised prostate cancer: cT1-T2a and Gleason score 2-6 and prostate-specific
antigen < 10 ng/mL 45
9.2.1 Stage T1a-T1b prostate cancer 45
9.2.2 Stage T1c and T2a prostate cancer 46
9.3 Intermediate-risk, localised prostate cancer: cT2b-T2c or Gleason score = 7 or
prostate-specific antigen 10-20 ng/mL 46
9.3.1 Oncological results of radical prostatectomy in low- and intermediate-risk
prostate cancer 46
9.4 High-risk, localised prostate cancer: cT3a or Gleason score 8-10 or
prostate-specific antigen > 20 ng/mL 47
9.4.1 Locally advanced prostate cancer: cT3a 47
9.4.2 High-grade prostate cancer: Gleason score 8-10 48
9.4.3 Prostate cancer with prostate-specific antigen > 20 ng/mL 48
9.5 Very-high-risk, localised prostate cancer: cT3b-T4 N0 or any T, N1 49
9.5.1 cT3b-T4 N0 49
9.5.2 Any T, N1 49
9.6 Indication and extent of extended pelvic lymph node dissection 49
9.6.1 Conclusions 50
9.6.2 Extent of extended lymph node dissection 50
9.6.3 Therapeutic role of extended lymph node dissection 50
9.6.4 Morbidity 50
9.6.5 Conclusions extended lymph node dissection 50
9.7 Summary of radical prostatectomy in high-risk localised disease 50
9.8 Neoadjuvant hormonal therapy and radical prostatectomy 51
9.8.1 Summary of neoadjuvant and adjuvant hormonal treatment and radical
prostatectomy 51
9.9 Complications and functional outcome 51
9.10 Summary of indications for nerve-sparing surgery 52
9.11 Conclusions and recommendations for radical prostatectomy 53
9.12 References 53

10. TREATMENT: DEFINITIVE RADIATION THERAPY 59
10.1 Introduction 59
10.2 Technical aspects: three-dimensional conformal radiotherapy (3D-CRT) and intensity
modulated external beam radiotherapy (IMRT) 60
10.3 Radiotherapy for non-metastatic prostate cancer 60
10.3.1 Prophylactic irradiation of pelvic lymph nodes in high-risk localised PCa 61
10.4 Innovative techniques 61
10.4.1 Intensity modulated radiotherapy 614 
10.4.2 Proton beam and carbon ion beam therapy 61
10.5 Transperineal brachytherapy 62
10.6 Late toxicity 63
10.7 Immediate and delayed post-operative external irradiation after radical prostatectomy 64
10.8 Locally advanced PCa: T3-4 N0, M0 65
10.8.1 Neo-adjuvant and concomitant short-term androgen deprivation therapy 66
10.8.2 Neo-adjuvant and concomitant hormonal therapy 66
10.8.3 Concomitant and long-term adjuvant hormonal therapy 66
10.8.4 Long-term adjuvant hormonal therapy 66
10.8.5 Neo-adjuvant, concomitant and long-term adjuvant hormonal therapy 67
10.8.6 Short-term or long-term adjuvant hormonal treatment 67
10.8.7 Dose escalation with hormonal therapy 67
10.9 Very high-risk PCa: c or pN1, M0 67
10.10 Guidelines summary for definitive radiation therapy 68
10.11 References 68

11. EXPERIMENTAL LOCAL TREATMENT OF PROSTATE CANCER 74
11.1 Background 74
11.2 Cryosurgery of the prostate (CSAP) 74
11.2.1 Indication for CSAP 74
11.2.2 Results of modern cryosurgery for PCa 74
11.2.3 Complications of CSAP for primary treatment of PCa 75
11.2.4 Summary conclusions for CSAP 75
11.3 HIFU of the prostate 75
11.3.1 Results of HIFU in PCa 76
11.3.2 Complications of HIFU 77
11.4 Focal therapy of PCa 77
11.4.1 Pre-therapeutic assessment of patients 77
11.4.2 Patient selection for focal therapy 77
11.5 Summary of experimental therapeutic options to treat clinically localised PCa 78
11.6 References 78

12. HORMONAL THERAPY 80
12.1 Introduction 80
12.1.1 Basics of hormonal control of the prostate 80
12.1.2 Different types of hormonal therapy 80
12.2 Testosterone-lowering therapy (castration) 80
12.2.1 Castration level 80
12.2.2 Bilateral orchiectomy 81
12.2.3 LHRH agonists 81
12.2.3.1 Achievement of castration levels 81
12.2.3.2 Flare-up phenomenon 81
12.2.4 LHRH antagonists 81
12.2.4.1 Abarelix 82
12.2.4.2 Degarelix 82
12.2.4.3 Conclusions 82
12.3 Oestrogens 82
12.3.1 Diethylstilboesterol (DES) 82
12.3.2 Renewed interest in oestrogens 82
12.3.3 Strategies to counteract the cardiotoxicity of oestrogen therapy 83
12.3.4 Conclusions 83
12.4 Anti-androgens 83
12.4.1 Steroidal anti-androgens 83
12.4.1.1 Cyproterone acetate (CPA) 83
12.4.1.2 Megestrol acetate and medroxyprogesterone acetate 84
12.4.2 Non-steroidal anti-androgens 84
12.4.2.1 Nilutamide 84
12.4.2.2 Flutamide 84
12.4.2.3 Bicalutamide 85
12.5 Combination therapies 86
12.5.1 Complete androgen blockade (CAB) 86
12.5.2 Minimal androgen blockade (or peripheral androgen blockade) 86
12.5.3 Intermittent versus continuous ADT 87
12.5.4 Immediate versus deferred ADT 89
12.6 Indications for hormonal therapy 90
12.7 Contraindications for various therapies 91
12.8 Outcome 91
12.9 Side-effects, QoL, and cost of hormonal therapy 91
12.9.1 Sexual function 91
12.9.2 Hot flashes 91
12.9.2.1 Hormonal therapy 91
12.9.2.2 Antidepressants 91
12.9.2.3 Other options 92
12.9.3 Other systemic side-effects of ADT 92
12.9.3.1 Non-metastatic bone fractures 92
12.9.3.2 Lipid levels 93
12.9.3.3 Metabolic syndrome 93
12.9.3.4 Cardiovascular disease 93
12.10 Quality of life (QoL) 93
12.11 Cost-effectiveness of hormonal therapy options 94
12.12 Conclusions and guidelines for hormonal therapy in prostate cancer 94
12.13 References 95

13. MANAGEMENT OF PROSTATE CANCER IN OLDER MEN 102
13.1 Introduction 102
13.2 Treatment-related complications 103
13.3 References 104

14. QUALITY OF LIFE OF PATIENTS WITH LOCALISED PROSTATE CANCER 105
14.1 Introduction 105
14.2 Active surveillance 106
14.3 Radical prostatectomy 106
14.4 External-beam radiation therapy (EBRT) and low-dose rate (LDR) brachytherapy 107
14.5 Comparison of HRQoL between treatment modalities 107
14.6 References 109
15. SUMMARY OF GUIDELINES ON PRIMARY TREATMENT OF PCa 112
16. FOLLOW-UP: AFTER TREATMENT WITH CURATIVE INTENT 114
16.1 Definition 114
16.2 Why follow-up? 114
16.3 How to follow-up? 114
16.3.1 PSA monitoring 114
16.3.2 Definition of PSA progression 114
16.3.3 PSA monitoring after radical prostatectomy 115
16.3.4 PSA monitoring after radiation therapy 115
16.3.5 Digital rectal examination (DRE) 115
16.3.6 Transrectal ultrasonography (TRUS) and biopsy 115
16.3.7 Bone scintigraphy 116
16.3.8 Computed tomography (CT) or magnetic resonance imaging (MRI) 116
16.4 When to follow-up? 116
16.5 Guidelines for follow-up after treatment with curative intent 116
16.6 References 116
17. FOLLOW-UP AFTER HORMONAL TREATMENT 118
17.1 Introduction 118
17.2 Purpose of follow-up 118
17.3 Methods of follow-up 118
17.3.1 Prostate-specific antigen monitoring 118
17.3.2 Creatinine, haemoglobin and liver function monitoring 1186 
17.3.3 Bone scan, ultrasound and chest X-ray 119
17.4 Testosterone monitoring 119
17.5 Monitoring of metabolic complications 119
17.6 When to follow-up 120
17.6.1 Stage M0 patients 120
17.6.2 Stage M1 patients 120
17.6.3 Castration-refractory PCa 120
17.7 Guidelines for follow-up after hormonal treatment 120
17.8 References 120

18. TREATMENT OF BIOCHEMICAL FAILURE AFTER TREATMENT WITH CURATIVE INTENT 122
18.1 Background 122
18.2 Definitions 122
18.2.1 Definition of treatment failure 122
18.2.2 Definitions of recurrence 123
18.3 Local or systemic relapse 123
18.3.1 Definition of local and systemic failure 123
18.4 Evaluation of PSA progression 124
18.4.1 Diagnostic procedures for PSA relapse following RP 124
18.4.2 Diagnostic studies for PSA relapse following radiation therapy 126
18.4.3 Diagnostic procedures in patients with PSA relapse 127
18.5 Treatment of PSA-only recurrences 127
18.5.1 Radiation therapy for PSA-only recurrence after RP 127
18.5.1.1 Dose, target volume, toxicity 128
18.5.2 Hormonal therapy 129
18.5.2.1 Adjuvant hormonal therapy after RP 129
18.5.2.2 Post-operative hormonal therapy for PSA-only recurrence 129
18.5.3 Observation 131
18.5.4 Management of PSA relapse after RP 131
18.6 Management of PSA failures after radiation therapy 131
18.6.1 Salvage radical prostatectomy 131
18.6.1.1 Summary of salvage RP 132
18.6.2 Salvage cryosurgical ablation of the prostate (CSAP) for radiation failures 132
18.6.3 Salvage brachytherapy for radiation failures 133
18.6.4 Observation 133
18.6.5 High-intensity focused ultrasound (HIFU) 133
18.6.5.1 Salvage HIFU therapy 134
18.6.6 Guidelines for the management of PSA relapse after radiation therapy 134
18.7 Guidelines for second-line therapy after treatment with curative intent 135
18.9 References 135

19. CASTRATION-RESISTANT PCa (CRPC) 142
19.1 Background 142
19.1.1 Androgen-receptor-independent mechanisms 142
19.1.2 AR-dependent mechanisms 143
19.2 Definition of relapsing prostate cancer after castration 143
19.3 Assessing treatment outcome in androgen-independent PCa 144
19.3.1 PSA level as marker of response 144
19.3.2 Other parameters 144
19.3.3 Trial end-points 145
19.3.4 Recommendations for assessing therapeutic response 145
19.4 Androgen deprivation in castration-resistant PCa 145
19.5 Secondary hormonal therapy 145
19.6 Anti-androgen withdrawal syndrome 146
19.7 Treatment alternatives after initial hormonal therapy 147
19.7.1 Bicalutamide 147
19.7.2 Switching to an alternative anti-androgen therapy 147
19.7.3 Anti-androgen withdrawal accompanied by simultaneous ketoconazole 147
19.7.4 Oestrogens 147
19.7.5 The future for agents targeting the androgen receptor and endocrine pathways 147
19.7.5.1 MDV3100 148
19.7.5.2 Abiraterone acetate 148
19.8 Non-hormonal therapy (cytotoxic agents) 148
19.8.1 Timing of chemotherapy in metastatic CRPC 149
19.8.2 Mitoxantrone combined with corticosteroids 149
19.8.3 Alternative combination treatment approaches 149
19.8.4 Estramustine in combination therapies 149
19.8.5 Oral cyclophosphamide 150
19.8.6 Cisplatin and carboplatin 150
19.8.7 Specific bone targets 150
19.8.8 Salvage chemotherapy 150
19.9 Palliative therapeutic options: bone targeted therapies in CRPC 151
19.9.1 Painful bone metastases 151
19.9.2 Common complications due to bone metastases 151
19.9.3 Bisphosphonates 151
19.9.4 RANK ligand inhibitors 152
19.10 Summary of treatment after hormonal therapy 152
19.11 Recommendations for cytotoxic and pre/post-docetaxel therapy in CRPC 152
19.12 Recommendations for palliative management of CRPC 153
19.13 References 153

20. ABBREVIATIONS USED IN THE TEXT 1638 
1. INTRODUCTION
1.1 Introduction
The European Association of Urology (EAU) Guidelines Group for Prostate Cancer have prepared this guidelines document to assist medical professionals assess the evidence-based management of prostate
cancer. The multidisciplinary panel of experts include urologists, radiation oncologists, a medical oncologist, and a pathologist specialized in prostate cancer.
1.2 Data identification and evidence sources
The recommendations provided in the current guidelines are based on a systemic literature search performed by the panel members (1). MedLine, Embase, and Web of Science databases were searched to identify original articles, review articles and editorials addressing “epidemiology”, “risk factors”, “diagnosis”,“staging” and "treatment” of prostate cancer. The controlled vocabulary of the Medical Subject Headings(MeSH) database was used alongside a “free-text” protocol, combining “prostate cancer” with the terms“diagnosis”, “screening”, “staging”, “active surveillance”, “radical prostatectomy”, “external beam radiation”,“brachytherapy”, “androgen deprivation”, “chemotherapy”, “relapse”, “salvage treatment”, and “follow-up” to ensure sensitivity of the searches.

All articles published between January 2010 (previous update) and November 2011 were considered for review. The expert panel reviewed these records to select the articles with the highest evidence, according to a rating schedule adapted from the Oxford Centre for Evidence-based Medicine Levels of Evidence (1).
Additionally, publications from the major urological (EAU, AUA) and oncological meetings (ASCO, ESMO, ASTRO) have been considered.Where possible, abstracts will be replaced by the full scientific publications when these become available. Also no major recommendations can be based on evidence from abstract only.
It must be emphasised that clinical guidelines present the best evidence available but following the recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, also taking individual circumstances and patient preferences into account.
1.3 Level of evidence and grade of recommendation
The level of evidence (LE) and grade of recommendation (GR) provided in this guideline follow the listings in Tables 1 and 2. The aim of grading the recommendations is to provide transparency between the underlying evidence and the recommendation given.
Table 1: Level of evidence*

*Modified from Sackett, et al. (1).
It should be noted that when recommendations are graded, there is not an automatic relationship between the level of evidence and the grade of recommendation. The availability of RCTs may not necessarily translate into a grade A recommendation if there are methodological limitations or disparities in the published results. Conversely, an absence of high-level evidence does not necessarily preclude a grade A recommendation if there is overwhelming clinical experience and consensus. In addition, there may be exceptional situations in which corroborating studies cannot be performed, perhaps for ethical or other reasons. In this case, unequivocal recommendations are considered helpful for the reader. Whenever this occurs, it has been clearly indicated in the text with an asterisk as ‘upgraded based on panel consensus’. The quality of the underlying scientific evidence is a very important factor, but it has to be balanced against benefits and burdens, values and preferences and costs when a grade is assigned (2-4).The EAU Guidelines Office does not perform cost assessments, nor can they address local/national preferences in a systematic fashion. However, whenever such data are available, the expert panels will include the information.
Table 2: Grade of recommendation*

*Modified from Sackett, et al. (1).
1.4 Publication History
The Prostate Cancer Guidelines were first published in 2001, with partial updates achieved in 2003 and 2007, followed by a full text update in 2009. Also in 2011 a considerable number of sections of the PCa guidelines were revised. This 2012 publication includes updated chapters and sections as detailed below. The literature for all chapters has been revisited and, where available, new literature has been included.

The 2012 PCa guidelines publication underwent a blinded peer-review process before publication.

Standard procedure for EAU publications includes an annual assessment of newly published literature in this
field, guiding future updates. An ultra-short reference document is being published alongside this publication.
All documents are available with free access through the EAU website Uroweb (http://www.uroweb.org/
guidelines/online-guidelines/).

Summary of updated and new information
Chapter 6 “Diagnosis”:
• All literature has been revisited, new data has been added;
• Most notably in sections 6.2.3 (PCA3 marker), 6.4.8 (Antibiotics prior to biopsy), 6.4.11
(Complications), 6.5 (Pathology of prostate needle biopsies) and 6.6.2.3 (Definition of extraprostatic extension).
• In section 6.4.8 (Antibiotics prior to biopsy), the quinolones resistance related to infectiouscomplications after biopsy.
Chapter 8 “Watchful waiting/active surveillance”:
• Additional data on the impact of radical prostatectomy compared to watchful waiting (WW) has beenadded.
• Data have been added supporting that comorbidity status is the leading cause of death at ten years,especially for Charlson score > 2, irrespective of age, even for those with an aggressive tumour.
• Active surveillance as appropriate for highly selected, low risk patients only. Early re-biopsy plays asan increasingly important role in the patient’s selection process.
• In general, repeat biopsies are a major tool for patient follow-up.
Chapter 9 “Treatment: Radical prostatectomy”;
• Additional data have been included in section 9.1 (Introduction) on robot-assisted laparoscopicprostatectomy (RALP)
• Added emphasis is given to the need for a multidisciplinary approach in the treatment of high-risk localised disease Section 9.4 (High-risk localised PCa).
Chapter 10 “Treatment: Definitive radiation therapy”;
• Additional data has been added on the various hormonal therapy options, section 10.8 (Locally advanced PCa: T3-4, N0M0).
Chapter 11 “Experimental local treatment of prostate cancer”;
• Additional data has been added on oncological outcomes and treatment-associated complications (Section 11.3 -HIFU of the prostate).
• Additional data on salvage radical prostatectomy versus CSAP has been included (Section 16.6.2 -Salvage cryosurgical ablation of the prostate for radiation failures).
• A new section has been added on salvage high-intensity focused ultrasound (HIFU).
Chapter 12 “Hormonal treatment”;
• Data from the largest randomised controlled trial on PCa patients relapsing after radiotherapy hasbeen incorporated, showing that intermittent androgen-deprivation therapy (ADT) proved to be as effective as continuous ADT. 10 
• Additional data regarding bone protection and the potential role of denosumab in delaying secondary bone metastases. However, denosumab does not impact overall survival or cancer-specific survival.
• Further data on androgen deprivation therapy (ADT) was included. ADT is associated with increased cardiac morbidity, not an increase in cardiac mortality. The presence of a congestive heart failure or myocardial infarction increases the mortality risk
Chapter 15 “Follow up after hormonal treatment”;
• The literature has been revisited. The importance of bone- and testosterone monitoring is reinforced.
Chapter 16 “Treatment of biochemical failure after treatment with curative intent”
• In section 16.4 (Evaluation of PSA progression), additional data has been added on the role of choline PET/CT in the diagnosis of men with rising PSA following radical prostatectomy.
Chapter 17 “Castration resistant prostate cancer”;
• For section 17.4 (Recommendations for assessing therapeutic response), new literature has been incorporated and recommendations have changed;
• 17.8.5.2 (Abiraterone acetate), new information has been added;
• 17.9.10 (Specific bone targets), information from the ENTHUSE study has been included.
New topics included in this 2012 print
• Quality of life of patients with localised prostate cancer
• Chapter 16, A section has been added on salvage high-intensity focused ultrasound (HIFU)
• Chapter 17, Section 17.10.4 RANK ligand inhibitors
1.5 Potential conflict of interest statement
The expert panel have submitted potential conflict of interest statements which can be viewed on the EAU website: http://www.uroweb.org/guidelines/online-guidelines/.
1.6 References
1. Oxford Centre for Evidence-Based Medicine Levels of Evidence (May 2009). Produced by Bob
Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since
November 1998. Updated by Jeremy Howick March 2009.
http://www.cebm.net/index.aspx?o=1025 [Access date January 2012]
2. Atkins D, Best D, Briss PA, et al; GRADE Working Group. Grading quality of evidence and strength of
recommendations.BMJ 2004 Jun 19;328(7454):1490.
http://www.ncbi.nlm.nih.gov/pubmed/15205295
3. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence
and strength of recommendations. BMJ 2008 Apr;336(7650):924-6.
http://www.ncbi.nlm.nih.gov/pubmed/18436948
4. Guyatt GH, Oxman AD, Kunz R, et al; GRADE Working Group. Going from evidence to
recommendations. BMJ 2008 May 10;336(7652):1049--51.
http://www.bmj.com/content/336/7652/1049.long

2. BACKGROUND
Cancer of the prostate (PCa) is now recognised as one of the most important medical problems facing the male population. In Europe, PCa is the most common solid neoplasm, with an incidence rate of 214 cases per 1000 men, outnumbering lung and colorectal cancer (1). Furthermore, PCa is currently the second most common cause of cancer death in men (2). In addition, since 1985, there has been a slight increase in most countries in the number of deaths from PCa, even in countries or regions where PCa is not common (3).

Prostate cancer affects elderly men more often than young men. It is therefore a bigger health concernin developed countries with their greater proportion of elderly men. Thus, about 15% of male cancers are PCa in developed countries compared to 4% of male cancers in undeveloped countries (4). It is worth mentioning that there are large regional differences in incidence rates of PCa. For example, in Sweden, where there is a long life expectancy and mortality from smoking-related diseases is relatively modest, PCa is the most common malignancy in males, accounting for 37% of all new cases of cancer in 2004 (5).
2.1 References
1. Boyle P, Ferlay J. Cancer incidence and mortality in Europe 2004. Ann Oncol 2005 Mar;16(3):481-8.
http://www.ncbi.nlm.nih.gov/pubmed/15718248
2. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008 Mar-Apr;58(2):71-96.
http://www.ncbi.nlm.nih.gov/pubmed/18287387
3. Quinn M, Babb P. Patterns and trends in prostate cancer incidence, survival, prevalence and mortality.
Part I: international comparisons. BJU Int 2002 Jul;90(2):162-73.
http://www.ncbi.nlm.nih.gov/pubmed/12081758
4. Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000: the global picture. Eur J Cancer
2001Oct;37(Suppl 8):S4-66.
http://www.ncbi.nlm.nih.gov/pubmed/11602373
5. Persson G, Danielsson M, Rosén M, et al. Health in Sweden: The National Public Health Report 2005.
Scand J Public Health 2006; 34(Suppl 67): 3-10
http://sjp.sagepub.com/cgi/reprint/34/67_suppl/3.pdf
3. CLASSIFICATION
The 2009 TNM (Tumour Node Metastasis) classification for PCa is shown in Table 3 (1).
Table 3: Tumour Node Metastasis (TNM) classification of PCa*

M1c Other site(s)
1 Tumour found in one or both lobes by needle biopsy, but not palpable or visible by imaging, is classified asT1c.
2 Invasion into the prostatic apex, or into (but not beyond) the prostate capsule, is not classified as pT3, but as pT2.
3 Metastasis no larger than 0.2 cm can be designated pN1 mi.
4 When more than one site of metastasis is present, the most advanced category should be used.

Prognostic grouping

Note: When either PSA or Gleason is not available, grouping should be determined by cT category and whichever of either PSA of Gleason is available. When neither is available prognostic grouping is not possible, use stage grouping
3.1 Gleason score
The ISUP 2005 Gleason score is the current standard for grading adenocarcinoma of the prostate on core biopsy and operative specimens (2). The Gleason score is the sum of the two most common patterns (grades 1-5) of tumour growth found. The Gleason score ranges between 2 and 10, with 2 being the least aggressive and 10 the most aggressive. In needle biopsies, the worst grade should always be incorporated in the Gleason score, even if comprising < 5% of the cancer (2).
3.2 References
1. Sobin LH, Gospodariwicz M, Wittekind C (eds). TNM classification of malignant tumors. UICC International Union Against Cancer. 7th edn. Wiley-Blackwell, 2009 Dec; pp. 243-248.
http://www.uicc.org/tnm/
2 Epstein JI, Allsbrook WC Jr, Amin MB, et al; ISUP grading committee. The 2005 International Society of Urologic Pathology (ISUP) Consensus Conference on Gleason grading of Prostatic Carcinoma. Am J Surg Pathol 2005 Sep;29(9):1228-42.
http://www.ncbi.nlm.nih.gov/pubmed/16096414
4. RISK FACTORS
The factors that determine the risk of developing clinical PCa are not well known, although a few have been identified. There are three well-established risk factors for PCa:
• increasing age;
• ethnic origin;
• heredity.
If one first-line relative has PCa, the risk is at least doubled. If two or more first-line relatives are affected, the risk increases by 5-11-fold (1,2). A small subpopulation of individuals with PCa (about 9%) has true hereditary PCa. This is defined as three or more affected relatives, or at least two relatives who have developed earlyonset disease, i.e. before age 55 (3). Patients with hereditary PCa usually have an onset 6-7 years prior to spontaneous cases, but do not differ in other ways (4).

The frequency of autopsy-detected cancers is roughly the same in different parts of the world (5). This finding is in sharp contrast to the incidence of clinical PCa, which differs widely between different geographical areas, being high in the USA and Northern Europe and low in Southeast Asia (6). However, if Japanese men move from Japan to Hawaii, their risk of PCa increases. If they move to California their risk increases even more, approaching that of American men (7) (LE: 2).

These findings indicate that exogenous factors affect the risk of progression from so-called latent PCa to clinical PCa. Factors such as food consumption, pattern of sexual behaviour, alcohol consumption, exposure to ultraviolet radiation, chronic inflammation (8) and occupational exposure have all been discussed as being aetiologically important (9). Prostate cancer is an ideal candidate for exogenous preventive measures, such as dietary and pharmacological prevention, due to some specific features: high prevalence, long latency, endocrine dependency, availability of serum markers (PSA), and histological precursor lesions (atypical small acinar proliferation [ASAP] or prostatic intraepithelial neoplasia [PIN]) (8). Dietary/nutritional factors that may influence disease development include total energy intake (as reflected by body mass index), dietary fat, cooked meat, micronutrients and vitamins (carotenoids, retinoids, vitamins C, D, and E), fruit and vegetable intake, minerals (calcium, selenium), and phyto-oestrogens (isoflavonoids, flavonoids, lignans), or statins and/or cholesterol intake. Since most studies reported to date are case-control analyses, there remain more questions than evidence-based data available to answer them. Several ongoing large randomised trials are trying to clarify the role of such risk factors and the potential for successful prostate cancer prevention (10).In summary, hereditary factors are important in determining the risk of developing clinical PCa, while exogenous factors may have an important impact on this risk. The key question is whether there is enough evidence to recommend lifestyle changes (lowered intake of animal fat and increased intake of fruit, cereals, and vegetables) in order to decrease the risk (11). There is some evidence to support such a recommendation and this information can be given to male relatives of PCa patients who ask about the impact of diet (LE: 2-3).
4.1 References
1. Steinberg GD, Carter BS, Beaty TH, et al. Family history and the risk of prostate cancer. Prostate
1990;17(4):337-47.
http://www.ncbi.nlm.nih.gov/pubmed/2251225
2. Gronberg H, Damber L, Damber JE. Familial prostate cancer in Sweden. A nationwide register cohort
study. Cancer 1996 Jan;77(1):138-43.
http://www.ncbi.nlm.nih.gov/pubmed/8630920
3. Carter BS, Beaty TH, Steinberg GD, et al. Mendelian inheritance of familial prostate cancer. Proc
NatlAcad Sci USA 1992 Apr 15;89(8):3367-71.
http://www.ncbi.nlm.nih.gov/pubmed/1565627
4. Bratt O. Hereditary prostate cancer: clinical aspects. J Urol 2002 Sep;168(3):906-13.
http://www.ncbi.nlm.nih.gov/pubmed/12187189
5. Breslow N, Chan CW, Dhom G, et al. Latent carcinoma of prostate at autopsy in seven areas. The
International Agency for Research on Cancer, Lyons, France. Int J Cancer 1977 Nov 15;20(5):680-8.
http://www.ncbi.nlm.nih.gov/pubmed/924691
6. Quinn M, Babb P. Patterns and trends in prostate cancer incidence, survival, prevalence and mortality.
Part I: international comparisons. BJU Int 2002 Jul;90(2):162-73.
http://www.ncbi.nlm.nih.gov/pubmed/12081758
7. Zaridze DG, Boyle P, Smans M. International trends in prostatic cancer. Int J Cancer 1984 Feb
15;33(2):223-30.
http://www.ncbi.nlm.nih.gov/pubmed/6693200
8. Nelson WG, De Marzo AM, Isaacs WB Prostate cancer. N Engl J Med 2003 Jul 24;349(4):366-81.
http://www.ncbi.nlm.nih.gov/pubmed/1287874514 
9. Kolonel LN, Altshuler D, Henderson BE. The multiethnic cohort study: exploring genes, lifestyle and
cancer risk. Nat Rev Cancer 2004 Jul;4(7):519-27.
http://www.ncbi.nlm.nih.gov/pubmed/15229477
10. Schmid H-P, Engeler DS, Pummer K, et al. Prevention of prostate cancer: more questions than data.
Recent Results Cancer Res 2007;174:101-7.
http://www.ncbi.nlm.nih.gov/pubmed/17302190
11. Schulman CC, Zlotta AR, Denis L, et al. Prevention of prostate cancer. Scand J Urol Nephrol
2000;(205):50-61.
http://www.ncbi.nlm.nih.gov/pubmed/11144904
5. SCREENING AND EARLY DETECTION
Population or mass screening is defined as the examination of asymptomatic men (at risk). It usually takes place as part of a trial or study and is initiated by the screener. In contrast, early detection or opportunistic screening comprises individual case findings, which are initiated by the person being screened (patient) and/or his physician. The primary endpoint of both types of screening has two aspects:
1. Reduction in mortality from PCa. The goal is not to detect more carcinomas, nor is survival the
endpoint because survival is strongly influenced by lead-time from diagnosis.
2. The quality of life is important as expressed by quality-of-life adjusted gain in life years (QUALYs).
Prostate cancer mortality trends range widely from country to country in the industrialised world (1). Decreased mortality rates due to PCa have occurred in the USA, Austria, UK, and France, while in Sweden the 5-year survival rate has increased from 1960 to 1988, probably due to increased diagnostic activity and greater detection of non-lethal tumours (2). However, this trend has not been confirmed in a similar study from the Netherlands (3). The reduced mortality seen recently in the USA is often attributed to the widely adopted aggressive screening policy, but there is still no absolute proof that prostate-specific antigen (PSA) screening reduces mortality due to PCa (4) (LE: 2).

A non-randomised screening project in Tyrol (Austria) may support the hypothesis that screening can be effective in reducing mortality from PCa. An early detection programme and free treatment have been used to explain the 33% decrease in the PCa mortality rate seen in Tyrol compared to the rest of Austria (5) (LE: 2b). In addition, a Canadian study has claimed lower mortality rates in men randomised to active PCa screening(6), though these results have been challenged (7). Positive findings attributed to screening have also been contradicted by a comparative study between the US city of Seattle area (highly screened population) and the US state of Connecticut (seldom screened population) (8). The study found no difference in the reduction in the rate of PCa mortality (LE: 2b), even allowing for the very great diversity in PSA testing and treatment.

In 2009, the long awaited results of two prospective, randomised trials were published. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial randomly assigned 76,693 men at 10 US centres to receive either annual screening with PSA and DRE, or standard care as the control. After 7 years’ follow-up, the incidence of PCa per 10,000 person-years was 116 (2,820 cancers) in the screening group and 95 (2,322 cancers) in the control group (rate ratio, 1.22) (9). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screened group and 1.7 (44 deaths) in the control group (rate ratio, 1.13). The data at 10 years were 67% complete and consistent with these overall findings. The PLCO project team concluded that PCarelated mortality was very low and not significantly different between the two study groups (LE: 1b).

The European Randomized Study of Screening for Prostate Cancer (ERSPC) included a total of 162,243 men from seven countries aged between 55 and 69 years. The men were randomly assigned to a group offered PSA screening at an average of once every 4 years or to an unscreened control group. During a median follow-up of 9 years, the cumulative incidence of PCa was 8.2% in the screened group and 4.8% in the control group (10). The rate ratio for death from PCa was 0.80 in the screened group compared with the control group. The absolute risk difference was 0.71 deaths per 1,000 men. This means that 1,410 men would need to be screened and 48 additional cases of PCa would need to be treated to prevent one death from PCa. The ERSPC investigators concluded that PSA-based screening reduced the rate of death from PCa by 20%, but was associated with a high risk of over-diagnosis (LE: 1b).

Both trials have received considerable attention and comments. In the PLCO trial, the rate of compliance in the screening arm was 85% for PSA testing and 86% for DRE. However, the rate of contamination in the control arm was as high as 40% in the first year and increased to 52% in the sixth year for PSA testing and ranged from 41% to 46% for DRE. Furthermore, biopsy compliance was only 40-52% versus 86% in the ERSPC. Thus, the PLCO trial will probably never be able to answer whether or not screening can influence PCa mortality.In an update of the Gothenburg section of the ERSPC trial, which includes 20,000 men, the authors reported a reduction in PCa mortality of 50% after a median follow-up of 14 years. However, this finding was accompanied by a substantial risk of over-diagnosis (11).In the complete ERSCP trial, the real benefit will only be evident after 10-15 years of follow-up, especially once the 41% reduction of metastasis in the screening arm has had an impact. A longer follow-up may reduce the number needed to screen and to treat (12).
Based on the results of these two large, randomised trials, most if not all of the major urological societies conclude that at present widespread mass screening for PCa is not appropriate. Rather, early detection (opportunistic screening) should be offered to the well-informed man (see also Section 6, Diagnosis).
Two key questions remain open:
• At what age should early detection start?
• What is the screening interval for PSA and DRE?
A baseline PSA determination at age 40 years has been suggested, upon which the subsequent screening interval may then be based (13) (GR: B). A screening interval of 8 years might be enough in men with initial PSA levels < 1 ng/mL (14). Further, PSA testing in men older than 75 years is not recommended because its early detection would not have any clinical impact (15).
5.1 References
1. Oliver SE, May MT, Gunnell D. International trends in prostate-cancer mortality in the ‘PSA-ERA’. Int J
Cancer 2001 Jun;92(6):893-8.
http://www.ncbi.nlm.nih.gov/pubmed/11351313
2. Helgesen F, Holmberg L, Johansson JE, et al. Trends in prostate cancer survival in Sweden, 1960
through 1988, evidence of increasing diagnosis of non-lethal tumours. J Natl Cancer Inst 1996
Sep;88(17):1216-21.
http://www.ncbi.nlm.nih.gov/pubmed/8780631
3. Post PN, Kil PJ, Coebergh JW. Trends in survival of prostate cancer in southeastern Netherlands
1971-1989. Int J Cancer 1999 May;81(4):551-4.
http://www.ncbi.nlm.nih.gov/pubmed/10225443
4. Ilic D, O’Connor D, Green S, et al. Screening for prostate cancer: a Cochrane systematic review.
Cancer Causes Control 2007 Apr;18(3):279-85.
http://www.ncbi.nlm.nih.gov/pubmed/17206534
5. Bartsch G, Horninger W, Klocker H, et al. Tyrol Prostate Cancer Screening Group. Prostate cancer
mortality after introduction of prostate specific antigen mass screening in the Federal State of Tyrol,
Austria. Urology 2001 Sep;58(3):417-24.
http://www.ncbi.nlm.nih.gov/pubmed/11549491
6. Labrie F, Candas B, Dupont A, et al. Screening decreases prostate cancer death: first analysis of
the1988 Quebec prospective randomized controlled trial. Prostate 1999 Feb;38(2):83-91.
http://www.ncbi.nlm.nih.gov/pubmed/9973093
7. Boer R, Schroeder FH. Quebec randomized controlled trial on prostate cancer screening shows no
evidence of mortality reduction. Prostate 1999 Jul;40(2):130-4.
http://www.ncbi.nlm.nih.gov/pubmed/10386474
8. Lu-Yao G, Albertsen PC, Stanford JL, et al. Natural experiment examining impact of aggressive
screening and treatment on prostate cancer mortality in two fixed cohorts from Seattle area and
Connecticut. BMJ 2002 Oct;325(7367):740.
http://www.ncbi.nlm.nih.gov/pubmed/12364300
9. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Mortality results from a randomized prostate-cancer
screening trial. N Engl J Med 2009 Mar 26;360(13):1310-9.
http://www.ncbi.nlm.nih.gov/pubmed/19297565
10. Schröder FH, Hugosson J, Roobol MJ, et al.Screening and prostate-cancer mortality in a randomized
European study. N Engl J Med 2009 Mar 26;360(13):1320-8.
http://www.ncbi.nlm.nih.gov/pubmed/19297566
11. Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Göteborg randomised populationbased prostate-cancer screening trial. Lancet Oncol 2010 Aug;11(8):725-32
http://www.ncbi.nlm.nih.gov/pubmed/20598634
12. Gulati R, Mariotto AB, Chen S, et al. Long-term projections of the harm-benefit trade-off in prostate
cancer screening are more favorable than previous short-term estimates. J Clin Epidemiol 2011
Dec;64(12):1412-7.
http://www.ncbi.nlm.nih.gov/pubmed/2203275316 
13. Börgermann C, Loertzer H, Hammerer P, et al. [Problems, objective, and substance of early
detectionof prostate cancer]. Urologe A 2010 Feb;49(2):181-9. [Article in German]
http://www.ncbi.nlm.nih.gov/pubmed/20180057
14. Roobol MJ, Roobol DW, Schröder FH. Is additional testing necessary in men with prostate-specific
antigen levels of 1.0 ng/mL or less in a population-based screening setting? (ERSPC, section
Rotterdam). Urology 2005 Feb;65(2):343-6.
http://www.ncbi.nlm.nih.gov/pubmed/15708050
15. Schaeffer EM, Carter HB, Kettermann A, et al. Prostate specific antigen testing among the elderly;
when to stop? J Urol 2009 Apr:181(4):1606-14;discussion 1613-4.
http://www.ncbi.nlm.nih.gov/pubmed/19246059
6. DIAGNOSIS*
The main diagnostic tools to obtain evidence of PCa include DRE, serum concentration of PSA and transrectal ultrasonography (TRUS). Its definite diagnosis depends on the histopathologic verification of adenocarcinoma in prostate biopsy cores or operative specimens.
6.1 Digital rectal examination (DRE)
Most prostate cancers are located in the peripheral zone of the prostate and may be detected by DRE when the volume is about 0.2 mL or larger. In about 18% of all patients, PCa is detected by a suspect DRE alone, irrespective of the PSA level (1) (LE: 2a). A suspect DRE in patients with a PSA level of up to 2 ng/mL has a positive predictive value of 5-30% (2) (LE: 2a). A suspect DRE is a strong indication for prostate biopsy as it is predictive for more aggressive (Gleason score > 7) prostate cancer (3,4).
6.2 Prostate-specific antigen (PSA)
The measurement of PSA level has revolutionised the diagnosis of PCa (5). PSA is a kallikrein-like serine protease produced almost exclusively by the epithelial cells of the prostate. For practical purposes, it is organspecific but not cancer-specific. Thus, serum levels may be elevated in the presence of benign prostatic hypertrophy (BPH), prostatitis and other non-malignant conditions. The level of PSA as an independent variable is a better predictor of cancer than suspicious findings on DRE or TRUS (6).

There are many different commercial test kits for measuring PSA, but no commonly agreed international standard exists (7). The level of PSA is a continuous parameter: the higher the value, the more likely is the existence of PCa. The finding that many men may harbour PCa, despite low levels of serum PSA, has been underscored by recent results from a US prevention study (8) (LE: 2a). Table 4 gives the rate of PCa in relation to serum PSA for 2,950 men in the placebo-arm and with PSA values < 4 ng / mL.
Table 4: Risk of PCa in relation to low PSA values

The findings in Table 4 clearly demonstrate the occurrence of aggressive PCa even at very low PSA levels, precluding an optimal PSA threshold value for detecting non-palpable, but clinically significant, PCa (LE: 3). Use of nomograms may help reducing the number of unnecessary prostate biopsies (9).

Several modifications of serum PSA value have been described, which may improve the specificity of PSA in the early detection of PCa. They include: PSA density, PSA density of the transition zone, age-specific reference ranges, and PSA molecular forms. However, these derivatives and PSA isoforms (cPSA [complex
* Acknowledgment: Section 6.4 is partly based on the Guidelines of the AUO Study Group Urologic Oncology of the AustrianSociety of Urologists and Andrologists (W. Höltl, W. Loidl, M. Rauchenwald, M. Müller, M. Klimpfinger, A. Schratter-Sehn,C. Brössner).PSA], proPSA [precursor isoforms of PSA], BPSA [benign PSA], iPSA [intact PSA]) have limited usefulness in the routine clinical setting and have therefore not been considered for inclusion in these guidelines.
6.2.1 Free/total PSA ratio (f/t PSA)
The free/total PSA ratio (f/t PSA) is the concept most extensively investigated and most widely used in clinical practice to discriminate BPH from PCa. The ratio is used to stratify the risk of PCa for men who have total PSA levels between 4 and 10 ng/mL and a negative DRE. In a prospective multicentre trial, PCa was found on biopsy in 56% of men with f/t PSA < 0.10, but in only 8% of men with f/t PSA > 0.25 (10) (LE: 2a). Nevertheless, the concept must be used with caution as several pre-analytical and clinical factors may influence the f/t PSA, e.g. instability of free PSA, variable assay characteristics and very large prostate size (11). For example, free PSA is unstable at both 4°C and at room temperature. In addition, assay characteristics may vary, and concomitant BPH in large prostates may result in a dilution effect (11). Furthermore, f/t PSA is of no clinical use in total serum PSA values > 10 ng/mL or during follow-up of patients with known PCa.
6.2.2 PSA velocity (PSAV), PSA doubling time (PSADT)
There are two methods of measuring PSA over time: (1) PSAV, which is defined as an absolute annual increase in serum PSA (ng/mL/year) (12) (LE: 1b); and (2) PSADT, which measures the exponential increase of serumPSA over time, reflecting a relative change (13). These two concepts may have a prognostic role in patients with treated PCa (14), but they have limited use in the diagnosis of PCa because of background noise (total volume of prostate, BPH), the variations in interval between PSA determinations, and acceleration/deceleration of PSAV and PSADT over time. Prospective studies have shown that these measurements do not provide additional information compared to PSA alone (15-18).
6.2.3 PCA3 marker
An increasingly studied new biomarker is PCA3, detectable in urine sediments obtained after three strokes of prostatic massage during digital rectal examination. The costly Progensa urine test for PCA3 is now commercially available. The amount of the prostate-specific non-coding mRNA marker, PCA3 normalized against PSA mRNA (urine sediment) gives a PCA3 score. The PCA3 score is superior to PSA total, and percent free PSA in detection of PCa in men with elevated PSA as it shows slight but significant increases in the AUC for positive biopsies (19-22). The PCA3 score may be used together with PSA and other clinical risk factors in a nomogram or other risk stratification tools to make a decision with regard to first or repeat biopsy (23). The PCA3 score increases with prostate cancer volume, but there is conflicting data about whether the PCA3 score independently predicts the Gleason score and its use as a monitoring tool in active surveillance has not been confirmed (23). The main current indication of the PCA3 urine test may be to determine whether a man needs a repeat biopsy after an initially negative biopsy outcome, but its cost-effectiveness remains to be shown.
6.3 Transrectal ultrasonography (TRUS)
The classic picture of a hypoechoic area in the peripheral zone of the prostate will not always be seen. Grayscale TRUS does not detect areas of PCa with adequate reliability (24). It is therefore not useful to replace systematic with targeted biopsies of suspect areas. However, additional biopsies of suspect areas may be useful.
6.4 Prostate biopsy
6.4.1 Baseline biopsy
The need for prostate biopsies should be determined on the basis of the PSA level and/or a suspicious DRE.The patient’s biological age, potential co-morbidities (ASA Index and Charlson Comorbidity Index), and the therapeutic consequences should also be considered (25). Risk stratification is becoming an important tool to reduce unnecessary prostate biopsies (25)

The first elevated PSA level should not prompt an immediate biopsy. The PSA level should be verifiedafter a few weeks by the same assay under standardised conditions (i.e. no ejaculation and no manipulations, such as catheterisation, cystoscopy or TUR, and no urinary tract infections) in the same diagnostic laboratory, using the same methods (26,27) (LE: 2a).

It is now considered the standard of care to perform prostate biopsies guided by ultrasound. Although a transrectal approach is used for most prostate biopsies, some urologists prefer to use a perineal approach.The cancer detection rates of perineal prostate biopsies are comparable to those obtained for transrectal biopsies (28,29) (LE: 1b).
The ultrasound-guided perineal approach is a useful alternative in special situations, e.g. after rectal amputation.18 
6.4.2 Repeat biopsy
The indications for a repeat biopsy are: (1) rising and/or persistently elevated PSA; (2) suspicious DRE (30); (3) atypical small acinar proliferation (ASAP); and (4) extensive (multiple biopsy sites) prostatic intraepithelial
neoplasia (PIN) (31).
High-grade PIN as an isolated finding is no longer considered an indication for repeat biopsy (32) (LE: 2a). A repeat biopsy should therefore be prompted by other clinical features, such as DRE findings and PSA level. If PIN is extensive (i.e. in multiple biopsy sites), this could be a reason for early repeat biopsy, because the risk of subsequent PCa is slightly increased. If clinical suspicion for PCa persists in spite of negative prostate biopsies, MRI may be used to investigate the possibility of an anterior located PCa, followed by TRUS or MRIguided biopsies of the suspicious area (33).
6.4.3 Saturation biopsy
The incidence of PCa detected by saturation repeat biopsy (> 20 cores) is between 30% and 43% and depends on the number of cores sampled during earlier biopsies (34) (LE: 2a). In special situations, saturation biopsy may be performed with the transperineal technique. This will detect an additional 38% of PCa. The high rate of urinary retention (10%) is a drawback (35) (LE: 2b).
6.4.4 Sampling sites and number of cores
On baseline biopsies, the sample sites should be as far posterior and lateral as possible in the peripheral gland. Additional cores should be obtained from suspect areas by DRE/TRUS. These should be chosen on an individual basis.
Sextant biopsy is no longer considered adequate. At a glandular volume of 30-40 mL, at least eight cores should be sampled. The British Prostate Testing for Cancer and Treatment Study has recommended 10 core biopsies (36) (LE: 2a) More than 12 cores are not significantly more conclusive (37) (LE: 1a).
6.4.5 Diagnostic transurethral resection of the prostate (TURP)
The use of diagnostic TURP instead of repeat biopsies is a poor tool for cancer detection (38) (LE: 2a).
6.4.6 Seminal vesicle biopsy
Indications for seminal vesicle (staging) biopsies are poorly defined. At PSA levels > 15-20 ng/mL, the odds of tumour involvement are 20-25% (39) (LE: 2a), but a biopsy is only useful if the outcome will have a decisive impact on treatment, i.e. if the biopsy result rules out radical removal for tumour involvement or radiotherapy with intent to cure.
6.4.7 Transition zone biopsy
Transition zone (TZ) sampling during baseline biopsies provides a very low detection rate and TZ sampling should therefore be confined to repeat biopsies (40) (LE: 1b).
6.4.8 Antibiotics prior to biopsy
Oral or intravenous antibiotics are state-of-the-art treatment. Optimal dosing and treatment time vary.
Quinolones are the drugs of choice, with ciprofloxacin superior to ofloxacin (41) (LE: 1b), but in the last few years increased resistance to quinolones has been reported (42) associated with a rise in severe infectious complications after biopsy (43).
6.4.9 Local anaesthesia prior to biopsy
Ultrasound-guided peri-prostatic block is state-of-the-art (44) (LE: 1b). It does not make any difference whether the depot is apical or basal. Intrarectal instillation of a local anaesthetic is clearly inferior to peri-prostatic infiltration (45) (LE: 1b).
6.4.10 Fine-needle aspiration biopsy
Fine-needle aspiration biopsy is no longer state of the art.
6.4.11 Complications
Complications include macrohaematuria and haematospermia (Table 5) (46). Severe post-procedural infections were initially reported in < 1% of cases, but this rate has increased in the last few years as a consequence of the evolution of antibiotic resistance strains with more post-biopsy hospitalizations for infectious complications while the rate of non-infectious complications has remained stable (43) .
Low-dose aspirin is no longer an absolute contraindication (47) (LE: 1b).
Table 5: Percentage given per biopsy session, irrespective of the number of cores*

* Adapted from NCCN Guidelines Prostate Cancer Early Detection. V.s.2010 (42).
6.5 Pathology of prostate needle biopsies
6.5.1 Grossing and processing
Prostate core biopsies taken from different sites are usually sent to the pathology laboratory in separate vials and should be processed in separate cassettes. Before processing, number of cores per vial and length of each core should be recorded. There is a significant correlation between the length of prostate biopsy tissue on the histological slide and the detection rate of PCa (48). To achieve optimal flattening and alignment of individual cores, one should embed a maximum of three cores per cassette and use sponges or paper to keep the cores stretched and flat (49,50). To optimise the detection of small lesions, blocks should be cut at three levels (40). It is helpful routinely to mount intervening tissue sections in case additional immunostaining is needed.
6.5.2 Microscopy and reporting
Diagnosis of prostate cancer is based on histological examination. Ancillary staining techniques (e.g. basal cell staining) and additional (deeper) sections should be considered if a suspect lesion is identified (51-53).
Diagnostic uncertainty in biopsies may often be resolved by intradepartmental consultation or a second opinion from an external institution (51). Table 6 lists recommended concise terminology to report prostate biopsies
(50).
Table 6: Recommended diagnostic terms to report prostate biopsy findings*

*From Van der Kwast, 2003 (49).
PIN = prostatic intra-epithelial neoplasia.
For each biopsy site, the proportion of biopsies positive for carcinoma and the ISUP 2005 Gleason score should be reported (54). A recent study has demonstrated the improved concordance of pattern and change of prognostic groups for the modified Gleason grading (55). According to current international convention, the (modified) Gleason score of cancers detected in prostate biopsy consists of the Gleason grade of the dominant (most extensive) carcinoma component plus the highest grade, irrespective of its extent (no 5% rule). When the carcinoma largely consists of grade 4/5 carcinoma, identification of a small portion (< 5% of the carcinoma) of Gleason grade 2 or 3 glands should be ignored. A diagnosis of Gleason score 4, or lower, should not be given on prostate biopsies (54). The presence of intraductal carcinoma and extraprostatic extension should be reported. In addition to a report of the carcinoma features for each biopsy site, an overall Gleason score based 
on findings in the individual biopsies is commonly provided.
The proportion (%) or length (mm) of tumour involvement per biopsy core correlates with tumour volume, extraprostatic extension, and prognosis after prostatectomy (56-58), and an extent of > 5 mm or > 50% of adenocarcinoma in a single core is used as a cut-off triggering immediate treatment versus active surveillance in patients with Gleason score 6 carcinoma. For these reasons a measure of the extent of cancer involvement (mm or %) should be provided for each core. Length of carcinoma and percentage of carcinoma involvement of the biopsy have equal prognostic impact (59).The extent of a single, small focus of adenocarcinoma, which is located in only one of the biopsies, should be clearly stated (e.g. < 1 mm or < 1%), as this might be an indication for further diagnostic workup before selecting therapy as this finding is associated with an increased risk of vanishing cancer (60-62). A prostate biopsy that does not contain glandular prostate tissue should be reported as inadequate for diagnostics, except for staging biopsies.
6.6 Pathohistology of radical prostatectomy (RP) specimens
6.6.1 Processing of the RP specimen
The histopathological examination of RP specimens aims to provide information about the actual pathological stage, grade, and surgical margin status of the prostate cancer. The weight and dimensions of the specimen are recorded before embedding it for histological processing. It is generally recommended that RP specimens are totally embedded to enable the best assessment of location, multifocality, and heterogeneity of the cancer.

However, for cost-effectiveness, partial embedding using a standard method may also be considered, particularly for large prostates (> 60 g). The most acceptable method includes the complete embedding of the posterior (dorsal) part of the prostate in addition to a single mid-anterior left and right section. Compared to total embedding, this method of partial embedding permitted detection of 98% of prostate cancers with a Gleason score > 7 and accurate staging in 96% of cases (63).

Upon receipt in the histopathology laboratory, the entire RP specimen is inked in order to appreciate the surgical margin status. The specimen is fixed by immersion in buffered formalin for a few days, preferably prior to incision of the sample, as incision causes distortion of the tissue. Fixation can be enhanced by injecting formalin using 21-gauge syringes, which provides a more homogeneous fixation and sectioning after 24 hours (64). After fixation, the apex is removed and cut with (para)sagittal or radial sections; the shave method is not recommended (65). Separate removal and sagittal sectioning of the bladder neck is optional. The remainder of the RP specimen is generally cut in transverse sections at 3-4 mm steps, perpendicularly to the posterior surface. The resultant tissue slices can be embedded and processed either as whole-mounts or after quadrant sectioning. Whole-mount processing provides better topographic visualisation of the carcinoma and faster histopathological examination. However, it is a more time-consuming and more expensive technique that requires specialised equipment and personnel. Although whole-mount sectioning may be necessary for research, its advantages do not outweigh its disadvantages for routine sectioning.
6.6.1.1 Recommendations for processing a prostatectomy specimen
Total embedding of a prostatectomy specimen is preferred, either by conventional (quadrant sectioning) or by
whole-mount sectioning.
The entire surface of RP specimens should be inked before cutting to evaluate the surgical margin status.
The apex should be separately examined using the cone method with sagittal or radial sectioning.
6.6.2 RP specimen report
The pathology report provides essential information on the prognostic characteristics relevant for making clinical decisions (Table 7). As a result of the complex information provided on each RP specimen, the use of synoptic-(like) or checklist reporting is recommended (Table 8). Synoptic reporting of surgical specimens results in more transparent and complete pathology reporting (66).
Table 7: Information provided by the pathology report

Table 8: Example checklist - reporting of prostatectomy specimens

6.6.2.1 Gleason score
Grading of conventional prostatic adenocarcinoma using the (modified) Gleason score system (54) is the single strongest prognostic factor for clinical behaviour and treatment response. The Gleason score is therefore one of the parameters incorporated in nomograms that predict the risk of recurrence after prostatectomy (67).
6.6.2.2 Interpreting the Gleason score
The Gleason score is the sum of the most dominant and second most dominant (in terms of volume) Gleason grade. If only one grade is present, the primary grade is doubled. If a grade comprises < 5% of the cancer volume, this grade is not incorporated in the Gleason score (5% rule). Both the primary and the secondary grade are reported in addition to the Gleason score (e.g. Gleason score 7 [4 + 3]). A global Gleason score is given when there are multiple tumours, but a separate tumour focus with a higher Gleason score should alsobe mentioned. A tertiary Gleason grade 4 or 5, particularly if exceeding 5% of the prostate cancer volume, is an unfavourable prognostic indicator for biochemical recurrence. The presence of the tertiary grade and its approximate proportion of the cancer volume should also be reported (68), in addition to the Gleason score.
6.6.2.3 Definition of extraprostatic extension
The TNM staging system of the International Union Against Cancer (UICC) is recommended for pathological staging of prostate carcinoma (65,69). Pathologic substaging of pT2 prostate cancer is optional, since 1) it does not correlate with clinical T2 substage and 2) it lacks prognostic significance (70).
Extraprostatic extension is the recommended term for the presence of tumour beyond the confines of the prostate. Extraprostatic extension is defined as carcinoma mixed with periprostatic adipose tissue, or bulging out beyond the contours of the prostate gland, e.g. at the neurovascular bundle or the anterior prostate. Bladder neck invasion is also considered to be an extraprostatic extension.

It is useful to report not only the location, but also the extent of extraprostatic extension because
extension is related to the risk of recurrence. There are no well-established and internationally accepted
definitions of the terms ‘focal’ and ‘non-focal’ or ‘extensive extraprostatic extension’. Some authors describe
focal as ‘a few glands‘ (71) or extension < 1 high-power field (72), whereas others measure the depth of extent
in mm (73). Currently, it is considered clinically useful to report the extent of extraprostatic extension (e.g. less
or more than 1 high-power field or 1 mm) (74).
At the apex of the prostate gland, tumour mixed with skeletal muscle does not constitute extraprostatic extension. In the bladder neck, microscopic invasion of small fibres of smooth muscle is not equated to (gross) bladder wall invasion, because it does not carry independent prognostic significance for PSA recurrence (75,76) and should be recorded as extraprostatic extension (pT3a). A positive margin at the bladder neck should be reported as an extraprostatic extension (pT3a) with positive margin and not as pT4 disease. Stage pT4 can only be assigned when tumour invades the muscle wall of the bladder as determined by the urologist (77).
6.6.3 Prostate cancer volume
The independent prognostic value of the volume of PCa in RP specimens has not been established (72,78-81). Nevertheless, a PCa volume cut-off of 0.5 mL continues to be an important parameter to distinguish insignificant from clinically relevant cancer (78). Continued improvement in radioimaging of the prostate gland has allowed more accurate measurement of cancer volume before surgery. Therefore, it may be recommended to assess the greatest dimension of the dominant tumour nodule, if identified, or to provide a rough estimate of the percentage of cancer tissue in the prostate .
6.6.4 Surgical margin status
Surgical margin status is an independent risk factor for biochemical recurrence. Margin status is positive if tumour cells are in touch with the ink on the surface of the specimen. Margin status is negative if tumour cells are very close to the inked surface of the margin (79) or when they are at the surface of the tissue lacking any ink.

If the tissue has severe crush artifacts (usually at the apex), it may not be possible to assign a surgical margin status (82). Surgical margin status is independent of the pathological stage and a positive margin is not evidence of extraprostatic extension (83). There is insufficient evidence to prove a relationship between the extent of positive margin and the risk of recurrence (72). However, some indication must be given of the multifocality and extent of margin positivity, such as the linear extent in millimetres, or number of blocks with positive margin involvement.
6.6.5 Other factors
According to the College of American Pathologists consensus statement (84), additional potential biomarkers have not been sufficiently studied to demonstrate their additional prognostic value and clinical usefulness outside the standard patient care setting (category III), including perineural invasion, neuroendocrine differentiation, microvessel density, nuclear roundness, chromatin texture, other karyometric factors, proliferation markers, prostate-specific antigen derivatives, and other factors (e.g. oncogenes, tumour suppressor genes, or apoptosis genes).
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7. CLINICAL STAGING
The primary extension assessment of prostate cancer (PCa) is usually made by digital rectal examination (DRE), prostate-specific antigen (PSA) measurement, and bone scan, supplemented with computed tomography (CT) or magnetic resonance imaging (MRI) and chest X-ray in specific situations.
7.1 T-staging
The first level is the assessment of local tumour stage, where the distinction between intracapsular (T1-T2) and extraprostatic (T3-T4) disease has the most profound impact on treatment decisions. DRE often underestimates the tumour extension; a positive correlation between DRE and pathological tumour stage wasfound in fewer than 50% of cases (1). However, more extensive examinations for adequate T-staging are only recommended in selected cases when more precise staging directly affects the treatment decision, i.e. when curative treatment is an option.

Serum PSA levels increase with advancing stage. Nevertheless, when PSA level is measured in an individual patient, it appears to have a limited ability to predict the final pathological stage accurately. Due to the production of PSA by benign and malignant prostatic tissue, there is no direct relationship between serum PSA concentration and the clinical and pathological tumour stage (2). A combination of serum PSA level, Gleason score on prostate biopsy and clinical T-stage, however, has been proven to be more useful in predicting the final pathological stage than the individual parameters per se (3).

The ability of the molecular forms of PSA to predict T-stage is controversial and their routine measurement is not indicated (4,5). The most commonly used method for viewing the prostate is transrectal ultrasound (TRUS). However, only 60% of tumours are visible with TRUS, and the remainder are not recognised due to their isoechogenicity. In a large multi-institutional study, TRUS was no more accurate at predicting organ-confined disease than was DRE (6). These findings were supported by another large study, which showed that there was no meaningful superiority of TRUS over DRE (7). A combination of DRE and TRUS can detect T3a PCa more accurately than either method alone (8) (LE: 3).

Three-dimensional TRUS (3D-TRUS) claimed to have better staging accuracy than 2-D techniques (9).Several adjuncts to 3D greyscale TRUS have been investigated. A greater sensitivity for cancer detection has been achieved with the addition of power colour Doppler and contrast agents (10-12).
Unfortunately, all TRUS techniques remain largely operator-dependent and are not able to differentiate between T2 and T3 tumours with sufficient accuracy to be recommended for routine use in staging.

Seminal vesicle invasion is predictive of local relapse and distant failure. Seminal vesicle biopsies may be used to increase the accuracy of pre-operative staging (13). This is not recommended as a first-line examination, but should be reserved for patients with a substantial risk of seminal vesicle invasion in whom a positive seminal vesicle biopsy would modify treatment decisions. Patients with a clinical stage greater than T2a and a serum PSA level of more than 10 ng/mL could be candidates for seminal vesicle biopsies (14,15). Patients with any of the basal biopsies positive for cancer are more likely to have positive seminal vesicle biopsies (16).

Of the prostate needle biopsy parameters examined, the percentage of tissue with cancer was the strongest predictor for positive surgical margins, seminal vesicle invasion and non-organ-confined disease (17).An increased number of biopsies involved with tumour independently predicts extraprostatic extension, margin involvement and lymph node invasion (18).

In a multivariate analysis, the best risk predictors of extracapsular extension on one side were the overall average of positive biopsy cores being 15% or greater, and the average from three ipsilateral biopsies being 15% or greater. When used in combination, these two factors yielded a model with a positive predictive value of 37%, and a negative predictive value of 95%. The high negative predictive value of the side-specific model identifies patients who are good candidates for nerve-sparing surgery (19). Furthermore, it may be useful
to correlate the bioptic Gleason score with the final pathological stage: about 70% of patients have localized disease when the biopsy Gleason score is < 6 (20).

It has been shown that transperineal three-dimensional prostate mapping biopsy (3D-PMB) provides more accurate determination of the extent and location of tumor compared to ultrasound guided 10-12 core biopsy, with Gleason score upgrading in 27.2% and up-staging in 45.6% of cases (21). The technique improves the differentiation between clinically significant cancers and low risk disease. Unlike transrectal saturation biopsy 3D-PMB has acceptable morbidity.

Both CT and MRI are now of a high technical standard, but neither modality is sufficiently reliable to make their use mandatory in the assessment of local tumour invasion (22,23). Endorectal MRI (e-MRI) may allow for more accurate local staging by complementing the existing clinical variables by improvements in spatial characterisation of the prostatic zonal anatomy and molecular changes (24). Image quality and localisation improves significantly with e-MRI compared with external coil MRI (25). When compared with DRE and TRUS prostate biopsy findings, e-MRI contributes significant incremental value for local PCa staging (26), particularly in the pre-operative identification of extraprostatic extension (EPE) and seminal vesicle invasion (SVI) when interpreted by dedicated genitourinary radiologists (27,28).
E-MRI could impact on the decision to preserve or resect the neurovascular bundle (NVB) at the time of radical surgery (27,29,30).

When assessed for the ability to predict organ-confined PCa, the contribution of e-MRI to staging nomograms was significant in all risk categories, but the greatest benefit was seen in the intermediate and high risk groups (31). The combination of dynamic contrast-enhanced MRI and T2-weighted MR imaging yields improved assessment of EPE and better results for PCa staging compared with either technique independently (32) (LE: 3).

MR spectroscopic imaging (MRSI) allows for the assessment of tumour metabolism by displaying the relative concentrations of citrate, choline, creatinine and polyamines. Differences in the concentrations of these chemical metabolites between normal and malignant prostate tissues allow for better tumour localization within the peripheral zone, increasing the accuracy of EPE detection among less-experienced readers, and decreasing interobserver variability (33). Furthermore, correlations have been demonstrated between the metabolic signal pattern and a pathological Gleason score, suggesting the potential for a non-invasive assessment of PCa aggressiveness (34).

Despite the proposed accuracy and benefit of e-MRI and MRSI in PCa characterisation and localisation, e-MRI has several limitations that hamper its widespread application in PCa staging, e.g. difficulties in interpreting signal changes related to post-biopsy haemorrhage and inflammatory changes of the prostate, and the unquantifiable but significant inter- and intra-observer variability seen between both non-dedicated and dedicated radiologists that may lead to under- or overestimation of tumour presence and the local extent of disease (LE: 3). The overall accuracy of
11C-choline positron emission tomography (PET) in defining local tumour stage (pT2 and pT3a-4) has been reported to be around 70%. PET tends to understage PCa, and has a limited value for making treatment decisions in patients with clinically localised PCa, especially if a nerve-sparing procedure is being considered (35) (LE: 2b).
7.2 N-staging
N-staging should be performed only when the findings will directly influence a treatment decision. This is usually the case in patients for whom potentially curative treatments are planned. High PSA values, stagesT2b-T3 disease, poor tumour differentiation and peri-neural tumour invasion have been associated with a higher risk of the presence of nodal metastases (3,36,37). The measurement of PSA level alone is unhelpful in predicting the presence of lymph node metastases for an individual patient.

The nomograms could be used to define a group of patients with a low risk of nodal metastasis (< 10%, see reference number 38). In such cases, patients with a serum PSA level of less than 20 ng/mL, stage T2a or less, and a Gleason score of 6 or less may be spared N-staging procedures before potentially curative treatment (3).

The extent of the Gleason 4 pattern in sextant biopsies has also been used to define the risk of N1 disease. If any core had a predominant Gleason 4 pattern, or > three cores any Gleason 4 pattern, the risk of nodal metastases was found to be 20-45%. For the remaining patients, the risk was 2.5%, supporting the idea that nodal staging is unnecessary in selected patients (39).

In the current published literature, the results indicate that CT and MRI perform similarly in the detection of pelvic lymph node metastases, although CT seems to be slightly superior (40) (LE: 2a). In either case, the decision about whether nodal involvement is present rests solely on whether there is enlargement of the investigated lymph nodes A threshold of 1 cm in the short axis for the oval nodes, and 0.8 cm for the round nodes, has been recommended as the criteria for the diagnosis of lymph node metastases (41).

A fine-needle aspiration biopsy (FNAB) might provide a decisive answer in cases of positive imaging results. However, the lymph node can be difficult to reach because of the anatomical position. In addition, FNAB is not a highly sensitive staging procedure, and a false-negative rate of 40% has been reported (41).

High-resolution MRI with lymphotrophic ultra-small super-paramagnetic iron oxide particles (USPIO)was more recently suggested in the detection of small and otherwise occult lymph node metastases in patients with PCa (42,43).

In asymptomatic patients with newly diagnosed PCa and a serum PSA level of less than 20 ng/mL, the likelihood of positive findings on CT or MRI is approximately 1% (32). CT scanning may therefore be warranted in patients with a very high risk of harbouring lymph node metastases, as the specificity of a positive scan is high (93-96%). Radio-immunoscintigraphy and PET have been investigated in order to improve the diagnosis of metastatic disease to the lymph nodes. Both methods are still under investigation, and further evaluation is needed before they can be recommended for routine use in clinical practice, especially as negative results should be interpreted with caution (44). The results obtainedusing 18F-choline PET/CT scans for initial N-staging were discouraging, especially in terms of inability to detect
small metastases/micrometastases (< 5 mm) (45). Furthermore, 11C-choline PET/CT has quite a low sensitivity for the detection of lymph node metastases, but performed better than clinical nomograms, with equal sensitivity and better specificity (46).

The gold standard for N-staging is operative lymphadenectomy, either by open or laparoscopic techniques. It is worth pointing out that recent studies with more extensive lymphadenectomy have shown that the obturator fossa is not always the primary site for metastatic deposits in the lymph nodes, and pelvic lymph node dissection that is limited to the obturator fossa will therefore miss about 50% of lymph node metastases (47,48). When deciding on pelvic lymph node dissection, extended lymphadenectomy should be considered, despite its disadvantages: it requires surgical experience; it is time-consuming; and it often leads to morecomplications than the limited procedures. Furthermore, it may fail to identify lymph node metastases, however present, even outside the region of extended dissection (49).

The primary removal of the so-called sentinel lymph node (SLN), defined as the first lymph node that receives lymphatic drainage from PCa, has the main aim of reducing the eventual morbidity associated with an extended pelvic node dissection, while preserving maximal sensitivity for diagnosis of metastatic disease (50) (LE: 3) (see section 9.7 ‘Treatment: radical prostatectomy, indication and extent of eLND’).
7.3 M-staging
The axial skeleton is involved in 85% of patients who die from PCa (51). The presence and extent of bone metastases accurately reflect the prognosis for an individual patient. Elevated skeletal alkaline phosphatase levels may indicate the presence of bony metastasis in 70% of affected patients (52). Furthermore, the measurement of skeletal alkaline phosphatase and PSA at the same time increases clinical effectiveness to approximately 98% (53). In a prospective study, multiple regression analysis showed the extent of bone disease to be the only variable influencing the serum levels of skeletal alkaline phosphatase and PSA. However, in contrast to serum PSA, skeletal alkaline phosphatase demonstrated a statistical correlation with the extent of bone disease (54).

Early detection of bone metastases will alert the clinician to the possible complications inherent in skeletal destruction. Bone scintigraphy remains the most sensitive method of assessing bone metastases, being superior to clinical evaluation, bone radiographs, serum alkaline phosphatase measurement and prostatic acid phosphatase (PAP) determination (55,56). Technetium diphosphonates are the optimum radiopharmaceuticals currently available because of their extremely high bone-to-soft tissue ratio (57).

Increased 18F-fluoride uptake in malignant bone lesions reflects the increase in regional blood flow and bone turnover that characterise these lesions.

Studies have shown that 18F-fluoride PET/CT is a highly sensitive and specific imaging modality for detection of bone metastases (58,59). However, no definitive results have been obtained and therefore no final recommendations can be made (60).

Besides bone, PCa may metastasise to any organ, but most commonly it affects distant lymph nodes, lung, liver, brain and skin. Clinical examination, chest X-ray, ultrasound, CT and MRI scans are appropriate methods of investigation, but only if symptoms suggest the possibility of soft-tissue metastasis.

The need for reliable serum markers to improve the pre-treatment staging of patients with PCa has long been recognised. At present, PSA is the marker of choice. A pre-treatment serum PSA level greater than 100 ng/mL has been found to be the single most important indicator of metastatic disease, with a positive predictive value of 100% (61). Furthermore, it has helped to reduce the number of patients with newly diagnosed PCa who require a bone scan. Patients with a low serum PSA concentration have only rarely been found to harbour detectable skeletal metastases. The correlation between serum PSA and bone scintigraphy in patients with newly diagnosed untreated PCa has been further investigated (62). Results suggest that a staging bone scan may be superfluous if the serum PSA concentration is less than 20 ng/mL in asymptomatic patients with well or moderately (up to 7: 3+4) differentiated tumours. In contrast, in patients with poorly differentiated tumours and locally advanced disease, a staging bone scan should be obtained irrespective of the serum PSA value (63).

7.4 Guidelines for the diagnosis and staging of PCa


CT = computed tomography; DCE-MRI = dynamic contrast-enhanced MRI; DRE = digital rectal examination;EPE = extraprostatic extension; MRI = magnetic resonance imaging; MRSI = magnetic resonance spectroscopic imaging; PCa = prostate cancer; PET = positron emission tomography; PLND = pelvic lymph-node dissection; PSA = prostate-specific antigen; SVI = seminal vesicle invasion; TRUS = transrectal ultrasound.
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prostate-specific antigen in predicting skeletal metastases in patients with adenocarcinoma of the
prostate. Eur Urol 1999;35(3):223-7.
http://www.ncbi.nlm.nih.gov/pubmed/10072624
8. TREATMENT: DEFERRED TREATMENT
(WATCHFUL WAITING/ACTIVE MONITORING)
8.1 Introduction
There is a great difference between the incidence of PCa and deaths from PCa. In 2007, in the USA, there were 240,890 new cases with only 33,720 deaths (1). Several autopsy studies of people dying from different causes have shown that while 60-70% of older men have histological PCa (2), a large proportion of these tumours will not progress. Prostate cancer is diagnosed in only 15-20% of men during their lifetime, with a 3% lifetime risk of death (3).

The incidence of small, localised, well-differentiated PCa is increasing, mainly as a result of prostatespecific antigen (PSA) screening and ‘multicore’ schemes of prostate biopsy. These data suggest that many men with localised PCa would not actually benefit from definitive treatment. With the aim of reducing the risk of overtreatment in this subgroup of patients, two conservative management strategies of ‘watchful waiting’ and ‘active surveillance’ have been proposed.
8.1.1 Definition
8.1.1.1 Watchful waiting (WW)
Watchful waiting is also known as ‘deferred treatment’ or ‘symptom-guided treatment’. This term was coined in the pre-PSA screening era (before 1990) and referred to the conservative management of PCa until the development of local or systemic progression. At this point, the patient would then be treated palliatively with transurethral resection of the prostate (TURP) or other procedures for urinary tract obstruction, and hormonal therapy or radiotherapy for the palliation of metastatic lesions.
8.1.1.2 Active surveillance (AS)
Active surveillance is also known as ‘active monitoring’. It is the new term for the conservative management of PCa. Introduced in the past decade, it includes an active decision not to treat the patient immediately. Instead, the patient is followed up under close surveillance and treated at pre-defined thresholds that classify progression (i.e. short PSA doubling time and deteriorating histopathological factors on repeat biopsy). The treatment options are intended to be curative.
8.2 Deferred treatment of localised PCa (stage T1-T2, Nx-N0, M0)
8.2.1 Watchful waiting (WW)
The rationale behind WW is the observation that PCa often progresses slowly, and is diagnosed in older men, in whom there is a high incidence of co-morbidity and related high competitive mortality (4). Watchful waiting can be considered as an option for treating patients with localised PCa and a limited life expectancy or for older patients with less aggressive cancers.

There have been several attempts to summarise the key papers dealing with deferred treatment in patients with presumed localised PCa (5-7). Most have presented the same results, as they analyse roughly the same series, but using somewhat different methodologies. The outcome studies in WW usually included patients, whose PSA readings were not always available and who had predominantly palpable lesions that would currently be defined as intermediate-risk tumours (8). The most recent study used data from the PSA era of the Surveillance, Epidemiology and End Results (SEER) database of the National Cancer Institute in the USA (9). These studies included patients with a follow-up of up to 25 years, for whom the endpoints are overall survival (OS) and disease-specific survival (DSS).

Several WW series show a very consistent DSS ratio at 10 years, ranging from 82-87% (5,10-14), and up to 80-95% if T1-T2 Gleason < 7 (9). In three studies with data beyond 15 years, the DSS was 80%, 79% and 58%, respectively (11,13,14). Two of them reported a 20-year DSS of 57% and 32%, respectively (11,13).Chodak et al. reported a pooled analysis of the original data from 828 patients treated by WW (5). The paper was based on patients from six non-randomised studies and described cancer-specific survival and metastasis-free survival after 5 and 10 years of follow-up (5) (LE: 2b).

Tumour grade is clearly significant, with very low survival rates for grade 3 tumours. Although the 10-year cancer-specific rate is equally good (87%) for grade 1 and 2 tumours, the latter have a significantly higher progression rate, with 42% of these patients developing metastases (Table 9).

Table 9: Outcome of deferred treatment in localised PCa in relation to tumour grade (6): percentage of
patients (95% confidence interval) surviving at 5 and 10 years

The importance of tumour grade on survival after conservative management of PCa was also underlined in a large register study using the SEER database (9) (LE: 3). Patients with grade 1, 2 and 3 tumours had 10-year cancer-specific survival rates of 91%, 90% and 74%, respectively, correlating with data from the pooled analysis.

The paper by Chodak et al. also specifically described the outcome for stage T1a patients (5), with cancer-specific 10-year survival rates of 96% and 94%, respectively, for grade 1 and 2 tumours. The metastasis-free survival rate was 92% for patients with grade 1 tumours, but 78% for those with grade 2 tumours, indicating a higher risk of progression in individuals with moderately differentiated tumours. This difference in progression rate correlates with other studies on stage T1a disease (15,16).

The impact of grade on the risk of tumour progression and ultimately death from PCa was also described in a paper by Albertsen et al. in the pre-PSA era (17). The study re-evaluated all biopsy specimens using the more widely accepted Gleason score, and showed that the risk of PCa death was very high in Gleason 7-10 tumours, intermediate in Gleason 6 tumours, but low in Gleason 2-5 cancers (Table 10) (18,19) (LE: 3).

This paper also showed that Gleason 6-10 tumours carry a continuously increasing risk of ending the patient’s life for up to 15 years of follow-up after conservative management. The cancer-specific survival curves for this group of patients have been published in a recent discussion article on different methods of assessing outcome in treatment for localised PCa (18).

Table 10: The 15-year risk of dying from PCa in relation to Gleason score at diagnosis in patients with
localised disease aged 55-74 years (17,18)

* The figures on the risk of cancer death differ for different age groups and represent the true risk in the studied population (taking actual competing mortality from other causes into consideration).
† The cancer-specific mortality compensates for differences in competing mortality and indicates the outcome if the patient actually lived for 15 years.

Three randomised clinical trials have reported long-term follow-up of patients randomised to WW or radical prostatectomy: the first was in the pre-PSA screening era (19); the second was at the beginning of PSAscreening (20); and the third was a recent study, the results of which have not yet been published (21).

Between 1967 and 1975, the Veterans Administration Cooperative Urological Research Group
randomised 142 patients affected by clinical localised PCa. The study was underpowered to detect treatment
differences (22).

Between 1989 and 1999, the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) randomised 695 patients with clinical stage T1-T2 to WW (348) or radical prostatectomy (347) (Table 11) (30). This study began after PSA screening was introduced into clinical practice, but only 5% of men were diagnosed by screening. After a median follow-up of 12.8 years, this study showed a significant decrease in cancer-specific mortality, overall mortality, metastatic risk progression and local progression in patients treated with radical prostatectomy versus WW (LE: 1b).

Table 11: Outcome of Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) at 15 years of
follow-up (median of 12.8 years) (20)

RP = radical prostatectomy; WW = watchful waiting.

Subgroup analysis showed that the overall difference was not modified by PSA level (below or above 10 ng/mL) or by the Gleason score (below 7 or above) at the time of diagnosis. However, age at that the time of randomisation had a profound impact, the benefit on overall survival and metastases free survival being only seen for those below 65 years of age. The Prostate Cancer Intervention Versus Observation Trial: VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT) is an ongoing, controlled, multicentre, randomised clinicaltrial comparing radical prostatectomy with WW in patients with clinical stage T1-T2 disease. Between 1994 and 2002, 731 patients with a median age of 67 years were enrolled. The median PSA was 7.8 ng/mL (mean 10.2 ng/mL). Three-quarters of the men had clinical stage T1c disease. Using previously developed tumour risk categorizations based on PSA levels, Gleason histological grade and tumour stage, approximately 43% of men had low-risk PCa, 36% had medium-risk PCa, and 20% had high-risk PCa. Follow-up is planned for 15 years, and the primary endpoint is the overall mortality. Men enrolled in PIVOT are more representative of men diagnosed and treated in everyday clinical practice than those enrolled in SPCG-4. Preliminary unpublished results have been presented at the latest AUA meeting (21). The results suggested that overall there was a lack of survival benefit. However, there appeared to be an overall survival benefit in men with an intermediate- and high-risk PCa, as well as a cancer specific survival benefit in men with high-risk PCa or with a PSA above 10 ng/mL. Full results are urgently awaited.

No data are available comparing WW and radiotherapy. Some data are available for hormonal treatment. For patients who choose deferred treatment, there appears to be a modest risk of disease progression, although shorter cancer-specific survival times have been reported after deferred therapy compared with immediate hormone therapy, in presumed localised PCa (not using PSA for staging) after 15 years of follow-up (22). In contrast to Lundgren et al. (22), the report of the Casodex Early Prostate Cancer Trialists’ Group programme showed a higher mortality in a group of men with localised PCa treated with bicalutamide, 150 mg/day, than in those who received placebo (23).

It appears that many small localised well-differentiated PCas will not progress, and radical therapy may lead to substantial overtreatment with resulting effects on the patients’ quality of life and treatments costs. This has been further confirmed by a recent analysis at 5 and 10 years of 19,639 patients > 65 years from the SEER database not given curative treatment. Based on comorbidities (Charlson score), most men with a Charlson score > 2 died from competing causes at 10 years, whatever their initial age (below or above 65 years). However, men with no or just one comorbidity had a low risk of death at 10 years, especially for well or moderately differentiated lesions (29). In men with a Charlson score > 2, tumour aggressiveness had little impact on overall survival, suggesting that perhaps these patients could have been spared the biopsies and diagnosis of cancer. This strengthens the major role of initial comorbidity evaluation, leading to an individual survival probability, before embarking an individual on any form of medical intervention such as biopsies or treatment (30).
8.2.2 Active surveillance
Active surveillance was conceived with the aim of reducing the ratio of overtreatment in patients with clinically confined very low-risk PCa, without giving up radical treatment, as happens with WW. Currently, the only data available is data from non-mature randomised clinical trials of active surveillance, with a follow-up of less than 10 years. Active surveillance can therefore only be proposed for highly selected low-risk patients, particularly as the data indicate there is a significant risk of tumour progression after conservative treatment for some patients with apparently localised PCa. This conclusion is also supported by other studies, which have shown that patients with a life expectancy > 10 years have a higher mortality rate from PCa in the absence of curative treatment. These studies include the Johansson series, which showed that there is a higher risk of dying from PCa in patients surviving more than 15 years with well- and moderately differentiated tumours at diagnosis (31) (LE: 3). In the light of these findings, it is essential that a more precise selection of candidates for active surveillance is carried out.

A multicentre clinical trial of active surveillance versus immediate treatment was opened in the USA in 2006. Its results are expected in 2025. Choo, Klotz and co-workers were the first to report on a prospective active surveillance protocol (32,33). The most advanced cohort to date was reported last year by Klotz (43). A total of 450 patients with clinical stage T1c or T2a, PSA < 10 ng/mL were enrolled with an overall Gleason score < 6 (PSA < 15), with patients > 70 years having a Gleason score < 7 [3 + 4]. Initially, six biopsies were
performed, followed by the usual extended 12-core protocol during the study. At a median follow-up of 6.8 years, the 10-year overall survival was 68%. At 10 years, the disease-specific survival was 97.2%, with 62% of men still alive on active surveillance. Subsequently, 30% of patients underwent a radical treatment for the following reasons: 48% for a PSA doubling time < 3 years; 27% for Gleason score progression on repeatbiopsies; and 10% because of patient preference.

A variety of additional studies on active surveillance in clinically organ confined disease (Tables 12 and 13) have now been published. All have confirmed that, in well-selected patients with very low-risk disease, there was a very low rate of progression and cancer-specific death, with only a few patients required delayed radical intervention. However, an extended follow-up is necessary to obtain definitive results. Thus, surveillance might mean no treatment at all for patients older than 70 years, while in younger patients, it might mean a possible treatment delayed for years. The repeated biopsies that are part of active surveillance might then become important for their potential side effect on nerve preservation if surgery is subsequently considered.
Table 12: Clinical trials of AS for organ-confined PCa: inclusion criteria

Table 13: Clinical trials of AS for organ-confined PCa: main results

OS = overall survival: CSS = cancer-specific survival; PFS =progression-free survival.
Different series have identified several eligibility criteria for enrolment (41):
• clinically confined PCa (T1-T2);
• Gleason score < 7 for most studies;
• PSA < 10-15 ng/mL.
Limited tumour volume is defined by a low number of involved cores and a low tumour length on each involved core. The role of other tools. e.g. MRI, to better define acceptable lesions remains controversial, except probably for anterior lesions (42). The PCA3 level may become a practical tool in the future (43).

Active surveillance is based on repeated DRE, PSA and most importantly repeated biopsies, usually every year. The place of early repeated biopsy has become an important part of the selection process, based on the risk of under-detection of grade 4 (35,40,44,45).
The criteria for active treatment are less well defined (5), but most groups have used:
• PSA doubling time with a cut-off value ranging between < 2 and < 4 years. This criterion is becoming
questionable because of a weak link between PSA doubling time and grade progression on repeated
biopsy (46).
• Gleason score progression to > 7 during follow-up systematic biopsies, at intervals ranging from 1-4
years.
• Patient’s request mainly based on anxiety. This is a significant factor (36) and might affect up to 10%of treated patients. No data is available regarding active surveillance. However, data from the SPCG-4 trial has suggested that, based on self-administered questionnaires 87% of the included patients), the treatment group always reported inferior well-being, depression and psychological status, but this difference was never significant (47).
8.3 Deferred treatment for locally advanced PCa (stage T3-T4, Nx-N0, M0)
The literature reporting on deferred treatment for locally advanced PCa is sparse. There are no randomised studies that compare more aggressive treatments, such as radiotherapy or surgery, with or without hormones.

Most patients whose disease progresses after deferred treatment of locally advanced PCa will be candidates for hormone therapy. There are reports from non-randomised studies showing that hormone treatment may safely be delayed until metastatic progression occurs, as no survival advantage was noted between patients treated with immediate orchiectomy compared with delayed treatment (48,49).

In a recent prospective randomised clinical phase III trial (EORTC 30981), 985 patients with T0-4 N0-2 M0 PCa were randomly assigned to immediate androgen-deprivation therapy (ADT) or received ADT only on symptomatic disease progression or occurrence of serious complications (50,51). After a median follow-up of 7.8 years, the overall survival hazard ratio was 1.25 (95% confidence interval [CI]: 1.05-1.48; non-inferiorityp > 0.1) favouring immediate treatment, seemingly due to fewer deaths of non-prostatic cancer causes (p = 0.06). The time from randomisation to progression of hormone-refractory disease did not differ significantly nor did prostate cancer-specific survival. The median time to the start of deferred treatment after study entry was 7 years. In this group, 126 patients (25.6%) died without ever needing treatment (44% of deaths in this arm). The conclusion drawn from this study is that immediate ADT resulted in a modest but statistically significant increase in overall survival, but no significant difference in PCa mortality or symptom-free survival. This raises the question of the usefulness of such a small statistical benefit.

Furthermore, the authors identified significant risk factors associated with a significantly worse outcome: in both arms. Patients with a baseline PSA > 50 ng/mL were at a > 3.5-fold higher risk of dying of PCa than patients with a baseline PSA < to 8 ng/mL. If the baseline PSA was between 8 ng/mL and 50 ng/ mL, the risk of PCa death was approximately 7.5-fold higher in patients with a PSA doubling time < 12 months than in patients with a PSA doubling time > 12 months. The time to PSA relapse following a response to immediate ADT correlated significantly with baseline PSA, suggesting that baseline PSA may also reflect disease aggressiveness.

However, when early and delayed treatments were compared in a large randomised trial carried out by the Medical Research Council (MRC), a survival benefit for immediate hormone therapy was demonstrated (62), comparable with the results of the Lundgren et al. study mentioned above (22) (LE: 1b). In addition, a comparison of bicalutamide, 150 mg/day, with placebo showed that progression-free survival (PFS) was better with early treatment in patients with locally advanced PCa (23) (LE: 1b).

Fifty selected asymptomatic patients (mean age 71 years) with highly or moderately differentiated stage T3 M0 PCa were followed up for 169 months (53). The 5- and 10-year cancer-specific survival rates were 90% and 74%, respectively, and the likelihood of being without treatment at 5 and 10 years was 40% and 30%, respectively. The authors concluded that WW might be a treatment option for selected patients with nonpoorly differentiated T3 tumours and a life expectancy of less than 10 years (LE: 3).
8.4 Deferred treatment for metastatic PCa (stage M1)
There are only very sparse data on this subject. The only candidates for such treatment should be asymptomatic patients with a strong wish to avoid treatment-related side-effects (LE: 4). As the median survival time is about 2 years, the time without any treatment (before symptoms occur) is very short in most cases. The MRC trial highlighted the risk of developing symptoms (pathological fractures, spinal cord compression), and even death from PCa, without receiving the possible benefit from hormone treatment (52,54) (LE:1b). If a deferred treatment policy is chosen for a patient with advanced PCa, close follow-up must be possible.
8.5 Summary of deferred treatment for prostate cancer

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J Urol 1994 Nov;74(5):637-41.
http://www.ncbi.nlm.nih.gov/pubmed/7827816
49. Parker MC, Cook A, Riddle PR, et al. Is delayed treatment justified in carcinoma of the prostate?
Br JUrol 1985 Dec;57(6):724-8.
http://www.ncbi.nlm.nih.gov/pubmed/4084734
50. Studer UE, Whelan P, Albrecht W, et al. Immediate or deferred androgen deprivation for patients
with prostate cancer not suitable for local treatment with curative intent: European Organisation for
Research and Treatment of Cancer (EORTC) Trial 30891. J Clin Oncol 2006 Apr;24(12):1868-76.
http://www.ncbi.nlm.nih.gov/pubmed/16622261
51. Studer UE, Collette L, Whelan P, et al; EORTC Genitourinary Group. Using PSA to guide timing of
androgen deprivation in patients with T0-4 N0-2 M0 prostate cancer not suitable for local curative
treatment (EORTC 30891). Eur Urol 2008 May;53(5):941-9.
http://www.ncbi.nlm.nih.gov/pubmed/18191322
52. [No authors listed] The Medical Research Council Prostate Cancer Working Party Investigators Group.
Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical
Research Council Trial. Br J Urol 1997 Feb;79(2):235-46.
http://www.ncbi.nlm.nih.gov/pubmed/9052476
53. Adolfsson J, Steineck G, Hedlund PO. Deferred treatment of locally advanced non-metastatic prostate
cancer: a long-term followup. J Urol 1999 Feb;161(2):505-8.
http://www.ncbi.nlm.nih.gov/pubmed/9915436
54. Walsh PC. Immediate versus deferred treatment for advanced prostatic cancer: initial results of
the Medical Research Council trial. The Medical Research Council Prostate Cancer Working Party
Investigators Group. J Urol 1997 Oct;158(4):1623-4.
http://www.ncbi.nlm.nih.gov/pubmed/9302187
9. TREATMENT: RADICAL PROSTATECTOMY
9.1 Introduction
The surgical treatment of prostate cancer (PCa) consists of radical prostatectomy (RP), which involves removal of the entire prostate gland between the urethra and bladder, and resection of both seminal vesicles, along with sufficient surrounding tissue to obtain a negative margin. Often, this procedure is accompanied by bilateral pelvic lymph node dissection. In men with localised PCa and a life expectancy > 10 years, the goal of RP by any approach must be eradication of disease, while preserving continence and whenever possible potency (1). There is no age threshold for RP and a patient should not be denied this procedure on the grounds of age alone (2). Increasing comorbidity greatly increases the risk of dying from non-PCa-related causes (3). An estimation of life expectancy is paramount in counselling a patient about surgery (4).

RP was first applied at the beginning of the 20th century by Young (5) using a perineal approach, while Memmelaar and Millin were the first to perform retropubic RP (6). In 1982, Walsh and Donker described the anatomy of the dorsal venous complex and the neurovascular bundles (NVBs). This resulted in a significant reduction in blood loss and improved continence and potency rates (7). Currently, RP is the only treatment for localised PCa to show a benefit for cancer-specific survival (CSS), compared with conservative management, as shown in a prospective randomised trial (8). Surgical expertise has decreased the complication rates of RP and improved cancer cure (9-12).

Total surgical removal is an excellent treatment option in well-selected patients with localised PCa. If performed by an experienced surgeon, the patient’s subsequent quality of life should be satisfactory. Lower rates of positive surgical margins for high-volume surgeons suggest that experience and careful attention to surgical details, adjusted for the characteristics of the cancer being treated, can decrease positive surgical margin rates and improve cancer control with RP (13,14).

Radical retropubic prostactectomy (RRP) and perineal prostatectomy are performed through open incisions, and more recently, minimally invasive laparoscopic radical prostatectomy (LRP) and robot-assisted laparoscopic prostatectomy (RALP) have been developed. RALP is displacing RRP as the gold standard surgical approach for clinically localised prostate cancer in the United States and is also being increasingly used in Europe and other parts of the world. This trend has occurred despite the paucity of high-quality evidence to support its relative superiority to more-established treatment modalities. Recent in-depth systematic reviews of the literature have compared the results of RRP versus LRP/RALP. It has been concluded that LRP and RALP are followed by significantly lower blood loss and transfusion rate, but the available data are not sufficient and of insufficient quality to prove the superiority of any surgical approach in terms of functional and oncological outcomes (15-17).

9.2 Low-risk, localised prostate cancer: cT1-T2a and Gleason score 2-6 and prostatespecific antigen < 10 ng/mL
Patients with low-risk, localised PCa should be informed about the results of the randomised trial comparing retropubic RP versus watchful waiting (WW) in localised PCa (8). In this study, the survival benefit was similar before and after 9 years of follow-up, was observed also among men with low-risk PCa, and was confined to men < 65 years of age. The number needed to treat to avert one death was 15 overall and seven for men < 65 years of age.
9.2.1 Stage T1a-T1b prostate cancer
Stage T1a PCa is defined as an incidental histological finding of cancer in < 5% of resected prostatic tissue [transurethral resection of the prostate (TURP) or open adenomectomy]. Stage T1b PCa is defined as > 5% cancer. Published series have shown a pT0 stage in 4-21% and an organ-confined stage in 47-85% of patients at subsequent RP (18).

A Swedish register-based study of 23,288 men with incidental PCa detected at TURP or open adenoma enucleation, mostly before the prostate-specific antigen (PSA) era, showed a 10-year PCa mortality of 26.6%. There were no details of the PSA level or Gleason score nor the numbers of cases with cT1a or cT1b PCa (19). Other older studies have shown that, even though the risk of disease progression of untreated T1a PCa after 5 years is only 5%, these cancers can progress in about 50% of cases after 10-13 years (20). Thus, it was believed that, in younger patients with a life-expectancy of > 15 years, the chance of disease progression was real. In contrast, most patients with T1b tumours were expected to show disease progression after 5 years, and aggressive treatment was often warranted (20). Patients with T1b lesions were offered RP when they had a life expectancy of > 10 years.
Nevertheless, it remains unclear whether these findings would still be valid in the PSA era. In a recent analysis
of T1a/b PCa:
• The only significant predictors of the presence of residual cancer at RRP were PSA measured before
and after surgery for BPH and Gleason score at surgery for BPH.
• The only independent predictors of biochemical recurrence after RRP were PSA measured after
surgery for BPH and Gleason score at surgery for BPH.
• The stage (cT1a or cT1b) lost its significance in predicting the above-mentioned outcomes.
A predictive model has been proposed, which incorporates the PSA level before and after surgery and the Gleason score at surgery for BPH. The model has a predictive accuracy of 83.2% for estimating residual tumour and 87.5% for estimating biochemical progression, but needs external validation before it can be used in daily practice (18).
Systematic prostate biopsies of the remnant prostate may be useful in detecting residual cancer or concomitant peripheral zone cancer, or to ascertain a more correct tumour grade. RP may be difficult after thorough TURP, when almost no residual prostate is left behind (21).
9.2.2 Stage T1c and T2a prostate cancer
Clinically unapparent tumour identified by needle biopsy because of an elevated PSA (cT1c) has become the most prevalent type of PCa. In an individual patient, it is difficult to differentiate between clinically insignificant and life-threatening PCa. Most reports, however, stress that cT1c tumours are mostly significant and should not be left untreated because up to 30% of cT1c tumours are locally advanced at final histopathological analysis (22). The proportion of insignificant tumours varies between 11% and 16% (23,24). Increasing the number of biopsies may carry the risk of detecting a higher number of insignificant cancers. However, a recent study has shown that increasing the number of biopsies to 12 did not increase the number of insignificant tumours (25). The major problem is how to recognise those tumours that do not need RP. The biopsy findings and the free PSA ratio are helpful in predicting insignificant disease (26). Partin tables may help better selection of patients who require surgical treatment, because of their ability to provide an estimation of the final pathological stage (27). Other authors have suggested the incorporation of biopsy information, such as the number of cores or the percentage of cores invaded (28). When only one or a few cores are invaded and the percentage of invasion in one core is limited, the chance of finding an insignificant PCa is more likely, certainly when the lesion is of low Gleason grade (29). It might be reasonable to follow up some patients whose tumours are most likely to be insignificant.

In general, however, RP should be advocated for patients with T1c tumours, bearing in mind that significant tumours will be found in most of these individuals. Stage T2a patients with a 10-year life expectancy should be offered RP because 35-55% of them will have disease progression after 5 years if not treated. If active monitoring is proposed for low-grade T2 cancer, it should be remembered that preoperative assessment of tumour grade by needle biopsy is often unreliable (30).Extended pelvic lymph node dissection (eLND) is not necessary in low-risk, localised PCa, because the risk for positive lymph nodes does not exceed 5% (31).
9.3 Intermediate-risk, localised prostate cancer: cT2b-T2c or Gleason score = 7 or
prostate-specific antigen 10-20 ng/mL
Patients with intermediate-risk, localised PCa should be informed about the results of the randomised trial comparing RRP versus WW in localised PCa (8). In this study, the survival benefit was similar before and after 9 years of follow-up and was confined to men < 65 years of age. The number needed to treat to avert one death was 15 overall and seven for men < 65 years of age. RP is one of the recommended standard treatments for patients with intermediate-risk PCa and a life expectancy of > 10 years (32). The prognosis is excellent when the tumour is confined to the prostate, based on pathological examination (33,34). A policy of WW has been proposed for some patients with intermediaterisk localised tumours (35). However, when the tumour is palpable or visible on imaging and clinically confined to the prostate, disease progression can be expected in most long-term survivors.

The median time to progression of untreated T2 disease has been reported as 6-10 years. Stage T2b cancer confined to the prostate, but involving more than half a lobe or both lobes, will progress in > 70% of patients within 5 years (36). These data have been confirmed by a large randomised trial comparing RP and WW that included mostly T2 PCa patients, with a significant reduction in disease-specific mortality in favour of RP (8).
eLND should be performed in intermediate-risk, localised PCa if the estimated risk for positive lymph nodes exceeds 5% (31). In all other cases, eLND can be omitted, which means accepting a low risk of missing positive nodes. Limited LND should no longer be performed, because this misses at least half of the nodes involved.
9.3.1 Oncological results of radical prostatectomy in low- and intermediate-risk prostate cancer
The results achieved in a number of studies involving RP are shown in Table 14.
Table 14: Oncological results of RP in organ-confined disease

The first externally validated nomogram predicting PCa-specific mortality after RP for patients treated in the PSA era was published recently. The nomogram predicts that few patients die from PCa within 15 years of RP, despite the presence of adverse clinical features. This nomogram can be used in patient counselling and clinical trial design (42).
9.4 High-risk, localised prostate cancer: cT3a or Gleason score 8-10 or prostate-specific
antigen > 20 ng/mL
The widespread use of PSA testing has led to a significant migration in stage and grade of PCa, with > 90% of men in the current era diagnosed with clinically localised disease (27). Despite the trends towards lower-risk PCa, 20-35% of patients with newly diagnosed PCa are still classified as high risk, based on either PSA > 20 ng/mL, Gleason score > 8, or an advanced clinical stage (43). Patients classified with high-risk PCa are at an increased risk of PSA failure, the need for secondary therapy, metastatic progression and death from PCa. Nevertheless, not all high-risk patients have a uniformly poor prognosis after RP (44).

There is no consensus regarding the optimal treatment of men with high-risk PCa. Decisions on whether to elect surgery as local therapy should be based on the best available clinical evidence. Provided that the tumour is not fixed to the pelvic wall, or that there is no invasion of the urethral sphincter, RP is a reasonable first step in selected patients with a low tumour volume. Management decisions should be made after all treatments have been discussed by a multidisciplinary team (including urologists, radiation oncologists, medical oncologists and radiologists), and after the balance of benefits and side effects of each therapy modality has been considered by the patients with regard to their own individual circumstances.
9.4.1 Locally advanced prostate cancer: cT3a
Stage T3a cancer is defined as cancer that has perforated the prostate capsule. In the past, locally advanced PCa was seen in about 40% of all clinically diagnosed tumours. This figure is lower today, although its management remains controversial. Surgical treatment of clinical stage T3 PCa has traditionally been discouraged (45), mainly because patients have an increased risk of positive surgical margins and lymph node metastases and/or distant relapse (46,47). Several randomised studies of radiotherapy combined with androgen-deprivation therapy (ADT) versus radiotherapy alone have shown a clear advantage for combination treatment, but no trial has ever proven combined treatment to be superior to RP (48). Another problem is “contamination” by the additional use of either adjuvant radiotherapy or immediate or delayed hormonal therapy (HT) in most series reporting the treatment of clinical T3 PCa. In recent years, there has been renewed interest in surgery for locally advanced PCa, and several retrospective case series have been published. Although still controversial, it is increasingly evident that surgery has a place in treating locally advanced disease (49-54).

Over-staging of cT3 PCa is relatively frequent and occurs in 13-27% of cases. Patients with pT2 disease and those with specimen-confined pT3 disease have similarly good biochemical and clinicalprogression-free survival (PFS) (53,54). In 33.5-66% of patients, positive section margins are present, and 7.9-49% have positive lymph nodes (55). Thus, 56-78% of patients primarily treated by surgery eventually require adjuvant or salvage radiotherapy or HT (53,54). Nevertheless, excellent 5-, 10- and 15-year overall survival (OS) and cancer-specific survival (CSS) rates have been published (Table 15). These rates surpass radiotherapyalone and are no different from radiotherapy combined with adjuvant HT (48).

The problem remains the selection of patients before surgery. Nomograms, including PSA level, stage and Gleason score, can be useful in predicting the pathological stage of disease (27,55). In addition, nodal imaging with computed tomography (CT), and seminal vesicle imaging with magnetic resonance imaging (MRI), or directed specific puncture biopsies of the nodes or seminal vesicles can help to identify those patients unlikely to benefit from a surgical approach (56). RP for clinical T3 cancer requires sufficient surgical expertise to keep the level of morbidity acceptable. Increased overall surgical experience must contribute to decreased operative morbidity and to better functional results after RP for clinical T3 cancer (53,57). It has been shown that continence can be preserved in most cases, and in selected cases, potency can also be preserved (58).
Table 15: OS and CSS rates for PCa.

BPFS = biochemical progression-free survival
9.4.2 High-grade prostate cancer: Gleason score 8-10
Although most poorly differentiated tumours extend outside the prostate, the incidence of organ-confined disease is 26-31%. Patients with high-grade tumours confined to the prostate at histopathological examination still have a good prognosis after RP. Furthermore, one-third of patients with a biopsy Gleason score > 8 may in fact have a specimen Gleason score < 7 with better prognostic characteristics. The PSA value and percentage of positive prostate biopsies may help to select men with high-grade PCa who are most likely to benefit from RP (59).
9.4.3 Prostate cancer with prostate-specific antigen > 20 ng/mL
Yossepowitch et al. have reported the results of RP as monotherapy in men with PSA > 20 ng/mL, in a cohort with mostly clinically organ-confined tumours, and found a PSA failure rate of 44% and 53% at 5 and 10 years, respectively (44). D’Amico et al. found that men with PSA levels > 20 ng/mL had a 50% risk of PSA failure at 5 years after RP (60). Spahn et al. published the largest multicentre clinical series of its kind, comprising 712 patients with PSA > 20 ng/mL, and reported a CSS of 90% and 85% at 10 and 15 years follow-up, respectively (61). In the same analysis, they demonstrated that the combination of PSA > 20 ng/mL with cT3 stage and/or biopsy Gleason score 8-10 significantly lowered CSS. More recently, Gontero and co-workers described a subanalysis of the same patient cohort. Ten-year CSS was 80%, 85% and 91% in patients with PSA > 100 ng/
mL, 50.1-100 ng/mL and 20.1-50 ng/mL, respectively. These results argue for aggressive management with RP as the initial step (62).

eLND should be performed in all high-risk cases, because the estimated risk for positive lymph nodes is 15-40% (31). Limited LND should no longer be performed, because it misses at least half the nodes involved.

9.5 Very-high-risk, localised prostate cancer: cT3b-T4 N0 or any T, N1
9.5.1 cT3b-T4 N0
Men with very-high-risk PCa generally have a significant risk of disease progression and cancer-related death if left untreated. Very-high-risk PCa presents two specific challenges. There is a need for local control as well as treatment of any microscopic metastases that are likely to be present but undetectable until disease progression.
The optimal treatment approach therefore often necessitates multiple modalities. The exact combinations, timing and intensity of treatment continue to be strongly debated. A recent US study has shown that 72 patients who underwent RP for cT4 disease had better survival than those who received HT or radiotherapy alone, and comparable survival to men who received radiotherapy plus HT (63). Another study has compared the outcomes of RP in very-high-risk PCa (T3-T4 N0-N1, N1, M1a) with those in localised PCa.
The two groups did not differ significantly in surgical morbidity except for blood transfusion, operative time,
and lymphoceles, which showed a higher rate in patients with advanced disease. OS and CSS at 7 years
were 76.69% and 90.2% in the advanced disease group and 88.4% and 99.3% in the organ-confined disease
group, respectively (64).

Provided that the tumour is not fixed to the pelvic wall, or there is no invasion of the urethral sphincter, RP is a reasonable first step in selected patients with very-high-risk PCa and low tumour volume. Management decisions should be made after all treatments have been discussed by a multidisciplinary team (including urologists, radiation oncologists, medical oncologists and radiologists), and after the balance of benefits and side effects of each therapy modality has been considered by the patients with regard to their own individual circumstances.
9.5.2 Any T, N1
The indication for RP in all previously described stages assumes the absence of clinically detectable nodal involvement. Lymph-node-positive (N+) disease will mostly be followed by systemic disease progression, and all patients with significant N+ disease ultimately fail treatment.

Nevertheless, the combination of RP and early adjuvant HT in N+ PCa has been shown to achieve a 10-year CSS rate of 80% (65,66). Most urologists are reluctant to perform RP for clinical N+ disease, or cancel surgery if a frozen section shows lymph node invasion. However, a recent study has shown a dramatic improvement in CSS and OS in favour of completed RP versus abandoned RP in patients who were found to be N+ at the time of surgery. These results suggest that RP may have a survival benefit and the abandonment of RP in N+ cases may not be justified (67). These findings have been corroborated in a contemporary series (68). RP resulted in superior survival of patients with N+ PCa after controlling for lymph node tumour burden. The findings from these studies support the role of RP as an important component of multimodal strategies of N+ PCa.

It should also be noted that definitive pathological examination after RP could show microscopic lymph node invasion. The incidence of tumour progression is lower in patients with fewer positive lymph nodes and in those with microscopic invasion only (69,70). In patients who prove to be pN+ after RP, early adjuvant HT has been shown to improve CSS and OS significantly in a prospective randomised trial. However, this trial included mostly patients with high-volume nodal disease and multiple adverse tumour characteristics. It is unclear whether early adjuvant HT should still be used in the present era of increased detection of microscopic involvement as a result of more eLND. The benefits should be judged against the side effects of long-term HT. Follow-up of PSA and HT in patients with increased PSA level is therefore an acceptable option in selected cases. Interestingly, maximal local control with radiotherapy of the prostatic fossa appears to be beneficial in PCa patients with pN+ after RP, treated adjuvantly with continuous ADT (71).
9.6 Indication and extent of extended pelvic lymph node dissection
Although it is generally accepted that eLND provides important information for prognosis (number of nodes involved, tumour volume within the lymph node, and capsular perforation of the node) that cannot be matched by any other current procedure, consensus has not been reached about when eLND is indicated and to what extent it should be performed. When making such decisions, many physicians rely on nomograms based on preoperative biochemical markers and biopsies (27).

According to these nomograms, patients with PSA < 10 ng/mL and biopsy Gleason score < 7 have a low risk of lymph node metastasis, and therefore, eLND might not be beneficial. However, the fact that most nomograms are based on a limited eLND (obturator fossa and external iliac vein) probably results in underestimation of the incidence of patients with positive nodes (31). Lymphography studies have shown that the prostate drains not only to the obturator and external iliac lymph nodes but also to the internal iliac andpresacral nodes. Performing eLND results in removal of all lymph nodes in these particular anatomical regions, producing a higher yield of excised lymph nodes (mean: 20 nodes) compared with limited LND (mean: 8-10 nodes).

In patients with PSA < 10 ng/mL and Gleason score > 7, the incidence of nodal involvement has been reported as 25% (72). Different reports mention that 19-35% of positive lymph nodes are found exclusively outside the area of the traditionally limited LND (73,74). Clearly, the removal of a greater number of nodes results in improved staging. In the largest study of its kind, a cut-off < 2 versus > 2 affected nodes was shown to be an independent predictor of CSS (69).
9.6.1 Conclusions
Extended LND is not necessary in low-risk, localised PCa, because the risk for positive lymph nodes does not exceed 5% (31).
Extended LND should be performed in intermediate-risk, localised PCa if the estimated risk for positive lymph nodes exceeds 5%, as well as in high-risk cases. In these circumstances, the estimated risk for positive lymph nodes is 15-40% (31). Limited LND should no longer be performed, because it misses at least half the nodes involved.
9.6.2 Extent of extended lymph node dissection
Extended LND 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 ileac artery. Some lymph node mapping studies have advocated extending the template to include the common iliac lymph nodes up to the ureteric crossing. With this template, 75% of all anatomical landing sites are cleared (75). For eLND to be representative, a mean of 20 lymph nodes should be removed (76). It is recommended that the nodes should be sent in separate containers for each region for histopathological analysis, because this will usually be associated with a higher diagnostic gain by the uropathologist.
9.6.3 Therapeutic role of extended lymph node dissection
Besides being a staging procedure, pelvic LND/eLND can be curative, or at least beneficial, in a subset of patients with limited lymph node metastases (77-79). In some series, the number of nodes removed during lymphadenectomy has correlated significantly with time to progression (80). In one population-based study with a 10-year follow-up, patients undergoing excision of at least four lymph nodes (node-positive and nodenegative patients) or > 10 nodes (only node-negative patients) had a lower risk of PCa-specific death at 10 years than those who did not undergo lymphadenectomy (81). Further studies should confirm these results.
9.6.4 Morbidity
Pelvic eLND remains a surgical procedure that increases morbidity in the treatment of PCa. When comparing extended versus limited LND, threefold higher complication rates have been reported by some authors (82). Complications consist of lymphocoeles, lymphoedema, deep venous thrombosis, and pulmonary embolism. Other authors, however, have reported more acceptable complication rates (83,84).
9.6.5 Conclusions extended lymph node dissection
Extended LND may play a role in the treatment of a subset of intermediate-risk cases with > 5% nomogram predicted risk of positive lymph nodes, and in all high-risk cases.Extended LND may increase staging accuracy and influence decision making with respect to adjuvant
therapy. The number of lymph nodes removed correlates with time to progression.Surgical morbidity must be balanced against the therapeutic effects, and decisions need to be made based on individual cases.
9.7 Summary of radical prostatectomy in high-risk localised disease
RP is a reasonable treatment option in selected patients with cT3a PCa, Gleason score 8-10 or PSA > 20. Furthermore, RP is optional in highly selected patients with cT3b-4 N0 or any cT N1 PCa in the context of a
multimodality approach.
Management decisions should be made after all treatments have been discussed by a multidisciplinary team (including urologists, radiation oncologists, medical oncologists and radiologists), and after the balance of benefits and side effects of each therapy modality has been considered by the patients with regard to their own individual circumstances.
If RP is performed, pelvic eLND must be performed, because lymph node involvement is common.The patient must be informed about the likelihood of a multimodal approach. In case of adverse tumour characteristics (positive section margin, extraprostatic extension, or seminal vesicle invasion), adjuvant radiotherapy may reasonably be used after recuperation from surgery. When nodal involvement is detected after surgery, adjuvant ADT may be selected.
9.8 Neoadjuvant hormonal therapy and radical prostatectomy
Neoadjuvant or up-front HT is defined as therapy given before definitive local curative treatment (e.g., surgery or radiotherapy). PCa is an androgen-dependent tumour, therefore, neoadjuvant hormonal therapy (NHT) is an appealing concept. Attempts to decrease the size of the prostate before RP were first reported by Vallett as early as 1944 (85). In a recent review and meta-analysis, the role of NHT and prostatectomy has been studied (86). NHT before prostatectomy did not improve OS or disease-free survival (DFS), but did significantly reduce positive margin rates [relative risk (RR): 0.49; 95% confidence interval (CI): 0.42-0.56, P < 0.00001), organ confinement (RR: 1.63; 95% CI: 1.37-1.95, P < 0.0001) and lymph node invasion (RR: 0.49; 95% CI: 0.42-0.56,P < 0.02). Thus, the absence of improvement in clinically important outcomes (OS, disease-specific survival
or biochemical DFS) was demonstrated despite improvements in putative pathological surrogate outcomes,
such as margin-free positive status. This calls into question the use of these pathological markers of treatment outcomes as valid surrogates for clinically relevant outcomes.

Further studies are needed to investigate the application of HT as both neoadjuvant treatment and with chemotherapy in early disease. More information is also needed to evaluate these agents in terms of side effects and quality of life, which was lacking in most studies presented in this review.

Further cost analyses should be undertaken to update the data. A recent Cochrane review and metaanalysis have studied the role of adjuvant HT following RP: the pooled data for 5-year OS showed an odds ratio (OR) of 1.50 and 95% CI: 0.79-2.84. This finding was not statistically significant, although there was a trend favouring adjuvant HT. Similarly, there was no survival advantage at 10 years. The pooled data for DFS gave an overall OR of 3.73 and 95% CI: 2.3-6.03. The overall effect estimate was highly significant (P < 0.00001) in favour of the HT arm.

It is noteworthy that the Early Prostate Cancer Trialists’ Group (EPC) trial was not included in the Cochrane review. The third update from this large randomised trial of bicalutamide, 150 mg once daily, in addition to standard care in localised and locally advanced, non-metastatic PCa was published in November 2005 (87). Median follow-up was 7.2 years. There was a significant improvement in objective PFS in the RP group. This improvement was only significant in the locally advanced disease group [hazard ratio (HR): 0.75;95% CI: 0.61-0.91]. There was no significant improvement in OS in the RP-treated groups (localised and locally advanced disease). In the WW group, there was an OS trend in favour of WW alone in the localised disease group (HR: 1.16; 95% CI: 0.99-1.37).
9.8.1 Summary of neoadjuvant and adjuvant hormonal treatment and radical prostatectomy

9.9 Complications and functional outcome
The postoperative complications of RP are listed in Table 16. The mortality rate is 0-1.5% (81); urinaryfistulas are seen in 1.2-4% of patients (88); and urinary incontinence persists after 1 year in 7.7% (89). In men undergoing prostatectomy, the rates of postoperative and late urinary complications are significantly reduced if the procedure is performed in a high-volume hospital and by a surgeon who performs a large number of such procedures (90-92).

Erectile dysfunction used to occur in nearly all patients, but this can be avoided by using nervesparing techniques in early-stage disease (93). Patients who benefit from nerve-sparing RP may have a higher chance of local disease recurrence and should therefore be selected carefully.
Table 16: Complications of RP

9.10 Summary of indications for nerve-sparing surgery* (100-104)

*Clinical criteria used by different authors when NOT to perform a nerve-sparing RP
Nerve-sparing RP can be performed safely in most men undergoing RP (99,100). In the past decade, a dramatic shift towards lower-stage tumours has become evident. More importantly, men are younger at the time of diagnosis and more interested in preserving sexual function. Nevertheless, clear contraindications are patients in whom there is a high risk of extracapsular disease, such as any cT3 PCa, cT2c, any Gleason score > 7 on biopsy, or more than one biopsy > 6 at the ipsilateral side. Partin tables help to guide decision making (27).

If any doubt remains regarding residual tumour, the surgeon should remove the neurovascular bundle (NVB). Alternatively, the use of intraoperative frozen-section analysis can help guide these decisions. This is especially helpful in patients with a lesion palpable close to the capsule during nerve-sparing RP. A wedge of the prostate can then be resected and inked differently. In case carcinoma is adherent to the capsule on frozen section analysis, the NVB is resected; otherwise, the NVB remains in situ. In patients with intraoperativelydetected tumour lesions during nerve-sparing, planned RP, frozen-section analysis objectively supports the decision of secondary NVB resection, as well as preservation (101).

The patient must be informed before surgery about the risks of nerve-sparing surgery, the potency rates achieved, and the possibility that, to ensure adequate cancer control, the nerves may be sacrificed despite any preoperative optimism favouring the potential for their salvage.

The early administration of intracavernous injection therapy could improve the definitive potency rates (102,103). Finally, the early use of phosphodiesterase-5 inhibitors in penile rehabilitation remains controversial. A recent placebo-controlled prospective study has shown no benefit from daily early administration of vardenafil versus on-demand vardenafil in the postoperative period (104), whereas another placebo-controlled prospective study has shown that sildenafil has a significant impact on return of normal spontaneous erections (105).
9.11 Conclusions and recommendations for radical prostatectomy

9.12 References
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5. Young H. Radical perineal prostatectomy. Johns Hopkins Hosp Bull 1905;16:315-21.
6. Memmelaar J. Total prostatovesiculectomy; retropubic approach. J Urol 1949 Sep;62(3):340-8. [no
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10. TREATMENT: DEFINITIVE RADIATION THERAPY
10.1 Introduction
There are no randomised studies comparing radical prostatectomy (RP) with either external beam radiation therapy (EBRT) or brachytherapy for localised PCa. However, the National Institutes of Health (NIH) consensus set up in 1988 (1) remains available: external irradiation offers the same long-term survival results as surgery;moreover, EBRT provides a QoL at least as good as that provided by surgery (2).

Intensity modulated radiotherapy (IMRT) +/- image guided (IGRT) is the gold standard and all centres unable to offer this should have a plan to introduce it as a routine for the definitive treatment of prostate cancer (PCa).

In addition to external irradiation, transperineal low-dose or high-dose rate brachytherapy are widely used. In localised and locally advanced PCa, several randomised phase III trials conducted by radiation therapy scientific societies, such as the Radiation Therapy Oncology Group (RTOG) and European Organisation for Research and Treatment of Cancer (EORTC), have established the indications for the combination of external irradiation and androgen deprivation treatment (ADT).

Whatever the technique used, the choice of treatment - after the appropriate assessment of tumour extension - must be based on a multidisciplinary approach and should consider the following:
• 2009 TNM classification;
• Gleason score defined on a sufficient number of core biopsies (at least 12);
• baseline PSA;
• age of the patient;
• patient’s co-morbidity, life expectancy and QoL;
IPSS score and uroflowmetry recordings;
• National Comprehensive Cancer Network (NCCN) and prognostic class D’Amico’s prognostic factor
classification (2b).
It is essential to obtain a patient’s informed consent after providing full information to him, regarding diagnosis, therapeutic modalities and morbidity. Additional information on the various aspects of radiotherapy in the treatment of PCa is available in a newly published extensive overview (3).
10.2 Technical aspects: three-dimensional conformal radiotherapy (3D-CRT) and intensity
modulated external beam radiotherapy (IMRT)
Anatomical data, acquired by scanning the patient in a treatment position, are transferred to the 3D treatment planning system, which visualises the clinical target volume and then adds a (surrounding) safety margin. At the time of irradiation, a multi-leaf collimator automatically and, in the case of IMRT, continuously, adapts to the contours of the target volume seen by each beam. Real-time verification of the irradiation field by means of portal imaging allows for comparison of the treated and simulated fields, and correction of deviations where displacement is more than 5 mm. Three-dimensional CRT improves local control through dose escalation, without increasing the risk of morbidity.

The use of IMRT is possible with linear accelerators equipped with the latest multileaf collimators and specific software. Movement of the leaves during the course of the irradiation allows for a more complex distribution of the dose to be delivered within the treatment field, and provides concave isodose curves, which are particularly useful as a means of sparing the rectum.

Whatever the techniques and their sophistication, quality assurance plays a major role in the management of radiotherapy, requiring the involvement of physicians, physicists, dosimetrists, radiographers, radiologists and computer scientists.
10.3 Radiotherapy for non-metastatic prostate cancer
Several randomized and non-randomised studies have shown that dose escalation (range, 76-80 Gy) has a significant impact on 5-year survival without biochemical relapse (5-7,10-12,15).
Two randomised trials focused on clinical stages T1-3 N0 M0 have paved the way for dose escalation:
• The MD Anderson study compared 78 Gy with 70 Gy conventional radiotherapy: it included 305 stage
T1-3 patients with a pre-treatment PSA level of more than 10 ng/mL and, with a median follow-up of 8.7 years, showed a significant increase in freedom from biochemical and/or clinical failure for low-risk patients (p = 0.04) (5).
• The PROG 95-09 study evaluated 393 T1b-T2b patients, of whom 75% had a Gleason score < 6 and a PSA < 15 ng/mL. Patients were randomised to receive an initial boost to the prostate alone, using conformal protons of either 19.8 Gy or 28.8 Gy, and then 50.4 Gy to a larger volume. With a median follow-up of 5.5 years, there was a significant increase in 5-year freedom from biochemical failure (p < 0.001) in favour of low-risk patients given a higher dose (79.2 Gy) versus those given a conventional dose (70.2 Gy) (6).
In daily practice, a minimum dose of > 74 Gy is recommended for EBRT + hormone therapy (expert opinion) (7).

The following phase III trials argue for the combination of ADT and RT, or for dose-escalated RT:
• A Dutch randomised phase III trial comparing 68 Gy with 78 Gy showed a significant increase in
5-year freedom from clinical or biochemical failure for patients in an intermediate-risk group (10).
• The phase III trial of the French Federation of Cancer Centres compared 70 Gy with 80 Gy in 306patients with a pelvic lymph node involvement risk of < 10% (Partin) or pN0, with no hormonal therapy allowed before, during, or after radiotherapy. With a median follow-up of 59 months, a high dose should provide a better 5-year biological outcome in intermediate-risk patients, especially if the initial PSA > 15 ng/mL (11).
• The RTOG 94-08 trial in 1979 patients with T1b-T2b, PSA < 20 ng/mL has shown that the addition of complete androgen blockade for 2 months before, and 2 months during conventional, lower-dose RT (66 Gy) significantly improved 10-year overall survival (62% vs 57%, p = 0,03) (12).
• Patients who are reluctant to accept short-term hormonal treatment (13) can receive definitive radiotherapy alone, provided that a dose escalation up to 78-80 Gy is proposed.
• The MRC RT01 study, comparing a dose of 64 Gy with 74 Gy, both with neoadjuvant hormonal therapy, showed an 11% difference in 5-year BDFS (14).
• The PROG 95-09 study showed a significant increase in 5-year freedom from biochemical failure (p <0.02) in favour of high-risk patients given a higher dose (79.2 Gy) versus those given a conventional dose (70.2 Gy) (10).
• An MD Anderson study showed a significant improvement in mestatases-free survival for high-risk patients (p = 0.004) (5).
• The EORTC trial 22991, comparing 3D-CRT +/- IMRT with a choice of three levels of dose (70 Gy, 74Gy or 78 Gy), with or without 6 months of neoadjuvant and concomitant hormonal therapy, was closed in April 2008 after recruiting 800 patients; its results are awaited (15).

A combination of external irradiation with short-term ADT improves overall survival, based on the results of a phase III randomised trial which included 206 patients with a PSA level of at least 10 ng/mL (maximum 40 ng/mL), a Gleason score of at least 7 (range 5-10), or radiographic evidence of extra-prostatic disease, compared 3D-CRT alone or in combination with 6 months of ADT. After a median follow-up of 7.6 years, intermediate- or high-risk patients without moderate or severe co-morbidity, who had been randomised to receive 3D-CRT + ADT, showed a 13% improvement in overall survival rate (p < 0.001) (13). In contrast, data from the EORTC-22961 randomised phase III trial, comparing 36 months of hormonal treatment + radiotherapy with 6 months of hormonal treatment + radiotherapy, showed that increased hormonal treatment improved overall survival in patients with high-risk PCa at 5 years (14).
10.3.1 Prophylactic irradiation of pelvic lymph nodes in high-risk localised PCa
Invasion of the pelvic lymph nodes is a poor prognostic factor and mandates systemic medical treatment because radiotherapy alone is insufficient (15). Prophylactic whole-pelvis irradiation has been abandoned since randomised trials failed to show that patients benefited from prophylactic irradiation (46-50 Gy) of the pelvic lymph nodes in high-risk cases. Such studies include the RTOG 77 06 study with 484 T1b-T2 patients (16), the Standford study with only 91 patients (17), and the GETUG-01 trial, which included 444 T1b-T3 N0 pNx M0 patients (18). Pelvic lymphadenectomy may be needed to improve the selection of patients who might benefit from pelvic lymph node irradiation and to supplement the use of Partin’s tables (19) and/or the Roach formula (20). The results of pelvic lymphadenectomy, particularly for young patients, will enable radiation oncologists to tailor both the planning target volume and the duration of ADT: specifically, no pelvic irradiation for pN0 patients, but pelvic irradiation for pN1 patients with long-term ADT. The benefits of pelvic nodal irradiation merit further investigation in a clinical trail (one trial using high-dose IMRT is currently being designed).
10.4 Innovative techniques
10.4.1 Intensity modulated radiotherapy
Intensity modulated radiotherapy enables radiation oncologists to increase radiation doses homogeneously, up to as much as 86 Gy within the target volume, while respecting the tolerance doses in organs at risk. Certainly, IMRT is the only safe means of treatment delivery for dose escalation beyond 75 Gy, using conventional 2 Gy fraction sizes, or for dose escalation using hypofractionated radiotherapy, in which there has been renewed interest. However, both treatment scenarios should be performed only within the confines of a properly designed clinical trial.

To date, no randomised trials have been published comparing dose escalation using IMRT and 3D-CRT. With dose escalation using IMRT, organ movement becomes a critical issue, in terms of both tumour control and treatment toxicity. Evolving techniques will therefore combine IMRT with some form of imageguided radiotherapy (IGRT), in which organ movement can be visualised and corrected for in real time, although the optimum means of achieving this is still unclear (21).

Another evolving technique for the delivery of IMRT is tomotherapy, which uses a linear accelerator mounted on a ring gantry that rotates as the patient is delivered through the centre of the ring, analogous to spiral computed tomography (CT) scanning. Preliminary data suggest that this technique is feasible in PCa treatment (22).
10.4.2 Proton beam and carbon ion beam therapy
In theory, proton beams are an attractive alternative to photon beam radiotherapy for PCa because 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. Additionally, there is a very sharp fall-off for proton beams beyond their deposition depth, meaning that critical normal tissues beyond this depth could be effectivelyspared. In contrast, photon beams continue to deposit energy until they leave the body, including an exit dose.

In practice, however, this has the disadvantage that dose distributions from protons are highly sensitive to changes in internal anatomy, such as might occur with bladder or rectal filling, and prostate proton therapy is usually delivered with lateral beams. It is also possible that high linear energy transfer (LET) radiation therapy using protons or carbon ions offers inherent biological advantages over photons, having more capacity for DNA damage dose-for-dose.

Only one randomised trial has incorporated proton therapy in one arm: the Loma Linda/Massachusetts General Hospital trial mentioned above compared standard-dose conformal radiotherapy with dose-escalated radiotherapy using protons for the boost dose (6). This trial cannot, however, be used as evidence for the superiority of proton therapy per se, as its use here could be viewed simply as a sophisticated method for dose escalation. A randomised trial comparing equivalent doses of proton beam therapy with IMRT is needed to compare the efficacy of protons versus photons; such a study is under consideration by the RTOG.

Two recent planning studies comparing conformal proton therapy with IMRT have yielded conflicting results; one study suggested that the two are equivalent in terms of rectal dose sparing, but that IMRT is actually superior in terms of bladder sparing (23); the other study suggested a clearer advantage to protons(24). Further studies are clearly needed. Meanwhile, proton therapy must be regarded as a promising, but experimental, alternative to photon beam therapy. Theoretically, proton therapy may be associated with a lower risk of secondary cancers compared with IMRT, because of the lower integral dose of radiation, but there are no data in patients treated for PCa to support this.

Carbon ions offer similar theoretical advantages as protons, as an alternative to photon beam therapy. In a phase II study, 175 patients with T1-3, N0-1, M0 PCa were treated with carbon ions in a dose equivalent to 66 Gy in 20 fractions over 5 weeks (25). Treatment appeared to be well tolerated, with no RTOG grade 3 or 4 bowel or genitourinary toxicity, and an overall four-year BDFR of 88% (24). As with protons, a randomised trial comparing carbon ions with IMRT and using equivalent doses is required.
10.5 Transperineal brachytherapy
Transperineal brachytherapy is a safe and effective technique. There is consensus on the following eligibility criteria:
• stage cT1b- T2a N0, M0;
• a Gleason score < 6 assessed on a sufficient number of random biopsies;
• an initial PSA level of < 10 ng/mL;
• < 50% of biopsy cores involved with cancer;
• a prostate volume of < 50 cm3
• an International Prostatic Symptom Score < 12 (IPSS) (26).
Patients with low-risk PCa are the most suitable candidates for low-dose rate (LDR) brachytherapy. Further guidelines on the technical aspects of brachytherapy have been published recently and are strongly recommended (27).

In 1983, Holm et al. described the transperineal method with endorectal sonography in which the patient is positioned in a dorsal decubitus gynaecological position (28). Implantation is undertaken under general anaesthesia or spinal block, and involves a learning curve for the whole team: the surgeon for delineation of the prostate and needle placement, the physicist for real-time dosimetry, and the radiation oncologist for source loading. The sonography probe introduced into the rectum is fixed in a stable position.
There are no randomised trials comparing brachytherapy with other curative treatment modalities, and outcomes are based on non-randomised case series. Results of permanent implants have been reported from different institutions, with a median follow-up ranging between 36 and 120 months (29). Recurrence-free survival after 5 and 10 years was reported to range from 71% to 93% and from 65% to 85%, respectively (30-37).

A significant correlation has been shown between the implanted dose and recurrence rates (38). Patients receiving a D90 of > 140 Gy demonstrated a significantly higher biochemical control rate (PSA < 1.0 ng/mL) at 4 years than patients receiving less than 140 Gy (92% vs 68%). There is no benefit from adding neoadjuvant or adjuvant ADT to LDR brachytherapy (29).

Some patients experience significant urinary complications following implantation, such as urinary retention (1.5-22%), post-implant transurethral resection of the prostate (TURP) (up to 8.7%), and incontinence (0-19%) (39b). A small randomised trial has suggested that prophylactic tamsulosin does not reduce the rates of acute urinary retention, but may improve urinary morbidity (39). This observation requires further study in a larger number of patients. Chronic urinary morbidity can occur in up to 20% of patients, depending on the severity of symptoms prior to brachytherapy. Previous TURP for benign prostatic hyperplasia increases the risk of post-implant incontinence and urinary morbidity.

The incidence of grade III toxicity is less than 5%. Erectile dysfunction develops in about 40% of patients after 3-5 years. In a recent retrospective analysis of 5,621 men who had undergone LDR brachytherapy (40), urinary, bowel and erectile morbidity rates were 33.8%, 21% and 16.7%, respectively, with invasive procedure rates of 10.3%, 0.8% and 4%, respectively.

In cases of permanent implants, iodine-125 in granular form is the radio-element of reference, while palladium-103 may be used for less differentiated tumours with a high doubling time. The dose delivered to the planning target volume is 144 Gy for iodine-125, and 125 Gy for palladium-103. A Gleason score of 7 remains a ‘grey area’, but patients with a Gleason score of 4 + 3 showed no difference in outcome (41).

A small randomised trial has suggested that the use of stranded rather than loose seeds is associated with better seed retention and less seed migration, and this should be the standard choice (42).

In cases of intermediate- or high-risk localised PCa, brachytherapy in combination with supplemental external irradiation (43) or neoadjuvant hormonal treatment (44) may be considered.

The optimum dose of supplemental EBRT is unclear. A randomised trial comparing 44 Gy with 20 Gy of EBRT + palladium-103 brachytherapy closed early, showing no difference in biochemical outcomes (45).

Non-permanent transperineal interstitial prostate brachytherapy using a high-dose rate iridium-192 stepping source and a remote afterloading technique can be applied with a total dose of 12-20 Gy in two to four fractions combined with fractionated external radiotherapy of 45 Gy (46). Higher doses of supplemental EBRT than this may best be delivered with IMRT; a report from Memorial Sloan-Kettering indicates that this approach is safe and feasible (47).

Recent data suggest an equivalent outcome in terms of BDFS compared with high-dose EBRT (HD EBRT) (48). In a retrospective analysis of modern series (49,50), BDFS rates of 85.8%, 80.3% and 67.8% in men with low-, intermediate- and high-risk PCa, respectively, are reported after a mean follow-up of 9.43 years. Quality-of-life changes are similar between high-dose EBRT and high-dose rate (HDR) brachytherapy in terms of diarrhoea and insomnia (51). However, the frequency of erectile dysfunction was significantly increased with HDR brachytherapy (86% vs 34%). A single randomised trial of EBRT versus EBRT + HDR brachytherapy has been reported (52). A total of 220 patients with organ-confined PCa were randomised to EBRT alone with a dose of 55 Gy in 20 fractions, or EBRT with a dose of 35.75 Gy in 13 fractions, followed by HDR brachytherapy
with a dose of 17 Gy in two fractions over 24 hours. Compared to EBRT alone, the combination of EBRT and HDR brachytherapy showed a significant improvement in biochemical relapse-free survival (p = 0.03). There were no differences in the rates of late toxicity. Patients randomised to EBRT + brachytherapy had a significantly better QoL as measured by their Functional Assessment of Cancer Therapy-prostate (FACT-P) score at 12 weeks. However, a very high, uncommon rate of early recurrences was observed in the EBRTarm alone, even after 2 years, possibly due to the uncommon fractionation used (52). There is still a need to compare dose-escalated EBRT + hormone therapy, with the same followed by a brachytherapy boost, in intermediate- and high-risk patients.

For T1-2 N0 M0 disease, the 5-year biochemical failure rates are similar for permanent seed implantation, high-dose (> 72 Gy) external radiation, combination seed/external irradiation, and RP, according to a study of 2991 patients diagnosed with T1-2 consecutive localised PCa treated between 1990 and 1998 at the Cleveland Clinic Foundation and Memorial Sloan-Kettering Cancer Center with a minimum of 1-year followup (48).
10.6 Late toxicity
Patients must be informed about the potential late genitourinary or gastrointestinal toxicity that may occur, as well as the impact of irradiation on erectile function. Late toxicity was analysed using a dose of 70 Gy in the prospective EORTC randomised trial 22863 (1987-1995) (53), in which 90% of patients were diagnosed as stage T3-4. A total of 377 patients (91%) out of 415 enrolled were evaluable for long-term toxicity, graded according to a modified RTOG scale. Eighty-six (22.8%) patients had grade > 2 urinary or intestinal complications or leg oedema, of which 72 had grade 2 (moderate) toxicity, 10 had grade 3 (severe) toxicity, and four died due to grade 4 (fatal) toxicity. Although four (1%) late treatment-related deaths occurred, long-term toxicity was limited, with fewer than 5% grade 3 or 4 late complications being reported (Table 17). These data can be used as a baseline for comparison with irradiation techniques currently in use, such as 3D-CRT or IMRT.
Table 17: Incidence of late toxicity by RTOG grade (from EORTC trial 22863)

GU = genitourinary; GI = gastrointestinal.
* Overall toxicity included GU and GI toxicity and leg oedema. As most patients had more than one type of toxicity, the overall toxicity does not result from simple addition.
† Two of the grade 4 patients were irradiated with cobalt-60.
Note: There was no other significant (> grade 2) toxicity among patients irradiated with cobalt-60 (n = 15) except for two patients with grade 4 GU (stated above) and only one patient with grade 2 GI toxicity. Radiotherapy affects erectile function to a lesser degree than surgery according to retrospective surveys of patients (2). A recent meta-analysis has shown that the 1-year rate of probability for maintaining erectile function was 0.76 after brachytherapy, 0.60 after brachytherapy + external irradiation, 0.55 after external irradiation, 0.34 after nerve-sparing radical prostatectomy, and 0.25 after standard radical prostatectomy. When studies with more than 2 years of follow-up were selected (i.e. excluding brachytherapy), the rates became 0.60, 0.52, 0.25, and 0.25, respectively, with a greater spread between the radiation techniques and surgical approaches (54).

Recent studies have demonstrated a significantly increased risk of developing secondary malignancies of the rectum and bladder following EBRT (55,56). In a retrospective evaluation of 30,552 and 55,263 men who had undergone either EBRT or RP, the risk of being diagnosed with rectal cancer increased 1.7-fold in comparison with the surgery group (55). Another analysis (56) showed that the relative risk of developing bladder cancer increased by 2.34-fold compared with a healthy control population. On the other hand, a re-analysis of SEER data with more than 100,000 patients demonstrated a risk of about 0.16% (i.e. 160 cases per 100,000 patients) of radiation-induced malignant tumours (57).

Corresponding data on late toxicity has also been reported by the Memorial Sloan-Kettering Cancer Center group, from its experience in 1,571 patients with T1-T3 disease treated with either 3D-CRT or IMRT in doses of between 66 Gy and 81 Gy, with a median follow-up of 10 years (57). Both acute GI and GU toxicity appeared to predict for corresponding late toxicity. The overall rates of NCIC-CTC grade 2 or more GI toxicity was 5% with IMRT, compared with 13% with 3D-CRT. The incidence of grade 2 or more late GU toxicity was 20% in patients treated with 81 Gy, compared with 12% in patients treated with lower doses. The overall incidence of grade 3 GI toxicity was 1%, and grade 3 GU toxicity was 3%. These data suggest that IMRT can successfully protect against late GI toxicity, but, interestingly, with dose escalation, GU toxicity may become the dominant morbidity (58).
10.7 Immediate and delayed post-operative external irradiation after radical prostatectomy
Extracapsular invasion (pT3) is associated with a risk of local recurrence, which can be as high as 30% (59). In a multifactorial analysis, the predictors of biochemical relapse are:
• PSA level (p = 0.005);
• Gleason score of the surgical specimen (p = 0.002);
• positive surgical margins (p < 0.001) (60).
Three prospective randomised trials have assessed the role of immediate post-operative radiotherapy (adjuvant radiotherapy, ART). The EORTC study 22911, with a target sample size of 1,005 patients, compared immediate post-operative radiotherapy (60 Gy) with radiotherapy delayed until local recurrence (70 Gy) in patients classified as pT3 pN0 with risk factors R1 and pT2R1 after retropubic RP. Immediate post-operative radiotherapy proved to be well tolerated, with a risk of grade 3-4 urinary toxicity of less than 3.5%, without significantly worsening the rate of incontinence and/or stricture of the anastomosis. The study concludes that immediate post-operative radiotherapy after surgery significantly improved 5-year clinical or biological survival: 72.2% versus 51.8% (p < 0.0001) (61). After re-evaluation by central pathological review, the highest impact (30%) was seen in patients with positive margins (R1), but there was also a positive effect of 10% after 5 years for pT3 with negative margins and other risk factors (62,63).

The most suitable candidates for immediate radiation therapy might be those with multifocal positive surgical margins and a Gleason score > 7. The conclusions of the ARO trial 96-02 (n = 385) appear to support those of the EORTC study. After a median follow-up of 54 months, the radiotherapy group demonstrated a significant improvement in biochemical progression-free survival of 72% versus 54%, respectively (p = 0.0015). However, of major interest and in contrast to other studies, patients were randomised after achieving an undetectable PSA following RP (< 0.1 ng/mL) and only pT3-tumours were included. This finding indicates that adjuvant radiotherapy works even in the setting of an undetectable PSA after RP and additional risk factors (63). Conversely, the updated results, with a median follow-up of more than 12 years, of the SWOG 8794 trial, which randomised 425 pT3 patients, showed that adjuvant radiation significantly improved metastasis-free survival, with a 10-year metastasis-free survival of 71% versus 61% (median prolongation of 1.8 years, p = 0.016) and a 10-year overall survival of 74% versus 66% (median: 1.9 years prolongation, p = 0.023) (65).

Thus, for patients classified as pT3 pN0 with a high risk of local failure after RP due to positive margins (highest impact), capsule rupture, and/or invasion of the seminal vesicles, who present with a PSA level of < 0.1 ng/mL, two options can be offered within the framework of an informed consent:
• either immediate radiotherapy (ART) to the surgical bed (61,63,65,66) upon recovery of urinary
function;
• or clinical and biological monitoring followed by salvage radiotherapy (SRT) before the PSA exceeds
0.5 ng/mL (67,68).

Early salvage radiotherapy provides the possibility of cure to patients with an increasing or persisting PSA after RP. More than 60% of patients who are treated before the PSA level rises to more than 0.5 ng/mL will achieve an undetectable PSA level again (67,68), so providing patients with the chance of about 80% being progression-free 5 years later (68). A retrospective analysis based on 635 patients undergoing RP from 1982-2004, followed up through to December 2007, who experienced biochemical and/or local recurrence and received no salvage treatment (397) or salvage radiotherapy alone (160) within 2 years of biochemical recurrence, has shown that SRT was associated with a threefold increase in PCa-specific survival relative to those who received no salvage treatment (p < 0.001). Salvage radiotherapy has also been effective in patients who have had a rapid PSA-doubling time (69). So far, the optimal SRT-dose has not been well defined. It should be at least 66 Gy. However, newer data suggest that higher total doses can achieve higher rates of biochemical control at 3 to 5 years (70,71).

The role of an additional ADT in combination with SRT remains controversial. The RTOG 9601 randomised, multi-centre phase III trial was designed to compare anti-androgen therapy (bicalutamide monotherapy 150 mg/dL) plus SRT (n = 387) to a placebo plus SRT alone (n = 383) in men with pT3 (n = 518)/pT2 R1 (n = 252) N0 M0 prostate cancer with an elevated PSA after surgery. The median follow-up in surviving patients was 7.1 years. The addition of 24 months of peripheral and androgen blockade during and after RT significantly improved freedom from PSA progression (FFP) 57% versus 40% (p < 0.0001) and reduced the incidence of metastatic PCa (7.4% versus 12.6%, p < 0.04), without adding significantly to radiation toxicity. Longer follow-up is required to assess the significance of benefit in overall survival and to provide analysis of risk-stratified subsets (72).

These two approaches, together with the efficacy of neoadjuvant hormone therapy, are currently being compared in the UK MRC RADICALS randomised trial. The role of short-term hormone therapy in combination with radiotherapy is being investigated in the EORTC 22043 randomised trial.
10.8 Locally advanced PCa: T3-4 N0, M0
The incidence of locally advanced PCa has declined as a result of individual or mass screening. Pelvic lymph node irradiation is optional for N0 patients, but the results of radiotherapy alone are very poor (73). Because of the hormonal dependence of PCa (74), ADT has been combined with external irradiation with the aim of:
• reducing the risk of distant metastases by potentially sterilising micrometastases already present at
the moment of diagnosis;
• decreasing the risk of non-sterilisation and/or local recurrence as a source of secondary metastases
(73) through the effect of radiation-induced apoptosis (75,76). Numerous randomised trials have confirmed the value of long-term administration.
10.8.1 Neo-adjuvant and concomitant short-term androgen deprivation therapy
The Trans-Tasman Radiation Oncology Group 96.01 trial included 818 men randomly assigned to RT alone (66 Gy/33 fractions) (77), 3 months of ADT with goserelin and flutamide starting 2 months before radiotherapy, or 6 months of ADT with the same regimen starting 5 months before RT. After a median follow-up of 10.6 years, those assigned to 3 months of ADT had a decreased cumulative incidence of PSA progression (p = 0.003), local progression (p = 0.0005), and event-free survival (p = 0.0001), compared with patients assigned to RT alone. Six months of ADT reduced PSA progression (p < 0.0001) and local progression (p = 0.0001) and led to a greater improvement in event-free survival (p < 0.0001). Furthermore, 6 months of ADT decreased distant progression (p = 0.001), cancer-specific mortality (p = 0.0008), and all-cause mortality (p = 0.0008) compared with RT alone (77).
10.8.2 Neo-adjuvant and concomitant hormonal therapy
The RTOG study 86-10 included 471 patients with bulky (5 x 5 cm) tumours T2-4 N0-X M0. Androgen deprivation therapy was administered at 2 months before irradiation and during irradiation, or in the case of relapse in the control arm. Thirty-two per cent of patients were diagnosed as T2, 70% as T3-4, and 91% as N0. The hormone treatment consisted of oral eulexine, 250 mg three times daily, and goserelin acetate (Zoladex), 3.6 mg every 4 weeks by subcutaneous injection. The pelvic target volume received 45 Gy and the prostatic target volume received 20-25 Gy. The 10-year overall survival estimates were 43% for ADT + irradiation versus 34% for hormonal treatment, although the difference was not significant (p = 0.12). There was a significant improvement in the 10-year disease-specific mortality (23% vs 36%; p = 0.01), disease-free survival (11%vs 3%; p <0.0001) and in biochemical failure (65% vs 80%; p < 0.0001), with the addition of ADT having no statistical impact on the risk of fatal cardiac events (78).
10.8.3 Concomitant and long-term adjuvant hormonal therapy
The EORTC study 22863 recruited 415 patients diagnosed with T1-2 grade 3 WHO (World Health Organization) or T3-4 N0 M0 and any histological grade, and compared radiotherapy + adjuvant ADT with radiotherapy alone.
The use of ADT was allowed in cases of relapse. A total of 82% of patients was diagnosed as T3, 10% as T4, and 89% as N0.

Hormonal treatment consisted of oral cyproterone acetate (CPA), 50 mg three times daily for 1 month, beginning 1 week before the start of radiotherapy, and goserelin acetate (Zoladex), 3.6 mg subcutaneously every 4 weeks for 3 years, starting on the first day of radiotherapy. The pelvic target volume received was 50 Gy, and the prostatic target volume was 20 Gy. With a median follow-up of 66 months, combination therapy compared with radiotherapy alone yielded significantly better survival (78% vs 62%, p = 0.001) (79). At a median follow-up of 9.1 years, the 10-year overall survival remained significantly higher at 58.1% vs 39.8% (p < 0.0001), as did clinical progression-free survival at 47.7% vs 22.7% (p < 0.0001). The 10-year cumulative incidence of PCa mortality was 11.1% versus 31% (p < 0.0001), and the 10-year cumulative incidence of cardiovascular mortality was 11.1% versus 8.2% (p = 0.75) (80).
10.8.4 Long-term adjuvant hormonal therapy
The RTOG study 8531 recruited 977 patients diagnosed with T3-4 N0-1 M0, or pT3, after RP. Androgen deprivation therapy was begun in the last week of irradiation and continued up to relapse (Group I) or was started at recurrence (Group II). A total of 15% of patients in Group I and 29% in Group II had undergone RP, and 14% of patients in Group I and 26% in Group II were pN1. Goserelin acetate, 3.6 mg subcutaneously, was administered every 4 weeks. The pelvis was irradiated with 45 Gy, while the prostatic bed received 20-25 Gy. Patients diagnosed with stage pT3 received 60-65 Gy. With a median follow-up time of 7.6 years for all patients, the 10-year overall survival was significantly greater for the adjuvant arm, at 49% versus 39% (p = 0.002) (81).

The National Cancer Institute of Canada (NCIC)/UK Medical Research Council (MRC)/Southwest Oncology Group (SWOG) intergroup PR3/PR07 study included 1205 patients with T3-4 (n = 1057) or T2, PSA > 40 ng/mL (n = 119), or T2, PSA > 20 ng and Gleason > 8 (n = 25) and N0-X M0 PCa, who were randomised to lifelong ADT (bilateral orchidectomy or LHRH agonist), with or without RT (65-70 Gy to prostate +/- 45 Gy to pelvic lymph nodes). With a median follow-up of 6 years, the addition of RT to ADT reduced the risk of death from any cause by 23% (p = 0.03) and the risk of death due to PCa by 46% (p = 0.0001) (82,83).

The GETUG trial included 273 patients with locally advanced PCa T3-4 or pT3 N0 M0, who were randomly assigned to lifelong ADT using an LHRH agonist (leuproreline), with or without RT (70 Gy to the prostate plus 48+/- 2Gy to pelvic lymph nodes). With a median follow-up of 67 months, there was a significant improvement in 5-year disease free survival (p < 0.001), metastases disease-free survival (p < 0.018) and locoregional progression-free survival (p < 0.0002), but the effect on overall survival was not reported (84).

The SPCG-7/SFUO-3 randomised study (85) compared hormonal treatment alone (i.e. 3 months of continuous androgen blockade followed by continuous flutamide treatment (n = 439) with the same treatment combined with radiotherapy (n = 436). After a median follow-up of 7.6 years, the 10-year cumulative incidence for prostate cancer-specific mortality was, respectively, 23.9% and 11.9% (95% CI: 4.9-19.1), and the 10-year cumulative incidence for overall mortality was 39.4% in the hormonal treatment-only group, and 29.6% in the hormonal + RT group (95% CI: 0.8-18%).
10.8.5 Neo-adjuvant, concomitant and long-term adjuvant hormonal therapy
The RTOG 9202 trial closed in 1995 after accruing 1554 patients. Statistically significant improvements were observed in actuarial biochemical freedom from disease control, distant metastatic failure, local control, and disease-free survival in patients receiving long-term ADT (before, during, and 2 years after radiotherapy), compared with short-term ADT (2 months before and during radiotherapy). With a median follow-up of 11.27 years of all survival patients, the long-term ADT arm showed significant improvement over the short-term ADT arm in all efficacy endpoints, except 10-year overall survival, which was 51.6% versus 53.9% (p = 0.36), respectively. In a subset of patients that was not part of the original study design, with Gleason score 8-10 tumours, the long-term ADT arm showed significantly better overall survival after 10 years than the short-term ADT arm, with 45% versus 32% (p = 0.006) (86).
10.8.6 Short-term or long-term adjuvant hormonal treatment
Following the EORTC trial 22863, the EORTC equivalence trial 22961 was set up to test whether similar survival could be achieved in patients who underwent irradiation (to 70 Gy) and 6 months of combined ADT without further ADT, i.e. short-term ADT arm, compared with patients with 2.5 years of further treatment with luteinising hormone-releasing hormone analogue, i.e. long-term ADT arm. Eligible patients had T1c-2b N1-2 or pN1-2, or T2c-4 N0-2 (UICC 1992) M0 PCa with PSA < 150 ng/mL.

Non-inferior survival was defined as a mortality hazard ratio (HR) = 1.35 for short-term ADT versus long-term ADT. A total of 970 patients were randomised. With a 5.2-year median follow-up, the 5-year overall survival rate was 85.3% on long-term ADT, and 80.6% on short-term ADT (HR = 1.43; 96.4% CI; 1.04-1.98), and failed to prove non-inferiority (87).
10.8.7 Dose escalation with hormonal therapy
Zelefsky et al. (88) reported a retrospective analysis of 2251 patients with T1-3 N0-X M0 PCa comprised of 571 low-risk patients (22.4%), 1074 intermediate-risk patients (42.1%) and 906 high-risk patients (35.5%), according to the National Comprehensive Cancer Network classification. Three-dimensional conformal radiotherapy (3D-CRT) or IMRT were given to the prostate and seminal vesicles only. The prostate dose ranged from 64.8 to 86.4 Gy; doses beyond 81 Gy were delivered within the last 10 years by employing image-guidedIMRT. Androgen deprivation therapy by complete androgen blockade with a luteinizing hormone releasing hormone (LHRH) agonist plus oral anti-androgen was given at the discretion of the treating physician to 1,249 patients (49%), including 623 high-risk patients (69%), 456 intermediate-risk patients (42%) and 170 low-risk (30%) patients. The duration of ADT was 3 months for low-risk patients and 6 months for intermediate-risk and high-risk patients, starting at 3 months prior to RT and continued during RT. The end-points were 10-year biochemical disease-free survival and distant metastases-free survival. With an 8-year median follow-up, the 10-year biochemical disease-free survival of each risk group was significantly improved by dose escalation: 84% (> 75.6 Gy) versus 70% for low-risk patients (p = 0.04), 76% (> 81 Gy) vs 57% for intermediate- risk patients (p = 0.0001), and 55% (> 81 Gy) versus 41% for high-risk patients (p = 0.0001). The 6-month ADT also influenced the biochemical disease-free survival of intermediate-risk and high-risk patients, with 55% versus 36% for high-risk patients (p < 0.0001). In multivariate analysis, a dose greater than 81 Gy (p = 0.027) and ADT (p = 0.052) were significant predictors for distant metastases-free survival, but none of these parameters influenced PCa mortality or overall survival. There were very low rates of grade 3-4 acute or late toxicity (89).
10.9 Very high-risk PCa: c or pN1, M0
Patients with a pelvic lymph node involvement lower than the iliac regional nodes, younger than 80 years old, with a WHO performance status 0-1, and no severe co-morbidity may be candidates for EBRT plus immediate long-term hormonal manipulation. The RTOG 85-31 randomised phase III trial has shown, with a median follow-up of 6.5 years, that 95 patients out of the 173 pN1 patients who received pelvic radiotherapy with immediate hormonal therapy had better 5-year (54%) and 9-year (10%) progression-free survival (PSA < 1.5 ng/mL) versus 33% and 4%, respectively, with radiation alone and hormonal manipulation instituted at the time of relapse (p < 0.0001). Multivariate analysis showed that this combination had a statistically significant impact on overall survival, disease-specific failure, metastatic failure and biochemical control (90). The GETUG 12 trial has addressed the impact of neoadjuvant chemotherapy with docetaxel on progression-free survival in a cohort of 413 high-risk patients, defined as having one or more of the following criteria: T3-4, Gleason score > 8, PSA > 20 ng/mL, pN+. Patients were randomly assigned to either goserelin, 10.8 mg every 3 months for 3 years, plus 4 cycles of docetaxel, 70 mg/m2 every 3 weeks plus estramustine 10 mg/kg/dL on days 1 to 5 (arm 1), or goserelin alone (arm 2). Local therapy was administered at 3 months and consisted of RT in 358 patients (87%). Toxicity included grade 3-4 neutropenia (27%) with neutropenic fever in 2%, but no toxicity-related death and no secondary leukaemia. With a median follow-up of 4.6 years, the 4-year progression-free survival was 85% in arm 1 versus 81% in arm 2 (p = 0.26), but the data need to mature (91).
10.10 Guidelines summary for definitive radiation therapy

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Jul;168(1):9-12.
http://www.ncbi.nlm.nih.gov/pubmed/12050481
75. Zietman AL, Prince EA, Nakfoor BM, et al. Androgen deprivation and radiation therapy: sequencing
studies using the Shionogi in vivo tumour system. Int J Radiat Oncol Biol Phys 1997 Jul;38(5):1067-70.
http://www.ncbi.nlm.nih.gov/pubmed/9276373
76. Joon DL, Hasegawa M, Sikes C, et al. Supraadditive apoptotic response of R3327-G rat prostate
tumours to androgen ablation and radiation. Int J Radiat Oncol Biol Phys 1997 Jul;38(5):1071-7.
http://www.ncbi.nlm.nih.gov/pubmed/9276374
77. Denham JW, Steigler A, Lamb DS, et al. Short term neoadjuvant androgen deprivation and
radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised
trial. Lancet Oncol 2011 May;12(5):451-9.
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78. Roach M, Bae K, Speight J, et al. Short-term neodajuvant androgen deprivation therapy and externalbeam radiotherapy for locally advanced prostate cancer: long term results of RTOG 8610. J Clin Oncol
2008 Feb;26(4):585-91.
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79. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and
external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III
randomized trial. Lancet 2002 Jul;360(9327):103-6.
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80. Bolla M, Collette L, Van Tienhoven G, et al. Ten year results of long term adjuvant androgen
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81. Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in
prostate carcinoma--long-term results of phase III RTOG 85-31.
http://www.ncbi.nlm.nih.gov/pubmed/15817329
82. Warde, P, Mason, M, Ding, K, et al and for the NCIC CTG PR.3/MRC UK PR07 investigators.
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83. Mason M, Warde P, Sydes M, et al; The National Cancer Institute of Canada Clinical Trials Group PR3/;
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84. Mottet N, Peneau M, Mazeron J et al. Impact of radiotherapy (RT) combined with androgen deprivation
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85. Widmark A, Klepp O, Solberg A, et al for the Scandinavian Prostate Cancer Group Study, the Swedish
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86. Horwitz EM, Bae K, Hanks GE, et al. Ten-year follow-up of radiation therapy oncology group protocol
92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate
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87. Bolla M, de Reijke TM, Van Tienhoven G, et al; EORTC Radiation Oncology Group and Genito-Urinary
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88. Zelefsky MJ, Pei X, Chou JF, et al. Dose escalation for prostate cancer radiotherapy: predictors of
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89. Zelefsky MJ, Levin EJ, Hunt M. et al. Incidence of later rectal and urinary toxicities after three
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90. Lawton CA, Winter K, Grignon D, et al. Androgen suppression plus radiation versus radiation alone for
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91. Fizazi K, Lesaunier F, Delva R et al. Docetaxel-estramustine in high-risk localized prostate cancer: first
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abstr 4513).
11. EXPERIMENTAL LOCAL TREATMENT OF
PROSTATE CANCER
11.1 Background
Besides radical prostatectomy (RP), external beam radiation and/or brachytherapy, cryosurgical ablation of the prostate (CSAP) and high-intensity focused ultrasound (HIFU) have emerged as alternative therapeutic options
in patients with clinically localised PCa (1-4).
Although HIFU is still considered to be an experimental treatment, CSAP has been recognised as a true therapeutic alternative according to the guidelines of the American Urological Association. Both HIFU and CSAP have been developed as minimally invasive procedures, which have potentially the same therapeutic efficacy as established surgical and non-surgical options, with reduced therapy-associated morbidity.
11.2 Cryosurgery of the prostate (CSAP)
Cryosurgery uses freezing techniques to induce cell death by:
• dehydration resulting in protein denaturation;
• direct rupture of cellular membranes by ice crystals;
• vascular stasis and microthrombi, resulting in stagnation of the microcirculation with consecutiveischaemia;
• apoptosis (1-4).
Freezing of the prostate is ensured by placement of 12-15 17G-cryoneedles under transrectal ultrasound (TRUS) guidance, placement of thermosensors at the level of the external sphincter and bladder neck, 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.
11.2.1 Indication for CSAP
Patients who are ideal candidates for CSAP are those who have organ-confined PCa and those identified as having minimal tumour extension beyond the prostate (1-3). The prostate should be < 40 mL in size. Prostate glands > 40 mL should be hormonally downsized to avoid any technical difficulty in placing cryoprobes under the pubic arch. Prostate-specific antigen (PSA) serum levels should be < 20 ng/mL, and the biopsy Gleason score should be < 7. It is important that patients with a life expectancy > 10 years should be fully informed that there are no data, or only minimal data, on the long-term outcome for cancer control at 10 and 15 years.
11.2.2 Results of modern cryosurgery for PCa
When comparing treatment modalities, it is important to bear in mind that, in modern RP patients with clinically organ-confined PCa, there is a very low risk (2.4%) of dying from PCa at 10 years after surgery (5). Therapeutic
results have improved over time with enhanced techniques, such as gas-driven probes and transperineal probe placement, as used in third-generation cryosurgery (6-11).

An objective assessment of PSA outcome is not easily performed because some institutions use PSA values < 0.1 ng/mL as an indicator of therapeutic success, whereas others use the American Society of Therapeutic Radiology and Oncology (ASTRO) criteria, which requires three consecutive increases in PSA level.

With regard to second-generation CSAP, if a PSA nadir < 0.5 ng/mL is used, biochemical disease-free survival (BDFS) at 5 years is 60% and 36% for low-risk and high-risk patients, respectively (6,7).
Long et al. (6) have performed a retrospective analysis of the multicentre, pooled, CSAP results of 975 patients stratified into three risk groups. Using PSA thresholds of 1.0 ng/mL and < 0.5 ng/mL at a mean follow-up of 24 months, the 5-year actuarial BDFS rate was:
• 76% and 60%, respectively, for the low-risk group;
• 71% and 45%, respectively, for the intermediate-risk group;
• 61% and 36%, respectively, for the high-risk group.

However, according to a recent meta-analysis of 566 cryosurgery-related publications, there were no controlled trials, survival data or validated biochemical surrogate end-points available for analysis (12).Cryosurgery showed progression-free survival (PFS) of 36-92% (projected 1- to 7-year data), depending on risk groups and the definition of failure. Negative biopsies were seen in 72-87% of cases, but no biopsy data were available for the currently used third-generation cryotherapy machines.With regard to third-generation cryosurgery, clinical follow-up is short, with a 12-month PSA follow-up carried out in only 110/176 (63%) patients (6-11). Eighty of these (73%) patients still had a PSA nadir < 0.4 ng/mL, whereas 42/65 (64.6%) low-risk patients remained free from biochemical progression using the 0.4 ng/mL cut-off.

Longer follow-up has been reported by Bahn et al. (9), who have analysed the therapeutic results of 590 patients undergoing CSAP for clinically localised and locally advanced PCa. At a PSA cut-off level of < 0.5 ng/mL, the 7-year BDFS for low-, medium- and high-risk groups was 61%, 68% and 61%, respectively.Nerve-sparing cryosurgery, as reported recently (13), must still be considered an experimental therapeutic option. Nerve-sparing surgery was performed in nine patients with unilateral PCa confirmed on repeated biopsies; CSAP was carried out on the side of the positive biopsy, whereas the negative biopsy side was spared from freezing.
11.2.3 Complications of CSAP for primary treatment of PCa
Erectile dysfunction occurs in about 80% of patients and remains a consistent complication of the CSAP procedure, independent of the generation of the system used. The complication rates described in third generation cryosurgery include tissue sloughing in about 3%, incontinence in 4.4%, pelvic pain in 1.4% and urinary retention in about 2% (6-11). The development of fistula is usually rare, being < 0.2% in modern series. About 5% of all patients require transurethral resection of the prostate (TURP) for subvesical obstruction.

Quality of life and sexuality following CSAP have been investigated in a clinical phase II trial recruiting 75 men (14). Quality-of-life analysis by the prostate-specific FACT-P questionnaire showed that most subscales return to pre-treatment levels by 12 months after CSAP. Furthermore, no significant changes are seen when comparing data at 36 months with those at 12 months. With regard to sexuality, 37% of men were able to have intercourse 3 years after CSAP.

In a recent, prospective, randomised clinical trial, 244 men with newly diagnosed organ-confined PCa were randomised to receive either external beam radiation therapy (EBRT) or to undergo CSAP (15). After a follow-up of 3 years, sexual function was significantly less impaired in the EBRT group.
11.2.4 Summary conclusions for CSAP
Patients with low-risk PCa (PSA < 10 ng/mL, < T2a, Gleason score < 6) or intermediate-risk PCa (PSA > 10 ng/mL, or Gleason score > 7, or stage > 2b) represent potential candidates for CSAP.
Prostate size should be < 40 mL at the time of therapy.Long-term results are lacking, whereas 5-year BDFS rates are inferior to those achieved by RP in low-risk patients. Patients must be informed accordingly.
11.3 HIFU of the prostate
HIFU consists of focused ultrasound waves emitted from a transducer, which cause tissue damage by mechanical and thermal effects as well as by cavitation (16). The goal of HIFU is to heat malignant tissues above 65°C so that they are destroyed by coagulative necrosis.

HIFU is performed under general or spinal anaesthesia, with the patient lying in the lateral position. The procedure is time-consuming, with about 10 g prostate tissue treated per hour.

In a recent review, 150 papers related to HIFU were identified and evaluated with regard to various oncological and functional outcome parameters (12). No controlled trial was available for analysis, and no survival data were presented. No validated biochemical, surrogate end-point was available for HIFU therapy.
11.3.1 Results of HIFU in PCa
As with CSAP, it appears to be difficult to interpret oncological outcome in patients undergoing HIFU because various PSA thresholds are defined, and no international consensus exists on objective response criteria. The results of HIFU are limited, with outcome data from < 1,000 PCa cases published in the literature.

According to the recent review mentioned above (12), HIFU showed PFS (based on PSA ± biopsy data) of 63-87% (projected 3- to 5-year data), but median follow-up in the studies ranged from 12-24 months only.

In one of the largest single-centre studies, 227 patients with clinically organ-confined PCa were treated with HIFU, and their outcome data were analysed after a mean follow-up of 27 months (range: 12-121 months) (17). The projected 5-year BDFS was 66%, or only 57% if patients had exhibited a pre-therapeutic PSA value of 4-10 ng/mL. Incontinence and bladder neck stricture decreased over time from 28% and 31% to 9% and 6%, respectively. In one of the studies (18), a significant decrease in pre-treatment PSA serum levels from 12 to 2.4 ng/mL was observed. However, 50% of the 14 patients demonstrated positive prostate biopsies during follow-up. In another study (19), a complete response rate (i.e., PSA < 4 ng/mL) and six negative biopsies were achieved in 56% of the patients.

Thüroff et al. (19) have summarised the efficacy results of a European multicentre study comprising the data of 559 patients with mainly low- and intermediate-risk PCa, and have reported a negative biopsy rate of 87.2% in 288 men with a follow-up of at least 6 months. A PSA nadir after 6 months’ follow-up could be determined in 212 patients, and was 1.8 ng/mL. However, following the initial procedure, it could be demonstrated that the PSA nadir might be reached in 12-18 months.

Blana et al. have reported the results of 146 patients undergoing HIFU with a mean follow-up of 22.5 months (20). The mean PSA level at initiation of therapy was 7.6 ng/mL; the PSA nadir achieved after 3 months was 0.07 ng/mL. However, after 22 months, the median PSA level was 0.15 ng/mL. Of the 137 men available for analysis, 93.4% demonstrated a negative control biopsy. The PSA nadir appeared to be strongly associated with treatment failure (21) (P < 0.001). Patients with a PSA nadir of 0.0-0.2 ng/mL had a treatment failure rate of only 11% compared with 46% in patients with a PSA nadir of 0.21-1.00 ng/mL, and 48% with a PSA nadir of > 1.0 ng/mL. Recently, the group has updated its results, with a total of 163 men treated for clinically organconfined PCa. Within the 4.8 ± 1.2 years of follow-up, the actuarial DFS rate at 5 years was 66%, with salvage treatment initiated in 12% of patients (22).

In another study, 517 men with organ-confined or locally advanced PCa were treated with HIFU (23). Biochemical failure was defined as the PSA nadir + 2 ng/mL, according to the Phoenix guidelines with regard to radiotherapy. After a median follow-up of 24 months, the BDFS was 72% for the entire cohort. The BDFS in patients with stage T1c, T2a, T2b, T2c and T3 groups at 5 years was 74%, 79%, 72%, 24% and 33%, respectively (P < 0.0001). The BDFS in patients in the low-, intermediate- and high-risk groups at 5 years was 84%, 64% and 45%, respectively (P < 0.0001). The BDFS in patients treated with or without neoadjuvant hormonal therapy at 7 years was 73% and 53% (P < 0.0001), respectively. Postoperative erectile dysfunction was noted in 33 out of 114 (28.9%) patients who were preoperatively potent.

In a recent retrospective study, 137 patients with PCa underwent HIFU (24). After a median follow-up of 36 months, 22% of the patients relapsed according to the Phoenix criteria. The 5-year DFS rate was 78% based on these criteria, and 91%, 81% and 62% in the low-, intermediate- and high-risk group, respectively. Urge incontinence (16 cases) and dysuria (33 cases) occurred after removal of the urethral catheter in 11.8% and 24.1%, respectively.

To evaluate whether the location (apex/midgland/base) of PCa influences the risk of incomplete transrectal HIFU ablation, Bouiter et al. (25) analysed 99 patients who underwent PCa HIFU ablation (Ablatherm; EDAP,Vaulx-en-Velin, France) with a 6-mm safety margin at the apex, and had systematic biopsies at 3-6 months after treatment. After treatment, residual cancer was found in 36 patients (36.4%) and 50 sextants (8.4%); 30 (60%) positive sextants were in the apex, 12 (24%) in the midgland, and eight (16%) in the base. Statistical analysis showed that the mean (95% CI) probability for a sextant to remain positive after HIFU ablation was 8.8% (3.5-20.3%) in the base, 12.7% (5.8-25.9%) in the midgland, and 41.7% (27.2-57.89%) in the apex. When a 6-mm apical safety margin was used, treatment-associated side effects, especially incontinence and erectile dysfunction, were fewer but residual cancer after HIFU ablation was significantly more frequent in the apex. Komura et al. (26) have analysed the oncological outcome in 144 patients with T1/T2 PCa and a median follow-up of 47 (2-70) months. Thirty-nine percent patients relapsed and approximately 40% developed a clinical or subclinical urethral stricture postoperatively. Most interestingly, the 5-year DFS was significantly better in those with a stricture as compared to those without (78.2% vs. 47.8%, P < 0.001), indicating the need for more aggressive treatment especially at the apex of the prostate.
11.3.2 Complications of HIFU
Urinary retention appears to be one of the most common side effects of HIFU, developing in almost all patients, with the mean interval of catheterisation via a suprapubic tube varying between 12 and 35 days (16-18). Grade
I and II urinary stress incontinence occurs in about 12% of patients. Subsequent TURP or bladder neck incision to treat subvesical obstruction is common, and is sometimes even performed at the time of HIFU. Postoperative impotence occurs in 55-70% of patients.

Elterman et al. (27) have treated 95 patients with clinically organ-confined PCa using the Sonablate-500 device, and have evaluated the type and frequency of treatment-associated complications. With a minimum follow-up of 6 months, 17% (7/41) of the men had significant incontinence and 2% developed significant erectile dysfunction. Early and late subvesical obstruction necessitating surgical treatment occurred in 17 (17.9%) and 20 (21.1%) patients, respectively.
11.4 Focal therapy of PCa
During the past two decades, there has been a trend towards earlier diagnosis of PCa due to greater public and professional awareness, leading to the adoption of both formal and informal screening strategies. The effect of this has been to identify men with smaller tumours at an earlier stage, which occupy only 5-10% of the prostate volume, with a greater propensity for unifocal or unilateral disease (28-30).

Most focal therapies to date have been achieved with ablative technologies; cryotherapy, HIFU or photodynamic therapy. So far, three groups have proposed that non-diseased prostate tissue be left untreated in the hope and expectation that genitourinary function might be preserved and the tumour treated adequately (31-33). Although focal therapy is currently not the standard for men with organ-confined PCa, it is the therapeutic approach with the most important future potential.
11.4.1 Pre-therapeutic assessment of patients
The high number of random and systematic errors associated with TRUS-guided biopsy regimens means that this procedure is not sufficiently accurate for selecting candidates for focal therapy. The current standard
for characterising men considering focal therapy is transperineal prostate biopsy using a template-guided approach (34,35). When used with a 5-mm sampling frame, this approach can rule in and rule out PCa foci of 0.5 and 0.2 mL volume, with 90% certainty (36). Thus, the exact anatomical localisation of the index lesion - defined as the biologically most aggressive- can be accurately determined.
11.4.2 Patient selection for focal therapy
The primary objective of treatment must be the eradication of measurable and biologically aggressive disease. However, although treatment is usually intended to be one-off, patients should know that further treatment
might be necessary in the future.Based on published data, the following criteria identify possible candidates for currently ongoing trials of focal treatment:
• Candidates for focal therapy should ideally undergo transperineal template mapping biopsies.
However, a state-of-the-art multifunctional MRI with TRUS biopsy at expert centres may be
acceptable.
• Focal therapy should be limited to patients with a low to moderate risk. The clinical stage of the
tumour should be < cT2a and the radiological stage < cT2b.
• Patients with previous prostate surgery should be counselled with caution because no data on
functional and oncological outcomes are available. Patients who have undergone radiation therapy of
the prostate are not candidates for focal therapy.
• Patients must be informed that the therapy is still experimental and that there is a possibility of repeattreatment.
11.5 Summary of experimental therapeutic options to treat clinically localised PCa

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significant impact on prostate cancer management. J Clin Oncol 2009 Sep;10:27(26):4321-6.
http://www.ncbi.nlm.nih.gov/pubmed/19652073
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patients for focal prostate cancer therapy. Urol Oncol 2008 Sep-Oct;26(5):506-10.
http://www.ncbi.nlm.nih.gov/pubmed/18774464
36. Crawford ED, Wilson SS, Torkko KC, et al. Clinical staging of prostate cancer: a computer-simulated
study of transperineal prostate biopsy. BJU Int 2005 Nov;96(7):999-1004.
http://www.ncbi.nlm.nih.gov/pubmed/16225516
12. HORMONAL THERAPY
12.1 Introduction
In 1941, Huggins and Hodges assessed the effect of surgical castration and oestrogen administration on the progression of metastatic prostate cancer (PCa). They demonstrated for the first time the responsiveness of PCa to androgen deprivation (1,2). Since then, androgen-suppressing strategies have become the mainstay of advanced PCa management. More recently, there has been a move towards the increasing use of hormonal treatment in younger men with earlier disease (i.e. non-metastatic) or recurrent disease after definitive treatment, either as the primary single-agent therapy or as a part of a multimodality approach (3).
However, even if hormonal treatment effectively palliates the symptoms of advanced disease, there is currently no conclusive evidence to show that it extends life.
12.1.1 Basics of hormonal control of the prostate
Prostate cells are physiologically dependent on androgens to stimulate growth, function and proliferation. Testosterone, although not tumorigenic, is essential for the growth and perpetuation of tumour cells (4). The testes are the source of most androgens, with adrenal biosynthesis providing only 5-10% of androgens (i.e. androstenedione, dihydroepiandrosterone and dihydroepiandrosterone sulphate).

Testosterone secretion is regulated by the hypothalamic-pituitary-gonadal axis. Hypothalamic luteinising hormone-releasing hormone (LHRH) stimulates the anterior pituitary gland to release luteinising hormone (LH) and follicle-stimulating hormone (FSH). Luteinising hormone stimulates the Leydig cells of the testes to secrete testosterone. Within the prostate cell, testosterone is converted to 5-α-dihydrotestosterone (DHT) by the enzyme 5-α-reductase; DHT is an androgenic stimulant about 10 times more powerful than testosterone. Meanwhile, circulating testosterone is peripherally aromatised and converted to oestrogens, which, together with circulating androgens, exert a negative feedback control on hypothalamic LH secretion.

If prostate cells are deprived of androgenic stimulation, they undergo apoptosis (programmed cell death). Any treatment that results ultimately in suppression of androgen activity is referred to as androgen deprivation therapy (ADT).
12.1.2 Different types of hormonal therapy
Androgen deprivation can be achieved by either suppressing the secretion of testicular androgens by surgical or medical castration or inhibiting the action of circulating androgens at the level of their receptor in prostate cells using competing compounds known as anti-androgens. These two methods of androgen deprivation (surgical or medical castration and the use of anti-androgens) can be combined to achieve what is commonly known as complete (or maximal or total) androgen blockade (CAB).
12.2 Testosterone-lowering therapy (castration)
12.2.1 Castration level
Surgical castration is still considered the ‘gold standard’ for ADT, against which all other treatments are rated. Removal of the testicular source of androgens leads to a considerable decline in testosterone levels and induces a hypogonadal status, although a very low level of testosterone (known as the ‘castration level’) persists.

The standard castrate level is < 50 ng/dL. It was defined more than 40 years ago, when testosterone level testing was limited. However, current testing methods using chemiluminescence have found that the mean value of testosterone after surgical castration is 15 ng/dL (5). This has led to a revisiting of the current definition of castration, with some authors suggesting < 20 ng/dL as a more appropriate level.
12.2.2 Bilateral orchiectomy
Bilateral orchiectomy, either total or by means of a subcapsular technique (i.e. with preservation of tunica albuginea and epididymis), is a simple and virtually complication-free surgical procedure. It is easily performed under local anaesthesia (6) and is the quickest way to achieve a castration level, usually within less than 12 hours.

The main drawback of orchiectomy is that it may have a negative psychological effect: some men consider it to be an unacceptable assault on their manhood. In addition, it is irreversible and does not allow for intermittent treatment. The use of bilateral orchiectomy has declined in recent years, probably because of stage migration towards earlier disease and the introduction of equally effective pharmacological modalities of castration.

12.2.3 LHRH agonists
Long-acting LHRH agonists (busereline, gosereline, leuproreline, triptoreline) have been used in advanced PCa for more than 15 years and are currently the main forms of ADT (3). They are synthetic analogues of LHRH, generally delivered as depot injections on a 1-, 2-, 3-, or 6-monthly basis. Initially, they stimulate pituitary LHRH receptors, inducing a transient rise in LH and FSH release. This then elevates testosterone production (known as the ‘testosterone surge’ or ‘flare-up’ phenomenon), which begins about 2-3 days after the first injection and lasts for about the first week of therapy.
12.2.3.1 Achievement of castration levels
Chronic exposure to LHRH agonists eventually results in down-regulation of LHRH-receptors. This then suppresses pituitary LH and FSH secretion and testosterone production, so that testosterone levels decrease to castration levels usually within 2-4 weeks (7). However, about 10% of patients treated with LHRH agonists fail to achieve castration levels (8). This proportion rises to 15% if the castration threshold is defined as 20 ng/dL.

A recent meta-analysis evaluating single-therapy ADT for advanced PCa showed that LHRH agonists have comparable efficacy to orchiectomy and DES (9) (LE: 1a). This finding raises a question about the clinical impact of changing the definition of the castrate testosterone level from 50 ng/dL to 20 ng/dL. In addition, although only based on indirect comparison, the LHRH agonists seemed equally effective whatever their formulation (9) (LE: 3).
12.2.3.2 Flare-up phenomenon
Today, LHRH agonists have become the ‘standard of care’ in hormonal therapy because they avoid the physical and psychological discomfort associated with orchiectomy and lack the potential cardiotoxicity associated with DES. However, the main concerns associated with the administration of LHRH agonists are the potentially detrimental effects associated with ‘flare phenomenon’ in advanced disease, namely increased bone pain, acute bladder outlet obstruction, obstructive renal failure, spinal cord compression, and fatal cardiovascular events due to hypercoagulation status.

A review (10) concluded that clinical flare needs to be distinguished from the more common biochemical flare (i.e. increasing levels of PSA), and even from asymptomatic radiographic evidence of progression. The review also identified that patients at risk of clinical flare are usually patients with high-volume, symptomatic, bony disease, which account for only 4-10% of M1 patients.

Anti-androgen treatment
Concomitant therapy with an anti-androgen decreases the incidence of clinical relapse (i.e. clinical flare), but does not completely remove the possibility of its occurrence. Anti-androgens should be started on the same day as the depot LHRH injection and should be continued for a 2-week period. However, other strategies for immediately ablating testosterone levels, such as bilateral orchiectomy or LHRH-antagonists, must be used in patients with impending spinal cord compression. Except in this patient group, the clinical impact of the flareup observation is unknown.
Long-term use of LHRH agonists
Some “mini-flares” have also been observed with the long-term use of LHRH agonists. The clinical impact is unknown but it has been suggested that a mini-flare is associated with a negative impact on overall survival (see Section 17.4).

12.2.4 LHRH antagonists
In contrast to LHRH agonists, LHRH antagonists bind immediately and competitively to LHRH receptors in the pituitary gland. The effect is a rapid decrease in LH, FSH and testosterone levels without any flare. This seemingly more desirable mechanism of action has made LHRH antagonists very attractive. However, practical shortcomings have limited clinical studies, as many LHRH antagonists have been associated with serious and life-threatening histamine-mediated side-effects and, until recently, no depot formulation was available.
12.2.4.1 Abarelix
Two published phase III randomised multicentre trials compared the LHRH antagonist, abarelix, with the LHRH agonist, leuprorelin acetate (11), and with CAB (12), in patients with metastatic or recurrent PCa. Both trials showed no difference in achieving and maintaining castration levels of testosterone and in reducing serum PSA. The biochemical ‘flare up’ phenomenon was not reported in the abarelix arm and the overall incidence of severe adverse events (including allergic reactions) was similar across all treatment groups. Data on survival end-points and long-term safety are not yet available.

The US Food and Drug Administration has recently licensed the clinical use of abarelix, but only in metastatic and symptomatic PCa, for which no other treatment option is available. However, based on prolonged analysis, the FDA have issued a warning about allergic reactions with the long-term use of abarelix, which has resulted in suspension of its further development.
12.2.4.2 Degarelix
Degarelix is another LHRH antagonist that has shown promising preliminary results in a monthly subcutaneous formulation. Following phase II trials, a large, randomised, non-inferiority, dose-finding study (n = 610) compared two degarelix dosages with 7.5 mg monthly leuprorelin injections (13). The study showed that the standard dosage of degarelix should be 240 mg the first month, followed by 80 mg monthly injections. More than 95% of patients achieved a castrate level at day 3 with degarelix, which was associated with a quicker decline in PSA as quickly as day 14. No allergic reaction was observed. The main criterion (suppression of testosterone < 0.5 ng/mL at all monthly measurements) was similar in the three treatment groups at 1 year. The main specific side-effect of degarelix was a painful injection (moderate or mild) reported in 40% of patients, mainly after the first injection. An extended follow-up has been recently published (median 27.5 months), suggesting that degarelix might result in better progression-free survival compared to monthly leuprorelin (14).
12.2.4.3 Conclusions
Overall, this new family of agents seems appealing, but their advantages over LHRH agonists are far from proven. Further trials are needed to confirm the preliminary observed increased efficacy compared to leuprorelin. The use of LHRH antagonists is limited by a monthly formulation, compared with 3-month and 6-month depot formulations for the available LHRH analogues. Suppression of the initial flare-up with monotherapy is only clinically relevant in a few symptomatic metastatic patients.
12.3 Oestrogens
Oestrogens have several mechanisms of action:
• down-regulation of LHRH secretion;
• androgen inactivation;
• direct suppression of Leydig cell function;
• direct cytotoxicity to the prostate epithelium (in-vitro evidence only) (15).
12.3.1 Diethylstilboesterol (DES)
Diesthylstilboesterol (DES) is the most commonly used oestrogen in PCa. Early studies by the Veterans Administration Co-operative Urological Research Group (VACURG) tested oral DES at a dosage of 5 mg/day, as it was the dosage used in CAB. However, this dosage was associated with high cardiovascular morbidity and mortality, due to first-pass hepatic metabolism and formation of thrombogenic metabolites. Lower oral doses of 1 mg/day and 3 mg/day were therefore tested and were both found to provide a therapeutic efficacy similar to that of bilateral orchiectomy. However, 3 mg daily of DES was still associated with high cardiotoxicity. Although 1 mg daily of DES resulted in much fewer adverse cardiovascular events than 5 mg daily of DES, the side-effects were still significantly greater than with castration. Because of these concerns and the introduction of LHRH agonists and anti-androgens, the use of DES was greatly reduced. There has been renewed interest in using oestrogens (9).
12.3.2 Renewed interest in oestrogens
There are three main reasons for a renewed interest in using oestrogens to treat PCa:
1. LHRH agonists have a number of deleterious side-effects and their long-term widespread use is costly, while oestrogens suppress testosterone levels and do not seem to lead to bone loss and cognitive decline (16) (LE: 3).
2. In phase II trials with patients diagnosed with hormone-refractory PCa (HRPC), oestrogenic compounds (DES, DES-diphosphate) have induced prostate-specific antigen (PSA) response rates as high as 86%.
3. Discovery of a new oestrogen receptor- (ER-), possibly involved in prostate tumorigenesis (15).
12.3.3 Strategies to counteract the cardiotoxicity of oestrogen therapy
Two strategies have been used to try and neutralise the cardiotoxicity associated with oestrogen therapy, which is its main disadvantage:
• parenteral route of administration - so avoiding first-pass hepatic metabolism;
• concomitant use of cardiovascular-protective agents.
The Scandinavian Prostatic Cancer Group Study 5 set up a prospective randomised trial of more than 900 men with metastatic PCa, which compared a parenteral oestrogen (polyoestradiol phosphate) with CAB (orchiectomy, or an LHRH agonist + flutamide). The trial found no significant difference in disease-specific survival and OS between the treatment groups, and no significant increase in cardiovascular mortality in the oestrogen-treated group. However, in the oestrogen-treated group, there was a significantly higher incidence of non-fatal adverse cardiovascular events, particularly ischaemic and heart decompensation events (17).

In addition, thromboembolic complications have been observed in recent (though small) phase II trials of patients with advanced PCa or CRPC. The trials evaluated the combination of DES, 1 mg/day or 3 mg/ day, with either a low dose of warfarin sodium, 1 mg/day, or a low dose of aspirin, 75-100 mg/day, for the prevention of cardiovascular toxicity (18,19).
12.3.4 Conclusions
Diethylstilboesterol is one of the classic forms of hormonal therapy. Its efficacy was demonstrated many years ago and was recently re-confirmed in a meta-analysis as comparable to that of bilateral orchiectomy (9) (LE:1a). However, there is still concern about the significant cardiovascular side-effects of DES, even at lower dosages. Further data are needed before oestrogens can be re-admitted into clinical practice as a standard first-line treatment option.
12.4 Anti-androgens
Anti-androgens compete with testosterone and DHT at the receptor level in the prostate cell nucleus, thus promoting apoptosis and inhibiting PCa growth (20).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 is the sole action of non-steroidal anti-androgens. In addition, steroidal anti-androgens have progestational properties due to central inhibition of the pituitary gland. As a consequence, non-steroidal antiandrogens do not lower testosterone levels, which remain normal or, conversely, slightly elevated.
12.4.1 Steroidal anti-androgens
These compounds are synthetic derivatives of hydroxyprogesterone. In addition to peripherally blocking androgen receptors, they have progestational properties and inhibit the release of gonadotrophins (LH and FSH) and suppress adrenal activity. At high doses, megestrol acetate is cytotoxic. Since steroidal antiandrogens lower testosterone levels, the main pharmacological side-effects are loss of libido and erectile dysfunction, while gynaecomastia is quite rare. The non-pharmacological side-effects are cardiovascular toxicity (4-40% for CPA) and hepatotoxicity.
12.4.1.1 Cyproterone acetate (CPA)
Cyproterone acetate was the first anti-androgen to be licensed and is the most widely used. However, it is the least studied, with many questions about its use unanswered, e.g. the optimal dose, or unclear, e.g. comparison with standard forms of castration, surgical or with an agonist.

Comparison of CPA with medical castration
There has been only one randomised trial (21) comparing CPA with standard hormonal therapy, i.e. medical castration. Patients in arm A (no contraindications to DES) were randomly assigned to CPA, goserelin or DES, while patients in arm B (contraindications to DES) were assigned to CPA or goserelin. In arm A, treatment with CPA was associated with a significantly poorer median OS than goserelin only; adjusting for baselinecharacteristics did not account for this difference. Although there are other studies in CPA monotherapy, methodological limitations prevent firm conclusions being made from their results about the relative efficacy of CPA and castration.

Dosage regimen of CPA
Because there have been no dose-finding studies of CPA monotherapy, the most effective dose 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 (22).

Comparative study of CPA with flutamide
The only comparative study on anti-androgens as monotherapy was recently published by the European Organisation for Research and Treatment of Cancer (EORTC). The final analysis of Protocol 30892 (a randomised trial of 310 patients comparing CPA with flutamide in metastatic PCa) showed no difference in cancer-specific survival and OS at a median follow-up of 8.6 years, although the study was underpowered (23) (LE: 1b).

12.4.1.2 Megestrol acetate and medroxyprogesterone acetate
Very limited information is available on these two compounds. Early studies with megestrol acetate demonstrated a symptomatic and partially beneficial clinical response, both in previously untreated metastatic PCa (24,25) and less so in CRPC (26). No apparent dose-response correlation was found (27). The overall poor efficacy has prevented megestrol acetate and medroxyprogesterone acetate from being recommended for either primary- or second-line hormonal therapy.

The only prospective randomised trial evaluating medroxyprogesterone acetate as primary therapy in advanced (M0-1) PCa is the EORTC 30761 study (28), in which 236 patients were given CPA, DES or medroxyprogesterone acetate. There was no difference in cancer-specific survival and OS between CPA and DES. However, medroxyprogesterone acetate resulted in a less favourable course, with a shorter survival time and time to progression than CPA or DES.
12.4.2 Non-steroidal anti-androgens
The use of non-steroidal anti-androgens as monotherapy has been promoted on the basis of improved quality of life (QoL) and compliance compared to castration. They do not suppress testosterone secretion and it is claimed that libido, overall physical performance and bone mineral density (BMD) are preserved (29). Although they have not been directly compared in a monotherapy setting, the severity of pharmacological side-effects, namely gynaecomastia, breast pain and hot flashes, appears similar for the three available non-steroidal antiandrogens. However, there are differences in non-pharmacological side-effects, with bicalutamide showing a more favourable safety and tolerability profile than nilutamide and flutamide (30). All three agents share a common liver toxicity and liver enzymes must be monitored regularly.
12.4.2.1 Nilutamide
There are no comparative trials of nilutamide monotherapy with castration or with other anti-androgens.A large randomised controlled trial in 457 patients with M1 PCa showed a significant benefit for cancer-specific survival and OS with orchiectomy + nilutamide, 300 mg/day, versus orchiectomy + placebo (31). Nilutamide has recently shown encouraging results as a second-line hormonal therapy in HRPC (32,33).Non-pharmacological side-effects are visual disturbances (i.e. delayed adaptation to darkness), alcohol intolerance, nausea, hepatotoxicity, and interstitial pneumonitis. Even if exceptional, interstitial pneumonitis is potentially life-threatening and is specific to nilutamide. Nilutamide is not licensed for monotherapy.
12.4.2.2 Flutamide
Flutamide was the first non-steroidal anti-androgen available for clinical use. Although it has been studied as monotherapy for more than 20 years, there are no dose-finding studies against a currently accepted end-point (e.g. PSA response). Flutamide is a pro-drug, and the half-life of the active metabolite is 5-6 hours, so it must be administered three times daily to maintain therapeutic serum levels. The recommended daily dosage is 750 mg (22).

Early phase II trials demonstrated the efficacy of flutamide in advanced PCa, even though the reported response rates cannot be correlated with currently recommended end-points. The main advantage shown in these small single-arm studies was the preservation of sexual function, which was maintained in up to 80% of patients with no pre-treatment erectile dysfunction. This rate has not been confirmed in the above-mentioned EORTC trial 30892 (23), in which as few as 20% of men treated with flutamide maintained sexual activity for up to 7 years.

Although several phase III studies have been conducted, the results are often difficult to evaluate because of several drawbacks, such as the use of non-standard combinations, short-term follow-up and underpowering. Of these studies, survival data for advanced PCa has been reported in only one published phase III randomised trial comparing flutamide monotherapy with CAB (34).

No significant difference in OS for flutamide or castration in patients with a PSA < 100 ng/mL (34). At a higher PSA, flutamide was inferior. However, both trials were underpowered. Results are eagerly awaited from an ongoing Swedish study, which randomised 700 patients with M1 PCa to flutamide, 250 mg three times daily, or CAB (29). The non-pharmacological side-effects of flutamide are diarrhoea and hepatotoxicity (occasionally fatal).
12.4.2.3 Bicalutamide
Dose-finding studies of bicalutamide
Early studies with bicalutamide monotherapy used the 50 mg/day dosage licensed for use in CAB. Although this dosage provided clinical benefits, it resulted in a poorer OS than with castration (median difference 97 days) (35). Subsequent dose-finding studies established that bicalutamide, 150 mg once daily, achieved a similar PSA response to castration, while maintaining a good tolerability profile (36). Accordingly, the 150 mg dosage was chosen for further evaluation as both primary and adjuvant monotherapy.

Primary monotherapy with bicalutamide
Bicalutamide, 150 mg/day, as first-line monotherapy has been compared to medical or surgical castration in two large prospective randomised trials with identical study designs, including a total of 1,435 patients with locally advanced M0 or M1 PCa (37). A pooled analysis showed:
• In M1 patients, an improvement in OS with castration, although the difference in median survival
between the groups was only 6 weeks (37);
• In M0 patients (n = 480), no significant difference was noted in OS (38) based on the Kaplan-Meiertest, with median survival being 63.5 months in the bicalutamide arm compared with 69.9 months in the castration one.

In two smaller randomised trials, high-dose bicalutamide was compared with CAB. In the first trial (251 patients with predominantly M1 stage), there was no apparent difference in OS (39). In the second trial (220 patients with M0 and M1 stage), there was no difference in OS for well-differentiated tumours or tumours that were only moderately well-differentiated (40) (LE: 1b). However, both studies were underpowered, and the first one has not yet been fully published.
Adjuvant therapy with bicalutamide
In the adjuvant setting, the ongoing Early Prostate Cancer Programme (EPCP) is a study comprising three different clinical trials (known as Trials 23, 24 and 25) of similar design. The programme included 8,113 patients worldwide and evaluated the efficacy and tolerability of high-dose (150 mg/day) bicalutamide versus placebo, given in addition to standard primary care (i.e. radical prostatectomy, radiotherapy or watchful waiting) in either localised PCa (T1-2, N0-X) or locally advanced PCa (T3-4, any N, or any T N+). The first combined analysis of the programme showed that, after a median follow-up of 3 years, adjuvant bicalutamide reduced the risk of objective disease progression by 42% compared with standard care alone (41).

After a median follow-up of 5.4 years, the positive effects of bicalutamide were obvious in patients with locally advanced disease (stage M0). Bicalutamide significantly improved PFS, irrespective of standard care. However, survival appeared to be reduced in patients with localised disease treated with bicalutamide versus those given placebo (42). After a median follow-up of 7.4 years, there appeared to be no benefit to PFS from the addition of bicalutamide to standard care in localised PCa, with a trend towards decreased survival in patients otherwise undergoing watchful waiting (WW) (hazard ratio [HR], 1.16; 95% CI: 0.99-1.37; p = 0.07).

The same overall results were observed in the most recent analysis of the bicalutamide treatment arm of the EPCP 24 trial (43). Bicalutamide significantly improved OS in patients receiving radiotherapy (HR, 0.65;95% CI: 0.44-0.95; p = 0.03), mainly due to a lower risk of PCa-related deaths. Bicalutamide produced a trendtowards improved OS in patients with locally advanced disease otherwise undergoing WW (HR, 0.81; 95%CI:0.66-1.01; p = 0.06). No survival difference was evident in the subgroup undergoing radical prostatectomy(42).

Even though the EPCP is a combination of three trials and among the largest conducted in PCa patients, it is difficult to draw clear conclusions because of the following problems with the protocols:
• The three trials grouped for analysis were different in terms of patients; 80% of patients underwentprostatectomy in Trial 23 versus 13% in Trial 25. In addition, treatment duration was 2 years in Trial 23, but treatment was prolonged until progression in Trials 24 and 25.
• The OS benefit claimed with radiotherapy is mainly driven by a respiratory or cardiovascularimprovement, and not by a cancer-specific survival benefit, which is different to other trials with LHRH agonists.
• Furthermore, the EPCP trials are underpowered for locally advanced patients, compared with orientedtrials such as the Bolla (44) or Pilepich (45) trials.
• Direct protocol analysis revealed quite different results, such as those from EPCP Trial 23 (80%prostatectomy, 19% radiotherapy) (46). At a median 7.7 years of follow-up, no PFS benefit was observed (HR, 1.00; 95% CI: 0.84-1.19; p = 0.991). Likewise, OS did not differ. Even after stratifying for disease stage, no PFS benefit was apparent.
• The OS benefit must be balanced by the very prolonged (mainly permanent) use of bicalutamidecombined with radiotherapy in contrast to the more limited use of agonists (6 months to 3 years).
• Although a QoL benefit has been claimed, in fact a QoL benefit cannot be demonstrated becausenone of the EPCP trials used a systematic, validated QoL questionnaire. The only available data were derived from a specific questionnaire and a limited population. The observed benefit was only significant for physical capacity and sexual interest (not function!). For all other QoL items (emotional well-being, vitality, social function, pain, activity limitation and bed disability), there was no difference compared with castration (38). The breast problems related to bicalutamide are also important, as they can lead to a 16.4% treatment cessation (47).

The lack of data means that many questions are still debatable with bicalutamide, such as the practical management after progression under bicalutamide. Furthermore, the clear trend (even if not statistically significant) towards a decreased OS in localised disease otherwise treated with WW is a clear argument against the use of bicalutamide in such situations (42). The mechanisms involved remain unclear.

Conclusions for the use of bicalutamide in primary and adjuvant therapy
High-dose bicalutamide has emerged as an alternative to castration for patients with locally advanced (M0) if PFS is the target, and in highly selected, well-informed cases of M1 PCa with a low PSA.Bicalutamide monotherapy should be avoided in patients with localised PCa. The expected benefit of bicalutamide for QoL compared with castration is far from being proven. The survival benefit observed with adjuvant use after radiotherapy in locally advanced PCa must be considered with caution, as the EPCP trials do not have the clear power of trials conducted with LHRH agonists. The lack of any direct comparison between both bicalutamide and LHRH agonists in combination with radiotherapy leads to a major limitation of any guidelines, which should therefore be based on unquestionable trials, which are mainly those with analogues.

Side-effects of bicalutamide
Non-pharmacological side-effects are mainly gynaecomastia (70%) and breast pain (68%), which may be prevented by anti-oestrogens (49-51), prophylactic radiotherapy (52), or treatment with surgical mastectomy or radiotherapy (53). However, bicalutamide clearly offers bone protection compared with LHRH analogues and probably LHRH antagonists (54,55).
12.5 Combination therapies
12.5.1 Complete androgen blockade (CAB)
Although castration reduces serum testosterone levels by up to 95%, an intraprostatic androgen stimulus is sustained by the conversion of circulating androgens of adrenal origin into DHT within the prostate cells. However, the action of these adrenal androgens can be blocked by the addition of an anti-androgen to either surgical or pharmacological castration, a concept known as complete (or maximal or total) androgen blockade (CAB).

The many studies comparing CAB with monotherapy (castration through LHRH analogues) have produced contrasting results (56). According to the most recent systematic reviews and meta-analyses, at a follow-up of 5 years, CAB appears to provide a small survival advantage (< 5%) versus monotherapy (57-60) (LE: 1a). However, some of the largest trials included were methodologically flawed (61). It remains debatable whether this small advantage, if any, is useful in everyday clinical practice, as the survival benefit seems limited to patients taking non-steroidal antiandrogens (62) and only appears after 5 years of follow-up.

Gastrointestinal, ophthalmological, and haematological side-effects are worse with CAB. Although LHRH analogues and non-steroidal anti-androgens have the highest estimated quality-adjusted survival, there is an incremental cost of more than US$1 million per quality-adjusted life-year for CAB over orchiectomy alone.
12.5.2 Minimal androgen blockade (or peripheral androgen blockade)
Minimal androgen blockade is produced by combining finasteride with a non-steroidal anti-androgen. Finasteride reduces intraprostatic levels of DHT by inhibiting 5-α-reductase, while the anti-androgen competes with the binding of the residual DHT to its receptor. This enables testosterone levels to be maintained within normal ranges to ensure acceptable sexual function and a reasonable QoL.

Several phase II trials (63-67) have evaluated the association of finasteride and flutamide, either given together or sequentially, using the PSA response rate in patients with advanced or biochemically recurrent PCa. Notwithstanding the small sample and short follow-up, nearly all patients experienced a substantial decline in PSA (by up to 96% compared with the baseline level at entry). In a long-term follow-up of one study, stronger end-points were reported, including castration-free survival (median: 37 months), androgen independent PCafree survival (median: 48.6 months) and OS (65% at 5 years). These results indicated that combination therapy was able to induce an overall period of hormone-responsive disease exceeding 4 years (68). In all these trials, sexual function was preserved in 55-86% of men studied.

The preliminary data make minimal androgen blockade a very attractive option in the management of patients for whom QoL is the main concern. However, while awaiting the results of follow-up and larger controlled trials, this treatment should be considered investigational.
12.5.3 Intermittent versus continuous ADT
For reasons beginning to be clarified, long-term CAB, which stimulates prostate cell apoptosis, fails to eliminate the entire malignant cell population. Thus, after a variable period (averaging 24 months), the tumour inevitably relapses, characterised by an castrate-independent state of growth. Experimental data indicate that castrate-independent progression may begin early after the administration of hormonal therapy, coinciding with the cessation of androgen-induced differentiation of stem cells (69). It has therefore been suggested that stopping androgen deprivation prior to progression of androgen-independent cells would mean any subsequent tumour growth would be solely sustained by the proliferation of androgen-dependent stem cells. The stem cells should therefore be susceptible once again to androgen withdrawal. Thus, intermittent androgen blockade (IAD) would delay the emergence of the androgen-independent clone. It should be noted that this rationale has been developed mainly through models (e.g. the Shionoggi model), which may be significantly different from the behaviour of total tumour in men.Other possible benefits of IAD include the preservation of QoL in off-treatment periods and a reduction in the cost of treatment.
Phase II results
A detailed systematic review was recently published (70), with no other trials published since this review. According to the review, several phase II trials demonstrated the feasibility of IAB in metastatic or biochemically recurrent disease (70). Both PSA response rates and symptom improvement were similar to those seen with CAB. However, these trials included very heterogeneous patients and used different PSA thresholds for decisions regarding castration. This should be borne in mind when considering the main findings.
• Most patients were treated with an LHRH agonist, with or without an anti-androgen.
• The cycle lengths were quite stable regarding the off-treatment periods.
• Testosterone recovery, when tested, was frequent during the first cycle, but tended to decrease during
subsequent cycles.
• Early occurrence of early refractory status was quite uncommon.
• Overall tolerability was acceptable, and sometimes there was a QoL benefit, especially for sexual function.
These findings suggest a potential benefit for IAD. However, randomised trials are required to clarify the potential survival benefit suggested by animal models.

Randomised controlled trials
Overall, eight randomised trials are underway, only some of which have published findings. Most of the trials included a mixed patient population of both locally advanced and metastatic disease. Only three trials included only metastatic patients, and two trials only relapsing patients. The two largest trials each contained more than 1,300 patients, with one trial focused only on metastatic patients (SWOG 9346) and the other on relapsing patients after radiotherapy (SWOG PR7). Few fully published trials are available, some are pending. But, all available results are similar so far, allowing the inclusion of abstract-only references. A short summary of the most important published findings from these trials follows.
• The South West Oncology Group (SWOG) trial 9346 randomised 1,134 men with stage D2 PCa tointermittent and continuous ADT after 7 months’ induction ADT with PSA reduction < 4 ng/mL. A very preliminary analysis has identified no significant differences with regard to survival between treatment groups (71). A PSA reduction to < 0.2 ng/mL, < 4 ng/mL and > 4 ng/mL was identified as a significant prognostic factor with regard to survival, achieving 13 months, 44 months and 75 months, respectively. In a similar patient population and using a quite similar protocol, no difference was
observed in OS or in PFS between IAD and CAB in 173 randomised patients (72), with a mean followup of 47 months. No QoL benefit was observed in any treatment arm. The same lack of difference in OS was seen with CPA in another randomized study of 366 patients (73), after a mean follow-up of 66 months.
• The largest trial available so far (still unpublished) has been presented at several meetings (74). Atotal of 1,386 patients relapsing after radiotherapy, given as either primary treatment or for relapsing patients after surgery, were randomized to continuous ADT or intermittent ADT. Continuous treatment was for a fixed 8-month period. Intermittent ADT was stopped when PSA < 4 ng/mL and resumed when above 10 ng/mL. After a median 7 years of follow-up, the median OS was 9.1 years in the continuous arm and 8.8 years in the intermittent arm (HR: 1.02:; 95% CI= 0.86-1.21).
• In other studies (75,76) of mixed populations of locally advanced and metastatic PCa, there has alsobeen no evidence found of decreased survival using IAD. The larger study (76) included 478 patients with either M1 disease (40%) or N+ (N1-3) disease. In this study, 335 patients were randomised to IAD after 6 months of CAB if the PSA decreased to < 4 ng/mL or a decrease of > 90% was observed. The mean initial level of PSA was 158 ng/mL in the IAD-treated group and 139 ng/mL in the CAB-treated group. In the IAD group, treatment was resumed if the PSA rose > 10 ng/mL and stopped when it decreased < 4 ng/mL. However, after a median follow-up of 50.5 months, no significant difference was observed in the median PFS (16.6 months in the IAD group vs 11.5 months in the CAB group, p = 0.17) in either the total study population or in the N+ or M1 subgroup populations. In the IAD arm, 88% of patients were off-treatment for more than 50% of the time and normalised their testosterone in a mean of 70 days after stopping treatment.
• To date, the largest fully published trial (n = 766) has been carried out by the South European UroOncological Group (SEUG) (77). Patients followed an induction regimen of 3 months, in which CPA was given for 2 weeks followed by monthly LHRH + CPA. Patients with a PSA < 4 ng/mL or a PSA
decrease > 80% were randomised to IAD or CAB. In the IAD-treated group, treatment was resumed, if the PSA level rose to > 10 ng/mL for symptomatic patients. For patients whose PSA level dropped to < 80% of the initial value, therapy was restarted when the PSA level rose to > 20% above the nadir. The primary end-point was time to progression. After a median follow-up of 51 months, there was no difference in either time to progression (HR: 0.81; p = 0.11) or OS (HR: 0.99). Metastatic status andPSA at randomisation were associated with specific death rates. No overall QoL benefit was seen, except for more frequent side-effects in the CAB-treated group. However, there was a clear benefit for improved sexual function in the IAD group versus the CAB group (28% sexually active vs 10% at 15 months after randomisation, respectively). After follow-up for a median of 7 years, it should be highlighted that both the IAD treatment arm and the continuous treatment arm showed similar nonsignificant specific death increases. This finding suggests that, even if continuous treatment provides a specific survival difference compared to IAD, the survival difference is completely counterbalanced by the increased specific toxicity of continuous ADT, which therefore results in a lack of difference in OS survival, the increasing of which remains the main objective.
Alternative IAD regimen
Recently, a published randomised trial (n = 129) suggested an alternative IAD regimen, which alternated fixed 6-month periods of CAB treatment and surveillance (78). The PSA response was not used to guide treatment in the heterogeneous study population. After a mean follow-up of 44.8 months, no difference was observed in OS, cancer-specific survival or PFS. The QoL also showed no difference between the two groups, except that painkillers were required more often in the IAD arm, and the ability to get and maintain an erection was better in the IAD arm.
Other benefits of IAD
Intermittent androgen deprivation has not been shown to be associated with prolonged hormone-sensitive status or OS increase. This modality is well accepted by patients, urologists and oncologists. Although the QoL benefit is less than expected or absent, except in two studies (73,74), IAD is better tolerated and sometimes benefits sexual functioning (76,77). Other possible long-term benefits, which are not clearly proven, include bone protection (79,80) and/or a protective effect against metabolic syndrome. Testosterone recovery is seen in most studies (70), leading to an intermittent castration (not just an intermittent treatment delivery).
Optimal threshold for stopping or resuming ADT
The optimal thresholds at which ADT must be stopped or resumed are empirical (70). The best candidates for IAD have still not been completely defined (70,80), but are probably patients with locally advanced or relapsing disease, provided a perfect response is obtained (see below). Nevertheless, several points are clear (70,81):
• Because IAD is based on intermittent castration, only drugs leading to castration are suitable for use in IAD.
• It is unclear if an LHRH agonist may be used alone, as published experiences are based on CAB. An LHRH antagonist might be a valid alternative, provided clear results are obtained from randomised trials.
• The initial (induction) cycle must last between 6 and 9 months, otherwise testosterone recovery is unlikely.
• The treatment is stopped only if patients have fulfilled all the following criteria:
ο well-informed and compliant patient
ο no clinical progression, i.e. a clear PSA response, empirically defined as a PSA < 4 ng/mL in metastatic disease, or 0.5 ng/mL in relapsing disease.
• Strict follow-up must be applied once treatment has stopped, with clinical examination every 3-6months. The more advanced the disease, the closer is the follow-up). The PSA level should be measured by the same laboratory to ensure standardization of testing.
• Treatment is resumed when the patient reaches either a clinical progression, or a PSA value above a predetermined, empirically fixed threshold. This is usually 4-10 ng/mL in non-metastatic situations or 10-15 ng/mL in metastatic patients (80).
• The same treatment is used for at least 3-6 months.
• Subsequent cycles of treatment are based on the same rules until the first sign is seen of hormonerefractory status.
In conclusion, IAD is currently widely offered to patients with PCa in various clinical settings, and its status should no longer be regarded as investigational (LE: 2).

Increased duration of off-treatment periods in IAD
There have recent attempts to increase the duration of off-treatment periods in IAD. Although hormonal manipulation using finasteride (82) has been suggested, finasteride has never been tested in randomised trials and its use in PCa has been recently questioned (83). However, there have been trials of non-hormonal compounds, including a COX-2 inhibitor (84) and anti-angiogenic drugs (85). In a study of the anti-angiogenic drug, thalidomide, 159 patients, who had relapsed after local treatment, were randomized to an LHRH antagonist for 6 months, followed by placebo or thalidomide, 200 mg daily. When PSA progression occurred, a crossover was done using the same regimen. A non-significant difference was observed in the time-to-PSA progression during the first treatment round (15 vs 9.6 months). However, after crossover, the time-to-PSA progression showed a highly significant difference (17.1 vs 6.6 months, p = 0.0002) in favour of the thalidomide treatment arm. This finding was not linked to any hormonal effect. This observation provides proof of principle and warrants further larger studies, particularly because thalidomide required dose reduction in 47% of patients due to intolerability.
12.5.4 Immediate versus deferred ADT
There is still controversy over the most appropriate time to introduce hormonal therapy in patients with advanced PCa. Should ADT be given immediately upon diagnosis in locally advanced and asymptomatic metastatic disease or deferred until there are signs and symptoms of clinical progression? (This has already been partly discussed in Section 8.3.)

The controversy over whether only immediate treatment with ADT has a positive effect on survival and QoL has arisen because of the lack of properly conducted randomised controlled trials. Many trials are methodologically flawed because of small size and underpowering, heterogeneity of patient enrolment with advanced PCa (i.e. locally advanced, nodal and metastatic stages of disease), and variation in the hormonal treatments given and in the follow-up schedules and modalities used.

Bearing these limitations in mind, the evidence for immediate versus deferred ADT is provided by four systematic reviews of the literature (including a meta-analysis). A report by the Agency for Health Care Policy and Research (AHCPR) indicated a possible survival advantage for early ADT in single studies where hormonal treatment was the primary therapy (86). Furthermore, androgen suppression was shown to be the most costeffective therapy if initiated after patients had experienced symptoms from metastatic disease (87).

The Cochrane Library review extracted four, good-quality, randomised, controlled trials, i.e. namely VACURG I and II studies, the MRC trial and the Eastern Cooperative Oncology Group (ECOG) 7887 study, which were all conducted in the pre-PSA era. The studies included patients with advanced PCa, who received early versus deferred ADT, either as primary therapy or adjuvant to radical prostatectomy (but not to radiotherapy). Early androgen suppression significantly reduced disease progression and complication rates due to progression itself. However, it did not improve cancer-specific survival and provided a relatively small benefit in OS, with an absolute risk reduction of 5.5% after 10 years (88). Finally, a systematic review was published last year, highlighting again the benefit of immediate versus deferred ADT in term of overall survival (+ 10%) and specific survival (+ 20%) (89). In the PSA era, the EORTC 30891 study (90) has produced the same results, namely a small benefit in OS, but no cancer-specific survival benefit. Furthermore, only young patients with a high PSA are likely to clearly benefit.

Based on a systematic review of the literature, recently published ASCO guidelines on initial hormonal treatment for androgen-sensitive, metastatic, recurrent or progressive PCa concluded that no recommendation can be made on when to start hormonal therapy in advanced asymptomatic PCa, until data becomes available from studies using modern diagnostic and biochemical tests and standardised follow-up schedules (48).

Based on meta-analyses published, treatment appears to be most cost-effective when started after the onset of symptoms. Based on exploratory analysis, treatment with anti-androgen monotherapy does not lead to a survival benefit in men with localised PCa managed with non-definitive therapy, and the impact is still questionable after external beam therapy. This was explored in detail above with regard to the EPCP trials (see Section 12.4.2.3).

For asymptomatic patients with locally or regionally advanced PCa who undergo radiotherapy, several randomised controlled trials have produced good evidence to show that concomitant and/or adjuvant hormonal therapy provides longer time-to-disease progression and/or longer OS than radiotherapy alone followed by androgen suppression at progression (see Section 12.8) (LE: 1b).

The detailed discussion on immediate or deferred ADT combined with surgery or radiation therapy is discussed in Section 8.3.
12.6 Indications for hormonal therapy
Table 18 lists the indications for hormonal therapy.
Table 18: Indications for hormonal therapy

12.7 Contraindications for various therapies
Table 19 lists the contraindications for various therapies.
Table 19: Contraindications for various therapies.

12.8 Outcome
Outcome depends on the stage and grade of disease at diagnosis.
In M1 cases, the median OS ranges between 28 and 53 months (9). Only 7% of patients with metastatic cancer treated with hormonal therapy have been reported alive at 10 years or longer (93). Survival
is likely to depend on the PSA level at diagnosis, the Gleason score, the volume of metastatic disease, and the presence of bony symptoms.
In locally advanced M0 patients, the median OS is frequently reported to exceed 10 years (57).
12.9 Side-effects, QoL, and cost of hormonal therapy
The many deleterious side-effects of long-term ADT have been well known for years. Some can have a detrimental effect on QoL, especially in young men, while others may contribute to an increased risk of serious health concerns associated with ageing.

Many patients with PCa for whom long-term ADT is indicated are still young and physically and sexually active. Quality of life is an issue of paramount importance when considering the various hormonal treatment options. Thus, in selected patients, monotherapy with a non-steroidal anti-androgen (e.g. bicalutamide) is becoming more popular because it maintains normal (or even higher) serum testosterone levels and has a good tolerability profile.
12.9.1 Sexual function
Loss of libido and erectile dysfunction are well-known side-effects of hormonal therapy. The management of erectile dysfunction is not specific.
12.9.2 Hot flashes
Hot flashes are probably the most common side-effect of ADT. They appear 3 months after starting ADT, persist long term in most patients and can have a significant impact on QoL in some patients. Treatments include hormonal therapy and antidepressants.
12.9.2.1 Hormonal therapy
Oestrogen-receptor modulators or low-dose oestrogen therapies, e.g. DES, 0.5-1 mg/day, reduce the frequency and severity of hot flashes. Both treatments carry a risk of cardiovascular complications (94). Soya phytoestrogens have shown efficacy for hot flashes in breast cancer patients (95), but have not been evaluated in men. Progesterone-based treatments, such as megestrol acetate, medroxyprogesterone acetate and CPA, have also demonstrated efficacy, with 80% of patients showing an improvement with CPA (96) or chlormadinone (97).
12.9.2.2 Antidepressants
Antidepressants may have some efficacy against hot flashes, including venlafaxine (a non-specific selective noradrenaline and serotonin reuptake inhibitor), which has shown efficacy in breast cancer patients, and the selective serotonin reuptake inhibitor, sertraline, which appears to be effective in men with PCa.
Recently, a randomised trial (n = 919) compared three drugs: venlafaxine, 75 mg daily, medroxyprogesterone, 20 mg daily, or CPA, 100 mg daily (98). After 6 months of LHRH, only 311 men had significant hot flushes and were randomized. Venlafaxine was clearly inferior compared to the hormonal agents, which showed similar efficacy to each other.
12.9.2.3 Other options
Other treatments have also been tested, including clonidine and veralipride, and even acupuncture (99). With a placebo effect influencing up to 30% of patients (100), few treatments are approved for the control of hot flashes in men with PCa. There is a lack of large, prospective, randomised controlled trials in this area.
12.9.3 Other systemic side-effects of ADT
More recently, other systemic side-effects have been described and require increased attention, including bone problems, obesity and sarcopenia, lipid alterations and insulin resistance, metabolic syndrome, diabetes, and cardiovascular disease (101).
12.9.3.1 Non-metastatic bone fractures
Androgen deprivation therapy increases the risk of non-metastatic bone fracture due to increased bone turnover and decreased BMD in a time-dependent manner, and there is an increased risk of fracture of up to 45% relative risk with long-term ADT (102). This is an important side-effect, as hip fractures in men are associated with a significant risk of death (103). Increased exercise, calcium and vitamin D supplementation are protective. Bicalutamide monotherapy could also be a bone-protective method based on a small, prospective, randomised trial, including 103 patients comparing bicalutamide, 150 mg/day, or medical castration (104) (LE: 1b).
Bisphosphonates
Recently, bisphosphonates, such as pamidronate, alendronate or zoledronic acid, have been shown to increase BMD in the hip and spine by up to 7% in 1 year. The optimal regimen for zoledronic acid is unclear. One study recommends treatment every 3 weeks (105), while another trial has produced similar results with an annual injection (106). The optimal regimen is very important because of the risk of jaw necrosis, which may be both dose- and time-related (107). The initial BMD could be used to guide the choice of regimen (108). Thus, a 3-month injection might be given in osteoporotic patients for whom a yearly injection is likely to provide insufficient protection.

As previously observed in breast cancer, a significant benefit in OS has recently been demonstrated for biphosphonates in PCa, particularly oral first-generation clodronate versus placebo. After at least 10 years of follow-up, an absolute 8% increase in OS was observed at 8 years in a clodronate-treated group of PCa patients, who had an overall survival of 22% versus 14% in the placebo group (109). The benefit for OS applied only to M1 patients, but not to M0 patients. Although this is a post-hoc analysis and the results are surprising because clodronate has no bone protective effect in PCa, this study again highlights the potential impact of bone-targeted drugs and the need for continuous trials, e.g. the Zeus trial, which uses a more recent biphosphonate.
Denosumab
In 2009, a major advance in bone protection was made with the introduction of denosumab, a fully human monoclonal antibody against RANKL, which is a key mediator for osteoclast function, activation and survival. A total of 1,468 men with non-metastatic PCa receiving ADT were randomised to denosumab, 60 mg subcutaneous every 6 months, or placebo (110). The primary end-point was the percentage change in lumbar spine BMD at 2 years. Denosumab was associated with 5.6% increase in the lumbar BMD versus 1% decrease in the placebo arm. There were also significant BMD increases at the total hip, femoral neck and distal third of the radius. The vertebral fracture rate was less in the denosumab-treated group versus the placebo-treated group (1.5% vs 3.9%, p = 0.006). This benefit was 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, as the rates of adverse events were the same in both groups, without any jaw osteonecrosis or delayed healing in vertebral fractures. Denosumab may therefore represent a major advance in bone protection.

In addition, this drug has been shown to postpone bone metastases in non-metastatic patients in a large RCT of 1,432 patients (111). Denosumab, 120 mg every 4 weeks, increased the time to bone metastasisfree survival by 4.2 months compared to placebo, but was accompanied by the side effects of jaw necrosis in 5% of treated patients versus 0% in the placebo arm and hypocalcaemia in 2% of treated patients versus less than 1% in the placebo arm. However, the increase in bone metastasis-free survival had no impact on overall survival, which was 43.9 months in the denosumab group compared to 44.8 months in the placebo group. These results highlight the potential importance of targeting the bone microenvironment. However, the daily use of denosumab remains questionable because of related side effects and cost.
Lifestyle changes before starting long-term ADT
Patients should be encouraged to adopt lifestyle changes, e.g. increased physical activity, cessation of smoking, decreased alcohol consumption and normalisation of their body mass index (BMI). A precise evaluation of BMD should be performed by dual emission X-ray absorptiometry before starting long-term ADT. An initial low BMD (T-score > 2.5, or > 1 if other risk factors are present) indicates a high risk of subsequent non-metastatic fracture, suggesting the need for early preventive bisphosphonate therapy.
Obesity and sarcopenia
Obesity and sarcopenia are common and often occur early, during the first year of ADT. There is an expected increase in body fat mass by up to 10%, and a decrease in lean tissue mass by up to 3% (112). Both changes are linked to an increased risk of fracture.
12.9.3.2 Lipid levels
Lipid alterations are common and may occur as early as the first 3 months of treatment (112). Androgen deprivation therapy also decreases insulin sensitivity and increases fasting plasma insulin levels, which is a marker of insulin resistance. Once again, exercise must be recommended as a protective tool.
12.9.3.3 Metabolic syndrome
Metabolic syndrome is an association of independent cardiovascular disease risk factors, often associated with insulin resistance. The risk factors include:
• waist circumference > 102 cm;
• serum triglyceride > 1.7 mmol/L;
• blood pressure > 130/80 mmHg;
• HDL cholesterol < 1 mmol/L;
• glycaemia > 6.1 mmol/L.
The prevalence of metabolic syndrome is higher during ADT compared with untreated men (113).
12.9.3.4 Cardiovascular disease
Androgen deprivation therapy has been associated with an increased risk of diabetes mellitus, cardiovascular disease, and myocardial infarction in several studies (114).

Analysis of the RTOG 92-02 data has confirmed an increase in cardiovascular risk, which is unrelated to the duration of ADT. No increase in cardiovascular mortality was found (115). Similar findings were observed in the RTOG 94-08 trial (116). These observations have been much discussed because no increase in cardiovascular mortality has been reported in trials RTOG 8531, 8610, 9202, EORTC 30891 or EORTC 22863. However, an increase in cardiovascular mortality has been reported in patients suffering from previous congestive heart failure or myocardial infarction in a retrospective database analysis (117).

In summary, since 6 or less months of ADT may already be associated with increased cardiovascular morbidity the FDA issued a warning and a consensus paper from the American Heart, Cancer Society and Urological Associations was published (118). However, to date, the data on cardiovascular mortality remain inconsistent. Preventive advice is associated with non-specific measures, such as loss of weight, increased exercise, improved nutrition and the cessation of smoking.
12.10 Quality of life (QoL)
There is little data on QoL during hormone treatment. The only large, prospective, randomised study is a double-blind, placebo-controlled trial including 739 patients with M1 PCa, which compared orchiectomy + flutamide versus orchiectomy + placebo. The QoL was assessed in the first 6 months of treatment. Combined therapy resulted in a lower QoL, with statistically significant differences in two QoL parameters, namely more frequent diarrhoea and worse emotional functioning, compared with castration alone (119).

A prospective, non-randomised, observational study, which included 144 patients with locally advanced PCa or PSA failure after definitive local treatment, found that patients who received immediate ADT (by means of bilateral orchiectomy, LHRH agonist or CAB) reported a lower overall QoL (increased fatigue, emotional distress, and decreased physical functioning) than patients in the deferred hormone treatment arm (120) (LE: 2a).

A retrospective, non-randomised study included 431 patients with stage PCa who received orchiectomy or LHRH agonists as their primary therapy within 12 months of initial diagnosis. The study assessed health-related quality of life (HRQoL) outcomes at 12-months’ follow-up. 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 were orchiectomised patients. The stage at diagnosis had no significant independent effect on health outcome. However, the study was underpowered (121) (LE: 2b).

A recent, small, randomised, controlled trial evaluated the HRQoL of patients with non-localised PCa allocated to leuprorelin, goserelin, CPA or no treatment at 1-year follow-up. Both sexual and cognitive function significantly declined in men on all forms of androgen suppression, while emotional distress significantly increased in those assigned to CPA or no treatment (122) (LE: 1b).

Intermittent androgen deprivation may be associated with an improved overall QoL based on the normal testosterone levels during off-treatment periods. Until recently, the results were inconclusive, showing either no benefit, or only a marginal one, in QoL. However, recent results from the JPR7 trial have shown a clear benefit for QoL (74).

As for LHRH agonists, QoL has been evaluated in the previously mentioned studies of bicalutamide monotherapy using a specific non-validated questionnaire. At 12 months, bicalutamide showed a significant advantage over castration in the domains of physical capacity and sexual interest (not sexual function) (38) (LE: 1b).

A further post-hoc analysis, including only patients with sexual interest at study entry, found that significantly more patients receiving bicalutamide, 150 mg/day, maintained their interest in sex and felt that they were still sexually attractive (123,124), or had a preserved libido and erectile function compared to castration (125).

The most common side-effects during non-steroidal anti-androgen monotherapy are gynaecomastia and breast pain, which are caused by an imbalance in the androgen-to-oestrogen ratio within breast tissue. In bicalutamide studies, these events were reported by up to 66% and 73% of patients, respectively, and may have led to treatment cessation in 16.4% of patients.
12.11 Cost-effectiveness of hormonal therapy options
A recent formal meta-analysis and literature review evaluated the cost-effectiveness of various long-term androgen suppression options in advanced PCa (e.g. bilateral orchiectomy, DES, LHRH-agonist, non-steroidal anti-androgen monotherapy, and CAB using non-steroidal anti-androgens).For the analysis, a sophisticated statistical model was generated, assuming the base case at entry to be a 65-year-old man with clinically evident local recurrence of PCa and no distant metastases, followed for a 20-year time horizon. The study concluded that, for men who can accept it, bilateral orchiectomy is the most cost-effective form of ADT providing a higher quality-adjusted survival, while CAB is the least economically attractive option, yielding small health benefits for a high relative cost. Furthermore, the greatest QoL gains and least costs may be obtained by starting ADT when symptoms from distant metastases have occurred (87) (LE: 1a).

Finally, once ADT is started, if a clear response is obtained (see Section 12.3.3), then IAD might be a useful way to lower treatment costs.

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119. Moinpour CM, Savage MJ, Troxel A, et al. Quality of life in advanced prostate cancer: results of a
randomized therapeutic trial. J Natl Cancer Inst 1998 Oct;90(20):1537-44.
http://www.ncbi.nlm.nih.gov/pubmed/9790546
120. Herr HW, O’Sullivan M. Quality of life of asymptomatic men with non-metastatic prostate cancer on
androgen deprivation therapy. J Urol 2000 Jun;163(6):1743-6.
http://www.ncbi.nlm.nih.gov/pubmed/10799173
121. Potoski AL, Knopf K, Clegg LX, et al. Quality-of-life outcomes after primary androgen deprivation
therapy: results from the Prostate Cancer Outcomes Study. J Clin Oncol 2001 Sep;19(17):3750-7.
http://www.ncbi.nlm.nih.gov/pubmed/11533098
122. Cherrier MM, Aubin S, Higano CS. Cognitive and mood changes in men undergoing intermittent
combined androgen blockade for non-metastatic prostate cancer. Psychooncology 2009 Mar;18(3):
237-47.
http://www.ncbi.nlm.nih.gov/pubmed/18636420
123. Green HJ, Pakenham KI, Headley BC, et al. Quality of life compared during pharmacological
treatments and clinical monitoring for non-localized prostate cancer: a randomized controlled trial.
BJU Int 2004 May;93(7):975-9.
http://www.ncbi.nlm.nih.gov/pubmed/15142146
124. Iversen P, Melezinek I, Schmidt A. Non-steroidal antiandrogens: a therapeutic option for patients with
advanced prostate cancer who wish to retain sexual interest and function. BJU Int 2001 Jan;87(1):
47-56.
http://www.ncbi.nlm.nih.gov/pubmed/11121992
125 Boccardo F, Rubagotti A, Barichello M, et al; for the Italian Prostate Cancer Project. Bicalutamide
monotherapy versus flutamide plus goserelin in prostate cancer patients: results of an Italian Prostate
Cancer Project study. J Clin Oncol 1999 Jul;17(7):2027-38.
http://www.ncbi.nlm.nih.gov/pubmed/10561254
13. MANAGEMENT OF PROSTATE CANCER IN
OLDER MEN
13.1 Introduction
Prostate cancer is the most prevalent cancer in men, with a median age at diagnosis of 68 years. Two-thirds of prostate cancer-related deaths occur in men aged > 75 years (1). Older men tend to have larger tumours of a higher grade than younger patients (2,3). Treatment decisions for older men should take into consideration the risk of dying from PCa (which depends on the grade and stage of the tumour), potential adverse effects of treatment, and patient preference. Interventions that might decrease health-related quality of life (HRQoL)without prolonging survival should be avoided. Evidence suggests that in both the USA (4) and Europe (5) older patients are under-treated: only a minority of older adults with localised prostate cancer receive curative treatment. However, curative treatment should neither be denied where appropriate, nor limited to androgen deprivation therapy (ADT).

Life expectancy is a major determinant of the potential for benefit from therapy. The International Society of Geriatric Oncology (SIOG) Prostate Cancer Working Group recommends that the decision-making process for treating older men with PCa should be based on a systematic evaluation of health status, most importantly comorbidities, dependence status, and nutritional status (6). These factors influence patient survival and can also affect the ability to tolerate treatment-related side-effects (6).
For localised disease, treatment benefit is usually considered to be seen only beyond 10 years, which leads to a treatment frontier of 75 years. This should be reconsidered, given that Walter (7) has shown that survival probability is linked not only to legal age, but more importantly to overall health status. For example, a healthy 80-year-old senior can expect a median 10.8 years of survival, compared to 6.7 years for a vulnerable, and 3.3 years for a frail senior. At 85 years of age, healthy seniors can expect to survive 8 years. These figures date back 10 years, and are likely to have increased with life expectancy.

Comorbidity is a major predictor of PCa mortality. Tewari et al. demonstrated that comorbidity evaluated by the Charlson index was the strongest predictor of death from causes other than PCa in men with localised PCa treated with RP (8). This was recently confirmed in a cohort of patients from the Surveillance, Epidemiology and End Results (SEER) database, all of whom had treatment-resistant PCa. At 10 years, most men with a Charlson score > 2 died from competing causes, irrespective of age or tumour aggressiveness (9). Currently the Cumulative Illness Score Rating-Geriatrics (CISR-G) is the best available tool for assessing the risk for death unrelated to PCa. Whereas the Charlson index considers only potentially lethal comorbid conditions, the CISR-G also rates nonlethal conditions according to their severity and level of control (10,11).

Level of dependence in daily activities is another factor that influences survival in senior adult patients (12,13). Dependence can be evaluated using the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales. The ADL scale rates an ability to accomplish basic activities of daily living, while the IADL scale rates activities that require a higher level of cognition and judgement (for example the ability to manage money or medication, or to use transportation or the telephone).Malnutrition has also been shown to be associated with an increased mortality rate in senior adult patients (14). Nutritional status can be estimated by the variation of weight during the previous 3 months:
• good nutritional status < 5% of weight loss;
• risk of malnutrition - weight loss 5-10%;
• severe malnutrition - weight loss > 10%.
Evaluation of comorbidity, dependence and malnutrition is recommended by The SIOG Prostate Cancer
Working Group in order to classify patients into one of 4 groups:
1. ‘Fit’ or ‘healthy’ older men should receive the same standard treatment as younger patients.
2. ‘Vulnerable’ patients (i.e. reversible impairment) should receive standard treatment after resolution of
any geriatric problems through geriatric interventions.
3. ‘Frail’ patients (i.e. irreversible impairment) should receive an adapted treatment.
4. Patients who are ‘too sick’ with ‘terminal illness’ should receive only symptomatic palliative treatment
(6).
“Fit” and “vulnerable” older men with localised PCa in the high-risk group defined by D`Amico et al. (18), with a chance of surviving for more than 10 years are likely to benefit from curative treatment. Older men in the low risk and possibly intermediate risk classification are most likely to benefit from a watchful-waiting approach.The urological approach in older men with PCa should be the same as in younger patients, based on existing recommendations (15-17). Older men with PCa should be managed according to their individual health status which is mainly driven by the severity of associated comorbid conditions and not according to chronological age.
13.2 Treatment-related complications
The risk of short-term postoperative complications appears to be related more to the severity of comorbidities than chronological age. Conversely, the risk of long-term incontinence after RP is more influenced by increasing age than comorbidity (19,20). External Beam Radiotherapy (EBRT) has similar outcomes in terms of cancer control and treatment related comorbidities in both older and younger patients, assuming a dose of > 70Gy using intensity modulated radiotherapy (IMRT) or image guided radiotherapy (IGRT). Brachytherapy might be a suitable option in older patients, but survival benefit in older men with low risk disease has not been established. Urinary, bowel and erectile complications after brachytherapy increase significantly with both increasing age and severity of comorbidities (15). For those with locally advanced disease, a combined modality of EBRT and long term hormonal treatment must be considered. The drawback of ADT in older patients has been discussed earlier (see Chapter 14). Cardiac status should be specially checked if ADT is considered, as it might be associated with increased morbidity, but not mortality. Comorbidity by itself could also be a discriminating factor, as suggested recently in localised high risk patients (21).

In patients with non-metastatic localised PCa unsuitable for curative treatment, immediate ADT should be used only in patients requiring symptom palliation (22,23) . In the case of locally advanced T3-T4 disease immediate ADT can be of benefit in patients with PSA > 50ng/mL and PSA doubling time of < 12 months (22,23). ADT is the first-line treatment in hormone-sensitive metastatic PCa. The SIOG Prostate Cancer Working Group recommends evaluation of bone mineral status and prevention of osteoporosis. All men receiving ADT should receive calcium and vitamin D supplementation. The routine use of biphosphonates to prevent skeletal complications in patients undergoing ADT is not recommended unless there is a documented risk for fracture or castration-resistant PCa with skeletal metastasis (6). However, in a recent randomised trial Denosumab was shown to improve metastases free survival in patients without distant metastases and rising PSA (29.5 months vs 25.2 months, p = 0.0028) and increase time to first bone lesion (33.2 months vs 29.5 months, p = 0.0032) (24).

In metastatic castration-resistant prostate cancer (CRPC), chemotherapy with docetaxel (75 mg/m2every 3 weeks) is the standard for fit and vulnerable older men. The tolerability of the docetaxel 3-weekly regimen has not been specifically studied in frail older men. In a retrospective analysis of 175 patients aged > 75 years treated with docetaxel, patients with a good performance status responded to docetaxel therapy to a similar extent as younger patients. Docetaxel was generally well tolerated. The weekly regimen showed less febrile neutropenia than the 3-weekly regimen but a higher rate of fatigue, resulting in frequent treatment discontinuation (25). The place of weekly docetaxel in metastatic CRPC should be further evaluated. Palliative treatments in CRPC include palliative surgery, radiopharmaceuticals, EBRT, and medical treatments for pain and symptoms.
13.3 References
1. Ries LAG, Melbert D, Krapcho M et al. eds. SEER Cancer Statistics Review, 1975-2005. Bethesda,
MD: National Cancer Institute, 2008. Available at: http://seer.cancer.gov/csr/1975-2005/, based on
December 2009 SEER data submission.
2. Richstone L, Bianco FJ, Shah HH, et al. Radical prostatectomy in men aged >or=70 years: effect
of age on upgrading, upstaging, and the accuracy of a preoperative nomogram. BJU Int 2008
Mar;101(5):541-6.
http://www.ncbi.nlm.nih.gov/pubmed/18257855
3. Sun L, Caire AA, Robertson CN, et al. Men older than 70 years have higher risk prostate cancer and
poorer survival in the early and late prostate specific antigen eras. J Urol 2009 Nov;182(5):2242-8.
http://www.ncbi.nlm.nih.gov/pubmed/19758616
4. Bubolz T, Wasson JH, Lu-Yao G, et al. Treatments for prostate cancer in older men: 1984-1997.
Urology 2001 Dec;58(6):977-82.
http://www.ncbi.nlm.nih.gov/pubmed/11744472
5. Houterman S, Janssen-Heijnen ML, Hendrikx AJ, et al. Impact of comorbidity on treatment and
prognosis of prostate cancer patients: a population-based study. Crit Rev Oncol Hematol 2006
Apr;58(1):60-7.
http://www.ncbi.nlm.nih.gov/pubmed/16213153
6. Droz JP, Balducci L, Bolla M, et al. Management of prostate cancer in older men: recommendations of
a working group of the International Society of Geriatric Oncology. BJU Int 2010 Aug;106(4):462-9.
http://www.ncbi.nlm.nih.gov/pubmed/20346033
7. Walter LC, Covinsky KE. Cancer screening in elderly patients: a framework for individualized decision
making. JAMA 2001 Jun 6;285(21):2750-6.
http://www.ncbi.nlm.nih.gov/pubmed/11386931
8. Tewari A, Johnson CC, Divine G, et al. Long-term survival probability in men with clinically localized
prostate cancer: a case-control, propensity modeling study stratified by race, age, treatment and
comorbidities. J Urol 2004 Apr;171(4):1513-9.
http://www.ncbi.nlm.nih.gov/pubmed/15017210
9. Albertsen PC, Moore DF, Shih W, et al. Impact of comorbidity on survival among men with localized
prostate cancer. J Clin Oncol 2011 Apr 1;29(10):1335-41.
http://www.ncbi.nlm.nih.gov/pubmed/21357791
10. Extermann M. Measuring comorbidity in older cancer patients. Eur J Cancer 2000 Mar;36(4):453-71.
http://www.ncbi.nlm.nih.gov/pubmed/10717521
11. Linn BS, Linn MW, Gurel L. Cumulative illness rating scale. J Am Geriatr Soc 1968 May;16(5):622-6.
http://www.ncbi.nlm.nih.gov/pubmed/5646906
12. Katz S, Ford AB, Moskowitz RW, et al. Studies of illness in the aged. The index of ADL: a standardized
measure of biological and psychosocial function. JAMA 1963 Sep;185:914-9.
http://www.ncbi.nlm.nih.gov/pubmed/14044222
13. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of
daily living. Gerontologist 1969 Autumn;9(3):179-86.
http://www.ncbi.nlm.nih.gov/pubmed/5349366
14. Blanc-Bisson C, Fonck M, Rainfray M, et aI. Undernutrition in elderly patients with cancer: target for
diagnosis and intervention. Crit Rev Oncol Hematol 2008 Sep;67(3):243-54.
http://www.ncbi.nlm.nih.gov/pubmed/18554922
15. Heidenreich A, Bellmunt J, Bolla M, et al. [EAU guidelines on prostate cancer. Part I: screening,
diagnosis, and treatment of clinically localised disease.] Actas Urol Esp 2011 Oct;35(9):501-14. [article
in Spanish]
http://www.ncbi.nlm.nih.gov/pubmed/21757259
16. Thompson I, Thrasher JB, Aus G, et al. Guideline for the management of clinically localized prostate
cancer: 2007 update. J Urol 2007 Jun;177(6):2106-31.
http://www.ncbi.nlm.nih.gov/pubmed/17509297
17. National Comprehensive Cancer Network. NCCN Clinical Cancer for senior adult oncology. V.1.2012.
Available at: http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp.
18. D’Amico AV, Moul J, Carroll PR, et al. Cancer-specific mortality after surgery or radiation for patients
with clinically localized prostate cancer managed during the prostate-specific antigen era. J Clin Oncol
2003 Jun;21(11):2163-72.
http://www.ncbi.nlm.nih.gov/pubmed/12775742
19. Begg CB, Riedel ER, Bach PB, et al. Variations in morbidity after radical prostatectomy. N Engl J Med
2002 Apr;346(15):1138-44.
http://www.ncbi.nlm.nih.gov/pubmed/11948274
20. Stanford JL, Feng Z, Hamilton AS, et al. Urinary and sexual function after radical prostatectomy
for clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA 2000 Jan
19;283(3):354-60.
http://www.ncbi.nlm.nih.gov/pubmed/10647798
21. D’Amico AV, Chen MH, Renshaw AA, et al. Androgen suppression and radiation vs radiation alone for
prostate cancer: a randomized trial. JAMA 2008 Jan;299(3):289-95.
http://www.ncbi.nlm.nih.gov/pubmed/18212313
22. Studer UE, Whelan P, Albrecht W, et al. Immediate or deferred androgen deprivation for patients
with prostate cancer not suitable for local treatment with curative intent: European Organisation for
Research and Treatment of Cancer (EORTC) Trial 30891. J Clin Oncol 2006 Apr 20;24(12):1868-76.
http://www.ncbi.nlm.nih.gov/pubmed/16622261
23. Studer UE, Collette L, Whelan P, et al. Using PSA to guide timing of androgen deprivation in patients
with T0-4 N0-2 M0 prostate cancer not suitable for local curative treatment (EORTC 30891). Eur Urol
2008 May;53(5):941-9.
http://www.ncbi.nlm.nih.gov/pubmed/18191322
24. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation
therapy for prostate cancer. J Clin Oncol 2006 Sep 20;24(27):4448-56.
http://www.ncbi.nlm.nih.gov/pubmed/16983113
25. D’Amico AV, Denham JW, Crook J, et al. Influence of androgen suppression therapy for prostate
cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol 2007 Jun
10;25(17):2420-5.
http://www.ncbi.nlm.nih.gov/pubmed/17557956
14. QUALITY OF LIFE OF PATIENTS WITH
LOCALISED PROSTATE CANCER
14.1 Introduction
The increase in life expectancy of patients with localised PCa has made the quality of life after treatment a key issue for PCa survivors. The term ‘health-related quality of life’ (HRQoL) is typically used to refer to the impact that disease and treatment have on a person’s well-being and physical, emotional and social functioning, including daily functioning (1-4). HRQoL is a patient-centered outcome which is rated by the patient himself, particularly as physicians often underestimate the impact of disease and treatment on their patients’ lives (5). In PCa, HRQoL is usually divided into PCa-specific and PCa-general issues. PCa-specific HRQoL refers to the disease-specific outcome of PCa, including urinary, bowel, and sexual functioning. PCa-general HRQoL refers to generic issues of well-being, including physical, social, emotional, and cognitive functioning, vitality/fatigue, pain, general health status, global quality of life and life satisfaction (6).

HRQoL is measured using standardised questionnaires, which collect patient-centric data and provide an objective assessment and perception of both generic and disease-specific domains. Several comprehensive HRQoL questionnaires have undergone validation and have been used to measure early stage PCa outcomes. The most frequently used questionnaires include the EPIC (Expanded Prostate Cancer Index Composite), the Symptom indexes constructed by Clark and Talcott, and the Prostate Module appendix for the EORTC-QLQ C30 (7-9).

Various forms of therapies have different impacts on HRQoL. A comparison of the most common contemporary therapies for localised PCa (radical prostatectomy, brachytherapy, external-beam radiation therapy and active surveillance) is necessary to inform patients about treatment options and to address individual patient preferences for the various possible outcomes. There is still very little objective data about HRQoL for PCa treatment, mainly because of a lack of prospective trials.
14.2 Active surveillance
Although active surveillance avoids treatment-related side effects, it carries an increased risk of psychological distress, which can have significant effects on the patient’s HRQoL. There are certain risk factors for patients who may not do well on active surveillance. These factors include the patient’s perception that the physician is making most of the decision-making, a poor physical health score, a high neuroticism (anxiety) score, and a high PSA value. All these factors were found to have significant positive associations with lower HRQoL scores in multivariate analysis (10). Anxiety and distress did not increase and remained low during the first 9 months of surveillance in men enrolled in the active surveillance PRIAS study (11). Additional research with a longer follow-up is needed to define the significance of negative effects of active surveillance on HRQoL (LE: 1b). Data from an RCT on anxiety comparing WW and RP (13) found that depression, well-being and psychological status were not significantly different between treatment groups, even if they were systematically inferior in the treated group (LE: 1b).
14.3 Radical prostatectomy
Several trials have shown that RP has a significant negative effect on multiple QoL domains, including a lower sexual function score, lower urinary function and incontinence scores, and a lower physical HRQoL (13-16). In the Prostate Cancer Outcomes Study (PCOS), 8.7% of men at 24 months were bothered by a lack of urinary control and 41.9% reported that sexual function was a moderate-to-big problem in their daily lives (17). Sexual function and interest are the two prostate-specific domains that decline most after surgery and remain most affected after 1 year (18). The recovery of sexual dysfunction and urinary incontinence occurs over 2 to 3 years (19-21). Sanda and colleagues (14) recently reported that urinary incontinence was at its worst by 2 months after surgery, after which time it improved in most patients. At 1 year after RP, 26% of patients reported that sexual function was a ‘big problem’, while 76% reported that urinary incontinence was a ‘very small’ problem or ‘no problem at all’ (LE: 2a).

Although certain advances have been made that help diminish these side effects, such as nerve-sparing RP or robotic-assisted radical prostatectomy (RALP), their impact on HRQoL remain controversial.

Preserving the neurovascular bundles reduces the incidence of impotence (14,22) and can also help to improve urinary function (21,22). Both RALP and open RP have demonstrated comparable functional outcomes and should therefore theoretically have similar HRQoL scores (24). Recently, Hu et al. (25) compared minimally invasive RP (all laparoscopic techniques) with traditional open RP using a dataset of nearly 2000 Medicare patients. The incontinence and erectile dysfunction rate were higher in the minimally invasive group compared with the open RP group (LE: 3). In a prospective, longitudinal study, Thornton et al. assessed changes in the cognitive, emotional, and interpersonal components of PCa-related QoL in 71 men who underwent RALP. Although some components of QoL returned to baseline by 1 year after surgery, there were enduring decreases in sexual intimacy, sexual confidence, and masculine self-esteem (26). More motivated patients seemed to experience greater distress and were less satisfied (27). Other general HRQoL domains that may be affected after surgery included pain and energy (18). Several studies have shown that pain and energy worsen immediately post-RP but usually improve by 12 months (19,21,28).

A new methodology for reporting outcomes after RP was proposed recently: the so-called trifecta (29) and pentafecta (30). The new method combines major outcomes, including continence, potency and cancer control (trifecta) and peri-operative complications and positive surgical margins rates (pentafecta). Pentafecta rates reflect post-operative patient expectations and satisfaction more accurately and can be used in counselling patients with clinically localised PCa. The use of trifecta and pentafecta outcomes in post-operative HRQoL assessment needs further validation.
14.4 External-beam radiation therapy (EBRT) and low-dose rate (LDR) brachytherapy
Patients undergoing EBRT and I125 LDR brachytherapy may have urinary, sexual and bowel dysfunction after treatment (31). Both methods can result in irritative voiding symptoms, such as urgency, frequency, and urge incontinence, that negatively affect overall urinary function and HRQoL. The most predominant severe acute toxicity after LDR brachytherapy is urinary retention requiring catheterisation (32). Roeloffzen et al. (32,33) reported that acute urinary retention after LDR brachytherapy occurs in 8-10.2% of patients and has a significant negative impact on patients’ HRQoL up to 6 years after treatment, in terms of both global QoL measures and urinary symptom scores (LE: 3).

A prospective multicentre study showed that the effects of EBRT on urinary symptoms had resolved at 12 months and improved over baseline at 24 months (14). In the same study, patients in the LDR brachytherapy group reported significant detriments in urinary irritation or obstruction and incontinence compared with baseline. Incontinence after LDR brachytherapy was reported by 4-6% of patients at 1-2 years after treatment. Eighteen percent of patients in the LDR brachytherapy group and 11% of those in the EBRT group reported moderate or worse distress from overall urinary symptoms at 1 year (14) (LE: 3).

It has been shown that both EBRT and LDR brachytherapy had a significant impact on the bowel and rectal HRQoL domains (14,34). Bowel/rectal problems appeared to have an overall impact close to that of the urinary v domain (35,36). The onset of symptoms occurred during or early after treatment, and sometimes persisted longer into follow-up. Sanda et al. reported rectal urgency, frequency, pain, fecal incontinence, or hematochezia-caused distress related to bowel function in 9% of patients at 1 year after EBRT or LDR brachytherapy (14). In a retrospective observational study of fecal incontinence in 143 men, who had received LDR brachytherapy for localised PCa, 13.2% (20) of patients at 2 years reported that fecal incontinence was impacting their ability to participate in daily activities (37). A multivariable analysis suggested that bowel and rectal symptoms were less profound after LDR brachytherapy than after EBRT (7) (LE: 2a).

Roeloffzen et al. (33) reported a statistically significant deterioration in HRQoL in patients treated with I125 LDR brachytherapy at 6 years for urinary symptoms, bowel symptoms, pain, physical functioning, and sexual activity. However, most of these changes were not clinically relevant. HRQoL scores returned to approximately baseline values at 1 year and remained stable up to 6 years after treatment. The only clinically relevant changes were seen for emotional functioning and sexual activity. Worse bowel and urinary function may play a stronger role than sexual function in predicting a patient’s overall physical and emotional HRQoL (38). Contemporary treatment refinements, such as 3-D conformal or intensity-modulated radiotherapy (IMRT), may be able to reduce the impact of EBRT on bowel symptoms, but this has not yet been shown in a multicentre setting. Recently, Sanda et al. showed that adjuvant androgen suppression exacerbated the adverse effects of external radiotherapy or brachytherapy on sexuality and vitality (14). The negative effects of adjuvant hormonal therapy have been shown in some other studies (31,39).

Among general domains, fatigue was commonly reported following EBRT. However, provided that fatigue was temporary, it did not appear to be emotionally distressing to most men (40,41). Men treated with interstitial LDR brachytherapy appeared to have only slight declines in general HRQoL (42). Physical and functional status declines have been reported in the first few months after implant, but pretreatment levels of function are regained by most men at 1 year after implant (43).
14.5 Comparison of HRQoL between treatment modalities
The limitations of all published studies assessing QoL include the lack of randomisation to treatment and therefore the presence of selection bias, which may influence outcomes. Thus, information regarding comparative outcome relies largely on results from non-randomised observational cohorts. Treatment comparison requires a long follow-up, as measures of quality of life may change with time. There are very few trials investigating a direct comparison of different treatment modalities.

Most early studies addressing general HRQL issues (general physical function, role function, social function, emotional well-being, body pain, general health, or vitality/energy) have found few differences across treatments for clinically localised disease (6,44). In more recent longitudinal studies, both surgery- and radiotherapy-treated men have reported some declines in role function and vitality/energy shortly after treatment, with surgically treated men reporting the most dysfunction (28,40). However most men recovered function by 1 year after treatment.

The presence of comorbid psychiatric conditions (i.e. prior psychiatric history, alcohol abuse, drug abuse) and the experience of pain after treatment were considered to be certain risk factors for poor general HRQoL in men after treatment for localised prostate cancer (45-47).

The PCOS was the first reported prospective study presenting treatment-specific QoL outcomes for PCa patients at 5 years after initial diagnosis (17). The cohort consisted of men with newly diagnosed localised PCa treated with RP (n = 901) or EBRT (n = 286). At 5 years after diagnosis, overall sexual function declined in both groups to approximately the same level, mostly because of a continuing decline in erectile function among EBRT patients between years 2 and 5. However, erectile dysfunction was more prevalent in the RP group (79.3% vs 63.5%, respectively). Approximately 14-16% of RP and 4% of EBRT patients were incontinent at 5 years. Bowel urgency and painful haemorrhoids were more common in the EBRT group (LE: 2a). Madalinska et al. evaluated the side effects of RP and EBRT in 278 patients from the ERSPC study at 6 and 12 months following treatment (35). RP patients reported significantly higher incidences of urinary incontinence (39- 49%) and erectile dysfunction (80-91%) than radiotherapy patients (6-7% and 41- 55%, respectively). Bowel problems (urgency) affected 30-35% of the EBRT group versus 6-7% of the RP group (LE: 2a). Downs et al. measured the impact of LDR brachytherapy alone on general HRQoL and disease-specific HRQoL compared to patients treated with RP (48). The authors studied 419 men from the CaPSURE database, whose primary treatment was (LDR) brachytherapy [n = 92] or RP [n = 327].Patients treated with LDR brachytherapy or RP did not differ greatly in general HRQoL after treatment. Both treatment groups showed early functional impairment in most general domains, with scores returning to or approaching baseline in most domains at 18 to 24 months after treatment. Patients treated with LDR brachytherapy had significantly higher urinary function scores at 0 to 6 months after treatment (84.5%) than patients treated with RP (63.3%). Urinary bother scores were not significantly different (67.7% vs 67.4%, respectively). Both treatment groups showed decreases in sexual function that did not return to pretreatment levels (LE: 2a).

A multicentre study that compared all three treatments (RP, EBRT, LDR brachytherapy) in a longitudinal prospective cohort was conducted by Talcott et al. (7). In 417 men, the authors assessed urinary, bowel and sexual function from before primary treatment to 24 months afterwards. Urinary incontinence increased sharply after RP, while bowel problems and urinary irritation/obstruction occurred after EBRT and LDR brachytherapy. Sexual function severely worsened immediately after surgery and then improved, while sexual function continued to decline after both radiation treatments. It has been shown that a surgical patient, who is impotent at 3 or 12 months after surgery, can expect to have a realistic hope of improvement while impotent EBRT patients probably should not. There was no change in urinary function and little change in overall bowel function after 12 months. The data showed that a patient with bowel dysfunction at 12 months after EBRT may expect modest improvement, with diverging trends for individual symptoms. Diarrhoea will continue to subside, tenesmus and rectal urgency will change little, and episodes of rectal bleeding will become more prevalent (7) (LE: 2a).

A recent, prospective, multicentre study of 435 patients with a longer follow-up of 36 months was reported by Pardo et al. (49). The study confirmed that there was a long-term change in adverse effects, e.g. an increase in urinary-related adverse effects after EBRT or sexual adverse effects with LDR brachytherapy, which tended to reduce any differences between treatments over time. However, these changes were only slight. In accordance with other reports, the RP-treated group showed greater deterioration in urinary incontinence and sexual function, but improved urinary irritative-obstructive results compared with the LDR brachytherapy group. In patients with urinary irritative-obstructive symptoms at baseline, improvement was observed in 64% of those treated with nerve-sparing RP. Higher bowel worsening was observed in the ERBT group, with 20% of patients reporting bowel symptoms. Relevant differences between treatment groups persisted for up to 3 years of follow-up (49) (LE: 2a). 

The American College of Surgeons Oncology Group phase III Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial compared RP and LDR brachytherapy, but was closed after 2 years due to poor accrual. Crook et al. (50) recently reported the HRQoL at a mean of 5.3 years for 168 trial-eligible men, who either chose or were randomly assigned to RP or brachytherapy following a multidisciplinary educational session (50). There were no differences in bowel or hormonal domains. However, men treated with LDR brachytherapy scored slightly better in the urinary domain (91.8 vs 88.1; p = 0.02) and sexual (52.5 vs 39.2; p =0.001) domain, and in patient satisfaction (93.6 vs 76.9; p < 0.001). It should be noted that treatment allocation was random in only 19% of cases (LE: 2a).

The quality of life of a patient’s spouse or partner may also be reduced as a result of their spouse or partner receiving treatment for PCa. In a prospective multicentre study of more than 1200 patients and 625 spouses or partners (14), patients in the LDR brachytherapy group reported long-lasting urinary irritation, bowel and sexual symptoms and transient problems with vitality or hormonal function. The adverse effects of RP on sexual function were mitigated by nerve-sparing procedures. Distress associated with the patient’s erectile dysfunction was reported by 44% of partners in the RP group, 22% of those in the EBRT group and 13% of those in the LDR brachytherapy group. After RP, urinary incontinence was observed, but urinary irritation and obstruction improved, particularly in patients with large prostates. Treatment-related symptoms were made worst by obesity, large prostate size, high prostate-specific antigen score and older age (LE: 2a).

Malcolm et al. (51) reported a single-institution study comparing the outcomes of surgery (RP, RALP), LDR brachytherapy and cryosurgical ablation of the prostate (CSAP) with a relatively short follow-up of 24 months (51). The HRQoL of patients treated with (LDR) brachytherapy and CSAP was associated with higher urinary function and higher bother score compared to open RP and RALP. LDR brachytherapy was associated with higher sexual function and higher bother score compared to all other treatment modalities. Unfortunately, the study used the UCLA-PCI questionnaire, which lacks items for evaluating irritative urinary symptoms often observed in patients after LDR brachytherapy (48). This may have significantly compromised the results of the HRQoL assessment (LE: 3).

In conclusion, many men treated for clinically localised PCa will experience some post-treatment problems that may impact their daily lives. Each patient therefore has to determine which side effect profile (34) is most acceptable to them when making a decision about treatment.
14.6 References
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5. Litwin M, Lubeck D, Henning J, et al. Differences in urologist and patient assessments of health
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6. Eton DT, Lepore SJ. Prostate cancer and health-related quality of life: a review of the literature.
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7. Talcott JA, Manola J, Clark JA, et al. Time course and predictors of symptoms after primary prostate
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9. Joly F, Brune D, Couette JE, Lesaunier F, et al. Health-related quality of life and sequelae in patients
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10. van den Bergh RC, Essink-Bot ML, Roobol MJ, et al. Anxiety and distress during active surveillance
for early prostate cancer. Cancer 2009 Sep 1;115(17):3868-78.
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11. van den Bergh RC, Essink-Bot ML, Roobol MJ, et al. Do anxiety and distress increase during active
surveillance for low risk prostate cancer? J Urol 2010 May;183(5):1786-91.
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12. Holmberg L, Bill-Axelson A, Helgesen F, et al; Scandinavian Prostatic Cancer Group Study Number 4.
A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer.
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13. Bellizzi KM, Latini DM, Cowan JE, et al. Fear of recurrence, symptom burden, and health-related
quality of life in men with prostate cancer. Urology 2008 Dec;72(6):1269-73.
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14. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostatecancer survivors. N Engl J Med 2008 Mar;358(12):1250-61.
http://www.ncbi.nlm.nih.gov/pubmed/18354103
15. Gacci M, Simonato A, Masieri L, et al. Urinary and sexual outcomes in long-term (5+ years) prostate
cancer disease free survivors after radical prostatectomy. Health Qual Life Outcomes 2009 Nov;7:94.
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16. Chen RC, Clark JA, Talcott JA. Individualizing quality-of-life outcomes reporting: how localized
prostate cancer treatments affect patients with different levels of baseline urinary, bowel, and sexual
function. J Clin Oncol 2009 Aug;27(24):3916-22.
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17. Potosky AL, Legler J, Albertsen PC, et al. Health outcomes after prostatectomy or radiotherapy
for prostate cancer: results from the Prostate Cancer Outcomes Study. J Natl Cancer Inst 2000
Oct;92(19):1582-92.
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18. Ku J, Krahn M, Trachtenberg J, et al. Changes in health utilities and health-related quality of life over
12 months following radical prostatectomy. Can Urol Assoc J 2009 Dec;3(6):445-52.
http://www.ncbi.nlm.nih.gov/pubmed/20019969
19. Litwin MS, Melmed GY, Nakazon T. Life after radical prostatectomy: a longitudinal study. J Urol. 2001
Aug;166(2):587-92.
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20. Stanford JL, Feng Z, Hamilton AS, et al. Urinary and sexual function after radical prostatectomy for
clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA 2000 Jan;283(3):
354-60.
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21. Smith DS, Carvalhal GF, Schneider K, et al. Quality-of-life outcomes for men with prostate carcinoma
detected by screening. Cancer 2000 Mar 15;88(6):1454-63.
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22. Abel EJ, Masterson TA, Warner JN, et al. Nerve-sparing prostatectomy and urinary function: a
prospective analysis using validated quality-of-life measures. Urology 2009 Jun;73(6):1336-40.
http://www.ncbi.nlm.nih.gov/pubmed/19362347
23. Nandipati KC, Raina R, Agarwal A, et al. Nerve-sparing surgery significantly affects long-term
continence after radical prostatectomy. Urology 2007 Dec;70(6):1127-30.
http://www.ncbi.nlm.nih.gov/pubmed/18158032
24. Coelho RF, Chauhan S, Palmer KJ, et al. Robotic-assisted radical prostatectomy: a review of current
outcomes. BJU Int 2009 Nov;104(10):1428-35.
http://www.ncbi.nlm.nih.gov/pubmed/19804427
25. Hu JC, Gu X, Lipsitz SR, et al. Comparative effectiveness of minimally invasive vs open radical
prostatectomy. JAMA 2009 Oct;302(14):1557-64.
http://www.ncbi.nlm.nih.gov/pubmed/19826025
26. Thornton AA, Perez MA, Oh S, et al. A prospective report of changes in prostate cancer related quality
of life after robotic prostatectomy. J Psychosoc Oncol 2011 Mar;29(2):157-67.
http://www.ncbi.nlm.nih.gov/pubmed/21391068 
27. Messaoudi R, Menard J, Ripert T, et al. Erectile dysfunction and sexual health after radical
prostatectomy: impact of sexual motivation. Int J Impot Res 2011 Mar-Apr;23(2):81-6.
http://www.ncbi.nlm.nih.gov/pubmed/21471982
28. Lubeck DP, Litwin MS, Henning JM, et al. Changes in health-related quality of life in the first year after
treatment for prostate cancer: results from CaPSURE. Urology 1999 Jan;53(1):180-6.
http://www.ncbi.nlm.nih.gov/pubmed/9886609
29. Bianco FJ Jr, Scardino PT, Eastham JA. Radical prostatectomy: long-term cancer control and recovery
of sexual and urinary function (“trifecta”). Urology 2005 Nov;66(5 Suppl):83-94.
http://www.ncbi.nlm.nih.gov/pubmed/16194712
30. Patel VR, Sivaraman A, Coelho RF, et al. Pentafecta: a new concept for reporting outcomes of robotassisted laparoscopic radical prostatectomy. Eur Urol 2011 May;59(5):702-7.
http://www.ncbi.nlm.nih.gov/pubmed/21296482
31. Wei JT, Dunn RL, Sandler HM, et al. Comprehensive comparison of health-related quality of life after
contemporary therapies for localized prostate cancer. J Clin Oncol 2002 Jan;20(2):557-66.
http://www.ncbi.nlm.nih.gov/pubmed/11786586
32. Roeloffzen EM, Hinnen KA, Battermann JJ, et al. The impact of acute urinary retention after iodine-125
prostate brachytherapy on health-related quality of life. Int J Radiat Oncol Biol Phys 2010 Aug
1;77(5):1322-8.
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33. Roeloffzen EM, Lips IM, van Gellekom MP, et al. Health-related quality of life up to six years after (125)I
brachytherapy for early-stage prostate cancer. Int J Radiat Oncol Biol Phys 2010 Mar;76(4):1054-60.
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34. Dandapani SV, Sanda MG. Measuring health-related quality of life consequences from primary
treatment for early-stage prostate cancer. Semin Radiat Oncol 2008 Jan;18(1):67-72.
http://www.ncbi.nlm.nih.gov/pubmed/18082590
35. Madalinska JB, Essink-Bot ML, de Koning HJ, et al. Health-related quality-of-life effects of radical
prostatectomy and primary radiotherapy for screen-detected or clinically diagnosed localized prostate
cancer. J Clin Oncol 2001 Mar;19(6):1619-28.
http://www.ncbi.nlm.nih.gov/pubmed/11250990
36. Miller DC, Sanda MG, Dunn RL, et al. Long-term outcomes among localized prostate cancer
survivors: health-related quality-of-life changes after radical prostatectomy, external radiation, and
brachytherapy. J Clin Oncol 2005 Apr;23(12):2772-80.
http://www.ncbi.nlm.nih.gov/pubmed/15837992
37. Lamb MN, Trabinino L, Hackford A. Patients’ perspectives on fecal incontinence after brachytherapy
for localized prostate cancer. Dis Colon Rectum 2011 May;54(5):615-21.
http://www.ncbi.nlm.nih.gov/pubmed/21471764
38. Steenland K, Goodman M, Liff J, et al. Quality of life among men with prostate cancer in rural Georgia.
Urology 2011 Apr;77(4):927-33.
http://www.ncbi.nlm.nih.gov/pubmed/21334050
39. Bestmann B, Kollakowski T, Weissbach L. [Quality of life after prostate cancer in members of support
groups: first results of the HAROW retro study.] Urologe A 2011 Mar;50(3):333-9. [Article in German]
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40. Beard CJ, Propert KJ, Rieker PP, et al. Complications after treatment with external-beam irradiation
in early-stage prostate cancer patients: a prospective multiinstitutional outcomes study. J Clin Oncol
1997 Jan;15(1):223-9.
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41. Monga U, Jaweed M, Kerrigan AJ, et al. Neuromuscular fatigue in prostate cancer patients undergoing
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2003 May;169(5):1653-61.
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43. Lee WR, McQuellon RP, Harris-Henderson K, et al. A preliminary analysis of health-related quality
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prostate cancer. Int J Radiat Oncol Biol Phys 2000 Jan;46(1):77-81.
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cancer. JAMA 1995 Jan;273(2):129-35.
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45. Schag CA, Ganz PA, Wing DS, et al. Quality of life in adult survivors of lung, colon and prostate
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15. SUMMARY OF GUIDELINES ON PRIMARY
TREATMENT OF PCA

DT = doubling time; NHT = neoadjuvant hormonal treatment; IPSS = International Prostatic Symptom Score;
PSA = prostatespecific antigen; TRUS = transrectal ultrasound; TURP =transurethral resection of the prostate
16. FOLLOW-UP: AFTER TREATMENT WITH
CURATIVE INTENT
16.1 Definition
Curative treatment is defined as radical prostatectomy or radiotherapy, either by external beam radiation or an interstitial technique, or any combination of these. Alternative treatment options that are not fully established, such as HIFU, do not have a well-defined, validated PSA-cut-point to define biochemical failure but do generally follow the outlines given below.
16.2 Why follow-up?
The first question to be answered is: ‘If failure after curative treatment is so common, are follow-up efforts worthwhile?’ The answer to this question is definitely ‘yes’. Recurrences will occur in a substantial number of patients who received treatment with intent to cure at various time points after the primary therapy. The second question to be answered is: ‘What is the reason for follow-up?’ Reasons may vary depending on the treatment given, patient age, co-morbidity and the patient’s own wishes. In general, patients who receive curative therapy may be followed-up for any of the following reasons:
• good responsible patient care;
• possibility of second-line treatment with curative intent;
• possibility of early hormonal therapy after failure;
• as part of a study protocol.
Chapter 18 discusses treatment options after failure of primary therapy.
16.3 How to follow-up?
The procedures indicated at follow-up visits vary depending on the clinical situation. The examinations discussed below are routinely used for the detection of PCa progression or residual disease. The PSA level, and eventually DRE, are the only tests that need to be carried out routinely. A disease-specific history should be mandatory at every follow-up visit and should include psychological aspects, signs of disease progression, and treatment-related complications. The examinations used for the evaluation of treatment-related complications must be individualised and are beyond the scope of these guidelines. The examinations used most often for cancer-related follow-up after curative surgery or radiation treatment are discussed below.
16.3.1 PSA monitoring
The measurement of PSA level is a cornerstone in the follow-up after curative treatment. There is a difference in what can be expected after radical prostatectomy and radiotherapy, but PSA recurrence nearly always precedes clinical recurrence after either treatment, in some cases by many years (1-5). It is recommended that the finding of a single, elevated, serum PSA level should be re-confirmed before second-line therapy is started solely based on the PSA elevation.
16.3.2 Definition of PSA progression
The level of PSA at which to define treatment failure differs between radical prostatectomy cases and radiation treated cases. Following radical retropubic prostatectomy, two consecutive values of 0.2 ng/mL or greater appear to represent an international consensus defining recurrent cancer (6,7). Other authors have argued for an even higher cut-off of 0.4 ng/mL to better define patients with a high risk for clinical progression (5). It has been shown that patients with a PSA level between 0.1 ng/mL and 0.2 ng/mL after radical prostatectomy had neither clinical nor biochemical disease progression (8). Therefore, the use of an ultra-sensitive PSA assay is not justified for routine follow-up after radical prostatectomy (4). If ongoing randomised trials show that early adjuvant treatment after radical prostatectomy (given before PSA reaches > 0.2 ng/mL) improves survival, this issue should be reconsidered.

Following radiation therapy, until recently, the definition of biochemical relapse was three consecutive increases according to the recommendation of ASTRO from 1996 (9). At the 2006 RTOG-ASTRO Consensus conference a new definition of radiation failure was established with as the main aim to establish a better correlation between the definition and clinical outcome. The new definition of radiation failure is a rise of 2 ng/mL above the post-treatment PSA-nadir (lowest value) (10). This definition is applicable for patients treated with or without hormonal therapy.

After HIFU or cryotherapy, a variety of definitions for PSA-relapse have been used (11). Most of these are based on a cut-off of around 1 ng/mL, eventually combined with a negative post-treatment biopsy. As yet, none of these end-points have been validated against clinical progression or survival and therefore it is not possible to give firm recommendations on the definition of biochemical failure.
16.3.3 PSA monitoring after radical prostatectomy
PSA is expected to be undetectable within 6 weeks after a successful radical prostatectomy (12). A persistently elevated PSA level means that PSA-producing tissue remains in the body. In patients treated with radical prostatectomy, this is generally thought to be residual cancer due to either micrometastases that were not detected or undetectable beforehand, or residual disease in the pelvis possibly due to positive surgical margins.

A rapidly increasing PSA level (high PSA velocity, short PSA doubling time) indicates distant metastases, while a later and slowly increasing concentration of PSA is most likely to indicate local disease recurrence. The time to PSA recurrence and tumour differentiation are also important predictive factors distinguishing between local and systemic recurrence (13,14). Both local treatment failure and distant metastases have been shown to occur with undetectable PSA levels. This is very rare and occurs almost only in patients with unfavourable pathology (undifferentiated tumours) (15,16).
This means that, in patients with a relatively favourable pathology (< pT3, pN0, Gleason score < 8), PSA measurement, together with the disease-specific history, could stand as the single test in follow-up after radical prostatectomy.
16.3.4 PSA monitoring after radiation therapy
The PSA level falls slowly after radiotherapy compared with radical prostatectomy. The optimal cut-off value for a favourable PSA nadir after radiotherapy is somewhat controversial. Achieving a PSA nadir of less than 0.5 ng/mL seems to be associated with a favourable outcome (17). The interval before reaching the nadir PSA may be very long and can sometimes take up to 3 years or more. A PSA rising more than 2 ng/mL above the nadir PSA is the current definition of biochemical failure after radiotherapy (10). Also, after radiotherapy, the PSA doubling time has been shown to correlate to the site of recurrence; patients with local recurrence had a doubling time of 13 months compared to 3 months for those with distant failure (18).
16.3.5 Digital rectal examination (DRE)
DRE is performed to assess whether or not there is any sign of local disease recurrence. It is very difficult to interpret the findings of DRE after curative therapy, especially after radiotherapy. A newly detected nodule should raise the suspicion of local disease recurrence. As mentioned previously, a local disease recurrence after curative treatment is possible without a concomitant rise in PSA level (15,16). However, this has only been proven in patients with unfavourable pathology, i.e. those with undifferentiated tumours. Thus, PSA measurement and DRE comprise the most
useful combination of tests as first-line examination in follow-up after radiotherapy or radical prostatectomy, but PSA measurement may well be the only test in cases with favourable pathology (19).
16.3.6 Transrectal ultrasonography (TRUS) and biopsy
TRUS and biopsy have no place in the routine follow-up of asymptomatic patients and nowadays only rarely after biochemical failure. TRUS cannot stand alone as a diagnostic tool, but must usually be combined with biopsy to establish the presence of local disease recurrence. The purpose of the investigation is to confirm a histological diagnosis of local disease recurrence. It is only warranted if the finding of a local recurrence affects the treatment decision (see Section 16 for a more detailed discussion).
16.3.7 Bone scintigraphy
The purpose of bone scintigraphy is to detect skeletal metastases. It is not recommended for the routine follow-up of asymptomatic patients, but may be indicated in individuals with elevated PSA levels for whom the findings will affect the treatment decision. It is also indicated in patients with symptoms arising from the skeleton, since metastatic disease may occur even if PSA is undetectable (15,16).
16.3.8 Computed tomography (CT) or magnetic resonance imaging (MRI)
CT or MRI have no place in the routine follow-up of asymptomatic patients. They may be used selectively in the evaluation after biochemical failure before treatment decisions are made (see Chapter 18).
16.4 When to follow-up?
Most patients who fail treatment for PCa do so early, even if failure only becomes clinically obvious after years. The patient should therefore be followed-up more closely during the first years after treatment when the risk of failure is highest. PSA measurement, disease-specific history and DRE are recommended at the following intervals: 3, 6 and 12 months postoperatively, every 6 months thereafter until 3 years, and then annually. The purpose of the first clinic visit is mainly to detect treatment-related complications and to assist patients in coping with the new situation. Tumour or patient characteristics may allow alterations to this schedule. For example, patients with poorly differentiated and locally advanced tumours or with positive margins may be followed-up more closely than those with a well-differentiated, intracapsular or specimenconfined tumour. Obviously, advanced age or associated co-morbidity may make further follow-up in asymptomatic patients superfluous.
16.5 Guidelines for follow-up after treatment with curative intent

16.6 References
1. Han M, Partin AW, Pound CR, et al. Long-term biochemical disease-free and cancerspecific survival
following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin
North Am 2001 Aug;28(3)555-65.
http://www.ncbi.nlm.nih.gov/pubmed/11590814
2. Rosser CJ, Chichakli R, Levy LB, et al. Biochemical disease-free survival in men younger than 60
years with prostate cancer treated with external beam radiation. J Urol 2002 Aug;168(2):536-41.
http://www.ncbi.nlm.nih.gov/pubmed/12131304
3. Horwitz EM, Thames HD, Kuban DA, et al. Definitions of biochemical failure that best predict clinical
failure in patients with prostate cancer treated with external beam radiation alone: a multi-institutional
pooled analysis. J Urol 2005 Mar;173(3):797-802.
http://www.ncbi.nlm.nih.gov/pubmed/15711272
4. Taylor JA III, Koff SG, Dauser DA, et al. The relationship of ultrasensitive measurements of
prostatespecific antigen levels to prostate cancer recurrence after radical prostatectomy. BJU Int 2006
Sep;98(3):540-3.
http://www.ncbi.nlm.nih.gov/pubmed/16925750
5. Stephenson AJ, Kattan MW, Eastham JA, et al. Defining biochemical recurrence of prostate
cancer after radical prostatectomy: a proposal for a standardized definition. J Clin Oncol 2006
Aug;24(24):3973-8.
http://www.ncbi.nlm.nih.gov/pubmed/16921049
6. Boccon-Gibod L, Djavan WB, Hammerer P, et al. Management of prostate-specific antigen relapse in
prostate cancer: a European Consensus. Int J Clin Pract 2004 Apr;58(4):382-90.
http://www.ncbi.nlm.nih.gov/pubmed/15161124
7. Moul JW. Prostate specific antigen only progression of prostate cancer. J Urol 2000 Jun;163(6):
1632-42.
http://www.ncbi.nlm.nih.gov/pubmed/10799151
8. Schild SE, Wong WW, Novicki DE, et al. Detection of residual prostate cancer after radical
prostatectomy with the Abbott Imx PSA assay. Urology 1996 Jun;47(6):878-81.
http://www.ncbi.nlm.nih.gov/pubmed/8677580
9. American Society for Therapeutic Radiology and Oncology Consensus Panel. Consensus statement:
guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997 Mar;37(5):1035-41.
http://www.ncbi.nlm.nih.gov/pubmed/9169810
10. Roach III M, Hanks G, Thames jr H, et al. Defining biochemical failure following radiotherapy with or
without hormonal therapy in men with clinically localized prostate cancer: recommendations of the
RTOG-ASTRO Phoenix consensus conference. Int J Radiat Oncol Biol Phys 2006 Jul;65(4):965-74.
http://www.ncbi.nlm.nih.gov/pubmed/16798415
11. Aus G. Current status of HIFU and cryotherapy in prostate cancer - a review. Eur Urol 2006 Nov;50(5):
927-34.
http://www.ncbi.nlm.nih.gov/pubmed/16971038
12. Stamey TA, Kabalin JN, McNeal JE, et al. Prostate specific antigen in the diagnosis and treatment of
adenocarcinoma of the prostate. II. Radical prostatectomy treated patients. J Urol 1989 May;141(5):
1076-83.
http://www.ncbi.nlm.nih.gov/pubmed/2468795
13. Partin AW, Pearson JD, Landis PK, et al. Evaluation of serum prostate-specific antigen velocity
after radical prostatectomy to distinguish local recurrence from distant metastases. Urology 1994
May;43(5):649-59.
http://www.ncbi.nlm.nih.gov/pubmed/7513108
14. Trapasso JG, deKernion JB, Smith RB, et al. The incidence and significance of detectable levels of
serum prostate specific antigen after radical prostatectomy. J Urol 1994 Nov;152(5 Pt 2):1821-5.
http://www.ncbi.nlm.nih.gov/pubmed/7523728
15. Oefelein MG, Smith N, Carter M, et al. The incidence of prostate cancer progression with
undetectable serum prostate specific antigen in a series of 394 radical prostatectomies. J Urol 1995
Dec;154(6):2128-31.
http://www.ncbi.nlm.nih.gov/pubmed/7500474
16. Leibman BD, Dilliouglugil O, Wheeler TM, et al. Distant metastasis after radical prostatectomy in
patients without an elevated serum prostate specific antigen level. Cancer 1995 Dec;76(12):2530-4.
http://www.ncbi.nlm.nih.gov/pubmed/8625081
17. Ray ME, Thames HD, Levy LB, et al. PSA nadir predicts biochemical and distant failure after external
beam radiotherapy for prostate cancer: a multi-institutional analysis. Int J Radiat Oncol Biol Phys 2006
Mar;64(4):1140-50.
http://www.ncbi.nlm.nih.gov/pubmed/16198506
18. Hancock SL, Cox RS, Bagshaw MA. Prostate specific antigen after radiotherapy for prostate cancer:
a reevaluation of long-term biochemical control and the kinetics of recurrence in patients treated at
Stanford University. J Urol 1995 Oct;154(4):1412-17.
http://www.ncbi.nlm.nih.gov/pubmed/7544843
19. Chaplin BM, Wildhagen MF, Schroder FH, et al. Digital rectal examination is no longer necessary in the
routine follow-up of men with undetectable prostate specific antigen after radical prostatectomy: the
implications for follow-up. Eur Urol 2005 Aug;48(6):906-10.
http://www.ncbi.nlm.nih.gov/pubmed/16126322118 
17. FOLLOW-UP AFTER HORMONAL TREATMENT
17.1 Introduction
A large proportion of patients treated with hormonal therapy have either metastatic or locally advanced tumours at diagnosis. This will affect the scheme of follow-up because biochemical failure is often associated with rapid symptomatic progression.
17.2 Purpose of follow-up
The main objectives of following-up these patients are to:
• monitor the response to treatment;
• ensure compliance with treatment;
• detect potential complications of endocrine therapy;
• guide the modalities of palliative symptomatic treatment at the time of CRPC.
It is important to be clear about which complementary investigations are helpful at different stages of the disease to avoid unnecessary patient examinations and excessive economic cost. In addition, strict recommendations for follow-up procedures are only useful if effective therapeutic strategies are available in cases of disease progression. To date, the issue of early versus late initiation of non-hormonal treatment in CRPC has still not been resolved, so follow-up should be performed on an individual basis. Based on current knowledge, it is not possible to formulate level 1 evidence guidelines for follow-up procedures following hormonal therapy.
17.3 Methods of follow-up
17.3.1 Prostate-specific antigen monitoring
Prostate-specific antigen is a good marker for following the course of metastatic PCa. The initial PSA level can be a reflection of the extent of metastatic disease, although some poorly differentiated tumours do not secrete PSA. In recent decades, the PSA value has been used to predict the duration of response to endocrine treatment, based on either the initial pre-treatment value or the PSA decrease during the first 3-6 months. However, the prognostic value of the pre-treatment PSA value is variably assessed in the literature and should not be used alone to predict the duration of treatment response (1).

Treatment response may be assessed using the change in serum PSA level as a surrogate endpoint for survival in patients with newly diagnosed metastatic PCa after hormonal treatment has been initiated. Patients with the lowest absolute value of serum PSA (< 0.2 ng/mL) have been shown to have the best survival compared to patients with a value of 0.2-4.0 ng/mL or > 4.0 ng/mL (2). Similar results have been seen in other studies of locally advanced and metastatic PCa (3-5). The PSA response has been shown to be equally important in patients treated with hormonal therapy, following a rising PSA after treatments with curative intent (radical prostatectomy, radiation therapy). Patients with the best response also had the best survival (6,7).

Despite its usefulness in determining treatment response in individual patients, the role of PSA as a surrogate end-point in clinical trials is more controversial (8). After the initial phase of response to endocrine treatment, patients should be regularly monitored to detect and treat any complications of endocrine escape. Clinical disease progression occurs after a median interval of about 12-18 months of treatment in patients with stage M1 disease. It is well established that regular PSA control in asymptomatic patients allows the earlier detection of biochemical escape because a rise in PSA level usually precedes the onset of clinical symptoms by several months. However, it must be stressed that the PSA level is not the absolute marker of escape and should not be used alone as a follow-up test. Clinical disease progression (usually bone pain) with normal PSA levels has been reported to occur.
17.3.2 Creatinine, haemoglobin and liver function monitoring
Creatinine monitoring has some value because it can detect upper urinary tract obstruction in cases of advanced cancer, which might need to be relieved by, for example, percutaneous nephrostomy or a JJ-stent.

Haemoglobin and liver function tests may suggest disease progression and/or toxicity of hormonal treatment, which can lead to interruption of hormonal treatment (i.e. liver toxicity from non-steroidal antiandrogens). It is important to remember that haemoglobin levels will decrease by about 20% with androgen deprivation (9).

Alkaline phosphatase and its bone-specific isoenzymes have the advantage of not being directly influenced by hormonal therapy compared with PSA. These markers may be used to monitor patients with stage M1b disease. It should be remembered that increases in serum alkaline phosphatase may be due to androgen-induced osteoporosis (10), and in this context, it may be helpful to determine the level of bonespecific alkaline phosphatase.
17.3.3 Bone scan, ultrasound and chest X-ray
In routine practice, asymptomatic patients with a stable PSA level should not undergo a bone scan at regular intervals, because disease progression is more reliably detected by PSA monitoring, which also has a lower cost (11,12).

Moreover, it is also sometimes difficult to interpret bone scans. Thus, in an asymptomatic patient, the therapeutic approach is not modified by the appearance of a new site of uptake or deterioration of pre-existing lesions. Recently, the PCWG2 has clarified the definition of bone scan progression as the appearance of at least two new lesions (13).

Clinical or laboratory suspicion of disease progression indicates the need for a chest X-ray or renal and hepatic ultrasound. Imaging modalities must also be guided by symptoms. However, these examinations are not recommended for routine use in asymptomatic patients. In CRPC disease, follow-up examinations should be individualised with the aim of maintaining the patient’s quality of life.

During long-term ADT, it may be necessary to introduce regular measurement of BMD (LE: 3), based on the initial T-score (14). Bone mineral density should be measured every 2 years if the initial T-score < 1.0, or every year if the T-score is between 1.0 and 2.5, in the absence of associated risk factors (LE: 4). Otherwise, active protective bone treatment should have started at the initiation of ADT (see Chapter 12).
17.4 Testosterone monitoring
Most PCa patients receiving LHRH analogues will achieve serum testosterone values at or below the castration level (< 20 ng/dL). However, about 13-38% of patients fail to achieve this therapeutic goal, while 2-17% of patients do not achieve a serum testosterone level below 50 ng/dL (15-17). Furthermore, up to 24% of men treated with LHRH analogues may experience testosterone surges (testosterone > 50 ng/dL) during long-term treatment upon re-administration of the agonist drug, which is described as the ‘acute on-chronic effect’ or ‘breakthrough responses’ (16,18).

In view of these findings, the measurement of serum testosterone levels, as well as serum PSA levels, should be considered as part of clinical practice for men on LHRH therapy. The timing of testosterone measurements is not clearly defined. The first evaluation of testosterone level can be recommended at 1 month after initiating LHRH therapy to check the nadir testosterone level achieved before re-administration of the agonist drug. A 6-month testosterone level assessment may be performed to evaluate the effectiveness of treatment and to ensure the castration level is being maintained. If it is not being maintained, switching to another LHRH agent or surgical orchiectomy can be attempted. In patients with a rising PSA and/or clinical signs of progression, serum testosterone must be evaluated in all cases to confirm a castrate-resistant state.
17.5 Monitoring of metabolic complications
Androgen deprivation therapy is beneficial in patients with prostate cancer, but has a greater range of complications than might be expected (see Chapter 12). The most common side-effects of low testosterone levels include hot flushes, lack of libido, erectile dysfunction, gynaecomastia and loss of bone mineral density. In addition, recent studies have suggested that men with low testosterone levels have a higher prevalence of metabolic complications (19), including insulin resistance, arterial stiffness, diabetes and metabolic syndrome. Research has shown that the metabolic syndrome is present in more than 50% of men undergoing longterm ADT, predisposing them to a higher cardiovascular risk (20). Men with metabolic syndrome are almost three times more likely to die of coronary heart disease and other cardiovascular diseases (21), which have now become the most common cause of death in prostate cancer patients, even exceeding prostate cancer mortality (22).

In view of these findings, a cardiology consultation may be beneficial in men with a history of cardiovascular disease and men older than 65 years prior to starting ADT. All patients should be screened for diabetes by checking fasting glucose and HbA1c (at baseline and then every 3 months [LE: 3]). In selected cases, glucose tolerance testing may be required. Men with impaired glucose tolerance and/or diabetes should be referred for an endocrine consultation. Patients on ADT should be given advice on modifying their lifestyle (e.g. diet, exercise, smoking cessation, etc.) and should be treated for any existing conditions, such as diabetes, hyperlipidaemia, and/or hypertension (23,24). The patient’s GP or family physician should probably be more involved in those patients at risk of cardiovascular disease, including monitoring of fasting glucose, lipids profile and blood pressure, which is recommended in all patients receiving long-term ADT. Furthermore, the risk-to-benefit ratio of ADT must be considered in patients with a higher risk of cardiovascular complications, especially if it is possible to delay starting ADT (19,25).

Monitoring bone health is also important, particularly serum levels of Vitamin D and calcium. If needed, supplements should be given so that the patient receives a daily intake of at least 1200 mg/day of calcium and 1000 UI of vitamin D. Preventive therapy with biphosphonates or denosumab should be considered in patients who have an initial T-score of less than -2.5 on dual-energy X-ray absorptiometry (DEXA), which is the definition of osteoporosis. However, optimal bone monitoring using DEXA is still controversial and should be prospectively evaluated. It is currently suggested that bone monitoring should be performed every 2 years after initiation of castration, provided there are no other risk factors (26), and every year if there are risk factors (27,28).
17.6 When to follow-up
After initiation of hormonal treatment, it is recommended that patients be followed-up at 3 and 6 months. These guidelines must be individualised, and each patient should be told to contact his physician in the event of troublesome symptoms.
17.6.1 Stage M0 patients
If there is a good treatment response, i.e. symptomatic improvement, good psychological coping, good treatment compliance, and a serum PSA level of less than 4 ng/mL, follow-up visits are scheduled every 6 months.
17.6.2 Stage M1 patients
If there is a good treatment response, i.e. good symptomatic improvement, good psychological coping, good treatment compliance, and a serum PSA level of less than 4 ng/mL, follow-up is scheduled every 3 to 6 months.
17.6.3 Castration-refractory PCa
Patients whose disease progresses, or who do not respond according to the criteria mentioned above, warrant an individualised follow-up scheme.
17.7 Guidelines for follow-up after hormonal treatment

17.8 References
1. Petros JA, Andriole GL. Serum PSA after antiandrogen therapy. Urol Clin North Am 1993
Nov;20(4):749-56.
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2. Hussain M, Tangen CM, Higano C, et al. Absolute prostate-specific antigen value after androgen
deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from
Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol 2006 Aug;24(24):3984-90.
http://www.ncbi.nlm.nih.gov/pubmed/16921051
3. Kwak C, Jeong SJ, Park MS, et al. Prognostic significance of the nadir prostate specific antigen level
after hormone therapy for prostate cancer. J Urol 2002 Sep;168(3):995-1000.
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4. Collette L, de Reijke TM, Schröder FH; EORTC Genito-Urinary Group. Prostate specific antigen: a
prognostic marker of survival in good prognosis metastatic prostate cancer? (EORTC 30892). Eur Urol
2003 Aug;44(2):182-9.
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5. Robinson D, Sandblom G, Johansson R, et al; Scandinavian Prostate Cancer Group (SPCG)-5.
Prediction of survival of metastatic prostate cancer based on early serial measurements of prostate
specific antigen and alkaline phosphatase. J Urol 2008 Jan;179(1):117-22; discussion 122-3.
http://www.ncbi.nlm.nih.gov/pubmed/17997442
6. D’Amico AV, Moul JW, Carroll PR, et al. Intermediate end point for prostate cancer-specific mortality
following salvage hormonal therapy for prostate-specific antigen failure. J Natl Cancer Inst 2004 Apr
7;96(7):509-15.
http://www.ncbi.nlm.nih.gov/pubmed/15069112
7. Stewart AJ, Scher HI, Chen MH, et al. Prostate-specific antigen nadir and cancer-specific mortality
following hormonal therapy for prostate-specific antigen failure. J Clin Oncol 2005 Sep 20;23(27):
6556-60.
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8. Collette L, BurzyKowski T, Carroll KJ, et al. Is prostate antigen a valid surrogate end point for survival
in hormonally treated patients with metastatic prostate cancer? Joint research of the European
Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and
AstraZeneca Pharmaceuticals. J Clin Oncol 2005 Sep 1;23(25):6139-48.
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9. Strum SB, McDermed JE, Scholz MC, et al. Anaemia associated with androgen deprivation in patients
with prostate cancer receiving combined hormone blockade. Br J Urol 1997 Jun;79(6):933-41.
http://www.ncbi.nlm.nih.gov/pubmed/9202563
10. Daniell HW. Osteoporosis due to androgen deprivation therapy in men with prostate cancer. Urology
2001 Aug;58(2 Suppl 1):101-7.
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11. Miller PD, Eardley I, Kirby RS. Prostate specific antigen and bone scan correlation in the staging and
monitoring of patients with prostatic cancer. Br J Urol 1992 Sep;70(3):295-8.
http://www.ncbi.nlm.nih.gov/pubmed/1384920
12. Sissons GR, Clements R, Peeling WB, et al. Can serum prostate-specific antigen replace bone
scintigraphy in the follow-up of metastatic prostatic cancer? Br J Radiol 1992;65(778):861-4.
http://www.ncbi.nlm.nih.gov/pubmed/1384917
13. Scher HI, Halabi S, Tannock I, et al; Prostate Cancer Clinical Trials Working Group. Design and end
points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone:
recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008 Mar
1;26(7):1148-59.
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14. Higano CS. Bone loss and the evolving role of bisphosphonate therapy in prostate cancer. Urol Oncol
2003 Sep-Oct;21(5):392-8.
http://www.ncbi.nlm.nih.gov/pubmed/14670551
15. Tombal B, Berges R. Corrigendum to: How good do current LHRH agonists control testosterone? Can
this be improved with Eligard®? [Eur Urol Suppl 4/8 (2005) 30-6]. Eur Urol 2006;49(5):937.
16. Morote J, Esquena S, Abascal JM, et al. Failure to maintain a suppressed level of serum testosterone
during long-acting depot luteinizing hormone-releasing hormone agonist therapy in patients with
advanced prostate cancer. Urol Int 2006;77(2):135-8.
http://www.ncbi.nlm.nih.gov/pubmed/16888418
17. Yri OE, Bjoro T, Fossa SD. Failure to achieve castration levels in patients using leuprolide acetate in
locally advanced prostate cancer. Eur Urol 2006 Jan;49(1):54-8; discussion 58.
http://www.ncbi.nlm.nih.gov/pubmed/16314038122 
18. Sharifi R, Browneller R; Leuprolide Study Group. Serum testosterone suppression and potential
for agonistic stimulation during chronic treatment with monthly and 3-month depot formulations of
leuprolide acetate for advanced prostate cancer. J Urol 2002 Sep;168(3):1001-4.
http://www.ncbi.nlm.nih.gov/pubmed/12187208
19. Saylor PJ, Smith MR. Metabolic complications of androgen deprivation therapy for prostate cancer.
J Urol 2009 May;181(5):1998-2006; discussion 2007-8.
http://www.ncbi.nlm.nih.gov/pubmed/19286225
20. Braga-Basaria M, Dobs AS, Muller DC, et al. Metabolic syndrome in men with prostate cancer
undergoing long-term androgen-deprivation therapy. J Clin Oncol 2006 Aug 20;24(24):3979-83.
http://www.ncbi.nlm.nih.gov/pubmed/16921050
21. Tsai HK, D’Amico AV, Sadetsky N, et al. Androgen deprivation therapy for localized prostate cancer
and the risk of cardiovascular mortality. J Natl Cancer Inst 2007 Oct 17;99:1516-24.
http://www.ncbi.nlm.nih.gov/pubmed/17925537
22. Lu-Yao G, Stukel TA, Yao SL. Changing patterns in competing causes of death in men with prostate
cancer: a population based study. J Urol 2004 Jun;171(6 Pt 1):2285-90.
http://www.ncbi.nlm.nih.gov/pubmed/15126804
23. Shahani S, Braga-Basaria M, Basaria S. Androgen deprivation therapy in prostate cancer and
metabolic risk for atherosclerosis. J Clin Endocrinol Metab 2008 Jun;93(6):2042-9.
http://www.ncbi.nlm.nih.gov/pubmed/18349064
24. Mohile SG, Mustian K, Bylow K, et al. Management of complications of androgen deprivation therapy
in the older man. Crit Rev Oncol Hematol 2009 Jun;70(3):235-55.
http://www.ncbi.nlm.nih.gov/pubmed/18952456
25. Schwandt A, Garcia JA. Complications of androgen deprivation therapy in prostate cancer. Curr Opin
Urol 2009 May;19(3):322-6.
http://www.ncbi.nlm.nih.gov/pubmed/19318949
26. Conde FA, Aronson WJ. Risk factors for male osteoporosis. Urol Oncol 2003 Sep-Oct;21(5):380-3.
http://www.ncbi.nlm.nih.gov/pubmed/14670549
27. Higano CS. Bone loss and the evolving role of bisphosphonate therapy in prostate cancer. Urol Oncol
2003 Sep-Oct;21(5):392-8.
http://www.ncbi.nlm.nih.gov/pubmed/14670551
28. Hamdy RC, Baim S, Broy SB, et al. Algorithm for the management of osteoporosis. South Med J 2010
Oct;103(10):1009-15; quiz 1016.
http://www.ncbi.nlm.nih.gov/pubmed/20818296
18. TREATMENT OF BIOCHEMICAL FAILURE
AFTER TREATMENT WITH CURATIVE INTENT
18.1 Background
Primary curative procedures, such as RP and radiotherapy, are well-established therapeutic options in the management of localised PCa. Technical advances in surgery and radiation therapy have improved therapeutic efficacy and decreased treatment-associated morbidity and toxicity, respectively. However, despite these improvements, there is still a significant risk of cancer recurrence after therapy. Between 27% and 53% of all patients undergoing RP or radiation therapy develop local or distant recurrences within 10 years of initial therapy and 16-35% of patients receive second-line treatment within five years of initial therapy (1-5,6).
18.2 Definitions
18.2.1 Definition of treatment failure
Treatment failure was previously defined as recurrence on DRE or the development of metastatic disease. Currently, treatment failure is defined as a rising PSA level based on a study of Pound et al. (7), which showed that no patient followed for more than five years developed any recurrence without a concomitant rise in PSA. The level of PSA that defines treatment failure differs between men who have undergone RP and men treated with radiotherapy. Following radical retropubic prostatectomy (RRP), there is an international consensus that recurrent cancer may be defined by two consecutive values of PSA > 0.2 ng/mL (6,8). However, the most appropriate definition of biochemical progression after RP remains uncertain. A retrospective analysis of 2782 men who had undergone RP for clinically localised PCa (9) was used to determine the best PSA cut-off point for defining biochemical recurrence. Another study found that once PSA recurrence was detected, there was a subsequent increase in PSA in 49%, 62% and 72% of patients with PSA levels of 0.2 ng/mL, 0.3 ng/mL, and 0.4 ng/mL, respectively (9). These data indicate that only half of patients with a PSA of 0.2 ng/mL will show further progression and can therefore be managed initially by surveillance.

Similar data have been presented by Stephenson et al. (10). The study identified a PSA value of > 0.4 ng/mL as the best cut-off level to explain the development of distant metastasis among 10 candidates. This level was estimated using definitions developed from a retrospective review of 75 patients, who had developed distant metastases following RP. A cut-off of 0.4 ng/mL is therefore appropriate to define progression with clinical relevance, i.e. necessitating salvage treatment. Following radiotherapy, three consecutive increases in PSA are considered to provide a reasonable definition of biochemical relapse, according to ASTRO (11). This new definition indicates a relapse if the PSA increase is > 2 ng/mL higher than the PSA nadir value, independent of the serum concentration of the nadir (12).
18.2.2 Definitions of recurrence
A recurrence of CaP can be defined as:
• Following RP, PSA values > 0.2 ng/mL confirmed by two consecutive measures.
• Following radiotherapy, a PSA value of 2 ng/mL above the nadir after radiotherapy.
18.3 Local or systemic relapse
Once a PSA relapse has been diagnosed, it is of major importance to determine whether the recurrence has developed at local or distant sites. About 50% of patients who have undergone radical retropubic prostatectomy will have local disease, while the remainder will have either distantdisease alone, or distant and local disease (11).
Several important parameters help to differentiate between local or distant relapse:
• timing of the PSA increase after surgery;
• PSA velocity;
• PSA doubling time (PSA DT);
• pathohistological stage;
• Gleason score of the prostatectomy specimen.
PSA elevations developing within the first 2 years following surgery are more often associated with distant recurrences (12). It has been shown that a median PSADT of 4.3 months might be associated with distant relapse, whereas a median PSA DT of 11.7 months predicts local failure (13). According to a recent study (14), a PSA velocity of < 0.75 ng/mL/y was observed in 94% of patients with local recurrence, whereas 56% of patients with distant metastases demonstrated a PSA velocity of > 0.75 ng/mL/y. There is no indication to perform ultrasound-guided biopsies of the vesicourethral anastomosis to diagnose local relapse as this method has low sensitivity and low predictive accuracy in men with rising PSA levels < 1.0 ng/mL.With radiotherapy, any continuously rising PSA following a nadir after radiation is an indicator for local recurrence, systemic metastatic spread or a combination of both (11,14-16). However, due to the well- known PSA bounce phenomenon, biochemical recurrence is defined by a PSA rise of 2 ng/mL above the PSA nadir according to ASTRO guidelines. After radiotherapy, a late and slowly rising PSA is a sign of local failure only.
Local recurrence of PCa is defined by:
• a prostatic biopsy demonstrating malignant cells at 18 months or longer after initial radiotherapy;plus
• an associated rise in PSA, although prostate biopsy is only indicated if the patient is a candidate for asecondary local salvage therapy with curative intent;plus
• no evidence of metastatic spread documented by CT or MR imaging and bone scintigraphy.
18.3.1 Definition of local and systemic failure
The definitions of local and systemic failure are as follows:
• Local failure following RP is predicted with an 80% probability by a PSA increase at 3 years after RP, aPSA DT > 11 months, a Gleason score < 6, and stage < pT3a pN0, pTx R1.
• Systemic failure following RP is predicted with > 80% accuracy by a PSA increase.
• At less than 1 year after RP, there is a PSA DT of 4-6 months, a Gleason score of 8-10, and stagepT3b, pTxpN1.
• Local failure after radiotherapy is documented by a positive prostatic biopsy and negative imaging studies.
• Prostatic biopsy after radiotherapy is necessary only if local procedures, such as salvage prostatectomy, are indicated in an individual patient.
18.4 Evaluation of PSA progression
Prior to an extensive diagnostic work-up in patients with PSA relapse following local treatment, men must be stratified into those who are candidates for salvage therapy and those who are not. Men must also be stratified into those who are candidates for local salvage treatment and those who might need systemic therapy. All diagnostic procedures should only be performed if the results will have therapeutic consequences.

In recent years, most patients with PSA progression following initial therapy with curative intent underwent physical and sonographic examinations, as well as radiology or biopsies of the prostatic fossa and the vesicourethral anastomosis to confirm the recurrence identified by serological studies. For patients with asymptomatic PSA-only progression, the yield is very low. Lange et al. (14) have shown that biochemical failure precedes clinical disease by 6-48 months.

In general, DRE is not useful in men with undetectable or very low PSA levels. In a recent study by Öbek et al. (17), it was shown that only 4/72 patients (5.5%) with a PSA recurrence following RP had an abnormal DRE.Imaging studies are used to differentiate local from systemic relapse to help select the most appropriate treatment modality. However, it must be remembered that most imaging studies are probably not sensitive enough to identify the anatomical location of relapsing PCA at PSA levels < 0.5-1.0 ng/mL.
18.4.1 Diagnostic procedures for PSA relapse following RP
Traditionally, bone scans and abdominal CT scans have been used to evaluate PSA elevations following primary treatment. However, both imaging studies have low sensitivity and specificity and can be safely omitted in the routine work-up of relapsing patients. A recent study (18) looked at bone scans in 144 patients, 122 of whom had undergone RP without hormone treatment, while 22 had received either neoadjuvant or adjuvant androgen-deprivation therapy (ADT). Bone scans in 93 patients with PSA recurrence identified metastatic disease in only 4.1% of men who had undergone RP and 27% of men who had been treated with ADT. The lowest PSA associated with positive findings was 46 ng/mL in the absence of adjuvant ADT, whereas the lowest PSA value was 15.47 ng/mL in patients who had received hormonal therapy.

The probability of a positive bone scan remains < 5% until the serum PSA reaches at least 40 ng/mL. Similar data have been achieved by other groups, which have demonstrated that patients with a true positive bone scan had an average PSA level of > 60 ng/mL and a PSA velocity of 22 ng/mL/year (19,20). Logistic regression analysis showed that PSA and PSA velocity were good predictors of bone scan results and PSA velocity for CT scan results. Of 132 patients with biochemical recurrence, 9.4% had a positive bone scan and 14% had a positive CT scan. However, there may be a slight difference between patients after radical retropubic prostatectomy and patients after radiation therapy, as shown by Johnstone et al. (21), who found that 5% and 30%, respectively, of bone scans, were positive.

In summary, bone scintigraphy and CT scans are of no additional diagnostic value, unless the PSA serum levels are higher than 20 ng/mL or the PSA velocity is more than 20 ng/mL/year.Endorectal coil imaging is a useful technique to detect local recurrences after RP (22). In a series of 48 patients, local recurrence was correctly identified in 81%, with the mean PSA being 2 ng/mL at diagnosis.The diagnostic accuracy of endorectal MRI (eMRI) was investigated in a series of 72 men with PSA relapse following RP (23). The mean total PSA was1.23 +/- 1.3 ng/mL, with men undergoing eMRI using a 1.5-Tesla system. The data were compared to standard references for local recurrence, including prostatectomy bed biopsy results, choline positron emission tomography results, PSA reduction or increase after pelvic radiotherapy, and PSA modification during active surveillance. Sensitivity, specificity, predictive positive value, negative predictive value and accuracy were 61.4%, 82.1%, 84.4%, 57.5% and 69.4% for unenhanced eMRI, and 84.1%, 89.3%, 92.5%, 78.1% and 86.1% for enhanced eMRI. The two evaluations showed a statistically significant difference in accuracy (chi(2) = 5.33, p = 0.02) and sensitivity (chi(2) = 9.00m, p = 0.0027). Although eMRI appears to be very sensitive and predictive in identifying local recurrences following RP, it is currently not a routine imaging modality to be performed in every case, as local versus systemic relapsemust be differentiated at PSA levels < 0.5 ng/mL (see Section 18.6). At this PSA level, eMRI is not sufficiently sensitive or accurate.

Positron emission tomography (PET) has been successfully applied in many human cancers for early identification of local or systemic recurrences. In PCa, there are few, but promising, published data on the clinical efficacy of PET in detecting local recurrences after RP (23-25). However, it must be kept in mind that the uptake of 11C-choline is not specific for PCa and may also be due to inflammatory intraprostatic lesions.

In a series of 31 patients with biochemical progression after RP, 11C-acetate-PET demonstrated a high sensitivity and specificity for the detection of local recurrences when the PSA serum level was > 1 ng/mL (24). In another recent series of 43 patients with newly diagnosed CaP, there was a significant correlation between 11C-choline uptake and the intraprostatic location of PCa in RP specimens (26). Similar results have been reported for the detection of locally recurrent PCa after radiation therapy (27). However, 11C-PET was significantly less sensitive at detecting extraprostatic extension compared with MRI.

The most recent series evaluating the role of 11C-choline PET/CT in men with biochemical recurrence after RP have shown that metastases were more likely to be identified at higher PSA levels. 11C-choline PET/CT was able to locate metastases in 20-36% of men with PSA levels < 1 ng/mL, increasing to 63-83% of men with PSA levels > 3 ng/mL (28-31).

In 190 patients with PSA relapse following RP, Castelucci et al. (32) investigated how the 11C-choline PET/CT detection rate was affected by:
• trigger PSA level (i.e. total PSA level at the time of the scan);
• PSA velocity (PSA VEL);
• PSA doubling time (PSA DT) (Table 20).
The study found that the mean PSA relapse was 4.2 ng/mL (median 2.1, range 0.2-25.4). Disease relapse was detected by 11C-choline PET/CT in 74/190 patients (38.9%). The study also found that trigger PSA values were statistically different between PET-positive patients (median PSA 4.0 ng/mL) and PET-negative patients (median PSA 1.4 ng/mL) (p = 0.0001), with the optimal cutoff point for trigger PSA being 2.43 ng/mL. In 106 patients, PSA DT and PSA level values were statistically different between patients with PET-positive (p = 0.04) and PETnegative scans (p = 0.03).

Table 20: Relationship between different measurements of PSA and 11C-choline PET/CT detection rate

A recent publication from Giovacchini et al. (32) comprising 109 patients with rising PSA level and negative conventional imaging studies concluded that 11C-choline PET/CT might be helpful in restaging PCA but it should not be used to guide therapy. The authors found that only 12 of 109 patients (11%) had positive PET/CT findings. Scans were positive in 5%, 15%, and 28% of patients with PSA < 1ng/mL, between 1 and 2 ng/mL, and > 2ng/mL, respectively (p < 0.05). The use of 11C-choline PET/CT in all men with a rising PSA level > 1 ng/mL would result in 85% incidence of unnecessary examinations, significant increase of medical costs, and no benefit for the individual patient.

Another retrospective study of 37 patients scheduled for salvage radiation therapy after RP (34) reported that about 13% of the patients demonstrated 11C-choline PET/CT-positive lymph nodes outside the prostatic fossa, implicating an extension of the target volume. However, none of the lesions was verified histologically, and the mean PSA of choline-positive patients (1.1 ng/mL, range 0.5-1.8 ng/mL) was significantly higher than in 11C-choline PET/CT-negative patients (0.4 ng/mL, range: 0.3-0.7 ng/mL).

The most recent review published by Picchio et al. (35) has concluded that the routine use of 11C-choline PET/CT cannot be recommended for PSA values < 1 ng/mL. Its accuracy is correlated to PSA value, PSA DT, and other pathological features. The authors propose that 11C-choline PET/CT may be proposed as a guide for individualised treatment of recurrence. A similar conclusion can be made from another recent study by Castellucci et al (32).

However, the indication to perform 11C-choline PET/CT must be placed in the context of the above-mentioned clinical parameters. It therefore remains doubtful whether a patient with elevated PSA, rapid PSA DT and a prostatectomy Gleason score > 8 will receive therapy other than ADT based on the findings of 11C-choline PET/CT.

In summary, the role and the diagnostic accuracy of 11C-choline PET/CT in men with rising PSA following RP is dependent on the absolute PSA, PSA DT, and PS AV. The higher the PSA level and the faster PSA DT, the better the predictive value of this imaging modality. However, even in patients with PSA values > 2 ng/mL and negative imaging studies, 11C-choline PET/CT is positive in only 28% of patients. There is therefore an urgent need for well-conducted and histologically controlled trials to explore the potential role of 11C-choline PET/CT.

The role of choline PET/CT to detect local or systemic recurrences in men with PSA relapse following radiotherapy is unclear and based on very few studies (36,37). Thus, no final recommendations can be made. Its sensitivity and specificity with regard to the detection of lymph node metastases are less reliable, and the routine use of 11C-PET cannot therefore be recommended, especially not for PSA values < 1 ng/mL.

It has been common practice to perform transrectal ultrasound (TRUS)-guided biopsies of the prostatic fossa, the anastomosis or the prostate gland to exclude local recurrence after radical retropubic prostatectomy or radiotherapy. However, according to available studies, routine biopsy of the vesicourethral anastomosis appears not to be justified based on a verification rate of only 54% (38-40). Only in the presence of a palpable lesion or a hypoechoic lesion on TRUS can the diagnostic yield of the biopsy be improved to approximately 80%. Furthermore, there is a strong correlation between the positive biopsy rate and PSA serum concentrations (38-40); 28% and 70% of the biopsies were positive if the PSA level was, respectively, below 0.5 ng/mL or greater than 2.0 ng/mL.Thus, it is now commonsense that routine anastomotic biopsy is not indicated, and the use of PSA and PSA DT is sufficient for clinical practice. In addition, PSA-free survival in biopsy-proven recurrences does not differ significantly compared with PSA-only recurrences.

18.4.2 Diagnostic studies for PSA relapse following radiation therapy
With regard to PSA relapses following radiation therapy, routine prostate biopsy should no longer be performed for the evaluation of PSA-only recurrences, according to an ASTRO consensus recommendation (15). However, prostate biopsy documenting local recurrence represents the main cornerstone in the decision-making process for salvage RP in patients with rising PSA levels following a nadir after radiation therapy (41). It is a general recommendation to wait about 18 months and three months following radiation therapy or seeds, and cryotherapy or high-intensity focused ultrasound (HIFU), respectively. Patients with rising PSA and viable cancer on biopsy 2 years after radiation therapy have true locally recurrent disease and might be candidates for salvage RP.

Recent studies have evaluated the role of eMRI, MRI spectroscopy and dynamic-contrast enhanced MRI in the identification of locally recurrent PCA following radiation therapy (42-44). These studies have demonstrated that locally recurrent PCA can be differentiated from benign nodules due to the low T2-weighted signal intensity. Endorectal MRI and MR spectroscopy were more sensitive than TRUS or TRUS-guided prostate biopsiesto detect viable PCa. Endorectal MRI has also contributed important information about the presence of extraprostatic extension and seminal vesicle invasion with a sensitivity of 86% and a specificity of 96%.Endorectal MRI is therefore strongly recommended in the diagnostic work-up of men with PSA relapse after radiation therapy, who might be candidates for secondary local salvage therapy with curative intent.
18.4.3 Diagnostic procedures in patients with PSA relapse
Following RP, CT scans of the pelvis and abdomen are of low sensitivity and specificity in patients with PSA levels < 20 ng/mL or a PSA velocity of < 2 ng/mL/y. Endorectal MRI or PET scans may help to detect local recurrences if PSA is > 1.0 ng/mL, but is not routine clinical practice for the early detection of local relapses. Following radiation therapy, local recurrence is documented by a positive biopsy > 18 months after the procedure. Endorectal MRI is of valuable importance for men who are candidates for radical salvage prostatectomy.
18.5 Treatment of PSA-only recurrences
The timing and mode of treatment of PSA-only recurrence after RP or radiation therapy remains controversial.
After RRP observation, the therapeutic options are:
• radiation therapy to the prostatic bed;
• (complete) androgen blockade (CAB);
• intermittent androgen deprivation (IAD);
• combination of antiandrogens with 5-α-reductase inhibitors;
• early chemohormonal approaches.
These same therapeutic options may be applied to PSA recurrences following radiation therapy. In addition, salvage prostatectomy, cryotherapy or brachytherapy may be indicated in carefully selected patients.
18.5.1 Radiation therapy for PSA-only recurrence after RP
Three large RCTs in adjuvant radiation have now been published (45-48). All three trials showed a benefit with adjuvant radiotherapy of at least 15% at 5 years in biochemical recurrence-free survival.

The largest trial (EORTC-22911, n = 1005) (46) and the smallest trial (ARO-96-02, n = 307) (47) trial were powered to detect a benefit in biochemical disease recurrence-free survival, while metastasis-free survival was the primary endpoint of the third trial, SWOG-S8794 (n = 431) (47). The three trials had similar inclusion criteria;however, the EORTC trial also included pT2R1 patients, while the other two trials allowed only pT3 cancers with or without a positive resection margin. In all three trials, quite a high proportion of patients (63-68%) had a positive surgical margin.

It should be noted that the post-operative PSA level of men before they were randomised to adjuvant radiotherapy was different between the three trials. In the German ARO-96-02 trial, only men with a PSA < 0.1 ng/mL were eligible for randomisation. In the EORTC trial, 11% of men had a PSA level > 0.2 ng/mL prior to randomisation and 34% in the SWOG trial. Thus, a substantial number of patients in the EORTC and SWOG trials received ‘salvage‘ radiation therapy rather than adjuvant radiotherapy for a non-normalised PSA. It is therefore interesting that not all men in the non-adjuvant arms of the trials were treated with salvage radiotherapy by the time of a biochemical recurrence: delayed or salvage radiotherapy to the prostatic fossa was administered to 55% of men with a rising PSA level in the EORTC trial and to 33% of men in the SWOG trial. Thus, the trials were not able to evaluate whether adjuvant radiation was superior to salvage radiation as in the control arm, as at most only half of the men received radiation at the time of PSA recurrence.

Indeed, the authors of the EORTC trial suggested that salvage radiation may be equivalent to adjuvant therapy provided the PSA is lower than 1 ng/mL (46). However, only the SWOG trial was powered to address the effect of delayed radiation since it was the only trial with metastasis-free survival as the primary endpoint. In the SWOG trial, men in the control arm were less likely to receive salvage radiation (33%). However, it took a median follow-up of over 12 years before metastasis-free survival improve d in the adjuvant treatment arm suggesting that adjuvant therapy may not be helpful in men with a life expectancy < 10 years (45,47). Recently, it has been demonstrated that patients in the control group had a higher frequency of Gleason score 8-10 CaP and were more likely to not receive ADT at the time of PSA relapse.
There have been many studies on the use of radiation therapy for PSA-only recurrence following RRP. As a result there is a growing body of parameters predicting outcome that may help to differentiate between the need for observation, radiation or hormonal therapy. As confirmed by various studies, the pre-radiation PSA level is critically important for optimal treatment results (41-44,49-53):
• Applying a pre-radiation cut-off of < 2.5 ng/mL, Wu et al. (49) and Schild et al. (50) reported diseasefree survival rates of 53% and 76%, compared with 8% and 26%, respectively, for patients with PSA serum levels > 2.5 ng/mL.
• Forman et al. (51) demonstrated a disease-free survival rate of 83% versus 33% in patients with aPSA-only recurrence of < 2.0 ng/mL and greater than 2.0 ng/mL, respectively.
• Nudell et al. (52) even reported progression-free survival rates of 58% and 21% in patients having undergone radiation of the prostate bed if PSA serum levels were below 1.0 ng/mL or greater than 1.0 ng/mL, respectively.

Based on these data, ASTRO has published a consensus paper recommending a dose of at least 64 Gy when the PSA level is < 1.5 ng/mL after RRP (15). Furthermore, recent papers (53-58) have corroborated the data of early salvage radiation therapy demonstrating a significant difference in 5-year biochemical-free and overall survival rates in patients treated for PSA-recurrence only or for palpable local recurrence. In another study, Stephenson et al. (59) evaluated prognostic models to predict the outcome of salvage radiation therapy on a cohort of 1603 men with PSA progression after RP and operated on in 17 North American tertiary referral centres.

The authors identified a significant relationship between PSA serum concentration at the time of radiation therapy and therapeutic outcome: the 6-year biochemical-free survival was 48% in men with PSA < 0.5 ng/mL, but only 40%, 28%, and 18% in men with PSA levels of 0.51-1 ng/mL, 1.01-1.5 ng/mL and > 1.5 ng/mL, respectively.
For the SWOG and EORTC non-adjuvant radiotherapy arms, the median interval to salvage radiotherapy was 2 and 2.2 years, respectively. In the SWOG 8974 study, 23% of men had a PSA > 1.5 ng/mL prior to salvage radiation. In a subanalysis of the SWOG 8974 trial, Swanson et al. (60) showed that men in all categories of post-prostatectomy PSA level (< 0.2, 0.2-1.0, > 1.0 ng/mL) showed an improvement with salvage radiotherapy in metastasis-free survival. However, the therapeutic benefit was most evident in the presence of minimal PSA serum levels. These data suggest that, although less effective, salvage radiation treatment may help improve metastasis-free survival.

In a recent multi-institutional, matched-control analysis of adjuvant and salvage post-operative radiation for pT3-4N0 PCa, Trabulsi et al. (61) have demonstrated a biochemical recurrence-free survival advantage in favour of adjuvant radiotherapy versus salvage radiotherapy. Interestingly, in a multivariate Cox regression analysis, adjuvant versus salvage radiotherapy were not independent predictors in metastatic progression-free survival, when corrected for adverse clinical and pathological factors.

Recently, data on overall survival and salvage radiation have become available. In a group of men with a median follow-up of 9 years after prostatectomy, the benefit of salvage radiation for prostate cancerspecific mortality was seen particularly in men with a PSA DT of less than 6 months, who had been given salvage radiation to the prostate fossa within 2 years after a rise in PSA (62). This suggests that local disease control may prolong prostate cancer-specific survival in men formerly thought to be at risk for systemic disease progression and less likely to benefit from (salvage) radiation. It has been suggested that men with slowly progressing disease, even though still at risk of systemic progression, may not benefit from salvage radiotherapy because they have a low risk of development of lethal PCa. Certainly, longer follow-up is needed to answer this question.
However, more data are required from prospective randomised trials.
18.5.1.1 Dose, target volume, toxicity
The three randomised trials on adjuvant radiation therapy all used dosages less than 66 Gy, which is currently the most frequently used dose for adjuvant and salvage radiation. However, it is important to note that, as with dose escalation studies in primary radiation for PCa, an increased dose in the salvage setting may improve the biochemical response without worsening local toxicity (63,64). Dosages up to 70 Gy showed better biochemical recurrence-free rates at higher doses, with 66.8 Gy radiation found to be the dose required for
50% biochemical recurrence-free survival (TCD50). Even higher doses may be considered, particularly when using improved imaging techniques, such as fiducial markers (65). The finding that 9% of men develop a local recurrence after adjuvant radiation of 60 Gy provides support for an increase in dosage and target volume (60). Target volume delineation has been found to vary by up to 65% between different radiotherapists administering adjuvant or salvage radiation to the prostatic fossa (66,67), despite the presence of guideline (68). It is therefore important not to overlook local toxicity. In the EORTC 22911 study, 3.1% of men had to interrupt adjuvant radiation because of local complaints, mainly diarrhoea. Although grade 3 or 4 toxicity is rare for either adjuvant or salvage radiation to the prostate fossa, it was almost doubled in the adjuvant arm of the EORTC 22911 study (2.6% vs 4.2%) and the SWOG S8794 study, particularly urethral stricture (relative risk [RR], 9) and incontinence (RR, 2.3).
18.5.2 Hormonal therapy
Systemic failure following RP is predicted with > 80% accuracy by PSA relapse < 1 year, PSA DT of 4-6 months, Gleason score 8-10 and stage pT3b, pTxpN1. There is some evidence that early hormonal therapy may help to delay progression and possibly achieve a survival benefit (69,70).
18.5.2.1 Adjuvant hormonal therapy after RP
In the absence of randomised controlled trials for post-operative PSA recurrence, it is necessary to rely on retrospective data or to extrapolate data from other clinical settings, such as men with metastatic disease or locally advanced non-metastatic disease. It is uncertain whether or not such data are relevant to men with rising post-operative PSA levels.

Two randomised studies have compared immediate hormonal therapy (after diagnosis) with deferred hormonal therapy (on progression) in patients with PCa. The Medical Research Council study in locally advanced or asymptomatic metastatic PCa and the EORTC study in newly diagnosed PCa (T0-4N0M0) illustrate that, although immediate hormonal therapy after diagnosis can delay disease progression in men with PCa, it does not necessarily result in an improved cancer-specific survival (71,72).The survival advantage for immediate (adjuvant) ADT after RP has only been proven in patients with positivelymph-node PCa in a single randomised study (69,70). The updated results of this multicentre Eastern Cooperative Oncology Group study after a median follow-up of 11.9 years showed a significant improvement in overall survival, cancer-specific survival, and progression-free survival in lymph-node positive (N+) patients treated with immediate ADT (70).

Adjuvant bicalutamide, 150 mg, could decrease progression in men with locally advanced PCa, but did not result in an overall survival benefit (73). Several retrospective analyses from the Mayo Clinic showed that adjuvant hormonal therapy after RP had a positive effect on time to progression and cancer death in patients with pT3b and N+ PCa (74-76). However, a recent large series from the Mayo Clinic with a median follow-up of 10.3 years showed that adjuvant hormonal therapy in patients with surgically managed N+ PCa decreased the risk of biochemical recurrence and local recurrence, but did not significantly impact systemic progression or cancer-specific survival (77). A recent retrospective study with a median follow-up of 5.2 years showed that immediate and delayed hormonal therapy (at PSA recurrence) in patients with surgically managed N+ PCa
provided similar outcomes (78).

An observational study showed that deferring immediate ADT in men with positive lymph nodes after RP may not significantly compromise survival. There was no statistically significant difference in survival with 90, 150, 180 and 365 days as the definition of adjuvant ADT. These results need to be validated in a prospective study (79).

18.5.2.2 Post-operative hormonal therapy for PSA-only recurrence
Androgen deprivation therapy
Although patients with post-operative PSA recurrence often undergo ADT before evidence of metastatic disease, the benefit of this approach is uncertain. A retrospective study including 1352 patients with postoperative PSA recurrence showed no significant difference in the time to clinical metastases with early ADT (after PSA recurrence, but before clinical metastases) versus delayed ADT (at the time of clinical metastases). However, upon risk stratification, early ADT could delay the time to clinical metastases in high-risk patients with a Gleason score > 7 and/or a PSA DT < 12 months. Androgen deprivation therapy had no overall impact on prostate cancer-specific mortality (80).

A recent retrospective study from the Mayo Clinic showed that adjuvant ADT (within 90 days of surgery) slightly improved the cancer-specific survival and systemic progression-free survival after RP in a large group of high-risk patients with PCa. However, the survival advantage was lost when ADT was delivered farther in the disease process, at the time of PSA recurrence or systemic progression. It should be emphasised that there was no overall survival advantage (83% for both groups) and that the difference in cancer-specific survival and systemic progression-free survival was only 3% and 5%, respectively (81). In a recent retrospective study, including 422 patients with post-operative PSA recurrence, 123 developed distant metastasis, of whom 91 patients with complete data received deferred ADT at the time of documented metastasis after RP. The authors concluded that patients when closely followed after PSA recurrence may have an excellent response to deferred ADT and a long survival with a median failure time of 169 months from RP to death (82). However, these three studies are limited by their retrospective design and in assessing the side effects of long-term ADT. Evidence from well-designed, prospective, randomised studies is needed before the use of early hormonal therapy can be advocated in clinical practice.
Antiandrogens
Although gynaecomastia and breast tenderness were the most predominant side effects for the treatment of organ-confined and locally advanced PCa, the incidence of hot flushes, loss of libido and impotence was significantly lower than expected for luteinising hormone-releasing hormone (LHRH) agonists and CAB (83). Antiandrogens may represent a viable alternative to other modes of androgen deprivation for the management of PSA-only recurrences, especially in young and otherwise healthy men. In a prospective, placebo-controlled, randomised trial of adjuvant bicalutamide, 150 mg, following RP in patients with locally advanced disease, the risk of objective progression of the disease was significantly reduced in patients receiving bicalutamide. However, overall survival did not differ between groups (84). Low-dose flutamide, 250 mg daily, is currently being investigated in men with PSA recurrence. Bicalutamide, 150 mg daily, has not yet been studied in this clinical setting (85).
Intermittent androgen deprivation
Intermittent androgen deprivation (IAD) has been examined as a potential alternative to CAD to:
• delay the time to androgen independence and hormone-refractory disease;
• minimise side-effects;
• reduce costs of prolonged therapy.
The Cochrane Collaboration revealed that there were no long-term data of large-scale randomised controlled trials that proved the superiority of IAD over CAD for survival. Limited information suggests that IAD may result in a slight reduction of adverse effects (86). However, in the setting of PSA-only recurrences, there are no prospective randomised trials and no clinical studies with sufficient data on long-term efficacy to justify the routine clinical application of IAD, despite its potential benefits. Summarising the series in which PSAonly recurrences were treated by IAD (87-91), PSA threshold levels at study-entry varied significantly, as did the PSA level at discontinuation of hormonal therapy. Only the study of 150 patients by Tunn et al. (91) had a sufficiently appropriate study design to allow the drawing of important clinical conclusions. Patients were
started on IAD for 9 months when the post-prostatectomy PSA serum level was greater than 3.0 ng/ mL, and all patients reached a nadir of less than 0.5 ng/mL. Intermittent androgen deprivation was re-started when PSA increased to more than 3.0 ng/mL. After a mean follow-up of 48 months, and a mean duration of hormonal therapy of 26.6 months, none of the patients had progressed to hormone-refractory disease. In the meantime, IAD remains attractive to selected, closely monitored and well-informed patients with post-operative PSA recurrence.
Minimal androgen blockade
In some studies, finasteride and flutamide have been combined to manage PSA-only recurrences since both agents work additively by blocking the intraprostatic conversion of testosterone to dihydrotestosterone (DHT) and blocking the intracytoplasmic DHT receptor (92-94). In the latest report (93) including 73 patients, the application of finasteride (10 mg/day) and low-dose flutamide (250 mg/day) resulted in a mean PSA nadir of 1.35 ng/mL within 6 months. However, only 62% of the patients studied reached a PSA nadir of < 0.2 ng/mL. After a mean follow-up of 15 months, none of the patients had progressed to traditional hormonal therapy. However, longer follow-up of a larger patient cohort is needed, and randomised phase III trials using modern antiandrogens with fewer gastrointestinal and hepatic side-effects are mandatory.

Hormonal therapy after RP combined with radiotherapy and/or chemotherapy
The addition of hormonal therapy to salvage radiotherapy (n = 78) was not associated with any additional increase in cancer-specific survival (94). A recent phase II trial including 74 patients with post-operative PSA recurrence showed that combined treatment with salvage radiotherapy plus 2 years of maximum androgen blockade (castration + oral antiandrogen) had relatively minor long-term effects on quality of life (95). However, more efficacy data are needed and the potential increase in side effects should be considered when combining therapies. Results are eagerly awaited from a recently completed randomised controlled phase III study from the Radiation Therapy Oncology Group (RTOG-9061) comparing radiotherapy + placebo versus the combination of radiotherapy + bicalutamide, 150 mg daily, in the post-operative setting.

Radiotherapy and Androgen Deprivation in Combination after Local Surgery is a recently started, large, randomised, controlled study, sponsored by the Medical Research Council. The study addresses the timing of radiotherapy (adjuvant vs early salvage) and the duration of hormonal therapy (none vs short-term vs longterm) used together with post-operative radiotherapy. The primary outcome measure will be cancer-specific survival. Secondary outcome measures will include overall survival, ADT administered outside the protocol, and reported treatment toxicity. The study also aims to assess the long-term effect of radiotherapy after RP on sexual, urinary and bowel function, and the long-term effect of ADT on sexual function and overall quality of life. Patients will be asked to complete four short questionnaires. These assessments will be done at baseline, 5 years and 10 years (96).

Currently, there is no indication for chemotherapy in patients with PSA-recurrence only. Chemotherapy should be considered as a treatment option for patients with castration-resistant PCa, but when to initiate a cytotoxic regime remains controversial (97).
18.5.3 Observation
Observation until the development of clinically evident metastatic disease might represent a viable option for patients with a Gleason score < 7, PSA recurrence longer than 2 years after surgery, and a PSA DT longer than 10 months. In these patients, the median actuarial time for the development of metastasis will be 8 years, and the median time from metastasis to death will be another 5 years (7).
18.5.4 Management of PSA relapse after RP

18.6 Management of PSA failures after radiation therapy
In a recent review of the data of the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) comprising 2336 patients with PCa, Grossfeld et al. (98) demonstrated that 92% of patients initially irradiated received ADT for secondary treatment of PSA progression. In the absence of salvage procedures, the mean time interval from biochemical to clinical progression is approximately 3 years. Therapeutic options in these patients are ADT or local procedures, such as salvage RP, cryotherapy and interstitial radiation therapy (41,99-108). Salvage RRP has not, however, gained widespread acceptance because of its associated morbidity, namely incontinence, local recurrences and rectal injuries. However, in well-selected patients, the procedure may result in long-term disease-free survival.
18.6.1 Salvage radical prostatectomy
Previously, most series reporting on salvage RP have included patients treated in the pre-PSA era without modern radiotherapeutic techniques, when local recurrences were usually detected at a late stage. Complications associated with the procedure were therefore quite high, with up to 65% of patients suffering from treatment-related morbidities. Up to 60% of patients who underwent salvage RP had to undergo anterior or total exenteration for locally extensive disease, associated with a high rate of local recurrences and a mean time to progression of only 1.3 years.

Recent reports analysing patients who were operated on during the past decade, have described far more optimistic outcomes after salvage RP. In the series examined by Gheiler et al. (103), 40 patients with a mean PSA of 14 ng/mL underwent salvage RP. When stratified by PSA < 10 ng/mL, the 3-year disease-specific survival was 68% and 26%, respectively. In the series reported by Garzotto and Wajsman (104), 24 patients underwent radical cystoprostatectomy or RP with neoadjuvant ADT. Neoadjuvant ADT was associated with a lower rate of positive surgical margins (21%) compared with patients in whom androgen deprivation failed and who exhibited a positive surgical margin rate of 80%. The authors demonstrated that disease-specific survival correlated strongly with the surgical margin status. At a mean follow-up of 5 years, the disease-specific survival rate was 95% and 44% for those with negative and positive surgical margins, respectively. Vaidya and Soloway
(105) demonstrated a low rate of complications, good post-operative continence and only one biochemical recurrence at 36 months after salvage RP.

Similar data have been achieved by Stephenson et al. (106), who reported on 100 consecutive patients undergoing salvage RP associated with a very low rate of peri-operative complications. The 5-year progression-free rates have improved, with results similar to those of standard RP in cases of similar pathological stages. In contemporary series, the 10-year cancer-specific survival and overall survival rates are 70-75% and 60-66%, respectively. In most contemporary series, organ-confined disease, negative surgical margins and the absence of seminal vesicle and/or lymph node metastases are favourable prognostic indicators associated with a better disease-free survival of approximately 70-80%, compared with 40-60% in patients with locally advanced PCa (107).

Recently, Heidenreich et al. (108) reported on the oncological and functional outcome of 55 patients who underwent radical salvage therapy for locally recurrent PCA after various types of modern state-of-the-art radiation therapy, performed in or after the year 2000. Forty (72.7%) and 15 (27.3%) patients demonstrated organ-confined and locally advanced PCa, respectively. Eleven patients (20%) and seven patients (14%) had lymph node metastases and positive surgical margins, respectively. On multivariate analysis, significant predictors of organ-confined PCa with negative surgical margins were:
• biopsy Gleason score prior to salvage RP (p = 0.02);
• < 50% positive biopsy cores (p = 0.001);
• PSA DT > 12 months (p = 0.001);
• low-dose brachytherapy (p = 0.001).
Urinary continence was achieved after a mean of 8 months in basically all men after low-dose-radiation brachytherapy, while incontinence persisted in about 20% of patients who underwent external beam radiation therapy or high-dose radiation brachytherapy. Salvage RP is a surgically challenging but effective secondary local treatment of radiorecurrent PCa with curative intent. The identified predictive parameters will help to select patients most suitable for salvage RP with long-term cure and good functional outcome.
18.6.1.1 Summary of salvage RP
In general, salvage RP should be considered only in patients with a low co-morbidity, a life expectancy of at least 10 years, an organ-confined PCa < T2, Gleason grade < 7, and pre-surgical PSA < 10 ng/mL. In all other patients, accurate pre-surgical staging is not easily defined after radiation therapy, increasing the risk not only for anterior and total extirpation procedures, but also for associated complications and decreased long-term disease-specific survival.
18.6.2 Salvage cryosurgical ablation of the prostate (CSAP) for radiation failures
Salvage cryosurgery has been proposed as an alternative to salvage RP because it has the potential to have less morbidity but equal efficacy. However, there have only been a very few studies, with disappointing results. Pisters et al. (109) reported on 150 patients who had undergone CSAP for PSA recurrences following radiotherapy (n = 110) or other extensive pre-treatment (n = 40). After a mean follow-up of 13.5 months, 58% of patients exhibited biochemical failure, while only 31% demonstrated undetectable PSA serum levels. The complications associated with salvage CSAP were significant, and occurred in virtually all patients, with the main complications being urinary incontinence (73%), obstructive symptoms (67%), impotence (72%) and severe perineal pain (8%). After 1-year follow-up, incontinence resolved in most patients, with persistent significant incontinence in 22% of patients.

According to a recent study by Cespedes et al. (110), the risk for urinary incontinence and impotence at least 12 months after CSAP are as high as 28% and 90%, respectively. In addition, 8-40% of patients complained about persistent rectal pain, and an additional 4% of men had undergone surgical procedures for the management of treatment-associated complications.

With regard to oncological outcome, recent studies demonstrated that a durable PSA-response can be achieved in about 50% of patients with a pre-cryosurgery PSA of < 10 ng/mL (111). In a recent multicentre study, the contemporary results of CSAP in 279 patients treated at a large number of centres, participating in the Cryo On-Line Data Registry, were analysed (112). Pre-treatment PSA was 7.6 +/- 8.2 ng/mL and the Gleason score was 7.5 +/- 1.1 (median 7). Patients were followed for 21.6 +/- 24.9 months and 47 were followed for longer than 5 years. The 5-year actuarial biochemical disease-free rate was 54.5% +/- 4.9% (Phoenix). As predicted, based on the preservation of some prostatic tissue, 83% +/- 3.5% of patients had a detectable PSA level > 0.2 ng/mL at 5 years. Positive biopsies were observed in 15 of the 46 patients (32.6%) who underwent prostate biopsy after salvage cryotherapy. The incontinence rate (requiring pad use) was 4.4%. The rectal fistula rate was 1.2% and 3.2% of patients underwent transurethral prostate resection to remove sloughed tissue.

Quite recently, a case-matched control study between RSP and CSAP was performed among men with radiorecurrent PCa. The authors compared the oncological outcome of both salvage treatment options after a mean follow-up of 7.8 and 5.5 years for the radical salvage prostatectomy group and the cryosurgery group, respectively. RSP resulted in a statistically significant biochemical disease-free survival at 5 years of 61% versus 21% for the cryosurgery procedure. Also, the 5-year overall survival was significantly superior for the RSP group (95% vs 85%, p < 0.001) (113).
18.6.3 Salvage brachytherapy for radiation failures
The experience with salvage brachytherapy for radiation failures is very limited. There is only one study that includes a representative number of patients and a mean follow-up of 64 months (114). Grado et al. (114) treated 49 patients with transperineal TRUS-guided brachytherapy and reported 3- and 5-year disease-free survival rates of 48% and 43%, respectively. Beyer (115) reported a 5-year biochemical freedom from relapse in 34-53% of patients, with local cancer control achieved in 98% of patients. However, the complication rate was quite severe:
• 27% became incontinent;
• 14% needed palliative transurethral resection due to acute urinary retention;
• 4% developed rectal ulcers;
• 2% required permanent colostomy.
Burri et al. (116) reported on the long-term outcomes and toxicity after salvage brachytherapy with palladium-103 or iodine-125 for local failure after initial radiotherapy for PCa in 37. Median follow-up was 86 months (range, 2-156). The median dose to 90% of the prostate volume was 122 Gy (range, 67-166). The 10-year biochemical disease-free survival and cancer-specific survival were 54% and 96%, respectively. There were three grade 3 toxicities and one grade 4 toxicity (10.8%). In conclusion, careful patient selection for salvage brachytherapy may result in improved outcomes and reduced toxicity.

In a similar approach, Moman et al. (117) retrospectively evaluated the outcome and toxicity after salvage iodine-125 implantation in 31 patients with locally recurrent PCa after primary iodine-125 implantation and external beam radiotherapy. The mean follow-up was 9 years (SD +/-4). Freedom from biochemical failure after 1-year follow-up was 51% and after 5 years was 20%. Fourteen (45%) patients died of PCa after a mean (+/-SD) follow-up of 73 (+/-39) months. Grade 1, 2, or 3 toxicity of the genitourinary tract was reported in 29%, 58% and 3% of the patients, respectively, in the acute phase, and in 16%, 39%, and 19%, respectively, in the late phase. Grade 1, 2, or 3 toxicity of the gastrointestinal tract was reported in 45%, 10%, and 0% of the patients, respectively, in the acute phase, and in 48%, 3%, and 6%, respectively, in the late phase. In conclusion, freedom from biochemical failure after salvage iodine-125 implantation for locally recurrent PCa after radiotherapy is limited, and both genitourinary and gastrointestinal toxicity occur frequently.
18.6.4 Observation
Patients with signs of local recurrence only (i.e. low-risk patients with late recurrence and a slow PSA rise), who are not opting for second-line curative options, are best managed by observation alone. A retrospective cohort analysis of hormonal therapy versus watchful waiting (WW) in 248 men with PSA failure after radiotherapy showed no advantage for hormonal therapy in the subgroup of men with a PSA DT of > 12 months after radiotherapy. The 5-year metastasis-free survival rate was 88% with hormonal therapy versus 92% with WW (p = 0.74) (118).
18.6.5 High-intensity focused ultrasound (HIFU)
The experience of HIFU for the treatment of locally recurrent PCa after radiation therapy is limited to a few retrospective studies. Zacharakis et al. (119) investigated the oncological and functional outcome of HIFU in a cohort of 31 men with biopsy-proven locally recurrent PCa following EBRT. The mean (range) pre-operative PSA level was 7.73 (0.20-20) ng/mL. The patients were followed for a mean (range) of 7.4 (3-24) months. Side effects included stricture or intervention for necrotic tissue in 11 patients (35%), urinary tract infection or dysuria syndrome in eight (26%) and urinary incontinence in two (6%). Rectourethral fistula occurred in two men (7%). Overall, 71% had no evidence of disease following salvage HIFU. 

Using a similar approach, Murat et al. (120) evaluated the safety and efficacy of salvage HIFU in 167 patients with local PCA recurrence after EBRT and to determine prognostic factors for optimal patient selection. Local cancer control was achieved with negative biopsy results in 122 (73%) patients. The median PSA nadir was 0.19 ng/mL. The mean follow-up period was 18.1 months (range, 3-121 months). Seventy-four patients required no hormonal therapy. The actuarial 5-year overall survival rate was 84%. The actuarial 3-year progression-free survival was significantly lower in three situations:
• worsening of the pre-EBRT stage with 53%, 42%, and 25% for low-, intermediate-, and high-riskpatients, respectively;
• an increase in the pre-HIFU PSA;
• use of ADT during PCa management.
In multivariate analyses, the risk ratios for intermediate- and high-risk patients were 1.32 and 1.96, respectively. The risk ratio was 2.8 if patients had been treated with ADT. No rectal complications were observed. Urinary incontinence accounted for 49.5% of the urinary sphincter implantations required in 11% of patients. Urinary incontinence and the development of rectourethral fistula are the most significant complications of salvage HIFU therapy (119-121). About 30% of men develop some type of incontinence, with significant urinary incontinence treated with an artificial urinary sphincter in about 10% of patients. The oncological control rate after a short median follow-up of about 2 years is 30-40%.
18.6.5.1 Salvage HIFU therapy
Ahmed et al. (122) evaluated the outcome of whole-gland HIFU in 84 patients with radiorecurrent CaP following external beam radiation therapy. After a mean follow-up of 19.8 months, the 1- and 2-year progression-free survival rates were 59% and 43%, respectively. Four men developed rectourethral fistula and another 20% needed to undergo surgical treatment for subvesical outlet obstruction.

Berge et al. (123) evaluated the health-related quality of life using the Los Angeles Prostate Cancer Index questionnaire in 61 patients following HIFU for radiorecurrent, clinically organ-confined CaP. The mean time between treatment and quality of life evaluation was 17.5 months The treatment of localised radiorecurrent PCa by salvage HIFU is associated with clinically significant reductions in urinary and sexual function domains, but not in mental domains.
18.6.6 Guidelines for the management of PSA relapse after radiation therapy

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

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19. CASTRATION-RESISTANT PCA (CRPC)
19.1 Background
Cancer of the prostate is a heterogeneous disease. Our knowledge of the mechanisms involved in androgen independence, which is now known as castration-resistant prostate cancer (CRPC), remains incomplete (1-4), but is starting to become clearer (5,6). In the past, it was thought that androgen ablation provides a selective advantage androgen-independent cells that grow and eventually comprise most of the tumour. An alteration in normal androgen signalling is thought to be central to the pathogenesis of androgen-independent PCa (7). It is thought that androgen independence (now called castration resistance) is mediated through two main, overlapping, mechanisms, which are androgen-receptor (AR)-independent and AR-dependent.
19.1.1 Androgen-receptor-independent mechanisms
Androgen-receptor-independent mechanisms may be associated with the deregulation of apoptosis through the deregulation of oncogenes. High levels of bcl-2 expression are seen with greater frequency as PCa progresses.The regulation of microtubule integrity may be a mechanism through which bcl-2 induces its anti-apoptotic effect (8,9). Indeed, most active chemotherapeutics in CRPC work by inhibiting microtubule formation. The tumour suppressor gene p53 is more frequently mutated in androgen-independent PCa. Overexpression of bcl-2 and p53 in prostatectomy specimens has been shown to predict an aggressive clinical course (10-12). Clinical trials are underway to target the bcl-2 pathway (13), as the MDM2 oncogene (14) and the PTEN (phosphatase and tensin homolog) suppressor gene may also be involved (15).
19.1.2 AR-dependent mechanisms
Direct AR-dependent mechanisms comprise the main pathway. Ligand-independent AR activation has been suspected, such as the tyrosine kinase activated pathway (IGF-1, KGF, EGF). Epidermal growth factor (EGF) is a potent mitogen of prostate stromal and epithelial cells. It is produced in high levels locally and acts as a paracrine stimulator. In AR-independent tumours, autocrine stimulation may become more important, which could allow unregulated growth (16).

Androgen receptor amplification and overexpression are observed in one-third of CRPC tissues (17,19) and may lead to AR hypersensitivity. Androgen receptor mutations may lead to a functional change in AR function (3,4,16). At the same time, there is an intracellular increase in androgens from in-situ conversion (20,21). This increase may be secondary to an increase in the intracellular enzymes involved in intracellular androgen
synthesis (22).

Because AR mutations are found in only a subpopulation of tumour cells, they are unlikely to be responsible for the entire spectrum of the AR-independent state (23). The AR mutations might be related to the selective pressure of anti-androgens (23). The recent discovery of gene fusion between the androgen-driven TMPRSS2 and the EGR-ETS oncogene family (24) raises the question of oncogene regulation through androgen regulation pathways. In gene fusion, an androgen-responsive element from an androgene-regulated gene becomes associated with genes that are usually not androgen-regulated, so that they too become subject to androgen regulation. Currently, their implication in CRPC is hypothetical. Even in castrated patients, metastatic tissues have repeatedly shown high levels of androgens, suggesting a high level of intracrine synthesis (22,25). It is possible that a high intraprostatic cholesterol level can activate specific androgen pathways (1).
19.2 Definition of relapsing prostate cancer after castration
The previously term, ‘hormone-refractory prostate cancer’ referred to a very heterogeneous disease. It included different patient cohorts with significantly different median survival times (Table 21).
Table 21: Estimated natural mean survival of patients with HRPC presenting with different clinical
scenarios

The precise definition of recurrent or relapsed PCa remains controversial and several groups have recently published practical recommendations for defining CRPC (25-26).

Various different terms have been used to describe prostate cancers that relapse after initial hormonal ablation therapy, including HRPC, androgen-independent cancers and hormone-independent cancers (1). Over the course of the past 5 to 8 years, the term castration-resistant prostate cancer (CRPC) has become more used than the term hormone refractory or androgen independent. This is based predominantly on the implications of recent findings suggesting that advancing prostate cancer is not uniformly refractory to further hormonal manipulation and that androgens and the progression of disease are frequently dependent on - not independent of - androgen-AR interactions. The castrate-resistant, but still hormone-sensitive, PCa (CRPC) has been clearly characterised, with new drugs targeting either the AR, such as MDV3100, or androgen synthesis, via the CYP 17 inhibition like abiraterone acetate or TAK700 (see below Section 17.8.5.2) (27). Table 22 lists the key defining factors of CRPC.
Table 22: Definition of CRPC

* Either anti-androgen withdrawal or one secondary hormonal manipulation should have been done in order tofulfil the criteria for CRPC if patients have been treated with antiandrogens in the context of maximum androgen blockade or step up therapy following PSA progression after failure of LHRH treatment.
† Progression of osseous lesions: progression or appearance of two or more lesions on bone scan or soft tissue lesions using RECIST (Response Evaluation Criteria in Solid Tumours) and with nodes > 2 cm in diameter.
19.3 Assessing treatment outcome in androgen-independent PCa
In general, the therapeutic outcome should be assessed using the guidelines for the evaluation of treatment response in solid tumours, recently published by the RECIST group (Response Evaluation Criteria In Solid Tumours) (28). However, 80-90% of patients do not have bi-dimensionally measurable disease. Patients with primarily soft tissue cancers often have a different prognosis to those with only osseous metastases. Osteoblastic bone metastases remain difficult to quantify accurately. Magnetic resonance imaging (MRI) might be useful for assessing axial metastases (29). Since the cause of death in PCa patients is often unreliable, a more valid end-point might be overall survival (OS) rather than a disease-specific one (30).
19.3.1 PSA level as marker of response
Many contemporary studies use PSA as a marker of response, even though there is no consensus about the magnitude and duration of a decline in PSA level. Although PSA is used as a rapid screening tool to test new agents for activity, there is conflicting evidence about the role of PSA as a response marker. Both the vaccine trials, Sipuleucel-T (Provenge) (31) and the TRICOM (PROSTVAC) study (32), demonstrated a significant OS benefit without any PSA change, raising questions about the value of PSA response for non-hormonal noncytotoxic drugs (33).In addition, wide fluctuations have been seen in PSA values due to a transient effect of drugs on PSA production. The effect of drugs on PSA expression should be considered when interpreting PSA response data, which should be viewed together with other clinical data (34-41).

Nevertheless, it has been reproducibly shown that > 50% PSA decline in pre-treatment PSA following therapy carries a significant survival advantage (42,43). Kelly et al. (42) reported a statistically significant survival advantage in 110 patients with > 50% PSA decline (> 25 months) versus those without a > 50% PSA decline (8.6 months). Smith et al. (43) showed that a PSA decline > 50% for at least 8 weeks resulted in a longer mean survival time of 91 weeks versus 38 weeks in patients showing a smaller PSA reduction.

An improved PSA response was also associated with prolonged survival in the TAX 327 study, with amedian survival of 33 months when the PSA was normalised (< 4 ng/mL) versus 15.8 months for an abnormal PSA. This study also showed that a PSA response was not a surrogate marker for survival; even though thesame PSA response rate was found in both docetaxel arms (45%), improved survival only occurred with the 3-weekly docetaxel regimen. According to the most recent evaluation of the TAX 327 and SWOG 99-16 studies, a PSA detection of > 30% is associated with a significant survival benefit (44,45).
19.3.2 Other parameters
The evaluation of molecular markers is just beginning. It includes a possible correlation between the positive findings of reverse transcriptase-polymerase chain reaction (RT-PCR) and poor survival (46), though these data must be corroborated before any clinical recommendations can be made. Another, probably more interesting, tool is the circulating tumour cell count (CTC count), which has been developed in parallel with abiraterone. The CTC count has been clearly related to survival in several trials (47-49) and may become a surrogate marker for survival. The FDA has recently approved an assay for CTC.

In patients with symptomatic osseous lesions, pain reduction or complete pain relief may be used as parameters to assess palliative therapeutic response (50). In a landmark analysis of TAX 327, PSA response and pain response, but not QoL response, were independently associated with survival (51).
19.3.3 Trial end-points
An increasing number of investigators advocate subjective end-points. However, investigators should currently apply the following:
• Use clearly defined end-points in trials, sufficiently powered to answer the hypothesis.
• Report each response parameter individually, rather than as a complete or partial response.
• Only use PSA response with other clinical parameters of response.
• Consider QoL end-points independently in symptomatic patients.
However, in everyday practice, the evaluation of treatment response must be based on symptom improvement, prolonged survival, or other pre-defined targets.
19.3.4 Recommendations for assessing therapeutic response
The Prostate Cancer Working Group 2 recommends that investigators measure early-response outcomes by the changes in the individual disease manifestations present initially for both cytotoxic and non-cytotoxic drugs with the same methods used at enrolment (25). If a protocol defines a composite end-point for progression, the specified progression in any measure (with the exception of early changes in PSA or pain) overrides a change or improvement in other measures.

HRQoL = health-related Quality of life; RECIST = Response Evaluation Criteria in Solid Tumours.
19.4 Androgen deprivation in castration-resistant PCa
The existence of androgen-resistant PCa shows that disease progression occurs despite castration. The castration levels of testosterone must therefore be documented and a serum testosterone level < 50 ng/dL (1.7 nmol/L) should be documented at initial relapse on hormonal therapy (52).

Continued testicular androgen suppression in CRPC has a minimal overall effect. The recommendation to continue androgen deprivation therapy (ADT) with LHRH analogues, despite PSA progression, is based on the data of Manni et al. (53). This study demonstrated significantly lower survival rates in patients without complete androgen blockade (CAB). However, these data have been challenged by two trials that showed only a marginal survival benefit for patients remaining on LHRH analogues during second- and third-line therapies (54,55).However, in the absence of prospective data, the modest potential benefits of a continuing castration outweigh the minimal risk of treatment. Androgen suppression should therefore be continued indefinitely in these patients.
19.5 Secondary hormonal therapy
For the patient with progressive disease after ADT, there are many therapeutic options. They include anti-androgen withdrawal, addition of anti-androgens, anti-androgen replacement, oestrogenic compounds, adrenolytic agents, and novel approaches (56). Figure 1 summarises the treatment modalities and expected responses.

19.6 Anti-androgen withdrawal syndrome
In 1993, Kelly and Scher (57) reported clinical and PSA responses in men who discontinued flutamide therapy upon the development of progressive disease. The anti-androgen withdrawal syndrome was a critical discovery in understanding the biology of androgen independence, interpreting clinical trials, and treating patients (58-61).

Approximately one-third of patients respond to anti-androgen withdrawal, as indicated by a > 50% PSA decrease, for a median duration of approximately 4 months (Table 22). Anti-androgen withdrawal responses have also been reported with bicalutamide and megestrol acetate (62-67). Recently, in the SWOG 9426 trial, PSA progression despite CAB was reported in a subgroup of 210 patients with a tumour stage of M0 or M1 (68). A response was observed in 21%, even though there was no radiographic response. Median progressionfree survival (PFS) was 3 months, with 19% (all M0) having 12 months’ or greater PFS. Factors associated with increased PFS and OS were a longer period of non-steroidal use, lower PSA at baseline and M0-stage. These results were obtained with patients on CAB following androgen withdrawal treatment. No data were available on the withdrawal effect following second-line anti-androgen treatment.

In conclusion, androgen withdrawal should be systematically considered as a first-line modality in relapsing patients, even if its efficacy is limited (LE: 2).

19.7 Treatment alternatives after initial hormonal therapy
Except in patients with non-castration testosterone levels, it is difficult to predict which subset of patients is most likely to respond to secondary hormonal strategies.
19.7.1 Bicalutamide
Bicalutamide is a non-steroidal anti-androgen with a dose response, with higher doses producing a greater reduction in PSA level (69). The largest cohort so far is based on 52 CRPC patients treated with bicalutamide, 150 mg (70). A palliative effect was clear and a 20% PSA response (at least 50% decrease) was observed, without any link to the palliative effect. Based on the affinity of dihydrotestosterone (DHT) for the androgen receptor, a large randomised trial (TARP) is ongoing comparing the effectiveness of bicalutamide 50 mg combined with either dutasteride or placebo in non-metastatic CRPC (71). The addition of an anti-androgen, such as bicalutamide or flutamide, to gonadal suppression at the time of PSA failure appears to result in declining PSA in only a few patients (72,73).
19.7.2 Switching to an alternative anti-androgen therapy
There has been recent interest in another simple modality: the alternative anti-androgen therapy (74). After CAB was stopped in 232 progressing patients (76% being M1b), a withdrawal effect was observed in 31 men (15.1%). A second-line hormonal treatment was performed by giving an alternative non-steroidal drug (i.e. initial flutamide was replaced by bicalutamide and vice versa). An overall > 50% decline in PSA was observed in 83 men (35.8%), irrespective of any previous withdrawal effect, which lasted more than 6 months. The higher the PSA at the start of second-line therapy, the shorter was the progression-free survival and the lower was the PSA response rate.
19.7.3 Anti-androgen withdrawal accompanied by simultaneous ketoconazole
The adrenal glands secrete approximately 10% of circulating androgen in humans. Some tumour cells in androgen-independent states must retain androgen sensitivity, as a clinical response is induced by a further decrease in circulating androgen levels following bilateral adrenalectomy or administration of drugs inhibiting adrenal steroidogenesis. Aminoglutethimide, ketoconazole and corticosteroids act mainly via this mechanism (75-79) to produce a PSA response in about 25% of patients for about 4 months. The simultaneous addition of ketoconazole to anti-androgen withdrawal, produced a significantly increased PSA response (32% vs 11%) and a longer time to PSA progression (8.6 vs 5.9 months) compared to anti-androgen withdrawal alone (79).
19.7.4 Oestrogens
Prostate cancer usually expresses oestrogen receptors, which are upregulated after androgen ablation in animal models. In-vitro oestrogens can activate mutant androgen receptors isolated from androgenindependent PCa, while high-dose oestrogens have achieved objective salvage responses. This may be due to the mitotic arrest of direct cytotoxic effects on the cells, perhaps through an apoptotic mechanism (80,81). Recently, diethylstilboestrol (DES) (82-84) achieved a positive PSA response between 24% and 80%, with an overall estimated survival of 63% at 2 years. However, even at low doses of DES, about one-third (31%) of patients developed deep venous thrombosis and 7% experienced myocardial infarction.
19.7.5 The future for agents targeting the androgen receptor and endocrine pathways
In the last 2 years, potential drugs have appeared in early phase I/II trials in CRPC and should be considered as potential major new tools, provided the randomised phase III trials confirm the early results. Furthermore, they confirm that the castrate-resistant status is far from meaning an hormonal-resistant status (see above Section 19.4).
19.7.5.1 MDV3100
The first agent, MDV3100, is a novel anti-androgen which blocks AR transfer to the nucleus, in contrast to currently available drugs where AR is able to transfer to the nucleus. This means that no agonist-like activity should ever occur. At the ASCO 2009 meeting, a phase I/II trial on 140 CRPC was reported (85). In this dosefinding study, a PSA decline > 50% was seen in 57% chemo-naïve patients, and in 45% chemo-refractory patients. Based on these results, a large phase III trial has been recently launched in metastatic CRPC patients after chemotherapy, on more than 1000 patients, with OS being the primary end-point. At the GU ASCO 2012 the final results of the AFFIRM study were presented demonstrating a significant survival benefit of 4.8 months in patients undergoing MDV3100 treatment as compared to placebo. The median survival was 18.4 months versus 13.6 months (p < 0.0001) in the MDV3100 and the placebo group, respectively. The relative risk reduction of death was 37%. The median progression-free was 8.3 months versus 3.0 months (p < 0.0001) (86).
19.7.5.2 Abiraterone acetate
The second agent is the CYP17 inhibitor, abiraterone acetate. In CRPC patients, this drug is able to decrease PSA > 50% in 85% chemo-naïve patients (87), by 50% after docetaxel (88,89), and even by 33% after ketoconazole (89). In chemo-naïve patients, a PSA decline of > 90% is seen in up to 40% of patients (87).

The largest cohort so far is based on 96 chemo-naïve men included in a phase I/II trial. At a dose of 1000 mg, a PSA decline > 50% was observed in 67% and > 90% in 19% of patients. A partial response (RECISTbased) was seen in 37% of patients. The median time to progression was about 1 year (6). These very promising results have led to two large phase III trials: one in chemo-refractory patients (n = 1158), the other in chemo-naïve patients (n = 1000, accrual completed). In both trials, OS is the primary endpoint. In the postchemotherapy trial (COU-301), patients with disease progression after docetaxel-based therapy were randomly assigned to receive abiraterone plus prednisone or prednisone plus placebo, with treatment continuing until disease progression or death. The results from the study demonstrated a significant improvement in overall survival in favour of abiraterone from 10.9 to 14.8 months, with a hazard ratio of 0.646. The PSA response proportion to abiraterone/prednisone was 38% versus 10% in this study, while grade 3 to 4 adverse events leading to discontinuation occurred in 10% of those treated with abiraterone and 13% of those treated with placebo. This study is a confirmation that CRPC remains hormone-driven, even in advanced stages of the disease and represents an outstanding opportunity for the future treatment of CRPC (90).
19.8 Non-hormonal therapy (cytotoxic agents)
Several proven chemotherapeutic options are available for metastatic disease in CRPC (Table 24). Multiple trials are underway, using very different approaches through all the known pathways. A detailed review is far beyond the scope of these guidelines (5), as most drugs are experimental, except perhaps docetaxel.

A significant improvement in median survival of about 2, 2.5 months occurred with docetaxel-based chemotherapy compared to mitoxantrone + prednisone therapy (91,92). In the SWOG 99-16 trial, pain relief was similar in both groups, although side-effects occurred significantly more often with docetaxel than with mitoxantrone.
Table 24: PSA response rates, mean survival, time to progression, and pain reduction in the large,
prospective, randomised phase III trials of chemotherapy in patients with CRPC

EMP = estramustine; HC = hydrocortisone; Pred = prednisone.

19.8.1 Timing of chemotherapy in metastatic CRPC
The timing of chemotherapy varies in metastatic CRPC. It is advisable to start it immediately in symptomatic patients, if possible every 3 weeks, as this schedule is associated with an improvement in survival. However, a weekly regimen will result in the same symptom improvement and must be considered in patients unable to receive the optimal regimen (LE: 1b), as it is more effective than best supportive care (93). In asymptomatic patients, timing is not so clear and must be discussed individually.

Several poor prognostic factors have been described, such as a PSA level > 114 ng/mL, PSA doubling time (PSA-DT) < 55 days, or the presence of visceral metastases (94). A better risk group definition has been recently presented, based on the TAX 327 study cohort. The predictive factors were visceral metastases, pain, anaemia (Hb < 13 g/dL), bone scan progression, and prior estramustine before docetaxel. Patients were categorised into three risk groups: good risk (0-1 factor), intermediate (2 factors) and high risk (3-4 factors), leading to three different median OS: 25.7, 18.7 and 12.8 months, respectively (46) . In addition, two independent studies have suggested that improved survival can be predicted by C-reactive protein (CRP) levels < 8 mg/L (hazard ratio [HR], 2.96) (95,96). Age by itself is not a contraindication to docetaxel (97).

Currently, the only indication for chemotherapy in CRPC non-metastatic patients is inside clinical trials and patients should be advised to participate.
19.8.2 Mitoxantrone combined with corticosteroids
Mitoxantrone combined with corticosteroids (98,99) has been extensively studied primarily in patients with symptomatic osseous lesions due to CRPC. In the CALGB 9182 study (99), 244 patients with symptomatic metastatic CRPC were randomised to receive either mitoxantrone + hydrocortisone, 12 mg/m2every 3 weeks, or hydrocortisone alone. No differences were observed with regard to survival, PSA response, and median time to progression. However, the QoL was significantly improved in the combination arm. In another trial (99), 161 men with painful osseous metastases due to CRPC were randomised to receive mitoxantrone + prednisone versus prednisone alone. There was a significant benefit in pain reduction in the combination group (29%) versus prednisone alone (12%, p = 0.01). Furthermore, the duration of palliation was longer in patients who received mitoxantrone (43 weeks vs 18 weeks, p < 0.0001). There were no significant differences with regard to PSA response and median survival time. However, again, QoL was improved significantly due to pain reduction.
19.8.3 Alternative combination treatment approaches
Encouraging results have been seen with alternative treatments evaluated in prospective clinical phase II trials (100-103), including pegylated doxorubicin, vinorelbine, a combination of paclitaxel, carboplatin + estramustine, a combination of vinblastine, doxorubicin + radionuclides, and a combination of docetaxel + mitoxantrone. The lack of representative randomised phase III trials and unknown long-term efficacy are major problems associated with all these studies.
19.8.4 Estramustine in combination therapies
The synergy observed for estramustine combined with other drugs that target microtubule action has generated promising results in prospective clinical trials.

Estramustine + vinblastine is the most studied estramustine combination. Although different doses of estramustine and vinblastine have been used in prospective randomised trials, significant PSA and measurable responses have been reported in three separate studies. Although time to progression and frequency of > 50% PSA decrease was significantly higher in the estramustine + vinblastine treatment arm, median survival did not differ significantly between the estramustine and the estramustine + vinblastine arms (104). A recent meta-analysis (105) concluded that the addition of estramustine to chemotherapy increased the time to PSA progression and OS. However, there was a significant increased risk of thromboembolic events, up to 7% (106), requiring systematic prevention with coumadin.
19.8.5 Oral cyclophosphamide
Intravenous cyclophosphamide has been tested in many trials. However, there is currently interest in oral cyclophosphamide, which seems to be less toxic than intravenous cyclophosphamide and may have greater activity. A study of oral cyclophosphamide + oral etoposide in 20 patients was similarly encouraging (107,108).
19.8.6 Cisplatin and carboplatin
Cisplatin and carboplatin have activity as single agents against PCa. They also have a well-documented synergy with etoposide or paclitaxel in vitro in other malignancies, such as lung and ovarian cancer. As estramustine is also synergistic with these drugs, combinations of these three agents are now being tested. A combination of estramustine, etoposide and cisplatin (or carboplatin) has significant activity against poorly differentiated CRPC. A combination of estramustine, etoposide and paclitaxel has produced high response rates (102,109).
19.8.7 Specific bone targets
Bone is a primary target for prostatic metastatic cells, leading to a rational for bone-protective drugs, preventing cancer cells from colonising and developing bone. Besides zoledronic acid and denosumab (see above Section 12.7.1), there are other promising drugs, mainly those targeting the endothelin-1 axis. The first of these agents (atrasentan) resulted in clear biological responses, but questionable clinical results (110), possibly secondary to an inappropriate trial design. However, the proof of principle has been made, and second-generation blockers (zibotentan) are under development after initially encouraging phase II trials (111), with large phase III trials in CRPC, either without metastases (> 1000 patients), with metastases (> 500 patients), or with docetaxel (> 1000 patients). Phase 3 trials in patients with CRPC are currently assessing docetaxel with or without atrasentan (NCT00134056) or zibotentan (ENTHUSE M1C; NCT00617669). However,recent results from the ENTHUSE M1 trial (NCT00554229) showed no significant improvement in OS with zibotentan monotherapy in men with mildly symptomatic CRPC (112). Moreover, it has been announced that the ENTHUSE M0 trial of zibotentan monotherapy in patients with non-metastatic CRPC has been discontinued after failing to meet the primary OS end-point. Phase 3 results for zibotentan/docetaxel treatment of bonemetastatic CRPC are still pending.
19.8.8 Salvage chemotherapy
Since all patients who receive docetaxel-based chemotherapy for CRPC will progress, there have been many clinical trials investigating the role of salvage chemotherapy. The results suggest the most appropriate approaches are cabazitaxel (113), intermittent docetaxel chemotherapy (114,115), and potentially moleculartargeted therapy (116,117).

Several groups have used second-line intermittent docetaxel in patients who had clearly responded to first-line docetaxel (114,115,118). In general, a PSA response can be achieved in about 60% of patients with a median time to progression of about 6 months, while treatment-associated toxicity is minimal and similar to that of firstline docetaxel. Another, recently identified approach is molecular-targeted therapy (116,117,119-122) though more research is needed in larger groups of patients.Platinum-based chemotherapeutic regimes have been investigated in patients with CRPC. Although the platinum complex, satraplatin, has shown activity against CRPC and some promise in clinical trials, the FDA rejected it for CRPC in 2008 (119).

Many new drugs, such as gefitinib, bevacizumab (phase III trial CALB 90401 ongoing), oblimersen (phase II trial EORTC 30021), and also a vaccine, G-Vax (122), have been tested in phase II/III trials without any positive impact on the primary end-point. The G-VAx trial was stopped prematurely because of a significantly higher mortality in the treatment arm as compared to the docetaxel control arm.

Positive results have been recently published from a prospective, randomised, phase III trial comparing the therapeutic efficacy of the taxane derivate, cabazitaxel, + prednisone versus mitoxantrone + prednisone in 755 patients with castration-resistant PCa, who had progressed after or during docetaxel-based chemotherapy (123). Patients received a maximum of 10 cycles of cabazitaxel (25 mg/m2) and mitoxantrone (12 mg/2), respectively. In both treatment arms, patients also received 10 mg prednisone daily for the entire treatment period. Overall survival was the primary endpoint and PFS, treatment response and safety were secondary endpoints. Patients in the cabazitaxel arm experienced a significantly increased OS of 15.1 versus 12.7 months (p < 0.0001) in the mitoxantrone arm. The cabazitaxel treatment arm also showed significant improvement in PFS (2.8 vs 1.4 months, p < 0.0001), as well as in the objective response rate according to RECIST criteria (14.4% vs 4.4%, p < 0.005) and the PSA response rate (39.2% vs 17.8%, p < 0.0002).Treatment associated WHO grade 3-4 side-effects developed significantly more often in the cabazitaxel arm, particularly haematological (68.2% vs 47.3%, p < 0.0002) and non-haematological toxicities (57.4% vs 39.8%, p < 0.0002) (113). Because of this and the risk of neutropenic sepsis associated with cabazitaxel, this drug should be administered by physicians with expertise in handling neutropenia and sepsis, possibly with granulocyte colony-stimulating factor.Whether cabazitaxel can be substituted for front-line docetaxel is the subject of a prospective phase III trial.

19.9 Palliative therapeutic options: bone targeted therapies in CRPC
CRPC is usually a debilitating disease, often affecting the elderly male. A multidisciplinary approach is often required with input from medical oncologists, radiation oncologists, urologists, nurses, psychologists and social workers (124).
19.9.1 Painful bone metastases
Most patients with CRPC have painful bone metastases. External beam radiotherapy is highly effective (125), even as single fraction (126). The two radioisotopes, strontium-89 and samarium-153, can partially or completely decrease bone pain in up to 70% of patients, but should not be given too late when pain is intractable. Early use can give rise to myelosuppression, making subsequent chemotherapy more difficult (127), even though a recent phase I trial has demonstrated manageable haematological toxicity with repeated administration of docetaxel and samarium-153. The use of samarium-153 as consolidation therapy, following a clear docetaxel response, may also help with initially painful bone metastases (128). Palliative treatment with another radioisotope emitter, radium-233, has shown very promising phase II results in patients with painful bone metastases in terms of palliation and OS, and only a mild haematological toxicity (129). Recently, survival results of the randomised phase 3 trial in men with CRPC and symptomatic bone metastases ineligible for or post-progresion to docetaxel with 223Ra (Alpharadin) (NCT00699751) have been reported at the ESMO 2011 meeting.The trial showed a survival advantage for alpharadine versus placebo (11.2 months versus 14.0 months HR 0.695; 95% CI, 0.552-0.875 P = .00185) met its primary endpoint of improved OS. Full data are awaited (130).
19.9.2 Common complications due to bone metastases
Common complications due to skeletal metastases include bone pain, vertebral collapse or deformity pathological fractures and spinal cord compression. Osteoporosis may also cause fractures and should be prevented (see above). Cementation is an effective treatment of painful fracture, clearly improving both pain and QoL (131). However, it is still important to offer standard palliative surgery, which can be very effective at managing osteoblastic metastases (132,133). Impending spinal cord compression is an emergency. It must be recognised early and patients educated to recognise the warning signs. Once suspected, highdose corticosteroids must be given and an MRI performed as soon as possible. A systematic neurosurgery consultation should be planned to discuss a possible decompression (134). Otherwise, external beam radiotherapy, with or without systemic therapy, is the treatment of choice.
19.9.3 Bisphosphonates
Recently, bisphosphonates have been used to inhibit osteoclast-mediated bone resorption and osteoclast precursors in CRPC to provide effective treatment of skeletal complications and to reduce pain or provide total pain relief. In the largest single phase III trial (135), 643 patients who had CRPC with bone metastases were randomised to receive zoledronic acid, 8 mg or 4 mg every 3 weeks for 15 consecutive months, or placebo. At 15 and 24 months of follow-up, patients treated with only 4 mg of zoledronic acid had fewer skeletal-related events compared to the placebo group (44% vs 33%, p = 0.021) and fewer pathological fractures (13.1% vs 22.1%, p = 0.015). Furthermore, the time to first skeletal-related event was longer in the zoledronate group, so improving QoL. Patients were initially randomised to 4 or 8 mg of zoledronic acid, but the 8 mg dosage was later modified to 4 mg because of toxicity.

Currently, bisphosphonates can be proposed to patients with CRPC bone metastases to prevent skeletal complications, even if the best dosing interval is unclear. At present, it is every 3 weeks or less. The toxicity, e.g. jaw necrosis, of these drugs, especially aminobisphosphonate, must always be kept in mind (135). Patients should have a dental examination before starting a bisphosphonate. The risk of jaw necrosis is increased by a history of trauma, dental surgery or dental infection, as well as intravenous long-term bisphosphonate administration (136).

Pain due to osseous metastases is one of the most debilitating complications of CRPC. Bisphosphonates have proven to be highly effective in reducing bone pain, but so far this has been investigated in small, open trials only. This data show that bisphosphonates seem to have a low side-effect profile which make them an ideal medication for palliative therapy of advanced CRPC (137-139). Bisphosphonates should be considered early in the management of symptomatic CRPC. Critical issues of palliation must be addressed when considering additional systemic treatment, including management of pain, constipation, anorexia, nausea, fatigue and depression, which often occur (i.e. palliative external beam radiation, cortisone, analgesics and anti-emetics).
19.9.4 RANK ligand inhibitors
Denosumab is a fully human monoclonal antibody directed against RANKL, a key mediator of osteoclast formation, function, and survival. Denosumab efficacy against CRPC bone metastases was initially assessed in a phase 2 study. Fifty patients with increased urinary NTX levels despite previous treatment with zoledronic acid were randomised to either continue on intravenous bisphosphonates or receive subcutaneous denosumab. Denosumab normalised NTX levels more frequently than continuing bisphosphonate treatment (140).The efficacy and safety of denosumab (n = 950) compared with zoledronic acid (n = 951) in patients with metastatic CRPC was assessed in a phase III trial. Denosumab was superior to zoledronic acid in delaying or preventing skeletal related events (SREs), as shown by time to first on-study SRE (pathological fracture, radiation or surgery to bone, or spinal cord compression) of 20.7 versus 17.1 months, respectively (HR 0.82;p = 0.008). Denosumab also extended time to first and subsequent on-study SRE (HR 0.82; p=0.008). Both urinary NTX and BAP were significantly suppressed in the denosumab arm compared with the zoledronic acid arm (p < 0.0001 for both). This was the last of three pivotal trials exploring denosumab treatment of bone metastases, which formed the basis of the recent FDA approval of denosumab for preventing SREs in patients with bone metastases from solid tumours.
19.10 Summary of treatment after hormonal therapy
(Until results from randomised controlled trials on novel agents MDV3100 and abiraterone become available,there are no significant changes in the treatment of prostate cancer after hormonal therapy [27]).

Comment: Four to six weeks after discontinuation of flutamide or bicalutamide, an eventual anti-androgenwithdrawal effect will be apparent.
19.11 Recommendations for cytotoxic and pre/post-docetaxel therapy in CRPC

19.12 Recommendations for palliative management of CRPC
Recommendations GR

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20. ABBREVIATIONS USED IN THE TEXT
This list is not comprehensive for the most common abbreviations
3D-US three-dimensional ultrasound
ADT androgen-deprivation therapy
AS active surveillance
ASCO American Society of Clinical Oncology
ASTRO American Society for Therapeutic Radiology and Oncology
AUA American Urological Association
BDFS biochemical disease-free survival
BMD bone mineral density
bNED actuarial biochemical freedom from disease
CAB complete (or maximal or total) androgen blockade
CPA cyproterone acetate
CRT conformal radiotherapy
CSAP cryosurgical ablation of the prostate
CSS cancer-specific survival
CT computed tomography
DES diethylstilboestrol
DRE digital rectal anticipation
DHT dihydrostestosterone
DSS disease-specific survival
EBRT external beam radiation therapy
ECOG Eastern Cooperative Oncology Group
eLND extended lymph node dissection
ELND elective lymph node dissection
e-MRI endorectal MRI
EORTC European Organisation for Research and Treatment of Cancer
EPC Early Prostate Cancer Trialists’ Group
EPCP Early Prostate Cancer Programme
EPE extraprostatic extension
ER- oestrogen receptor-
ESRPC European Randomized Screening for Prostate Cancer
FACT-P Functional Assessment of Cancer Therapy-prostate
FNAB fine-needle aspiration biopsy
FSH follicle-stimulating hormone
GI gastrointestinal
GR grade of recommendation
GU genitourinary
HD EBRT high-dose EBRT
HDR high-dose rate
HIFU high-intensity focused ultrasound
HR hazard ratio
HRPC hormone-refractory prostate cancer
HRQoL health-related quality of life
HT hormonal therapy
IAD intermittent androgen deprivation
IGRT image-guided radiotherapy
IMRT intensity modulated radiotherapy
IPSS International Prostatic Symptom Score
LDAT long-term ADT
LDR low-dose rate (LDR)
LE level of evidence
LET linear energy transfer
LH luteinising hormone
LHRH luteinising hormone-releasing hormone
LHRHa luteinising hormone-releasing hormone analogue
LND lymph node dissection
LRP laparoscopic radical prostatectomy
MRC Medical Research Council
MRI magnetic resonance imaging
MRSI magnetic resonance spectroscopy imaging
NHT neoadjvant hormonal therapy
NIH National Institutes of Health
NVB neurovascular bundle
OR odds ratio
OS overall survival
PAP prostate acid phosphatase
PCa prostate cancer
PET positron emission tomography
PFS progression-free survival
PIN prostatic intraepithelial neoplasia
PIVOT Prostate Cancer Intervention Versus Observation Trial: VA/NCI/AHRQ Cooperative
StudiesProgram #407
PLCO Prostate, Lung, Colorectal and Ovary
PSA prostate-specific antigen
PSA-ACT PSA complexed to antichymotrypsin
PSADT PSA doubling time
PSAV PSA velocity
PSMA prostate-specific membrane antigen for messenger RNA
QoL quality of life
QUALYs quality of life adjusted gain in life
RALP robot-assisted radical prostatectomy
RITA radio-frequency interstitial tumour ablation
RP radical prostatectomy
RRP radical retropubic prostatectomy
RTOG Radiation Therapy Oncology Group
SEER Surveillance, Epidemiology, and End Results
SLN sentinel lymph node
SPCG-4 Scandinavian Prostate Cancer Group Study Number 4
STAD short-term androgen deprivation
SVI seminal vesicle invasion
SWOG South West Oncology Group
TNM Tumour Node Metastasis
TZ transition zone
TRUS transrectal ultrasound
TURP transurethral resection of the prostate
UICC Union Against Cancer
USPIO ultra-small super-paramagnetic iron oxide particles
VACURG Veterans Administration Co-operative Urological Research Group
WHO World Health Organization
WW watchful waiting
Conflict of interest
All members of the Prostate Cancer Guidelines working group have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. 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.