1.INTRODUCTION

1.1.Aims and scope

The Prostate Cancer (PCa) Guidelines Panel have prepared this guidelines document to assist medical professionals in the evidence-based management of PCa.

It must be emphasised that clinical guidelines present the best evidence available to the experts but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - also taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2.Panel composition

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

All imaging sections in the text have been developed jointly with the European Society of Urogenital Radiology (ESUR) and the European Association of Nuclear Medicine (EANM). Representatives of the ESUR and the EANM in the PCa Guidelines Panel are (in alphabetical order): Prof.Dr. S. Fanti, Prof.Dr. O Rouvière and Dr. I.G. Schoots.

All radiotherapy sections have been developed jointly with the European Society for Radiotherapy & Oncology (ESTRO). Representatives of ESTRO in the PCa Guidelines Panel are (in alphabetical order): Prof.Dr. A.M. Henry, Prof.Dr. M.D. Mason and Prof.Dr. T. Wiegel.

All experts involved in the production of this document have submitted potential conflict of interest statements which can be viewed on the EAU website Uroweb: https://uroweb.org/guideline/prostate-cancer/?type=panel.

1.2.1.Acknowledgement

The PCa Guidelines Panel gratefully acknowledges the assistance and general guidance provided by Prof.Dr. M. Bolla, honorary member of the PCa Guidelines Panel.

1.3.Available publications

A quick reference document (Pocket guidelines) is available, both in print and as an app for iOS and Android devices. These are abridged versions which may require consultation together with the full text version. Several scientific publications are available [1,2] as are a number of translations of all versions of the PCa Guidelines.

All documents can be accessed on the EAU website: http://uroweb.org/guideline/prostate-cancer/.

1.4.Publication history and summary of changes

1.4.1.Publication history

The EAU PCa Guidelines were first published in 2001. This 2020 document presents a limited update of the 2019 PCa Guidelines publication.

1.4.2.Summary of changes

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

The following sections have been revised, or were added:

• Section 3.2.1 - Family history/genetics, has been updated resulting in a new recommendation.

5.1.3 Guidelines for screening and early detection

• Chapter 4 - Classification and staging systems, including two recommendations.

4.4 Guideline for classification and staging systems

• Section 5.2.4.2.7.3 - The role of risk-stratification, has been revised with the inclusion of a new table (Table 5.2.4.2: Impact of the PSA density on csPCa detection rates in patients with negative mpMRI findings) and amended recommendations.

5.2.4.4 Guidelines for imaging in PCa detection

• Section 5.3.2.3 - Prostate-specific membrane antigen-based PET/CT, has been completely revised.

• Section - 5.2.7.3 Tissue-based prognostic biomarker testing, includes the findings of a recently published multidisciplinary Guideline, resulting in one recommendation to be changed from 'Strong'to 'Weak'.

5.2.2.6 Guidelines for risk-assessment of asymptomatic men

• Chapter 5.2 - Clinical diagnosis, in particular Section 5.2.6 - Prostate biopsy procedure, was amended resulting in an changed recommendation.

5.2.8 Guidelines for the clinical diagnosis of prostate cancer

• Section 6.1.2 - Radical prostatectomy, has been completely revised.

• Section 6.1.3.1.3 - Hypofractionation, was revised, also including a new table (Table 6.1.8: Selected trials on hypofractionation for intact localised PCa).

• Section 6.1.4 - Hormonal therapy, new Section 6.1.4.1.1.6.4 - Darolutamide, has been added.

• Section 6.2.1 - Treatment of low-risk disease; the findings of an international collaborative multi-stakeholder consensus project addressing the deferred treatment with curative intent for localised have been incorporated, resulting in several changes to the recommendations for this section.
  

  New sections 6.2.1.1.3 - Imaging for treatment selection, 6.2.1.1.4 - Monitoring during active surveillance, and 6.2.1.1.5 - Active surveillance, when to change strategy, have been added. Due to the inclusion of new data, new sections and the findings of the international collaborative multi-stakeholder consensus project addressing the deferred treatment with curative intent for localised PCa, a number of recommendations were changed, and new recommendations have been added.

6.2.1.4 Guidelines for the treatment of low-risk disease

• 6.2.2.4 - Other options for the primary treatment of intermediate-risk PCa (experimental therapies), has been revised.

• Section 6.2.3 - Treatment of high-risk localised disease; due to the inclusion of new data, a recommendation was revised.

6.2.4.4 Guidelines for radical treatment of high-risk localised disease

• Section 6.2.4 - Treatment of locally-advanced prostate cancer, has been revised, also including a new section on the treatment of cN1 disease, resulting in a new recommendation:

6.2.4.5 Guidelines for radical treatment of locally-advanced disease

• Section 6.2.5 - Adjuvant treatment after radical prostatectomy, due to the inclusion of new data, two recommendations were revised.

6.2.5.6 Guidelines for adjuvant treatment options after radical prostatectomy

• Section 6.3.4 - The role of imaging in PSA-only recurrence, has been completely revised.

• Due to the inclusion of new data in the second-line treatment modalities, two recommendations have been added.

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

• Section 6.4 - Treatment of metastatic prostate cancer, has been considerably revised with additional data (including new Section - 6.4.4.2.2 - Combination with the new hormonal treatments [abiraterone, ezalutamide]) and the inclusion of a new table (Table 6.4.5: Results from the ENZAMET and TITAN studies), necessitating changes to the recommendations.

6.4.9 Guidelines for the first-line treatment of metastatic disease

• Section 6.5 - Treatment; Castration-resistant PCa, has been updated, also including additional information general aspects (Section 6.5.1.2) and sequencing of drugs. New section 6.5.7 - Gallium prostate specific membrane antigen (PSMA) therapy, has been included. Recommendations were changed in sections:

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

6.5.15 Guidelines for supportive care of castrate-resistant disease

These recommendations are in addition to appropriate systemic therapy.

6.5.16 Guidelines for non-metastatic castrate-resistant disease

• Chapter 7 - Follow-up, aside from revised data, includes new section 7.2.6 - Disease progression during androgen deprivation therapy.

• Due to the inclusion of new publications, new recommendations were added to Chapter 8 - Quality of life outcomes in prostate cancer:

8.3.2.1 Guidelines for quality of life in men undergoing systemic treatments

8.3.2.1 Guidelines for quality of life in men undergoing systemic treatments

2.METHODS

2.1.Data identification

For the 2020 PCa Guidelines, new and relevant evidence has been identified, collated and appraised through a comprehensive review of the GRADE forms [see definition below) and associated recommendation. Changes in recommendations were only considered on the basis of high level evidence (i.e. systematic reviews [SRs] with meta-analysis, randomised controlled trials [RCTs], and prospective comparative studies) published in the English language. A total of 223 additional references were added to the 2020 PCa Guidelines. Additional information can be found in the general Methodology section of this print, and online at the EAU website; http://www.uroweb.org/guideline/.

For each recommendation within the guidelines there is an accompanying online strength rating form, the basis of which is a modified GRADE methodology [3,4]. These forms address a number of key elements namely:

1. the overall quality of the evidence which exists for the recommendation, references used in this text are graded according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [5];
2. the magnitude of the effect (individual or combined effects);
3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study related factors);
4. the balance between desirable and undesirable outcomes;
5. the impact of patient values and preferences on the intervention;
6. the certainty of those patient values and preferences.

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

The results of an international collaborative multi-stakeholder consensus project addressing the deferred treatment with curative intent for localised PCa have been incorporated in the 2020 EAU-EANM-ESTRO-ESUR-SIOG PCa Guidelines update. The methodology used is presented in detail in the scientific publication [7].

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

2.2.Review

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

2.3.Future goals

Results of ongoing and new SRs will be included in the 2021 update of the PCa Guidelines:

• A SR on the deferred treatment with curative intent for localised PCa, explore heterogeneity of definitions, thresholds and criteria [8];
• A SR on progression criteria and quality of life (QoL) of patients diagnosed with PCa;
• A SR on the definition and the prognostic value of PSA persistence after radical prostatectomy (RP) for PCa;
• Care pathways for the various stages of PCa management are being developed. These pathways will, in due time, inform treatment flowcharts and an interactive app;
• A SR on surgeon/hospital volume for RP in non-metastatic PCa;
• A SR comparing oncological outcomes for nerve-sparing RP vs. non-nerve-sparing surgery in non-metastatic PCa;
• A SR on patient- and tumour-related characteristics as prognostic factors for post-RP incontinence in non-metastatic PCa.

3.EPIDEMIOLOGY AND AETIOLOGY

3.1.Epidemiology

Prostate cancer is the second most commonly diagnosed cancer in men, with an estimated 1.1 million diagnoses worldwide in 2012, accounting for 15% of all cancers diagnosed [9]. The frequency of autopsy-detected PCa is roughly the same worldwide [10]. A systematic review of autopsy studies reported a prevalence of PCa at age < 30 years of 5% (95% confidence interval [CI]: 3-8%), increasing by an odds ratio (OR) of 1.7 (1.6-1.8) per decade, to a prevalence of 59% (48-71%) by age > 79 years [11].

The incidence of PCa diagnosis varies widely between different geographical areas, being highest in Australia/New Zealand and Northern America (age-standardised rates [ASR] per 100,000 of 111.6 and 97.2, respectively), and in Western and Northern Europe (ASRs of 94.9 and 85, respectively), largely due to the use of prostate-specific antigen (PSA) testing and the aging population. The incidence is low in Eastern and South-Central Asia (ASRs of 10.5 and 4.5, respectively), whilst rates in Eastern and Southern Europe, which were low, have showed a steady increase [9,10].

There is relatively less variation in mortality rates worldwide, although rates are generally high in populations of African descent (Caribbean: ASR of 29 and Sub-Saharan Africa: ASRs ranging between 19 and 14), intermediate in the USA and very low in Asia (South-Central Asia: ASR of 2.9) [9].

3.2.Aetiology

3.2.1.Family history/genetics

Family history and racial/ethnic background are associated with an increased PCa incidence suggesting a genetic predisposition [12,13]. Only a small subpopulation of men with PCa (~9%) has true hereditary disease. This is defined as three or more affected relatives or at least two relatives who have developed early-onset PCa (< 55 years) [13]. Hereditary PCa is associated with a 6 to 7-year earlier disease onset but the disease aggressiveness and clinical course does not seem to differ in other ways [13,14]. The probability of high-risk PCa at age 65 in men with their father and two brothers affected was 11.4% (vs. a population risk of 1.4%) in a Swedish population-based study [15].

Men with one first-degree relative diagnosed with PCa still suffer an increased risk (relative risk [RR]: 1.8) of developing PCa, and this increases further in men with a father and brother (RR: 5.51) or two brothers (RR: 7.71) diagnosed with PCa [16]. Ancestry-specific risk loci have been identified [17] and genome-wide association studies have identified more than 100 common susceptibility loci contributing to the risk for PCa [18-20]. Of the underlying determinants of genomic diversity and mechanisms between genetic and environmental factors, much remains unknown. However, it is accepted that men of African descent show a higher incidence of PCa and generally have a more aggressive course of disease [21].

Germline mutations have also been increasingly identified amongst men with non-hereditary PCa. In metastatic PCa patients an incidence of 11.8% germline mutations was found in genes mediating DNA-repair processes [22]. Mutations were most commonly seen in BRCA2 (5.35%), ATM (1.6%), CHEK2 (1.9%), BRCA1 (0.9%), and PALB2 (0.4%). In 3,607 unselected PCa patients, 620 (17.2%) were found to have a pathogenic germline variant [23]. The percentage of BRCA1/2 mutations in this study was 5.99%. Germline mutations in genes such as BRCA1/2 and HOXB13 have been associated with an increased risk of PCa and targeted genomic analysis of these genes could offer options to identify families at high risk [24,25].

A prospective cohort study of male BRCA1 and BRCA2 carriers confirmed the association between BRCA2 and aggressive PCa [26]. BRCA mutation carriers were reported to have a worse outcome when compared to non-carriers after local therapy [27]. The IMPACT study evaluates targeted PCa screening (annually, biopsy recommended if PSA > 3.0 ng/mL) using PSA in men aged 40-69 years with germline BRCA1/2 mutations [28]. The authors found that after 3 years of screening, BRCA2 mutation carriers were associated with a higher incidence of PCa, a younger age of diagnosis, and more clinically significant tumours compared with non-carriers. The influence of BRCA1 mutations on PCa remains unclear. No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 non-carriers. Limitations of the IMPACT study include the lack of mpMRI data and targeted biopsies as it was initiated before that era.

3.2.2.Risk factors

A wide variety of exogenous/environmental factors have been discussed as being associated with the risk of developing PCa or as being aetiologically important for the progression from latent to clinical PCa [29]. Japanese men have a lower PCa risk compared to men from the Western world. However, as Japanese men move from Japan to California, their risk of PCa increases, approaching that of American men, implying a role of environmental or dietary factors [30]. However, currently there are no known effective preventative dietary or pharmacological interventions.

3.2.2.1.Metabolic syndrome (MetS)

The single components of MetS hypertension (p = 0.035) and waist circumference > 102 cm (p = 0.007) have been associated with a significantly greater risk of PCa, but in contrast, having > 3 components of MetS is associated with a reduced risk (OR: 0.70, 95% CI: 0.60-0.82) [31,32].

3.2.2.1.1.Diabetes/metformin

On a population level, metformin users (but not other oral hypoglycaemic agents) were found to be at a decreased risk of PCa diagnosis compared with never-users (adjusted OR: 0.84; 95% CI: 0.74-0.96) [33]. In 540 diabetic participants of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study, metformin use was not significantly associated with PCa and therefore not advised as a preventive measure (OR: 1.19, p = 0.50) [34]. The ongoing Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial assesses metformin use in advanced PCa [35].

3.2.2.1.2.Cholesterol/statins

A meta-analysis of 14 large prospective studies did not show an association between blood total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol levels and the risk of either overall PCa or high-grade PCa [36]. Results from the REDUCE study also did not show a preventive effect of statins on PCa risk [34].

3.2.2.1.3.Obesity

Within the REDUCE study, obesity was associated with lower risk of low-grade PCa in multivariable analyses (OR: 0.79, p = 0.01), but increased risk of high-grade PCa (OR: 1.28, p = 0.042) [37]. This effect seems mainly explained by environmental determinants of height/body mass index (BMI) rather than genetically elevated height or BMI [38].

3.2.2.2.Dietary factors

The association between a wide variety of dietary factors and PCa have been studied (Table 3.1).

Table 3.1: Dietary factors that have been associated with PCa

3.2.2.3.Hormonally active medication

3.2.2.3.1.5-alpha-reductase inhibitors (5-ARIs)

Although it seems that 5-ARIs have the potential of preventing or delaying the development of PCa (~25%, for ISUP grade 1 cancer only), this must be weighed against treatment-related side-effects as well as the potential small increased risk of high-grade PCa [56-58]. None of the available 5-ARIs have been approved by the European Medicines Agency (EMA) for chemoprevention.

3.2.2.3.2.Testosterone

Hypogonadal men receiving testosterone supplements do not have an increased risk of PCa [59]. A pooled analysis showed that men with very low concentrations of free testosterone (lowest 10%) have a below average risk (OR: 0.77) of PCa [60].

3.2.2.4.Other potential risk factors

Balding was associated with a higher risk of PCa death [61]. Gonorrhoea was significantly associated with an increased incidence of PCa (OR: 1.31; 95% CI: 1.14-1.52) [62]. Occupational exposure may also play a role, based on a meta-analysis which revealed that night-shift work is associated with an increased risk (2.8%, p = 0.030) of PCa [63]. Current cigarette smoking was associated with an increased risk of PCa death (RR: 1.24; 95% CI: 1.18-1.31) [64]. A meta-analysis on Cadmium (Cd) found a positive association (magnitude of risk unknown due to heterogeneity) between high Cd exposure and risk of PCa for occupational exposure, but not for non-occupational exposure, potentially due to higher Cd levels during occupational exposure [65]. Men positive for human papillomavirus-16 may be at increased risk [66].

A number of other factors previously linked to an increased risk of PCa have been disproved including vasectomy [67] and self-reported acne [68]. There are conflicting data about the use of aspirin or non-steroidal anti-inflammatory drugs and the risk of PCa and mortality [69,70].

Ultraviolet radiation exposure decreased the risk of PCa (hazard ratio [HR]: 0.91; 95% CI: 0.88-0.95) [71]. A review found a small but protective association of circumcision status with PCa [72]. Higher ejaculation frequency (> 21 times a month vs. 4 to 7 times) has been associated with a 20% lower risk of PCa [73].

The associations with PCa identified to date lack evidence for causality. As a consequence there is no data to suggest effective preventative strategies.

3.2.3.Summary of evidence and guidelines for epidemiology and aetiology

4.CLASSIFICATION AND STAGING SYSTEMS

4.1.Classification

The objective of a tumour classification system is to combine patients with a similar clinical outcome. This allows for the design of clinical trials on relatively homogeneous patient populations, the comparison of clinical and pathological data obtained from different hospitals across the world, and the development of recommendations for the treatment of these patient populations. Throughout these Guidelines the 2017 Tumour, Node, Metastasis (TNM) classification for staging of PCa (Table 4.1) [74] and the EAU risk group classification, which is essentially based on D'Amico's classification system for PCa, are used (Table 4.3) [75]. The latter classification is based on the grouping of patients with a similar risk of biochemical recurrence after radical prostatectomy (RP) or external beam radiotherapy (EBRT).

Table 4.1: Clinical Tumour Node Metastasis (TNM) classification of PCa [74]

1 Metastasis no larger than 0.2 cm can be designated pNmi.

2 When more than one site of metastasis is present, the most advanced category is used. (p)M1c is the most advanced category.

Clinical T stage only refers to DRE findings; imaging findings are not considered in the TNM classification. Pathological staging (pTNM) is based on histopathological tissue assessment and largely parallels the clinical TNM, except for clinical stage T1c and the T2 substages. All histopathologically confirmed organ-confined PCas after RP are pathological stage T2 and the current Union for International Cancer Control (UICC) no longer recognises pT2 substages [74].

4.2.Gleason score and International Society of Urological Pathology 2014 grade

The 2005 International Society of Urological Pathology (ISUP) modified Gleason score (GS) of biopsy-detected PCa comprises the Gleason grade of the most extensive (primary) pattern, plus the second most common (secondary) pattern, if two are present. If one pattern is present, it needs to be doubled to yield the GS. For three grades, the biopsy GS comprises the most common grade plus the highest grade, irrespective of its extent. When a carcinoma is largely grade 4/5, identification of < 5% of Gleason grade 2 or 3 glands should not be incorporated in the GS. A GS < 5 should not be given based on prostate biopsies [76,77]. In addition to reporting of the carcinoma features for each biopsy, an overall (or global) GS based on the carcinoma-positive biopsies can be provided. The global GS takes into account the extent of each grade from all prostate biopsies. The 2014 ISUP endorsed grading system [77,78] limits the number of PCa grades, ranging them from 1 to 5 (see Table 4.2), in order to:

1.align the PCa grading with the grading of other carcinomas;

2.eliminate the anomaly that the most highly differentiated PCas have a GS 6;

3.to further define the clinically highly significant distinction between GS 7(3+4) and 7(4+3) PCa [79].

Table 4.2: International Society of Urological Pathology 2014 grades

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

GS = Gleason score; ISUP = International Society for Urological Pathology; PSA = prostate-specific antigen.

4.3.Prognostic relevance of stratification

A more precise stratification of the clinically heterogeneous subset of intermediate-risk group patients could provide a better framework for their management. The adoption of the current ISUP grading system, defining the split-up of GS 7 cancers into ISUP grade 2 (primary Gleason grade 3) and ISUP grade 3 (primary Gleason grade 4) because of their distinct prognostic impact strengthens such a separation of the intermediate-risk group into a low-intermediate (ISUP grade 2) and high intermediate-risk (ISUP grade 3) group [78] (see Section 5.2.7.4.3).

Emerging clinical data support this distinction between favourable- and unfavourable-risk patient categories within the intermediate-risk group [79,80].

4.4.Guideline for classification and staging systems

5.DIAGNOSTIC EVALUATION

5.1.Screening and early detection

5.1.1.Screening

Population or mass screening is defined as the 'systematic examination of asymptomatic men (at risk)' and is usually initiated by health authorities. The co-primary objectives are:

• reduction in mortality due to PCa;
• a maintained QoL as expressed by QoL-adjusted gain in life years (QALYs).

Prostate cancer mortality trends range widely from country to country in the industrialised world [81]. Mortality due to PCa has decreased in most Western nations but the magnitude of the reduction varies between countries. Currently, screening for PCa still remains one of the most controversial topics in the urological literature [82].

Initial widespread aggressive screening in USA was associated with a decrease in mortality [83]. In 2012 the US Preventive Services Task Force (USPSTF) released a recommendation against non-selective PSA screening [84], which was adopted in the 2013 AUA Guidelines [85] and resulted in a reduction in the use of PSA for early detection [86]. While PCa mortality had decreased for two decades since the introduction of PSA [87], the incidence of advanced disease and, possibly, cancer-related mortality began to rise after 2012 [88]. Similarly, the reduction in the use of PSA testing was associated with higher rates of advanced disease at diagnosis (e.g., a 6% increase in the number of patients with metastatic PCa) [89-93]. Moreover, additional evidence suggests a long-term benefit of PSA in terms of reduction of cancer-specific mortality [94,95].

In 2017 the USPSTF issued an updated statement suggesting that men aged 55-69 should be informed about the benefits and harms of PSA-based screening as this might be associated with a small survival benefit. The USPSTF has now upgraded this recommendation to a grade C [96], from a previous grade of 'D' [96-98]. The grade D recommendation remains in place for men over 70 years old. This represents a major switch from discouraging PSA-based screening (grade D) to offering screening to selected patients depending on individual circumstances.

A comparison of systematic and opportunistic screening suggested over-diagnosis and mortality reduction in the systematic screening group compared to a higher over-diagnosis with a marginal survival benefit, at best, in the opportunistic screening regimen [99].

A Cochrane review published in 2013 [100], which has since been updated [101], presents the main overview to date. The findings of the updated publication (based on a literature search until April 3, 2013) are almost identical to the 2009 review:

• Screening is associated with an increased diagnosis of PCa (RR: 1.3; 95% CI: 1.02-1.65).
• Screening is associated with detection of more localised disease (RR: 1.79; 95% CI: 1.19-2.70) and less advanced PCa (T3-4, N1, M1) (RR: 0.80, 95% CI: 0.73-0.87).
• From the results of 5 RCTs, randomising more than 341,000 men, no PCa-specific survival benefit was observed (RR: 1.00, 95% CI: 0.86-1.17). This was the main endpoint in all trials.
• From the results of four available RCTs, no overall survival (OS) benefit was observed (RR: 1.00, 95% CI: 0.96-1.03).

The diagnostic tool (i.e. biopsy) was not associated with any mortality in the selected papers, which is in contrast with other known data [57,58]. Increased diagnosis has historically led to over-treatment with associated side-effects. However, despite this, the impact on the patient's overall QoL is still unclear. At a population level screening has never been shown to be detrimental [102-104]. Nevertheless, all these findings have led to strong advice against systematic population-based screening in most countries, including those in Europe.

In case screening is considered, a single PSA test is not enough based on the Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) trial. The CAP trial evaluated a single PSA screening vs. controls not undergoing PSA screening on PCa detection in men aged 50 to 69 years old. The single PSA screening intervention detected more low-risk PCa cases but had no significant effect on PCa mortality after a median follow-up of 10 years [105].

Since 2013, the European Randomized Study of Screening for Prostate Cancer (ERSPC) data have been updated with 16 years of follow up (see Table 5.1) [106]. The key message is that with extended follow up, the mortality reduction remains unchanged (21%, and 29% after non-compliance adjustment). However the number needed to screen (NNS) and to treat is decreasing, and is now below the NNS observed in breast cancer trials [106,107].

Table 5.1: Follow-up data from the ERSPC study [106]

5.1.2.Early detection

An individualised risk-adapted strategy for early detection may still be associated with a substantial risk of over-diagnosis. It is essential to remember that breaking the link between diagnosis and active treatment is the only way to decrease over-treatment, while still maintaining the potential benefit of individual early diagnosis for men requesting it [12,108].

Men at elevated risk of having PCa are those > 50 years [109] or at age > 45 years with a family history of PCa (either paternal or maternal [110]) or of African descent [111,112]. Men of African descent are more likely to be diagnosed with more advanced disease [113] and upgrade was more frequent after prostatectomy as compared to Caucasian men (49% vs. 26%) [114]. In 2014, as for breast cancer, a genetic abnormality associated with an increased risk has been shown prospectively i.e. BRCA2 [115,116]. Prostate-specific antigen screening in male BRCA2 carriers detected more significant cancers at a younger age compared to non-mutation carriers [28].

In addition, men with a PSA > 1 ng/mL at 40 years and > 2 ng/mL at 60 years are also at increased risk of PCa metastasis or death from PCa several decades later [117,118]. The long-term survival and QoL benefits of such an approach remain to be proven at a population level.

The use of DRE alone in the primary care setting had a sensitivity and specificity below 60%, possibly due to inexperience, and can therefore not be recommended to exclude PCa [119]. Informed men requesting an early diagnosis should be given a PSA test and undergo a DRE [120]. The optimal intervals for PSA testing and DRE follow-up are unknown as they varied between several prospective trials. A single PSA test in men between 50 and 69 years did not improve 10-year PCa-specific survival compared to standard care in a large RCT in a primary care setting [105]. A risk-adapted strategy might be a consideration, based on the initial PSA level. This could be every 2 years for those initially at risk, or postponed up to 8 to 10 years in those not at risk with an initial PSA < 1 ng/mL at 40 years and a PSA < 2 ng/mL at 60 years of age and a negative family history [121]. An analysis of ERSPC data supports a recommendation for an 8-year screening interval in men with an initial PSA concentration < 1 µg/L; fewer than 1% of men with an initial PSA concentration < 1 µg/L were found to have a concentration above the biopsy threshold of 3 µg/L at 4-year follow-up; the cancer detection rate by 8 years was close to 1% [122]. Data from the Goteborg arm of the ERSPC trial suggest that the age at which early diagnosis should be stopped remains controversial, but an individual's life expectancy must definitely be taken into account. Men who have less than a 15-year life expectancy are unlikely to benefit, based on data from the Prostate Cancer Intervention Versus Observation Trial (PIVOT) and the ERSPC trials. Furthermore, although there is no simple tool to evaluate individual life expectancy; comorbidity is at least as important as age. A detailed review can be found in Section 5.4 'Evaluating health status and life expectancy' and in the SIOG Guidelines [123,360].

Multiple tools are now available to determine the need for a biopsy to establish the diagnosis of a PCa, including imaging by MRI, if available (see Section 5.2.4). New biological markers such as TMPRSS2-ERG fusion, PCA3 [124,125] or kallikreins as incorporated in the Phi or 4Kscore tests [126,127] have been shown to add sensitivity and specificity on top of PSA, potentially avoiding unnecessary biopsies and lowering over-diagnosis (see Section 5.2.2.4). At this time there is too limited data to implement these markers into routine screening programmes.

Risk calculators may be useful in helping to determine (on an individual basis) what the potential risk of cancer may be, thereby reducing the number of unnecessary biopsies. Several tools developed from cohort studies are available including:

• the PCPT cohort: PCPTRC 2.0 http://myprostatecancerrisk.com/;
• the ERSPC cohort: http://www.prostatecancer-riskcalculator.com/seven-prostate-cancer-risk-calculators;
  An updated version was presented in 2017 including prediction of low and high risk now also based on the ISUP grading system and presence of cribriform growth in histology [128].
• a local Canadian cohort: https://sunnybrook.ca/content/?page=asure-calc (among others).

Since none of these risk calculators has clearly shown superiority, it remains a personal decision as to which one to use [129].

5.1.3.Guidelines for screening and early detection

5.2.Clinical diagnosis

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

5.2.1.Digital rectal examination

Most PCas are located in the peripheral zone and may be detected by DRE when the volume is > 0.2 mL. In ~18% of cases, PCa is detected by suspect DRE alone, irrespective of PSA level [130]. A suspect DRE in patients with a PSA level < 2 ng/mL has a positive predictive value (PPV) of 5-30% [131]. An abnormal DRE is associated with an increased risk of a higher ISUP grade and is an indication for biopsy [132,133].

5.2.2.Prostate-specific antigen

The use of PSA as a serum marker has revolutionised PCa diagnosis [134]. Prostate-specific antigen is organ but not cancer specific; therefore, it may be elevated in benign prostatic hypertrophy (BPH), prostatitis and other non-malignant conditions. As an independent variable, PSA is a better predictor of cancer than either DRE or transrectal ultrasound (TRUS) [135].

There are no agreed standards defined for measuring PSA [136]. It is a continuous parameter, with higher levels indicating greater likelihood of PCa. Many men may harbour PCa despite having low serum PSA [137]. Table 5.2.1 demonstrates the occurrence of GS > 7 (or ISUP > grade 2) PCa at low PSA levels, precluding an optimal PSA threshold for detecting non-palpable but clinically significant (cs) PCa. The use of nomograms may help in predicting indolent PCa [138].

Table 5.2.1: Risk of PCa in relation to low PSA values [137]

5.2.2.1.PSA density

Prostate-specific antigen density is the level of serum PSA divided by the prostate volume. The higher the PSA density, the more likely it is that the PCa is clinically significant (see Section 6.2.1 - Treatment of low-risk disease).

5.2.2.2.PSA velocity and doubling time

There are two methods of measuring PSA kinetics:

• PSA velocity (PSAV): absolute annual increase in serum PSA (ng/mL/year) [139];
• PSA doubling time (PSA-DT): which measures the exponential increase in serum PSA over time [140].

Prostate specific antigen velocity and PSA-DT may have a prognostic role in treating PCa but have limited diagnostic use because of background noise (total prostate volume, and BPH), different intervals between PSA determinations, and acceleration/deceleration of PSAV and PSA-DT over time [141]. These measurements do not provide additional information compared with PSA alone [142-145].

5.2.2.3.Free/total PSA ratio

Free/total (f/t) PSA must be used cautiously because it may be adversely affected by several pre-analytical and clinical factors (e.g., instability of free PSA at 4°C and room temperature, variable assay characteristics, and concomitant BPH in large prostates) [146]. Prostate cancer was detected in men with a PSA 4-10 ng/mL by biopsy in 56% of men with f/t PSA < 0.10, but in only 8% with f/t PSA > 0.25 ng/mL [147]. A systematic review including 14 studies found a pooled sensitivity of 70% in men with a PSA of 4-10 ng/mL [148]. Free/total PSA is of no clinical use if the total serum PSA is > 10 ng/mL or during follow up of known PCa. The clinical value of f/t PSA is limited in the light of novel serum tests.

5.2.2.4.Additional serum testing

Several assays measuring a panel of kallikreins in serum or plasma are now commercially available, including the U.S. Food and Drug Administration (FDA) approved Prostate Health Index (PHI) test, (combining free and total PSA and the [-2]pro-PSA isoform [p2PSA]), and the four kallikrein (4K) score test (measuring free, intact and total PSA and kallikrein-like peptidase 2 [hK2] in addition to age, DRE and prior biopsy status). Both tests are intended to reduce the number of unnecessary prostate biopsies in PSA-tested men. A few prospective multicentre studies demonstrated that both the PHI and 4K score test out-performed f/t PSA PCa detection, with an improved prediction of clinically significant PCa in men with a PSA between 2-10 ng/mL [127,149-151]. In a head-to-head comparison both tests performed equally [152].

5.2.2.5.Urine tests: PCA3 marker/SelectMDX/Mi Prostate score (MiPS)/ExoDX

Prostate cancer gene 3 (PCA3) is a prostate-specific, non-coding microRNA (mRNA) biomarker that is detectable in urine sediments obtained after three strokes of prostatic massage during DRE. The commercially available Progensa urine test for PCA3 is superior to total and percent-free PSA for the detection of PCa in men with elevated PSA as it shows significant increases in the area under the receiver-operator characteristic curve (AUC) for positive biopsies [153-156].

PCA3 score increases with PCa volume, but there are conflicting data about whether it independently predicts the ISUP grade [157]. Currently, the main indication for the Progensa test is to determine whether repeat biopsy is needed after an initially negative biopsy, but its clinical effectiveness for this purpose is uncertain [158]. Wei et al. showed 42% sensitivity at a cut-off of 60 in the primary biopsy setting with a high specificity (91%) and a PPV of 80% suggesting that the assay may be used in the primary setting [159].

The SelectMDX test is similarly based on mRNA biomarker isolation from urine. The presence of HOXC6 and DLX1 mRNA levels is assessed to provide an estimate of the risk of both presence of PCa on biopsy as well as presence of high-risk cancer [160].

TMPRSS2-ERG fusion, a fusion of the trans-membrane protease serine 2 (TMPRSS2) and the ERG gene can be detected in 50% of PCas [161]. When detection of TMPRSS2-ERG in urine was added to PCA3 expression and serum PSA (Mi(chigan)Prostate Score [MiPS]), cancer prediction improved [162]. Exosomes secreted by cancer cells may contain mRNA diagnostic for high-grade PCa [163,164]. Use of the ExoDx Prostate IntelliScore urine exosome assay resulted in avoiding 27% of unnecessary biopsies when compared to standard of care. However, currently, both the MiPS-score and ExoDx assay are considered investigational.

In 6 head-to-head comparison studies of PCA3 and PHI, only Seisen et al. found a significant difference; PCA3 detected more cancers, but for the detection of significant disease, defined as ISUP grade > 2, more than three positive cores, or > 50% cancer involvement in any core, PHI proved superior [165]. Russo et al. suggested in their systematic review that, based on moderate quality data, PHI and the 4K panel had a high diagnostic accuracy and showed similar performance in predicting the detection of significant disease [166]. However, in the screening population of the ERSPC study the use of both PCA3 and 4K panel when added to the risk calculator led to an improvement in AUC of less than 0.03 [124]. Based on the available evidence, some biomarkers could help in discriminating between aggressive and non-aggressive tumours with an additional value compared to the prognostic parameters currently used by clinicians [167]. However, upfront multiparametric magnetic resonance imaging (mpMRI) is also likely to affect the utility of above-mentioned biomarkers (see Section 5.2.4).

5.2.2.6.Guidelines for risk-assessment of asymptomatic men

5.2.3.Baseline biopsy

The need for prostate biopsy is based on PSA level and/or suspicious DRE and/or imaging (see Section 5.2.4). Age, potential comorbidity, and therapeutic consequences should also be considered and discussed beforehand [168]. Risk stratification is a potential tool for reducing unnecessary biopsies [168].

Limited PSA elevation alone should not prompt immediate biopsy. Prostate specific antigen level should be verified after a few weeks, in the same laboratory, using the same assay under standardised conditions (i.e. no ejaculation, manipulations, and urinary tract infections [UTIs]) [169,170]. Empiric use of antibiotics in an asymptomatic patient in order to lower the PSA should not be undertaken [171].

Ultrasound (US)-guided biopsy is now the standard of care. Prostate biopsy is performed by either the transrectal or transperineal approach. Cancer detection rates, when performed without prior imaging with MRI, are comparable between the two approaches [172], however some evidence suggests reduced infection risk with the transperineal route (see Section 5.2.6.4). Rectal disinfection with povidone-iodine may be considered [173,174].

Transurethral resection of the prostate should not be used as a tool for cancer detection [175].

5.2.4.The role of imaging in clinical diagnosis

5.2.4.1.Transrectal ultrasound and ultrasound-based techniques

Grey-scale TRUS is not reliable at detecting PCa [176] and the diagnostic yield of additional biopsies performed on hypoechoic lesions is negligible [177]. Prostate HistoScanning^TM provided inconsistent results across studies [178]. New sonographic modalities such as sonoelastography, contrast-enhanced US or high-resolution micro-ultrasound have given promising preliminary findings; either alone or combined in the so-called 'multiparametric US'. However, these techniques are still limited by lack of standardisation, lack of large-scale evaluation and unclear results in transition zones [179-184].

5.2.4.2.Multiparametric magnetic resonance imaging

5.2.4.2.1.Multiparametric magnetic resonance imaging performance in detecting ISUP grade > 2 PCa

Correlation with RP specimens shows that mpMRI has good sensitivity for the detection and localisation of ISUP grade > 2 cancers [185-187]. This was further confirmed in patients who underwent template biopsies. In a recent Cochrane meta-analysis which compared mpMRI to template biopsies (> 20 cores) in biopsy-naïve and repeat-biopsy settings, mpMRI had a pooled sensitivity of 0.91 (95% CI: 0.83-0.95) and a pooled specificity of 0.37 (95% CI: 0.29-0.46) for ISUP grade > 2 cancers [188]. For ISUP grade > 3 cancers, mpMRI pooled sensitivity and specificity were 0.95 (95% CI: 0.87-0.99) and 0.35 (95% CI: 0.26-0.46), respectively.

5.2.4.2.2.Multiparametric magnetic resonance imaging performance in detecting ISUP grade 1 PCa

Multiparametric MRI is less sensitive in identifying ISUP grade 1 PCa. It identifies less than 30% of ISUP grade 1 cancers smaller than 0.5 cc identified on RP specimens by histopathology analysis [185]. In series using template biopsy findings as the reference standard, mpMRI has a pooled sensitivity of 0.70 (95% CI: 0.59-0.80) and a pooled specificity of 0.27 (95% CI: 0.19-0.37) for identifying ISUP grade 1 cancers [188].

5.2.4.2.3.Does targeted biopsy improve the detection of ISUP grade > 2 as compared to systematic biopsy?

In pooled data of 25 reports on agreement analysis (head-to-head comparisons) between systematic biopsy (median number of cores, 8-15) and MRI-targeted biopsies (MRI-TBx; median number of cores, 2-7), the detection ratio (i.e. the ratio of the detection rates obtained by MRI-TBx alone and by systematic biopsy alone) was 1.12 (95% CI: 1.02-1.23) for ISUP grade > 2 cancers and 1.20 (95% CI: 1.06-1.36) for ISUP grade > 3 cancers, and therefore in favour of MRI-TBx [188]. However, the pooled detection ratios for ISUP grade > 2 cancers and ISUP grade > 3 cancers were 1.44 (95% CI: 1.19-1.75) and 1.64 (95% CI: 1.27-2.11), respectively, in patients with prior negative systematic biopsies, and only 1.05 (95% CI: 0.95-1.16) and 1.09 (95% CI: 0.94-1.26) in biopsy-naïve patients.

Three prospective multicentre trials evaluated MRI-TBx in biopsy-naïve patients. In the PRostate Evaluation for Clinically Important Disease: Sampling Using Image-guidance Or Not? (PRECISION) trial, 500 biopsy-naïve patients were randomised to either MRI-TBx only or TRUS-guided systematic biopsy only. The detection rate of ISUP grade > 2 cancers was significantly higher in men assigned to MRI-TBx (38%) than in those assigned to SBx (26%, p = 0.005, detection ratio 1.46) [189]. In the Assessment of Prostate MRI Before Prostate Biopsies (MRI-FIRST) trial, 251 biopsy-naïve patients underwent TRUS-guided systematic biopsy by an operator who was blinded to mpMRI findings, and MRI-TBx by another operator. MRI-TBx detected ISUP grade > 2 cancers in a higher percentage of patients but the difference was not significant (32.3% vs. 29.9%, p = 0.38; detection ratio: 1.08) [177]. However, MRI-TBx detected significantly more ISUP grade > 3 cancers than systematic biopsy (19.9% vs. 15.1%, p = 0.0095; detection ratio: 1.32). A similar trend for improved detection of ISUP grade > 3 cancers by MRI-TBx was observed in the Cochrane analysis, however, it was not statistically significant (detection ratio 1.11 [0.88-1.40]) [188]. The Met Prostaat MRI Meer Mans (4M) study included 626 biopsy-naïve patients; all patients underwent systematic biopsy, and those with a positive mpMRI (Prostate Imaging Reporting and Data System [PI-RADS] 3-5, 51%) underwent additional in-bore MRI-TBx. The results were close to those of the MRI-FIRST trial with a detection ratio for ISUP grade > 2 cancers of 1.09 (detection rate: 25% for MRI-TBx vs. 23% for systematic biopsy) [190]. However, in this study, MRI-TBx and systematic biopsy detected an equal number of ISUP grade > 3 cancers (11% vs. 12%; detection ratio: 0.92).

Thus, MRI-TBx significantly out-performs systematic biopsy for the detection of ISUP grade > 2 in the repeat-biopsy setting. In biopsy-naïve patients, the difference appears to be less marked and not significant in all series, but it remains in favour of MRI-TBx in most studies.

5.2.4.2.4.Does MRI-TBx reduce the detection of ISUP grade 1 PCa as compared to systematic biopsy?

In pooled data of 25 reports on agreement analysis (head-to-head comparisons) between systematic biopsy and MRI-TBx, the detection ratio for ISUP grade 1 cancers was 0.62 (95% CI: 0.44-0.88) in patients with prior negative biopsy and 0.63 (95% CI: 0.54-0.74) in biopsy-naïve patients [188]. In the PRECISION and 4M trials, the detection rate of ISUP grade 1 patients was significantly lower in the MRI-TBx group as compared to systematic biopsy (9% vs. 22%, p < 0.001, detection ratio of 0.41 for PRECISION; 14% vs. 25%, p < 0.001, detection ratio of 0.56 for 4M) [189,190]. In the MRI-FIRST trial, MRI-TBx detected significantly fewer patients with clinically insignificant PCa (defined as ISUP grade 1 and maximum cancer core length < 6 mm) than systematic biopsy (5.6% vs. 19.5%, p < 0.0001, detection ratio of 0.29) [177]. Consequently, MRI-TBx significantly reduces over-diagnosis of low-risk disease, as compared to systematic biopsy.

5.2.4.2.5.The added value of systematic and targeted biopsy

Magnetic resonance imaging-targeted biopsies can be used in two different diagnostic pathways: 1) the 'combined pathway', in which patients with a positive mpMRI undergo combined systematic and targeted biopsy, and patients with a negative mpMRI undergo systematic biopsy; 2) the 'MRI pathway', in which patients with a positive mpMRI undergo only MRI-TBx, and patients with a negative mpMRI are not biopsied at all.

Many studies evaluated combined systematic and targeted biopsy in the same patients and could therefore assess the absolute added value of each technique (i.e. the percentage of patients diagnosed by only one biopsy technique). Data from the Cochrane meta-analysis of these studies and from the MRI-FIRST and 4M trials suggest that the absolute added value of MRI-TBx for detecting ISUP grade > 2 cancers is higher than that of systematic biopsy (see Table 5.2.4.1).

Table 5.2.4.1: Absolute added values of targeted and systematic biopsies for ISUP grade > 2 and > 3 cancer detection

* 95% CI.

The absolute added value of a given biopsy technique is defined by the percentage of patients of the entire cohort diagnosed only by this biopsy technique.

ISUP = International Society for Urological Pathology (grade); MRI-TBx = magnetic resonance imaging-targeted biopsies; ND = not defined.

In Table 5.2.4.1 the absolute added values refer to the percentage of patients in the entire cohort; if the cancer prevalence is taken into account, the 'relative' percentage of additional detected PCa can be computed. Adding MRI-TBx to systematic biopsy in biopsy-naïve patients increases the number of ISUP grade > 2 and grade > 3 PCa by approximately 20% and 30%, respectively. In the repeat-biopsy setting, adding MRI-TBx increases detection of ISUP grade > 2 and grade > 3 PCa by approximately 40% and 50%, respectively. Omitting systematic biopsy in biopsy-naïve patients would miss approximately 16% of ISUP grade > 2 PCa and 18% of ISUP grade > 3 PCa. In the repeat-biopsy setting, it would miss approximately 10% of ISUP grade > 2 PCa and 9% of ISUP grade > 3 PCa.

5.2.4.2.6.Number of biopsy procedures potentially avoided in the 'MR pathway'

The diagnostic yield and number of biopsy procedures potentially avoided by the 'MR pathway' depends on the Likert/PI-RADS threshold used to define positive mpMRI. In pooled studies on biopsy-naïve patients and patients with prior negative biopsies, a Likert/PI-RADS threshold of > 3 would have avoided 30% (95% CI: 23-38) of all biopsy procedures while missing 11% (95% CI: 6-18) of all detected ISUP grade > 2 cancers (relative percentage) [188]. Increasing the threshold to > 4 would have avoided 59% (95% CI: 43-78) of all biopsy procedures while missing 28% (95% CI: 14-48) of all detected ISUP grade > 2 cancers [188]. Of note, the percentages of negative mpMRI (Likert/PI-RADS score < 2) in MRI-FIRST, PRECISION and 4M were 21.1%, 28.9% and 49%, respectively [177,189,190].

5.2.4.2.7.Other considerations

5.2.4.2.7.1.Multiparametric magnetic resonance imaging reproducibility

Despite the use of the PIRADSv2 scoring system [191], mpMRI inter-reader reproducibility remains moderate at best [192,193] which currently limits its broad use by non-dedicated radiologists. However, significant improvement in the accuracy of mpMRI and MRI-TBx can be observed over time, both in academic and community hospitals, especially after implementation of PIRADSv2 scoring and multidisciplinary meetings using pathological correlation and feedback [194-197]. An updated version of the PIRADS score (PIRADSv2.1) has been recently published to improve reader reproducibility [198], but it has not yet been fully evaluated. It is still too early to predict whether quantitative approaches and computer-aided diagnostic systems will improve the characterisation of lesions seen at mpMRI [199-201].

5.2.4.2.7.2.Targeted biopsy accuracy and reproducibility

Clinically significant PCa not detected by the 'MRI pathway' can be missed because of MRI failure (invisible cancer or reader's misinterpretation) or because of targeting failure (target missed or undersampled by MRI-TBx). In two retrospective studies of 211 and 116 patients with a unilateral mpMRI lesion, targeted biopsy alone detected 73.5-85.5% of all csPCa (ISUP grade > 2); combining MRI-TBx with systematic biopsy of the lobe with the MRI lesion detected 96-96.4% of all csPCas and combined targeted and systematic biopsy of the contralateral lobe only identified 81.6-92.7% of csPCas [202,203]. The difference may reflect targeting errors leading to undersampling of the tumour. Increasing the number of cores taken per target may partially compensate for guiding imprecision. In a retrospective study of 479 patients who underwent MRI-TBx with 4 cores per target that were sequentially labelled, the first 3 cores detected 95.1% of the csPCas detected by the 4-core strategy [204]. In two other retrospective studies of 330 and 744 patients who underwent MRI-TBx with up to 5 cores per target, the one-core and 3-core sampling strategies detected respectively 63-75% and 90-93% of the ISUP grade > 2 PCa detected by the 5-core strategy [205,206]. These percentages are likely to be influenced by the lesion size and location, the prostate volume or the operator's experience, but no study has quantified the impact of these factors yet.

5.2.4.2.7.3.Role of risk-stratification

The negative predictive value (NPV) of a diagnostic test decreases when the disease prevalence increases, i.e. when the a priori risk of the patient increases. Therefore, the excellent NPV reported for mpMRI in the literature may not apply to patients with a higher risk of disease [207] and evaluating the individual risk of csPCa is essential for interpreting mpMRI results. Prostate-specific antigen density (PSAD) is one of the strongest predictors of csPCa in risk-models and several studies found that PSAD and the PIRADS score were significant independent predictors of csPCa at biopsy [208,209]. In patients with negative mpMRI findings (PIRADS 1-2), the risk of finding csPCa at subsequent SBx is usually < 10% if the PSAD is < 0.15 ng/mL/cc. In contrast, it is 27-40% if the PSAD is > 0.15-0.20 ng/mL/cc [190,209-213] (Table 5.2.4.2).

Several groups have developed nomograms which combine mpMRI findings with simple clinical data as a tool to predict subsequent biopsy results. These nomograms require further validation, but in due time they may out-perform predictors such as the current risk calculators (e.g. ERSPC or PCPT) in the selection of patients who may benefit from systematic and/or MRI-TBx [214]. Combining mpMRI findings with the PCA3 score, the PHI density or the results of the Stockholm3 blood test may also improve risk stratification [215-217].

Table 5.2.4.2: Impact of the PSA density on csPCa detection rates in patients with negative mpMRI findings

Retrosp. = retrospective; n = number of patients; SBx = systematic transrectal biopsy; TBx = targeted biopsy; TTP = transperineal template biopsy; PSAD = PSA density; ISUP = international Society of Urological Pathology; MCCL = maximum cancer core length.

5.2.4.3.Summary of evidence and practical considerations on pre-biopsy mpMRI

Magnetic resonance imaging-targeted biopsies substantially improve the detection of ISUP grade > 2 PCa. This improvement is most notable in the repeat-biopsy setting, with marginal added value for systematic biopsies. It is less marked in biopsy-naïve patients in whom systematic biopsy retain a higher added value, at least for the detection of ISUP grade 2 cancers. Magnetic resonance imaging-targeted biopsies also detect significantly less ISUP grade 1 cancers than systematic biopsies.

The 'MRI pathway' is appealing since it could decrease the number of biopsy procedures, reduce the detection of low-grade PCa while maintaining (or even improving) the detection of csPCa, as compared to systematic biopsy. However, mpMRI findings must be interpreted in the light of the a priori risk of csPCa. Risk calculators or PSAD may help identify patients that can safely avoid biopsy in case of a negative mpMRI. Furthermore, without standardisation of mpMRI interpretation and of MRI-TBx technique the 'MR pathway' may lead to suboptimal care outside large-volume (expert) centres. Indeed, limitations of the 'MR pathway' are the moderate inter-reader reproducibility of mpMRI and the lack of standardisation of MRI-TBx, as well as the fact that MRI-TBx inter-operator reproducibility has not been evaluated. These caveats also apply to the systematic biopsy procedure. A substantial proportion of csPCa missed by the 'MR pathway' may be due to the imprecision of current targeting methods, and 3 to 5 biopsy cores per target may be needed to reduce the risk of missing or undersampling the lesion, even with US/MR fusion systems.

Finally, it must be emphasised that the 'MR pathway' has only been evaluated in patients in whom the risk of csPCa was judged high enough to deserve biopsy. Pre-biopsy mpMRI must not be used in patients who do not have an indication for prostate biopsy based on their family history and clinical and biochemical data. Because of its low specificity, mpMRI in very low-risk patients would result in an inflation of false-positive findings and subsequent unnecessary biopsies.

5.2.4.4.Guidelines for imaging in PCa detection

5.2.5.Repeat biopsy

5.2.5.1.Repeat biopsy after previously negative biopsy

The indications for repeat biopsy are:

• rising and/or persistently elevated PSA (see Table 5.2.1 for risk estimates);
• suspicious DRE, 5-30% PCa risk [130,131];
• atypical small acinar proliferation (i.e. atypical glands suspicious for cancer), 31-40% PCa risk on repeat
  biopsy [218,219];
• extensive (multiple biopsy sites, i.e. > 3) high-grade prostatic intraepithelial neoplasia (HGPIN), ~30% PCa risk [219,220];
• a few atypical glands immediately adjacent to high-grade prostatic intraepithelial neoplasia (i.e. PINATYP), ~50% PCa risk [221];
• intraductal carcinoma as a solitary finding, > 90% risk of associated high-grade PCa [222];
• positive multiparametric MRI (mpMRI) findings (see Section 5.2.4.2).

5.2.5.1.1.Tests to select men for a repeat biopsy

In men with an elevated risk of PCa with a prior negative biopsy, additional information may be gained by the Progensa-PCA3 and SelectMDX DRE urine tests, the serum 4Kscore and PHI tests or a tissue-based epigenetic test (ConfirmMDx). The role of PHI, Progensa PCA3, and SelectMDX in deciding whether to take a repeat biopsy in men who had a previous negative biopsy is uncertain and probably not cost-effective [158]. The ConfirmMDx test is based on the concept that benign prostatic tissue in the vicinity of a PCa focus shows distinct epigenetic alterations. In case PCa is missed at biopsy, demonstration of epigenetic changes in the benign tissue would indicate the presence of carcinoma. The ConfirmMDX test quantifies the methylation level of promoter regions of three genes in benign prostatic tissue. A multicentre study found a NPV of 88% when methylation was absent in all three markers, implying that a repeat biopsy could be avoided in these men [223]. Given the limited available data and the fact that the role of mpMRI in tumour detection was not accounted for, no recommendation can be made regarding the routine application of ConfirmMDX, in particular in the light of current use of mpMRI before biopsy.

Table 5.2.5.1: Description of additional investigational tests after a negative prostate biopsy*

*Isolated high-grade prostatic intraepithelial neoplasia (PIN) in one or two biopsy sites is no longer an indication

for repeat biopsy [224].

5.2.5.2.Saturation biopsy

The incidence of PCa detected by saturation repeat biopsy (> 20 cores) is 30-43% and depends on the number of cores sampled during earlier biopsies [225]. Saturation biopsy may be performed with the transperineal technique, which detects an additional 38% of PCa. The rate of urinary retention (10%) is a drawback [226].

5.2.6.Prostate biopsy procedure

5.2.6.1.Sampling sites and number of cores

On baseline biopsies, where no prior imaging with mpMRI has been performed, or where mpMRI has not shown any suspicious lesion, the sample sites should be bilateral from apex to base, as far posterior and lateral as possible in the peripheral gland. Additional cores should be obtained from suspect areas identified by DRE; suspect areas on TRUS might be consideration for additional biopsies. Sextant biopsy is no longer considered adequate. At least 8 systematic biopsies are recommended in prostates with a size of about 30 cc [227]. Ten to 12 core biopsies are recommended in larger prostates, with > 12 cores not being significantly more conclusive [228,229].

Where mpMRI has shown a suspicious lesion MR-TBx can be obtained through cognitive guidance, US/MR fusion software or direct in-bore guidance. Current literature does not show a clear superiority of one technique over another [230-233]. A minimum of 3 cores are taken from each lesion (see Section 5.2.4.2.7.2).

5.2.6.2.Antibiotics prior to biopsy

Oral or intravenous antibiotics are recommended. For transrectal biopsy, quinolones are the drugs of choice, with ciprofloxacin being superior to ofloxacin [234]. Antibiotic prophylaxis showed a significant reduction in UTIs post biopsy. A 3-day antibiotic prophylaxis regimen provided no benefit over single-dose prophylaxis [235]. Increased quinolone resistance is associated with a rise in severe post-biopsy infection [236,237]. Norwegian registry data show an increase in antibiotic resistance for both TMP-SMX and ciprofloxacin in recent years with an associated increase in 30-day mortality [238]. Risk factors for quinolone resistance include previous TRUS biopsy, a current indwelling catheter, and any of: urogenital infection, international travel or hospital admission within the previous 6 months. To minimise risk of severe infection due to quinolone resistant rectal flora, patients with any of these risk factors should be offered either TRUS biopsy with prior rectal swab culture or targeted antibiotic prophylaxis [173]. Rectal disinfection with povidone-iodine may be considered [173]. For transperineal biopsy, which avoids rectal flora, a single dose of intravenous cephazolin only is sufficient [239,240]. A 2017 systematic review [172] found no significant difference between transrectal and transperineal biopsies with respect to infection while a more recent meta-analysis including 7 comparative studies showed in twice the number of patients a RR of 0.26 (0.14-0.48) for the risk of fever after transperineal biopsies compared to transrectal biopsies [241].

5.2.6.3.Local anaesthesia prior to biopsy

Ultrasound-guided peri-prostatic block is recommended [242]. It is not important whether the depot is apical or basal. Intra-rectal instillation of local anaesthesia is inferior to peri-prostatic infiltration [243]. Local anaesthesia can also be used effectively for mpMRI-targeted transperineal biopsy [244]. Patients are placed in the lithotomy position. Bupivacaine is injected into the perineal skin and subcutaneous tissues, followed two minutes later by a peri-prostatic block. A systematic review evaluating pain in 3 studies comparing transperineal vs. transrectal biopsies found that the transperineal approach significantly increased patient pain (RR: 1.83 [1.27-2.65]). [241]. In a randomised comparison a combination of peri-prostatic and pudendal block anaesthesia reduced pain during transperineal biopsies compared to peri-prostatic anaesthesia only [245]. Targeted biopsies can then be taken via a brachytherapy grid or a freehand needle-guiding device under local infiltration anaesthesia [244,246,247].

5.2.6.4.Complications

Complications of TRUS biopsy are listed in Table 5.2.3 [248]. Severe post-procedural infections were initially reported in < 1% of cases, but have increased as a consequence of antibiotic resistance [249]. Low-dose aspirin is no longer an absolute contraindication [250]. A systematic review found favourable infection rates for transperineal compared to TRUS biopsies with similar rates of haematuria, haematospermia and urinary retention [251]. A meta-analysis of 4,280 men randomised between transperineal vs. TRUS biopsies in 13 studies found no significant differences in complication rates, however, data on sepsis compared only 497 men undergoing TRUS biopsy to 474 having transperineal biopsy. The transperineal approach required more (local) anaesthesia [172].

Table 5.2.6.1: Percentage of complications per TRUS biopsy session, irrespective of the number of cores

5.2.6.5.Seminal vesicle biopsy

Indications for seminal vesicle (staging) biopsies are poorly defined. At a PSA of > 15 ng/mL, the odds of tumour involvement are 20-25% [252]. A seminal vesicle staging biopsy is only useful if it has a decisive impact on treatment, such as ruling out radical tumour resection or for potential subsequent radiotherapy (RT). Its added value compared with mpMRI is questionable.

5.2.6.6.Transition zone biopsy

Transition zone sampling during baseline biopsies has a low detection rate and should be limited to repeat biopsies [253].

5.2.7.Pathology of prostate needle biopsies

5.2.7.1.Processing

Prostate core biopsies from different sites are processed separately. Before processing, the number and length of the cores are recorded. The length of biopsy tissue significantly correlates with the PCa detection rate [254]. To achieve optimal flattening and alignment, a maximum of three cores should be embedded per tissue cassette, and sponges or paper used to keep the cores stretched and flat [255,256]. To optimise detection of small lesions, paraffin blocks should be cut at three levels and intervening unstained sections kept for immunohistochemistry [253].

5.2.7.2.Microscopy and reporting

Diagnosis of PCa is based on histology. The diagnostic criteria include features pathognomonic of cancer, major and minor features favouring cancer and features against cancer. Ancillary staining and additional (deeper) sections should be considered if a suspect lesion is identified [257-259]. Diagnostic uncertainty is resolved by intradepartmental or external consultation [257]. Table 5.2.7.1 lists the recommended terminology for reporting prostate biopsies [255].

Table 5.2.7.1: Recommended terminology for reporting prostate biopsies [255]

Each biopsy site should be reported individually, including its location (in accordance with the sampling site) and histopathological findings, which include the histological type and the ISUP 2014 grade [77]. A global ISUP grade comprising all biopsies is also reported (see Section 4.2). The global ISUP grade takes into account all biopsies positive for carcinoma, by estimating the total extent of each Gleason grade present. For instance, if three biopsy sites are entirely composed of Gleason grade 3 and one biopsy site of Gleason grade 4 only, the global ISUP grade would be 2 (i.e. GS 7[3+4]) or 3 (i.e. GS 7[4+3]), dependent on whether the extent of Gleason grade 3 exceeds that of Gleason grade 4, whereas the worse grade would be ISUP grade 4 (i.e. GS 8[4+4]). Recent publications demonstrated that global ISUP grade is somewhat superior in predicting prostatectomy ISUP grade [260] and biochemical recurrence (BCR) [261].

Intraductal carcinoma, lymphovascular invasion (LVI) and extraprostatic extension (EPE) must each be reported, if identified. More recently, expansile cribriform pattern of PCa as well as intraductal carcinoma in biopsies were identified as independent prognosticators of metastatic disease [262] and PCa-specific survival [263].

The proportion of carcinoma-positive cores as well as the extent of tumour involvement per biopsy core correlate with the ISUP grade, tumour volume, surgical margins and pathologic stage in RP specimens and predict BCR, post-prostatectomy progression and RT failure. These parameters are included in nomograms created to predict pathologic stage and seminal vesicle invasion after RP and RT failure [264-266]. A pathology report should therefore provide both the proportion of carcinoma-positive cores and the extent of cancer involvement for each core. The length in mm and percentage of carcinoma in the biopsy have equal prognostic impact [267]. An extent of > 50% of adenocarcinoma in a single core is used in some AS protocols as a cut off [268] triggering immediate treatment vs. AS in patients with ISUP grade 1.

A prostate biopsy that does not contain glandular tissue should be reported as diagnostically inadequate. Mandatory elements to be reported for a carcinoma-positive prostate biopsy are:

• type of carcinoma;
• primary and secondary/worst Gleason grade (per biopsy site and global);
• percentage high-grade carcinoma (global);
• extent of carcinoma (in mm or percentage) (at least per biopsy site);
• if present: EPE, seminal vesicle invasion, LVI, intraductal carcinoma/cribriform pattern, peri-neural invasion;
• ISUP grade (global).

5.2.7.3.Tissue-based prognostic biomarker testing.

After a comprehensive literature review and several panel discussions an ASCO-EAU-AUA multidisciplinary expert panel made recommendations regarding the use of tissue-based PCa biomarkers. The recommendations were limited to 5 commercially available tests (Oncotype Dx, Prolaris, Decipher, Decipher PORTOS and ProMark) with extensive validation in large retrospective studies and evidence that their test results might actually impact clinical decision-taking [269].

The selected commercially available tests significantly improved the prognostic accuracy of clinical multivariable models for identifying men who would benefit of AS and those with clinically significant PCa requiring curative treatment, as well as for guidance of patient management after RP. In addition, a few studies showed that tissue biomarker tests and MRI findings independently improved the detection of clinically significant cancer in an AS setting, but it remains unclear which men would benefit of both tests. Since the long-term impact of the use of these commercially available tests on oncological outcome remains unproven and prospective trials are largely lacking, the Panel concluded that these tests should not be offered routinely, but only in subsets of patients where the test result provides clinically actionable information, such as for instance in men with favourable intermediate-risk PCa who might opt for AS or men with unfavourable intermediate-risk PCa at RP to decide on treatment intensification with hormonal therapy (HT).

5.2.7.4.Histopathology of radical prostatectomy specimens

5.2.7.4.1.Processing of radical prostatectomy specimens

Histopathological examination of RP specimens describes the pathological stage, histopathological type, grade and surgical margins of PCa. It is recommended that RP specimens are totally embedded, to enable assessment of cancer location, multifocality and heterogeneity. For cost-effectiveness, partial embedding may also be considered, particularly for prostates > 60 g. The most widely accepted method includes complete embedding of the posterior prostate, and a single mid-anterior left and right section. Compared with total embedding, partial embedding detected 98% of PCa with an ISUP grade > 2 with accurate staging in 96% of cases [270].

Ink the entire RP specimen upon receipt in the laboratory, to demonstrate the surgical margins. Specimens are fixed by immersion in buffered formalin for at least 24 hours, preferably before slicing. Fixation can be enhanced by injecting formalin, which provides more homogeneous fixation and sectioning after 24 hours [271]. After fixation, the apex and the base (bladder neck) are removed and cut into (para)sagittal or radial sections; the shave method is not recommended [76]. The remainder of the specimen is cut in transverse, 3-4 mm sections, perpendicular to the long axis of the urethra. The resultant tissue slices can be embedded and processed as whole-mounts or after quadrant sectioning. Whole-mounts provide better topographic visualisation, faster histopathological examination and better correlation with pre-operative imaging, although they are more time-consuming and require specialist handling. For routine sectioning, the advantages of whole mounts do not outweigh their disadvantages.

5.2.7.4.1.1.Guidelines for processing prostatectomy specimens

5.2.7.4.2.Radical prostatectomy specimen report

The pathology report provides essential information on the prognostic characteristics relevant for clinical decision-making (Table 5.2.7.1). As a result of the complex information to be provided for each RP specimen, the use of synoptic(-like) or checklist reporting is recommended (Table 5.2.7.2). Synoptic reporting results in more transparent and complete pathology reporting [272].

Table 5.2.7.1: Mandatory elements provided by the pathology report

Table 5.2.7.2: Example checklist: reporting of prostatectomy specimens

5.2.7.4.3.ISUP grade in prostatectomy specimens

Grading of conventional prostatic adenocarcinoma using the (ISUP 2014 modified) Gleason system is the strongest prognostic factor for clinical behaviour and treatment response [77]. The ISUP grade is incorporated in nomograms that predict disease-specific survival (DSS) after prostatectomy [273].

The ISUP grade is based on the sum of the most and second-most dominant (in terms of volume) Gleason grade. ISUP grade 1 is any GS < 6 (including < 5% Gleason grade 4). ISUP grades 2 and 3 represent carcinomas constituted of Gleason grade 3 and 4 components, with ISUP grade 2 when 50% of the carcinoma, or more, is Gleason grade 3 and ISUP grade 3 when the grade 4 component represents more than 50% of the carcinoma. ISUP grade 4 is largely composed of Gleason grade 4 and ISUP grade 5 of a combination of Gleason grade 4 and 5 or only Gleason grade 5. A global ISUP grade is given for multiple tumours, but a separate tumour focus with a higher ISUP grade should also be mentioned. Tertiary Gleason grade 5, particularly if > 5% of the PCa volume, is an unfavourable prognostic indicator for BCR. The tertiary Gleason grade and its approximate proportion of the cancer volume should also be reported in addition to the global ISUP grade (see Section 4.2) [274].

5.2.7.4.4.Definition of extraprostatic extension

Extraprostatic extension is defined as carcinoma mixed with peri-prostatic adipose tissue, or tissue that extends beyond the prostate gland boundaries (e.g., neurovascular bundle, anterior prostate). Microscopic bladder neck invasion is considered EPE. It is useful to report the location and extent of EPE because the latter is related to recurrence risk [275].

There are no internationally accepted definitions of focal or microscopic, vs. non-focal or extensive EPE. Some describe focal as a few glands [276] or extension as < 1 per high-power field (HPF) [277], whereas others measure the depth of extent in millimetres [278].

At the apex of the prostate, tumour mixed with skeletal muscle does not constitute EPE. In the bladder neck, microscopic invasion of smooth muscle fibres is not equated to bladder wall invasion, i.e. not as pT4, because it does not carry independent prognostic significance for PCa recurrence [279,280] and should be recorded as EPE (pT3a). A positive margin at the bladder neck should be reported as EPE (pT3a) with positive margin, and not as pT4.

Stage pT4 is only assigned when the tumour invades the bladder muscle wall as determined macroscopically [281].

5.2.7.4.5.PCa volume

The independent prognostic value of PCa volume in RP specimens has not been established [277,282-285]. Nevertheless, a cut-off of 0.5 mL is traditionally used to distinguish insignificant from clinically relevant cancer [282]. Improvement in prostatic radio-imaging allows more accurate pre-operative measurement of cancer volume. It is recommended that at least the diameter/volume of the dominant tumour nodule should be assessed, or a rough estimate of the percentage of cancer tissue provided [286].

5.2.7.4.6.Surgical margin status

Surgical margin is an independent risk factor for BCR. Margin status is positive if tumour cells are in contact with the ink on the specimen surface. Margin status is negative if tumour cells are close to the inked surface [283] or at the surface of the tissue lacking ink. In tissues that have severe crush artefacts, it may not be possible to determine margin status [287].

Surgical margin is separate from pathological stage, and a positive margin is not evidence of EPE [288]. There is insufficient evidence to prove a relationship between margin extent and recurrence risk [277]. However, some indication must be given of the multifocality and extent of margin positivity, such as the linear extent in mm of involvement: focal, < 1 mm vs. extensive, > 1 mm [289], or number of blocks with positive margin involvement. Gleason score at the positive margin was found to correlate with outcome, and should be reported [245].

5.2.8.Guidelines for the clinical diagnosis of prostate cancer

5.3.Diagnosis - Clinical Staging

The extent of PCa is evaluated by DRE and PSA, and may be supplemented with mpMRI, bone scanning and computed tomography (CT).

5.3.1.T-staging

The cT category used in the risk table only refers to the DRE finding. The imaging parameters and biopsy results for local staging are, so far, not part of the risk category stratification.

5.3.1.1.TRUS

Transrectal ultrasound is no more accurate at predicting organ-confined disease than DRE [290]. Some single-centre studies reported good results in local staging using 3D TRUS or colour Doppler but these good results were not confirmed by large-scale studies [291,292].

5.3.1.2.mpMRI

T2-weighted imaging remains the most useful method for local staging on mpMRI. At 1.5 Tesla, mpMRI has good specificity but low sensitivity for detecting T3 stages. Pooled data from a meta-analysis for EPE, SVI, and overall stage T3, showed a sensitivity and specificity of 0.57 (95% CI: 0.49-0.64) and 0.91 (95% CI: 0.88-0.93), 0.58 (95% CI: 0.47-0.68) and 0.96 (95% CI: 0.95-0.97), and 0.61 (95% CI: 0.54-0.67) and 0.88 (95% CI: 0.85-0.91), respectively [293]. Multiparametric MRI cannot detect microscopic EPE. Its sensitivity increases with the radius of extension within peri-prostatic fat. In one study, the EPE detection rate increased from 14 to 100% when the radius of extension increased from < 1 mm to > 3 mm [294]. In another study, mpMRI sensitivity, specificity and accuracy for detecting pT3 stage were 40%, 95% and 76%, respectively, for focal (i.e. microscopic) EPE, and 62%, 95% and 88% for extensive EPE [295].

The use of high field strength (3 Tesla) or functional imaging in addition to T2-weighted imaging improves sensitivity for EPE or SVI detection [293], but the experience of the reader remains of paramount importance [296] and the inter-reader agreement remains moderate with kappa values ranging from 0.41 to 0.68 [297]. Multiparametric MRI, although not perfect for local staging, may improve the prediction of the pathological stage when combined with clinical data [298,299]. Other MRI-derived parameters such as the tumour volume or the contact length of the tumour with the capsule [300-302], or the ISUP grade obtained through MRI-TBx [303] could further improve the local staging [303].

Given its low sensitivity for focal (microscopic) EPE, mpMRI is not recommended for local staging in low-risk patients [298,304,305]. However, mpMRI can still be useful for treatment planning.

5.3.2.N-staging

5.3.2.1.Computed tomography (CT) and magnetic resonance imaging

Abdominal CT and T1-T2-weighted MRI indirectly assess nodal invasion by using LN diameter and morphology. However, the size of non-metastatic LNs varies widely and may overlap the size of LN metastases. Usually, LNs with a short axis > 8 mm in the pelvis and > 10 mm outside the pelvis are considered malignant. Decreasing these thresholds improves sensitivity but decreases specificity. As a result, the ideal size threshold remains unclear [306,307]. Computed tomography and MRI sensitivity is less than 40% [308,309]. Among 4,264 patients, 654 (15.3%) of whom had positive LNs at LND, CT was positive in only 105 patients (2.5%) [306]. In a multicentre database of 1,091 patients who underwent pelvic LN dissection, CT sensitivity and specificity were 8.8% and 98%, respectively [310]. Detection of microscopic LN invasion by CT is < 1% in patients with ISUP grade < 4 cancer, PSA < 20 ng/mL, or localised disease [311-313].

Diffusion-weighted MRI may detect metastases in normal-sized nodes, but a negative diffusion- weighted MRI cannot rule out the presence of LN metastases [307,314].

5.3.2.2.Choline PET/CT

In a meta-analysis of 609 patients, pooled sensitivity and specificity of choline PET/CT for pelvic LN metastases were 62% (95% CI: 51-66%) and 92% (95% CI: 89-94%), respectively [315]. In a prospective trial of 75 patients at intermediate risk of nodal involvement (10-35%), the sensitivity was only 8.2% at region-based analysis and 18.9% at patient-based analysis, which is too low to be of clinical value [316]. The sensitivity of choline PET/CT increases to 50% in patients at high risk and to 71% in patients at very high risk, in both cases out-performing contrast-enhanced CT [317]. However, comparisons between choline PET/CT and diffusion-weighted MRI yielded contradictory results, with PET/CT sensitivity found to be superior [318], similar [319,320] or inferior [316] than that of diffusion-weighted MRI.

Due of its low sensitivity, choline PET/CT does not reach clinically acceptable diagnostic accuracy for detection of LN metastases, or to rule out a nodal dissection based on risk factors or nomograms (see Section 6.3.4.1.2).

5.3.2.3.Prostate-specific membrane antigen-based PET/CT

68Ga- or 18F-labelled prostate-specific membrane antigen (PSMA) positron-emission tomography (PET)/CT is increasingly used, because it provides excellent contrast-to-noise ratio, thereby improving the detectability of lesions. Prostate-specific membrane antigen is also an attractive target because of its specificity for prostate tissue, even if expression of PSMA in other non-prostatic malignancies, sarcoidosis or benign bone diseases, may cause incidental false-positive findings [321-324].

Recent assessment of PSMA PET/CT showed promising sensitivity for LN involvement, also suggesting that this modality may impact clinical decision making. From a meta-analysis of 37 articles, a subgroup analysis of 13 studies was performed in PCa patients prior to definitive therapy, using histological correlation as reference standard. The predictive ability of PSMA-PET imaging for primary staging was derived from 5 studies. On a per-LN analysis, the pooled sensitivity and specificity were 75% and 99%, respectively. On a per-patient analysis, the pooled sensitivity and specificity were 77% and 97%, respectively [325]. Another prospective, multicentre validation of 68Ga PSMA PET/CT in patients with newly diagnosed PCa and negative bone scan findings was recently published. In 103 eligible patients at increased risk for metastatic LNs prior to surgery, 97 eLNDs were performed, resulting in the identification of 85 LN metastases in 41 patients (42.3%). Positron emission tomography was positive in 17 patients, resulting in a per-patient-based sensitivity and specificity of 41.5% (95% CI: 26.7-57.8) and 90.9% (95% CI: 79.3-96.6), respectively. A treatment change occurred in 12.6% of patients [326].

Prostate-specific antigen may be a predictor of a positive PSMA PET scan. In the primary staging cohort from the meta-analysis [325], however, only 4 studies reported PSMA PET-positivity based on the PSA value, offering no robust estimates of positivity. The tracer uptake is also influenced by the ISUP grade and the PSA level. In a series of 90 patients with primary PCa, tumours with an ISUP grade between 1 and 3 showed significantly lower tracer uptake than tumours with an ISUP grade > 4. Similarly, patients with PSA levels > 10 ng/mL showed significantly higher uptake than those with PSA levels < 10 ng/mL [327].

Comparison between PSMA PET/CT and mpMRI was recently performed in a systematic review and meta-analysis, including 13 studies (n = 1,597) [328]. 68Ga- was found to have a higher sensitivity and a comparable specificity for staging pre-operative LN metastases in intermediate- and high-risk PCa. The pooled sensitivity and specificity of 68Ga-PSMA PET were 0.65 (95% CI: 0.49-0.79) and 0.94 (95% CI: 0.88-0.97), respectively, while the corresponding values of MRI were 0.41 (95% CI: 0.26-0.57) and 0.92 (95% CI: 0.86-0.95). 68Ga-PSMA PET was potentially a more effective and appropriate imaging modality to predict LN metastasis prior to surgery, as indicated by the area under the symmetric receiver-operating characteristic (SROC) curve. Another prospective trial reported superior sensitivity of PSMA PET/CT as compared to mpMRI for nodal staging of 36 high-risk PCa patients [329]. Therefore, PSMA PET/CT has higher sensitivity for LN metastases as compared to mpMRI, abdominal contrast-enhanced CT or choline PET/CT; however, small LN metastases, under the spatial resolution of PET (~5 mm), may still be missed.

5.3.3.M-staging

5.3.3.1.Bone scan

99mTc-Bone scan has been the most widely used method for evaluating bone metastases of PCa. A recent meta-analysis showed combined sensitivity and specificity of 79% (95% CI: 73-83%) and 82% (95% CI: 78-85%) at patient level and 59% (95% CI: 55-63%) and 75% (95% CI: 71-79%) at lesion level [330]. Bone scan diagnostic yield is significantly influenced by the PSA level, the clinical stage and the tumour ISUP grade and these three factors were the only independent predictors of bone scan positivity in a study of 853 patients [331]. The mean bone scan positivity rate in 23 different series was 2.3% in patients with PSA levels < 10 ng/ mL, 5.3% in patients with PSA levels between 10.1 and 19.9 ng/mL and 16.2% in patients with PSA levels of 20.0-49.9 ng/mL. It was 6.4% in men with organ-confined cancer and 49.5% in men with locally advanced cancers. Detection rates were 5.6% and 29.9% for ISUP grade 2 and > 3, respectively [306]. In two studies, a major Gleason pattern of 4 was found to be a significant predictor of positive bone scan [332,333].

Bone scanning should be performed in symptomatic patients, independent of PSA level, ISUP grade or clinical stage [306].

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

18F-sodium fluoride (18F-NaF) PET or PET/CT shows similar specificity and superior sensitivity to bone scan [334,335]. However, unlike choline PET/CT, 18F-NaF PET does not detect LN metastases, and is less cost- effective compared to bone scan [333]. A recent publication indicated that 18F-NaF PET offers no added value over bone scintigraphy in patients with newly diagnosed PCa and negative bone scintigraphy results [336]. It remains unclear whether choline PET/CT is more sensitive than bone scan, but it has higher specificity, with fewer indeterminate bone lesions [315,337,338].

Diffusion-weighted whole-body and axial MRI are more sensitive than bone scan and targeted conventional radiography in detecting bone metastases in high-risk PCa [339,340]. Whole-body MRI is also more sensitive and specific than combined bone scan, targeted radiography and abdominopelvic CT [341]. A meta-analysis found that MRI is more sensitive than choline PET/CT and bone scan for detecting bone metastases on a per-patient basis, although choline PET/CT had the highest specificity [330].

It is of note that choline PET/CT and diffusion-weighted MRI can also detect visceral metastases.

Bone scan and 18F-NaF PET/CT only assess the presence of bone metastases.

5.3.3.3.Prostate-specific membrane antigen-based PET/CT

There is growing evidence on the performance of 68Ga-PSMA PET/CT in initial staging. A recent systematic review including 12 studies and comprising a total of 322 patients reported high variation in sensitivity (range 33-99% median sensitivity on per-lesion analysis 33-92%, and on per-patient analysis 66-91%), with good specificity (per-lesion 82-100%, and per-patient 67-99%), with most studies demonstrating increased detection rates with respect to conventional imaging modalities (bone scan and CT) [342]. Table 5.3.1 reports the data of the 5 studies including histopathologic correlation.

Table 5.3.1: PSMA PET/CT results in primary staging alone [342]

NPV = negative predictive value; PPV = positive predictive value.

One prospective multicentre study evaluated changes in planned management before and after PSMA PET/CT in 108 intermediate- and high-risk patients referred for primary staging. As compared to conventional staging, additional LNs and bone/visceral metastases were detected in 25% and 6% of patients, respectively [343]; management changes occurred in 21% of patients. A recent retrospective review investigated the risk of metastases identified by Ga-PSMA at initial staging in 1,253 patients (high-risk disease in 49.7%) [344]. Metastatic disease was identified by PSMA PET in 12.1% of men, including 8.2% with a PSA level of < 10 ng/mL and 43% with a PSA level of > 20 ng/mL. Lymph node metastases were suspected in 107 men, with 47.7% outside the boundaries of an extended pelvic LN dissection (eLND). Skeletal metastases were identified in 4.7%. In men with intermediate-risk PCa metastases were identified in 5.2%, compared to 19.9% with high-risk disease.

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

The field of non-invasive nodal and metastatic staging of PCa is evolving very rapidly. Evidence shows that choline PET/CT, PSMA PET/CT and MRI provide a more sensitive detection of LN and bone metastases than the classical work-up with bone scan and abdominopelvic CT. It could be tempting to conclude that bone scan and abdominopelvic CT must be replaced by more sensitive tests in all patients undergoing initial PCa staging. Yet, the clinical benefit of detecting metastases at an earlier time-point remains unclear [325]. In addition the prognosis and ideal management of patients diagnosed as metastatic by these more sensitive tests is unknown. In particular, it is unclear whether patients with metastases, detectable only with PET/CT or MRI, should be managed using systemic therapies, or whether they should be subjected to aggressive local and metastases-directed therapies [345].

Results from RCTs evaluating the management and outcome of patients with (and without) metastases detected by choline PET/CT, PSMA PET/CT and MRI are awaited, before a decision can be made to treat patients based on the results of these tests [346].

5.3.5.Guidelines for staging of prostate cancer

5.4.Evaluating life expectancy and health status

5.4.1.Introduction

Evaluation of life expectancy and health status is important in clinical decision-making on screening, diagnosis, and treatment of PCa. Prostate cancer is common in older men (median age 68) and diagnoses in men > 65 will result in a 70% increase in annual diagnosis by 2030 in Europe and the USA [347,348].

Active treatment mostly benefits patients with intermediate- or high-risk PCa and longest expected survival. In localised disease, over 10 years life expectancy is considered mandatory for any benefit from local treatment and an improvement in CSS may take longer to become apparent. Older age and worse baseline health status have been associated with a smaller benefit in PCa-specific mortality (PCSM) and life expectancy of surgery vs. active surveillance (AS) [349]. Although in a RCT the benefit of surgery with respect to death from PCa was largest in men < 65 years of age (RR: 0.45), RP was associated with a reduced risk of metastases and use of androgen deprivation therapy (ADT) among older men (RR: 0.68 and 0.60, respectively) [350]. External beam radiotherapy shows similar cancer control regardless of age, assuming a dose of > 72 Gy when using intensity-modulated or image-guided RT [351].

Older men with a high incidence of PCa may be under-treated despite the high overall mortality rates [352,353]. Of all PCa-related deaths 71% occur in men aged > 75 years [354], probably due to the higher incidence of advanced disease and death from PCa despite higher death rates from competing causes [355-357]. In the USA, only 41% of patients aged > 75 years with intermediate- and high-risk disease receive curative treatment compared to 88% aged 65-74 [358].

5.4.2.Life expectancy

Life expectancy tables for European men are available at: https://ec.europa.eu/eurostat/web/products-eurostat-news/-/EDN-20191118-1. Survival may be very variable and therefore must be individualised. Gait speed is a good single predictive measure (from a standing start, at usual pace, generally over 6 meters). For men at age 75, 10-year survival ranged from 19% < 0.4 m/s to 87%, for > 1.4 m/s [359].

Figure 5.4.1: Predicted Median Life Expectancy by Age and Gait Speed for males* [359].

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

5.4.3.Health status screening

The International SIOG PCa Working Group recommends that treatment for senior adults should be based on a systematic evaluation of health status using the G8 (Geriatric 8) screening tool (Table 5.4.1) [360]. Healthy patients with a G8 score > 14 or vulnerable patients with reversible impairment after resolution of their geriatric problems should receive the same treatment as younger patients. Frail patients with irreversible impairment should receive adapted treatment. Patients who are too ill should receive only palliative treatment (Figure 5.4.1) [360]. Patients with a G8 score < 14 should undergo a full geriatric evaluation as this score is associated with 3-year mortality, assessing comorbidity, nutritional status, and cognitive and physical functions, to determine if the impairment is reversible [361].

5.4.3.1.Comorbidity

Comorbidity is a major predictor of non-cancer-specific death in localised PCa treated with RP and is more important than age [362,363]. Ten years after not receiving active treatment for PCa, most men with a high comorbidity score had died from competing causes, irrespective of age or tumour aggressiveness [362]. Measures for comorbidity include: Cumulative Illness Score Rating-Geriatrics (CISR-G) [364,365] (Table 5.4.2) and Charlson Comorbidity Index (CCI) [366].

5.4.3.2.Nutritional status

Malnutrition can be estimated from body weight during the previous 3 months (good nutritional status < 5% weight loss; risk of malnutrition: 5-10% weight loss; severe malnutrition: > 10% weight loss) [367].

5.4.3.3.Cognitive function

Cognitive impairment can be measured using mini-COG (https://mini-cog.com/), which assesses the patient's ability to make an informed decision which is an increasingly important factor in health status assessment
[368-370].

5.4.3.4.Physical function

Measures for overall physical functioning include: Karnofsky score and ECOG scores [371]. Measures for dependence in daily activities include: Activities of Daily Living (ADL; basic activities) and Instrumental Activities of Daily Living (IADL; activities requiring higher cognition and judgement) [372-374].

5.4.4.Conclusion

Individual life expectancy, health status, and comorbidity, not only age, should be central in clinical decisions on screening, diagnostics, and treatment for PCa. A life expectancy of 10 years is most commonly used as a threshold for benefit of local treatment. Older men may be undertreated. Resolution of impairments in vulnerable men allows a similar urological approach as in fit patients.

Table 5.4.1: G8 screening tool (adapted from [375])

Figure 5.4.1: Decision tree for health status screening (men > 70 years)** [360]

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

Rating Score - Geriatrics; CGA = comprehensive geriatric assessment.

*For Mini-COGTM, a cut-off point of < 3/5 indicates a need to refer the patient for full evaluation of potential dementia.

**Reproduced with permission of Elsevier, from Boyle H.J., et al. Eur J Cancer 2019:116; 116 [360].

Table 5.4.2: Cumulative Illness Score Rating-Geriatrics (CISR-G)

5.4.5.Guidelines for evaluating health status and life expectancy

6.TREATMENT

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

6.1.Treatment modalities

6.1.1.Deferred treatment (active surveillance/watchful waiting)

In localised disease a life expectancy of at least 10 years is considered mandatory for any benefit from local treatment. Indeed data is available on patients who did not undergo local treatment with up to 25 years of follow-up, and endpoints of OS and CSS. Several series have shown a consistent CSS rate of 82-87% at 10 years [376-381], and 80-95% for T1/T2 and ISUP grade < 2 PCas [382]. In three studies with data beyond 15 years, the DSS was 80%, 79% and 58% [378,380,381], and two reported 20-year CSS rates of 57% and 32%, respectively [378,380]. In addition, many patients classified as ISUP grade 1 would now be classified as ISUP grade 2-3 based on the 2005 Gleason classification, suggesting that the above-mentioned results should be considered as minimal. Patients with well-, moderately- and poorly-differentiated tumours had 10-year CSS rates of 91%, 90% and 74%, respectively, correlating with data from the pooled analysis [382]. Observation was most effective in men aged 65-75 years with low-risk PCa [383].

Remember that comorbidity is more important than age in predicting life expectancy in men with PCa. Increasing comorbidity greatly increases the risk of dying from non-PCa-related causes and for those men with a short life expectancy. In an analysis at 10 years follow up in 19,639 patients aged > 65 years who were not given curative treatment, most men with a CCI score > 2 died from competing causes at 10 years whatever their initial age. Tumour aggressiveness had little impact on OS suggesting that patients could have been spared biopsy and diagnosis of cancer. Men with a CCI score < 1 had a low risk of death at 10 years, especially for well- or moderately-differentiated lesions [362]. This highlights the importance of assessing co-morbidity before considering a biopsy.

In screening-detected localised PCa the lead-time bias is likely to be greater. Mortality from untreated screen-detected PCa in patients with ISUP grade 1-2 might be as low as 7% at 15 years follow-up [384]. Consequently, approximately 45% of men with PSA-detected PCa are suitable for close follow-up through a robust surveillance programme. There are two distinct strategies for conservative management that aim to reduce over-treatment: AS and WW (Table 6.1.1).

6.1.1.1.Definitions

Active surveillance aims to avoid unnecessary treatment in men with clinically localised PCa who do not require immediate treatment, but at the same time achieve the correct timing for curative treatment in those who eventually do [385]. Patients remain under close surveillance through structured surveillance programmes with regular follow-up, and curative treatment is prompted by predefined thresholds indicative of potentially life-threatening disease which is still potentially curable, while considering individual life expectancy.

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

Table 6.1.1: Definitions of active surveillance and watchful waiting [384]

DRE = digital rectal examination; PSA = prostate-specific antigen; mpMRI = multiparametric magnetic resonance imaging.

6.1.1.2.Active surveillance

No formal RCT is available comparing this modality to standard treatment. The Prostate Testing for Cancer and Treatment (ProtecT) trial is discussed later as it is not a formal AS strategy but rather Active Monitoring (AM), which is a significantly less stringent surveillance strategy in terms of clinical follow-up, imaging and repeat biopsies [386].

Several cohorts have investigated AS in organ-confined disease, the findings of which were summarised in a systematic review [387]. More recently, the largest prospective series of men with low-risk PCa managed by AS was published [388]. Table 6.1.2 summarises the results of selective AS cohorts. It is clear that the long-term OS and CSS for patients on AS are extremely good. However, more than one-third of patients are 'reclassified' during follow-up, most of whom undergo curative treatment due to disease upgrading, increase in disease extent, disease stage, progression or patient preference. There is considerable variation and heterogeneity between studies regarding patient selection and eligibility, follow-up policies (including frequency and type of imaging such as mpMRI scan, type and frequency of repeat prostate biopsies, such as MRI-targeted biopsies or transperineal template biopsies, use of PSA kinetics and density, and frequency of clinical follow-up), when active treatment should be instigated (i.e. reclassification criteria), and which outcome measures should be prioritised [385]. These will be discussed further in section 6.2.1.

Table 6.1.2: Active surveillance in screening-detected prostate cancer

* Patients receiving active therapy following initial active surveillance.

CSS = cancer-specific survival; FU = follow-up; mo = months; n = number of patients; n.r. = not reported; OS = overall survival; RP = radical prostatectomy.

6.1.1.3.Watchful Waiting

6.1.1.3.1.Outcome of watchful waiting compared with active treatment

The SPCG-4 study randomised patients to either WW or RP (Table 6.1.3) [350] before the PSA era and found RP to provide superior CSS, OS and progression-free survival (PFS) compared to WW at a median follow-up of 13.4 years (range 3 weeks-23.2 years). The PIVOT trial made a similar comparison in 731 randomised men (50% with non-palpable disease) [396] but in contrast to SPCG-4, it found no benefit of RP within a median follow-up period of 12.7 years (interquartile range, 7.3 to 15.5 years). Only patients with serum PSA  > 10 ng/mL or high-risk PCa had a significant OS benefit from RP, with a RR reduction in mortality of 33% and 31%, respectively. Patients who underwent RP also had a significant reduction in bone metastases (4.7% vs. 10.6%). Overall, no adverse effects on HRQoL and psychological well-being was apparent in the first years [397]. However, one of the criticisms of the PIVOT trial is the relatively high-observed overall mortality rate in the WW group (almost 50% at a median of 10 years), compared with more contemporary series.

Table 6.1.3: Outcome of SPCG-4 at 15-year follow-up [350]

CI = confidence interval; n.r. = not reported; RP = radical prostatectomy.

6.1.1.4.The ProtecT study

The ProtecT trial randomised 1,643 patients, three-ways, between active treatment (RP or EBRT) and AM [386]. In this AM schedule, patients with a PSA rise of more than 50% in 12 months underwent a repeat biopsy, but none had systematic repeat biopsies. Fifty-six percent of patients had low-risk disease, with 90% having a PSA < 10 ng/mL, 77% ISUP grade 1 (20% ISUP grade 2-3), and 76% T1c, while the other patients were mainly intermediate risk. After 10 years of follow up, the CSS was the same between those actively treated and those on AM (99% and 98.8%, respectively), as was the OS. Only metastatic progression differed (6% in the AM group as compared to 2.6% in the treated group).

The key finding is that AM is as effective as active treatment at 10 years, at a cost of increased progression and double the metastatic risk. Metastases remained quite rare (6%), but more frequent than seen with AS protocols probably driven by differences in intensity of monitoring and patient selection. It is important to note that the AM arm in ProtecT represents an intermediate approach between contemporary AS protocols and WW in terms of a monitoring strategy based almost entirely on PSA measurements alone; there was no use of mpMRI scan either at recruitment nor during the monitoring period, nor was there any protocol-mandated repeat prostate biopsies at regular intervals. In addition, approximately 40% of randomised patients had intermediate-risk disease.

Nevertheless, in spite of these caveats, the ProtecT study has reinforced the role of deferred active treatment (i.e. either AS or some form of initial AM) as a feasible alternative to active curative interventions for patients with low-grade and low-stage disease. Beyond 10 years, no data is available as yet, although AS is likely to give more reassurance, especially in younger men, based on initial patient selection and more stringent criteria regarding follow-up, imaging, repeat biopsy and reclassification. Individual life expectancy must be evaluated before considering any active treatment in low-risk situations, and for those with up to 10 years individual life expectancy.

6.1.2.Radical prostatectomy

6.1.2.1.Introduction

The goal of RP by any approach is the eradication of cancer, while whenever possible, preserving pelvic organ function [398]. The procedure involves removing the entire prostate with its capsule intact and seminal vesicles, followed by undertaking vesico-urethral anastomosis. Since its description in 1904, the technique has evolved markedly. Surgical approaches have expanded from perineal and retropubic open approaches to laparoscopic and robotic-assisted techniques; anastomoses have evolved from Vest approximation sutures to continuous-suture watertight anastomoses under direct vision and mapping of the anatomy of the dorsal venous complex (DVC) and cavernous nerves has led to excellent visualisation and potential for preservation of erectile function [399]. The main results from multicentre RCTs involving RP are summarised in Table 6.1.4.

Table 6.1.4: Oncological results of radical prostatectomy in organ-confined disease in RCTs

CSS = cancer-specific survival; FU = follow-up; mo = months; PSA = prostate-specific antigen; yr. = year.

6.1.2.2.Pre-operative preparation

6.1.2.2.1.Pre-operative patient education

As before any surgery, appropriate education and patient consent is mandatory prior to RP. Peri-operative education has been shown to improve long-term patient satisfaction following RP [401]. Augmentation of standard verbal and written educational materials, such as use of interactive multimedia tools [402,403] and pre-operative patient-specific 3D printed prostate models [404] has been shown to improve patient understanding and satisfaction and should be considered to optimise patient-centred care.

Pre-operative pelvic floor exercises

Although many patients who have undergone RP will experience a return to urinary continence [405], temporary urinary incontinence is common early after surgery, reducing quality of life. Pre-operative pelvic floor exercises (PFE), with or without biofeedback, have been used with the aim of reducing this early post-operative incontinence. A systematic review and meta-analysis of the effect of pre-RP PFE on post-operative urinary incontinence showed a significant improvement in incontinence rates at 3 months post-op with an OR of 0.64 (p = 0.005), but not at 1 month or 6 months [406]). Pre-operative PFE may therefore provide some benefit, however the analysis was hampered by the variety of PFE regimens and a lack of consensus on the definition of incontinence.

Prophylactic antibiotics

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

6.1.2.3.Surgical techniques

Prostatectomy can be performed by open-, laparoscopic- or robot-assisted (RARP) approaches. The initial open technique of RP described by Young in 1904 was via the perineum [399], but suffered from a lack of access to pelvic LNs. If lymphadenectomy is required during perineal RP, it must be done via a separate open retropubic (RRP)- or laparoscopic approach. The open retropubic approach was popularised by Walsh in 1982 following his anatomical description of the DVC, enabling its early control, and of the cavernous nerves, permitting a bilateral nerve-sparing procedure [407]. This led to the demise in popularity of perineal RP, and eventually to the first laparoscopic RP reported in 1997 using retropubic principles, but performed transperitoneally [408]. The initial 9 cases averaged 9.4 hours, indicating significant technical and ergonomic difficulties of the technique. Most recently, RARP was introduced using the da Vinci Surgical System® by Binder in 2002 [409]. This technology combined the minimally-invasive advantages of laparoscopic RP with improved surgeon ergonomics and greater technical ease of suture reconstruction of the vesico-urethral anastomosis, and has now become the preferred minimally-invasive approach, where the equipment is available.

In a randomised phase III trial, RARP was shown to have reduced admission times and blood loss but not early (12 weeks) functional or oncological outcomes, compared to open RP [410]. An updated analysis with follow-up at 24 months did not reveal any significant differences in functional outcomes between the approaches [411]. Increased surgical experience has lowered the complication rates of RP and improved cancer cure [380-383]. Lower rates of positive surgical margins for high-volume surgeons suggest that experience and careful attention to surgical details, can improve cancer control with RP [412-414]. There is a lack of studies comparing the different surgical modalities for these longer-term outcomes [379,396,397,415]. A first systematic review and meta-analysis of non-RCTs demonstrated that RARP had lower perioperative morbidity and a reduced risk of positive surgical margins compared with laparoscopic prostatectomy (LRP), although there was considerable methodological uncertainty [416]. There was no evidence of differences in urinary incontinence at 12 months and there was insufficient evidence to draw conclusions based on differences in cancer-related, patient-driven or erectile dysfunction (ED) outcomes. Another systematic review and meta-analysis included two small RCTs comparing RARP vs. LRP [417]. The results suggested higher rates of return of erectile function (RR: 1.51; 95% CI: 1.19-1.92) and return to continence function (RR: 1.14; 95% CI: 1.04-1.24) in the RARP group. However, a recent Cochrane review comparing either RARP or LRP vs. open RP included two RCTs and found no significant differences between the comparisons for oncological-, urinary function- and sexual function outcomes, although RARP and LRP both resulted in statistically significant improvements in duration of hospital stay and blood transfusion rates over open RP [418]. Therefore, no surgical approach can be recommended over another.

Outcome after prostatectomy has been shown to be dependent on both surgeon [419] as well as hospital volume [420]. Although various volume criteria have been set worldwide, the level of evidence is insufficient to pinpoint a specific lower volume limit.

6.1.2.3.1.Robotic anterior versus Retzius-sparing dissection

Robot-assisted RP has typically been performed via the anterior approach, first dropping the bladder to expose the space of Retzius. However, recently the posterior approach (Retzius-sparing - RS-RARP) has gained favour following two RCTs showing improved early post-operative continence.

Galfano et al. first described RS-RARP in 2010 [421]. This approach commences dissection posteriorly at the pouch of Douglas, first dissecting the seminal vesicles and progressing caudally behind the prostate. All of the anterior support structures are avoided, giving rise to the hypothetical mechanism for improved early post-operative continence. Retzius-sparing-RARP thus offers the same potential advantage as the open perineal approach, but without disturbance of the perineal musculature.

Both RCTs were single-surgeon studies comparing post-operative continence in RS-RARP vs. traditional anterior dissection RARP in men with low- to intermediate-risk PCa. Defining continence as 0-1 pad per day in 120 patients, Dalela et al. found a continence rate of 71% at 1 week post-catheter removal in the RS-RARP group vs. 48% in the control group (p = 0.01) [422]. The positive margin rate was higher in the RS-RARP group (25% vs. 13%), but this was not statistically significant (p = 0.1). Asimakopoulos et al. studied 102 patients, assessing continence more stringently as 0 pads at catheter removal [423]. Fifty-one percent of patients following RS-RARP were continent at catheter removal vs. 21% in the standard group (p = 0.001). Positive margin rates were again higher in the RS-RARP group (28% vs. 10%), however this was attributed to the higher incidence of pT3 disease in the RS-RARP group (44% vs. 23%).

Until these results are replicated in larger numbers in a multi-centre setting, it remains too early to recommend RS-RARP over the traditional anterior dissection, Furthermore, no high level evidence is available on high-risk disease, with some concerns that RS-RARP may confer an increased positive margin rate based on the pT3 results. In addition, RS-RARP may be more technically challenging in various scenarios such as anterior tumours, post-TURP, a grossly enlarged gland or a bulky median lobe [424].

6.1.2.3.2.Pelvic lymph node dissection

A recent systematic review demonstrated that performing PLND during RP failed to improve oncological outcomes, including survival [425]. However, it is generally accepted that eLND provides important information for staging and prognosis which cannot be matched by any other currently available procedure [425]. The individual risk of finding positive LNs can be estimated using pre-operative tools. Another systematic review and meta-analysis found similar diagnostic accuracy in predicting LN invasion for the Briganti, Partin and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms [426]. However, only a few of these tools are based on eLND templates and have been externally validated. A risk of nodal metastases over 5% (Briganti nomogram [427,428] or Roach formula [429] which has been shown to be almost as good as the nomogram) is an indication to perform nodal sampling by an extended nodal dissection [430-432]. 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 iliac artery. With this template, 94% of patients are correctly staged [433].

6.1.2.3.3.Sentinel node biopsy analysis

The rationale for a sentinel node biopsy (SNB) is based on the concept that a sentinel node is the first to be involved by migrating tumour cells. Therefore, when this node is negative it is possible to avoid an ePLND. There is heterogeneity and variation in techniques in relation to SNB (e.g. the optimal tracer), but a multidisciplinary collaborative endeavour attempted to standardise definitions, thresholds and strategies in relation to techniques of SNB using consensus methods [434].

Intraprostatic injections of indocyanine green (ICG) has been used to visualise prostate-related LNs during lymphadenectomy. In a randomised comparison, Harke et al. found more cancer containing LNs in men that underwent a LN dissection guided by ICG, but no difference in BCR at 22.9 month follow up [435]. A systematic review showed a sensitivity of 95.2% and NPV of 98.0% for SNB in detecting men with metastases at eLND [436]. However, there is still insufficient quality evidence supporting oncological effectiveness of SNB for nodal staging. Sentinel node biopsy is therefore still considered as an experimental nodal staging procedure.

6.1.2.3.4.Prostatic anterior fat pad dissection and histologic analysis

Several multi-centre and large single-centre series have shown the presence of lymphoid tissue within the fat pad anterior to the endopelvic fascia - the prostatic anterior fat pad (PAFP) [437-443]. This lymphoid tissue is present in 5.5-10.6% of cases and contains metastatic PCa in up to 1.3% of intermediate- and high-risk cases. When positive, the PAFP is often the only site of LN metastasis. The PAFP is therefore a rare but recognised route of spread of disease. Unlike PLND, there is no morbidity associated with removal of the PAFP. The PAFP is always removed at RP for exposure of the endopelvic fascia and should be sent for histologic analysis as per all removed tissue.

6.1.2.3.5.Management of the dorsal venous complex

Since the description of the anatomical open RP by Walsh and Donker in the 1980s, various methods of controlling bleeding from the DVC have been proposed to optimise visualisation [407]. In the open setting, blood loss and transfusion rates have been found to be significantly reduced when ligating the DVC prior to transection [444]. However, concerns have been raised regarding the effect of prior DVC ligation on apical margin positivity and continence recovery due to the proximity of the DVC to both the prostatic apex and the urethral sphincter muscle fibres. In the robotic-assisted laparoscopic technique, due to the increased pressure of pneumoperitoneum, whether prior DVC ligation was used or not, blood loss was not found to be significantly different in one study [445]. In another study, mean blood loss was statistically significantly less with prior DVC ligation (184 vs. 176 mL, p = 0.033), however it is debatable whether this was clinically significant [446]. The positive apical margin rate was not different, however the latter study showed earlier return to full continence at 5 months post-operatively in the no prior DVC ligation group (61% vs. 40%, p < 0.01).

Ligation of the DVC can be performed with standard suture or using a vascular stapler. One study found significantly reduced blood loss (494 mL vs. 288 mL) and improved apical margin status (13% vs. 2%) when using the stapler [447].

Given the relatively small differences in outcomes, the surgeon's choice to ligate prior to transection or not, or whether to use sutures or a stapler, will depend on their familiarity with the technique and the equipment available.

6.1.2.3.6.Nerve-sparing surgery

During prostatectomy, preservation of the neurovascular bundles with parasympathetic nerve branches of the pelvic plexus may spare erectile function [448,449].

Although age and pre-operative function may remain the most important predictors for postoperative erectile function, nerve-sparing has also been associated with improved continence outcomes and may therefore still be relevant for men with poor erectile function [450,451]. The association with continence may be mainly due to the dissection technique used during nerve-sparing surgery, and not due to the preservation of the nerve bundles themselves [450].

Extra-, inter-, and intra-fascial dissection planes can be planned, with those closer to the prostate and performed bilaterally associated with superior (early) functional outcomes [452-455]. Furthermore, many different techniques are propagated such as retrograde approach after anterior release (vs. antegrade), and athermal and traction-free handling of bundles [456-458]. Nerve-sparing does not compromise cancer control if patients are carefully selected depending on tumour location, size and grade [459-461].

6.1.2.3.7.Lymph-node-positive patients during radical prostatectomy

Although no RCTs are available, data from prospective cohort studies comparing survival of pN+ patients (as defined following pathological examination after RP) support that RP may have a survival benefit over abandonment of RP in node-positive cases [462]. As a consequence there is no role for performing frozen section of suspicious LNs.

6.1.2.3.8.Removal of seminal vesicles

The more aggressive forms of PCa may spread directly into the seminal vesicles (SVs). For oncological clearance, the SVs have traditionally been removed intact with the prostate specimen [463]. However, in some patients the tips of the SVs can be challenging to dissect free. Furthermore, the cavernous nerves run past the SV tips such that indiscriminate dissection of the SV tips could potentially lead to ED [464]. However, an RCT comparing nerve-sparing RP with and without SV-sparing found no difference in margin status, PSA recurrence, continence or erectile function outcomes. Another study of 71 consecutive RPs showed no cancer in any of the distal 1 cm of SVs, even in 12 patients with SV invasion [465]. Whilst complete SV removal should be the default, preservation of the SV tips may be considered in cases of low risk of involvement.

6.1.2.3.9.Techniques of vesico-urethral anastomosis

Following prostate removal, the bladder neck is anastomosed to the membranous urethra. The objective is to create a precisely aligned, watertight, tension-free, and stricture-free anastomosis that preserves the integrity of the intrinsic sphincter mechanism. Several methods have been described, based on the direct or indirect approach, the type of suture (i.e. barbed vs. non-barbed/monofilament), and variation in suturing technique (e.g. continuous vs. interrupted, or single-needle vs. double-needle running suture). The direct vesico-urethral anastomosis, which involves the construction of a primary end-to-end, inter-mucosal anastomosis of the bladder neck to the membranous urethra by using 6 interrupted sutures placed circumferentially, has become the standard method of reconstruction for open RP [466].

The development of laparoscopic- and robotic-assisted techniques to perform RP have facilitated the introduction of new suturing techniques for the anastomosis. A systematic review and meta-analysis [467] compared unidirectional barbed suture vs. conventional non-barbed suture for vesico-urethral anastomosis during robotic-assisted laparoscopic prostatectomy (RALP). The review included 3 RCTs and found significantly reduced anastomosis time, operative time and posterior reconstruction time in favour of the unidirectional barbed suture technique, but there were no differences in post-operative leak rate, length of catheterisation and continence rate. However, no definitive conclusions could be drawn due to the relatively low quality of the data. In regard to suturing technique, a systematic review and meta-analysis [468] compared continuous vs. interrupted suturing for vesico-urethral anastomosis during RP. The study included only one RCT [469] which had only 60 patients. Although the review found slight advantages of continuous suturing over interrupted suturing in terms of catheterisation time, anastomosis time and rate of extravasation, the overall quality of evidence was low, and no clear recommendations were possible. A recent RCT [470] compared the technique of suturing using a single absorbable running suture vs. a double-needle, single-knot running suture (i.e. Van Velthoven technique) [471] in laparoscopic RP. The study found slightly reduced anastomosis time with the single running suture technique, but anastomotic leak, stricture and continence rates were similar.

Overall, although there are a variety of approaches, methods and techniques for performing the vesico-urethral anastomosis, no clear recommendations are possible due to the lack of high certainty evidence. In practice, the chosen method should be based on surgeon experience and individual preference [466-477].

6.1.2.3.10.Bladder neck management

Bladder neck mucosal eversion

Some surgeons perform mucosal eversion of the bladder neck as its own step in open RP in the aim of securing a mucosa-to-mucosa vesico-urethral anastomosis and avoiding anastomotic stricture. Whilst bringing bladder and urethral mucosa together, by the everted bladder mucosa covering the bladder muscle layer, this step may actually retard healing of the muscle layers. An alternative is to simply ensure bladder mucosa is included in the full thickness anastomotic sutures. A non-randomised study of 211 patients with and without bladder neck mucosal eversion showed no significant difference in anastomotic stricture rate [478]. The strongest predictor of anastomotic stricture in RP is current cigarette smoking [479].

Bladder neck preservation

Whilst the majority of urinary continence is maintained by the external urethral sphincter at the membranous urethra (see below), a minor component is contributed by the internal lissosphincter at the bladder neck [480]. Preservation of the bladder neck has therefore been proposed to improve continence recovery post-RP. An RCT assessing incontinence recovery at 12 months and 4 years showed improved objective and subjective urinary continence in both the short- and long-term without any adverse effect on oncological outcome [481]. These findings were confirmed by a systematic review [482]. However, concern remains regarding margin status for cancers located at the prostate base.

A systematic review addressing site-specific margin status found a mean base-specific positive margin rate of 4.9% with bladder neck preservation vs. only 1.9% without [480]. This study was inconclusive, but it would be sensible to exercise caution when considering bladder neck preservation if significant cancer is known to be at the prostate base. Bladder neck preservation should be performed routinely when the cancer is distant from the base. Bladder neck preservation, however, cannot be performed in the presence of a large median lobe, or a previous TURP.

6.1.2.3.11.Urethral length preservation

The membranous urethra sits immediately distal to the prostatic apex and is chiefly responsible, along with its surrounding pelvic floor support structures, for urinary continence. It consists of the external rhabdosphincter which surrounds an inner layer of smooth muscle. Using pre-operative MRI, the length of membranous urethra has been shown to vary widely. A systematic review and meta-analysis has found that every extra millimetre of membranous urethral length seen on MRI pre-operatively improves early return to continence post-RP [483]. It is likely therefore that preservation of as much urethral length as possible during RP will maximise the chance of early return to continence. It may also be useful to measure this urethral length pre-operatively in order to advise patients on their relative likelihood of early post-operative continence.

6.1.2.3.12.Cystography prior to catheter removal

Cystography may be used prior to catheter removal to check for a substantial anastomotic leak. If such a leak is found, catheter removal may then be deferred to allow further healing and sealing of the anastomosis. However, small comparative studies suggest that a cystogram to assess anastomotic leakage is not indicated as standard of care before catheter removal 8-10 days after surgery [484]. If a cystogram is used, men with LUTS, large prostates, previous TURP, or bladder neck reconstruction may benefit, as these factors have been associated with leakage [485,486]. Contrast-enhanced transrectal US is an alternative [487].

6.1.2.3.13.Urinary catheter

A urinary catheter is routinely placed during RP to enable bladder rest and drainage of urine while the vesico-urethral anastomosis heals. Compared to a traditional catheter duration of around 1 week, some centres remove the transurethral catheter early (post-operative day 2-3), usually after thorough anastomosis with posterior reconstruction, or in patients selected peri-operatively on the basis of anastomosis quality [488-491]. No higher complication rates were found. Although shorter catheterisation has been associated with more favourable short-term functional outcomes, no differences in long-term function were found [492]. One RCT has shown no difference in rate of UTI following indwelling catheter (IDC) removal whether prophylactic ciprofloxacin was given prior to IDC removal or not, suggesting antibiotics should not be given at catheter removal [493].

As an alternative to transurethral catheterisation, suprapubic catheter insertion during RP has been suggested. Some reports suggest less bother regarding post-operative hygiene and pain [494-498], while others did not find any differences [499,500]. No impact on long-term functional outcomes were seen.

6.1.2.3.14.Use of a pelvic drain

A pelvic drain has traditionally been used in RP for potential drainage of urine leaking from the vesico-urethral anastomosis, blood, or lymphatic fluid when a PLND has been performed. Two RCTs in the robotic-assisted laparoscopic setting have been performed [501,502]. Patients with urine leak at intra-operative anastomosis watertight testing were excluded. Both trials showed non-inferiority in complication rates when no drain was used. When the anastomosis is found to be watertight intra-operatively, it is reasonable to avoid inserting a pelvic drain. There is no evidence to guide usage of a pelvic drain in PLND.

6.1.2.4.Acute and chronic complications of surgery

Post-operative incontinence and ED are common problems following surgery for PCa. A key consideration is whether these problems are reduced by using newer techniques such as RALP. Recent systematic reviews have documented complication rates after RALP [416,503-506], and can be compared with contemporaneous reports after radical retropubic prostatectomy (RRP) [507]. Recently, a prospective, controlled, non-RCT of patients undergoing RP in 14 centres using RALP or RRP was published. At 12 months after RALP, 21.3% were incontinent, as were 20.2% after RRP. The adjusted OR was 1.08 (95% CI: 0.87-1.34). Erectile dysfunction was observed in 70.4% after RALP and 74.7% after RRP. The adjusted OR was 0.81 (95% CI: 0.66-0.98) [508]. A RCT comparing RALP and RRP reported outcomes at 12 weeks in 326 patients and functional outcomes at 2 years [410]. Urinary function scores did not differ significantly between RRP vs. RALP at 6 and 12 weeks post-surgery (74-50 vs. 71-10, p = 0.09; 83-80 vs. 82-50, p = 0.48), with comparable outcomes for sexual function scores (30-70 vs. 32-70, p = 0.45; 35-00 vs. 38-90, p = 0.18). In the RRP group 14 (9%) patients had post-operative complications vs. 6 (4%) in the RALP group. The intra-and peri-operative complications of retropubic RP and RALP are listed in Table 6.1.5. The early use of phosphodiesterase-5 (PDE5) inhibitors in penile rehabilitation remains controversial resulting in a lack of clear recommendations (see Section 8.3.2).

6.1.2.4.1.Effect of anterior and posterior reconstruction on continence

Preservation of integrity of the external urethral sphincter is critical for continence post-RP. Less clear is the effect of reconstruction of surrounding support structures to return to continence. Several small RCTs have been conducted, however pooling analyses is hampered by variation in the definitions of incontinence, and surgical approach, such as open vs. robotic and intraperitoneal vs. extraperitoneal. In addition, techniques used to perform both anterior suspension or reconstruction and posterior reconstruction are varied. For example, anterior suspension is performed either through periosteum of the pubis or the combination of ligated DVC and puboprostatic ligaments (PPL). Posterior reconstruction from rhabdosphincter is described to either Denonvilliers fascia posterior to bladder or to posterior bladder wall itself.

Two trials assessing posterior reconstruction in RALRP found no significant improvement in return to continence [509,510]. A third trial using posterior bladder wall for reconstruction showed only an earlier return to 1 pad per day (median 18 vs. 30 days, p = 0.024) [511]. When combining both anterior and posterior reconstruction, where for anterior reconstruction, the PPL were sutured to the anterior bladder neck, another RCT found no improvement compared to a standard anastomosis with no reconstruction [512].

Four RCTs including anterior suspension have also shown conflicting results. Anterior suspension alone, through the pubic periosteum, in the setting of extraperitoneal RALRP, showed no advantage [513]. However, when combined with posterior reconstruction in RRP, one RCT showed significant improvement in return to continence at one month (7.1% vs. 26.5%, p = 0.047) and 3 months (15.4% vs. 45.2%, p = 0.016), but not at 6 months (57.9% vs. 65.4%, p = 0.609) [514]. Another anterior plus posterior reconstruction RCT using the Advanced Reconstruction of VesicoUrethral Support (ARVUS) technique and the strict definition of continence of no pads, showed statistically significant improvement in continence at 2 weeks (43.8% vs. 11.8%), 4 weeks (62.5% vs. 14.7%), 8 weeks (68.8% vs. 20.6%), 6 months (75% vs. 44.1%) and 12 months (86.7% vs. 61.3%), when compared to standard posterior Rocco reconstruction [515]. Anterior suspension alone through the DVC and PPL combined, without posterior construction in the setting of RRP has shown improvement in continence at one month (20% vs. 53%, p = 0.029), 3 months (47% vs. 73%, p = 0.034) and 6 months (83% vs. 100%, p = 0.02), but not at 12 months (97% vs. 100%, p = 0.313) [516]. Together, these results suggest a possible earlier return to continence, but no long-term difference.

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

6.1.2.4.2.Deep venous thrombosis prophylaxis

For EAU Guidelines recommendations on post-RP deep venous thrombosis prophylaxis, please see the Thromboprophylaxis Guidelines Section 3.1.6 [517]. However these recommendations should be adapted based on national recommendations when available.

Table 6.1.5: Intra-and peri-operative complications of retropubic RP and RALP (Adapted from [416])

RALP = robot-assisted laparoscopic prostatectomy; RP = radical prostatectomy; RRP = radical retropubic prostatectomy.

6.1.2.4.3.Early complications of extended lymph node dissection

Pelvic eLND increases morbidity in the treatment of PCa [425]. Overall complication rates of 19.8% vs. 8.2% were noted for eLND vs. limited LND, respectively, with lymphoceles (10.3% vs. 4.6%) being the most common adverse event. Other authors have reported more acceptable complication rates [518]. Similar rates of lymphoceles have been observed in RALP series; however, in one subgroup analysis lymphoceles were more common with the extraperitoneal approach (19%) vs. the transperitoneal approach (0%) [519,520]. Briganti et al. [521] also showed more complications after extended compared to limited LND. Twenty percent of men suffer a complication of some sort after eLND. Thromboembolic events occur in less than 1% of cases.

6.1.2.5.Comparing effectiveness of radical prostatectomy versus other interventions for localised disease

6.1.2.5.1.Radical prostatectomy versus deferred treatment

Currently, three large prospective RCTs have compared RP over deferred treatment (see Section 6.1.2). In summary, there was conflicting evidence regarding the benefit of RP over deferred treatment. The only study to find a benefit of RP over WW (SPCG-4) was conducted in the pre-PSA era [350]. When comparing RP against WW [396] or against AM [386], no statistically significant benefit in OS at 10 years' of follow-up was observed. These findings indicate the good prognosis for the majority of patients with low-risk localised PCa, and highlight the need to carefully risk stratify patients to ensure that patients are appropriately managed and treated.

6.1.2.5.2.Radical prostatectomy versus radiotherapy

ProtecT compared RP vs. AM vs. EBRT (combined with 6 months of ADT) [386]. At a median follow-up of 10 years, there were no differences between surgery vs. EBRT in all oncological outcomes.

6.1.2.5.3.Neoadjuvant androgen deprivation therapy

Several RCTs have analysed the impact of neoadjuvant ADT before RP, most of them using a 3-month period. The main findings were summarised in a Cochrane review [522]. Neoadjuvant ADT is associated with a decreased rate of pT3 (downstaging), decreased positive margins, and a lower incidence of positive LNs. These benefits are greater with increased treatment duration (up to 8 months). However, since neither the PSA relapse-free survival nor CSS were shown to improve, neoadjuvant ADT should not be considered as standard clinical practice. One recent RCT compared neoadjuvant luteinising hormone-releasing hormone (LHRH) alone vs. LHRH plus abiraterone plus prednisone prior to RP in 65 localised high-risk PCa patients [523]. Patients in the combination arm were found to have both significantly lower tumour volume and significantly lower BCR at > 4 years follow-up (p = 0.0014). Further supportive evidence is required before recommending combination neoadjuvant therapy including abiraterone prior to RP.

6.1.3.Radiotherapy

Intensity-modulated radiotherapy (IMRT), with or without image-guided radiotherapy (IGRT), is the gold standard for EBRT.

6.1.3.1.External beam radiation therapy

6.1.3.1.1.Technical aspects: intensity-modulated external-beam radiotherapy and volumetric arc external-beam radiotherapy (VMAT)

Intensity-modulated external-beam radiotherapy and VMAT employ dynamic multileaf collimators, which automatically and continuously adapt to the contours of the target volume seen by each beam. The advantage of VMAT over IMRT is shorter treatment times, generally two to three minutes. Both techniques allow for a more complex distribution of the dose to be delivered within the treatment field and provide concave isodose curves, which are particularly useful as a means of sparing the rectum. Radiotherapy treatment planning for IMRT and VMAT differs from that used in conventional EBRT, requiring a computer system capable of 'inverse planning', and the appropriate physics expertise. Treatment plans must conform to pre-specified dose constraints to critical organs at risk of normal tissue damage, and a formal quality assurance process should be routine.

With dose escalation using IMRT, 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 image-guided 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 [524]. Tomotherapy is another technique for the delivery of IMRT, using a linear accelerator mounted on a ring gantry that rotates as the patient is delivered through the centre of the ring, analogous to spiral CT scanning.

6.1.3.1.2.Dose escalation

Several RCTs have shown that dose escalation (range 74-80 Gy) has a significant impact on 5-year biochemical relapse [525-531]. These trials have generally included patients from several risk groups, and the use of neoadjuvant/adjuvant hormone therapy (HT) has varied (see Table 6.1.6). The best evidence of an OS benefit for patients with intermediate- or high-risk PCa, but not with low-risk PCa, comes from a non-randomised but well conducted propensity-matched retrospective analysis of the U.S. National Cancer Database covering a total of 42,481 patients [532]. In everyday practice, a minimum dose of > 74 Gy is recommended for EBRT plus HT, with no different recommendations according to the patient's risk group. If IMRT and IGRT are used for dose escalation, rates of severe late side-effects (> grade 3) for the rectum are 2-3% and for the GU tract 2-5% [528,531,533-546].

Table 6.1.6: Randomised trials of dose escalation in localised PCa

(B)CF = biochemical failure; BFS = biochemical progression-free survival; DM = distant metastases DSM = disease specific mortality; FFF = freedom from biochemical or clinical failure; HT = hormone therapy; mo. = months; n = number of patients; OS = overall survival; PSA = prostate-specific antigen; yr. = year.

6.1.3.1.3.Hypofractionation (HFX)

Fractionated RT utilises differences in the DNA repair capacity of normal and tumour tissue and slowly proliferating cells are very sensitive to an increased dose per fraction [548]. A meta-analysis of 25 studies including > 14,000 patients concluded that since PCa has a slow proliferation rate, hypofractionated RT could be more effective than conventional fractions of 1.8-2 Gy [549]. Hypofractionation (HFX) has the added advantage of being more convenient for the patient at with lower cost.

Moderate HFX is defined as RT with 2.5-4 Gy/fx. Several studies report on moderate HFX applied in various techniques and, in part, also including HT [550-560]. A systematic review concludes that studies on moderate HFX (2.5-4 Gy/fx) delivered with conventional three-dimensional conformal radiotherapy (3D-CRT)/IMRT have sufficient follow-up to support the safety of this therapy, but long-term efficacy data are still lacking [559]. Moderate HFX should only be done by experienced teams using high-quality EBRT using IGRT and IMRT in carefully selected patients and adhere to published phase III protocols (see Table 6.1.7 below).

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

ADT = androgen deprivation therapy; BCDF = biochemical or clinical disease failure; BED = biologically equivalent dose, calculated to be equivalent in 2 Gy fractions using an α/ß of 1.5 Gy; DFS = disease-free survival; EBRT = external beam radiotherapy; FU = follow-up; fx = fractions; HR = hazard ratio; mo. = month; n = number of patients; ISUP = International Society of Urological Pathology; NCCN = National Comprehensive Cancer Network; n.s. = not significant; yr. = year.

Ultra-HFX has been defined as radiotherapy with > 3.4 Gy per fraction [560]. It requires IGRT and stereotactic body radiotherapy (SBRT). Table 6.1.8 provides an overview of selected studies. Short-term biochemical control is comparable to conventional fractionation. However, there are concerns about high-grade GU and rectal toxicity and long-term side-effects may not all be known yet [559,561,562]. In the HYPO-RT-PC randomised trial by Widmark et al. (n = 1,200), no difference in failure-free survival was seen for conventional or ultra-HFX but acute Grade > 2 GU toxicity was 23% vs. 28% (p = 0.057), favouring conventional fractionation. There were no significant differences in long-term toxicity [563]. A systematic review by Jackson et al. included 38 studies with 6,116 patients who received RT with < 10 fractions and > 5 Gy per fraction. Five- and 7-year bRFS rates were 95.3% and 93.7%, respectively and estimated late grade > 3 genitourinary- and gastrointestinal toxicity rates were 2.0% and 1.1%, respectively [564]. The authors conclude that there is sufficient evidence to support SBRT as a standard treatment option for localised PCa, even though the median follow-up in this review was only 39 months and it included at least one trial (HYPO-RT-PC) which used "conventional" IMRT/VMAT for ultra-HFX. In their review on SBRT, Cushman and co-workers evaluated 14 trials, including 2,038 patients and concluded that despite a lack of long-term follow-up and the heterogeneity of the available evidence, prostate SBRT affords appropriate biochemical control with few high-grade toxicities [565]. In the Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B) trial, acute grade > 2 GU or GI toxicities did not differ significantly between conventional fractionation and ultra-HFX [566]. Therefore, it seems prudent to restrict extreme HFX to prospective clinical trials and to inform patients on the uncertainties of the long-term outcome.

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

FFS = failure-free survival; FU = follow-up; fx = number fractions; GI = gastrointestinal toxicity, GU: genitourinary toxicity, mo. = months; n = number of patients; TD = total dose; SBRT = stereotactic body radiotherapy; w = weeks, yr. = years.

6.1.3.1.4.Neoadjuvant or adjuvant hormone therapy plus radiotherapy

The combination of RT with LHRH ADT has definitively proven its superiority compared with RT alone followed by deferred ADT on relapse, as shown by phase III RCTs [567-571] (Table 6.1.9). The main message is that for intermediate risk a short duration of around 6 months is optimal, while a longer one, around 3 years, is needed for high-risk patients.

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

ADT = androgen deprivation therapy; CI = confidence interval; EBRT = external beam radiotherapy in standard fractionation; HR = hazard ratio; LHRH = luteinising hormone-releasing hormone; mo. = months; n = number of patients; OS = overall survival; RP = radical prostatectomy; RT = radiotherapy; wk = week; yr. = year.

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

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

ADT = androgen deprivation therapy; CSM = cancer-specific mortality; EBRT = external beam radiotherapy;

HR = hazard ratio; LHRH = luteinising hormone-releasing hormone; mo. = months; n = number of patients; OS = overall survival; RT = radiotherapy; 3D-CRT = three-dimensional conformal radiotherapy.

6.1.3.1.5.Combined dose-escalated radiotherapy and androgen-deprivation therapy

Zelefsky et al. reported a retrospective analysis comprising 571 patients with low-risk PCa, 1,074 with intermediate-risk PCa, and 906 with high-risk PCa. 3D-conformal RT or IMRT were administered [580]. The prostate dose ranged from 64.8 to 86.4 Gy; doses beyond 81 Gy were delivered during the last 10 years of the study using image-guided IMRT. Complete androgen blockade was administered at the discretion of the treating physician to 623 high-risk PCa (69%), 456 intermediate-risk PCa (42%) and 170 low-risk PCa (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 before RT. The 10-year biochemical disease-free rate was significantly improved by dose escalation: above 75.6 Gy in low risk, and above 81 Gy for the intermediate- and high-risk groups. It was also improved by adding 6 months of ADT in intermediate- and high-risk patients. In the multivariate analysis, neither the dose > 81 Gy, nor adding ADT influenced OS. Three RCTs have shown that the benefits of ADT are independent of dose escalation, and that the use of ADT would not compensate for a lower radiotherapy dose:

1.The GICOR study which shows a better biochemical DFS for high-risk patients for 3D-CRT radiation dose > 72 GY when combined with long-term ADT [538].

2.DART01/05 GICOR which shows that 2 years of adjuvant ADT combined with high-dose RT improved biochemical control and OS in high-risk patients [581].

3.EORTC trial 22991 which shows that 6 months ADT improves biochemical and clinical DFS whatever the dose (70, 74, 78 Gy) in intermediate-risk and low-volume high-risk localised PCa [582].

6.1.3.2.Proton beam therapy

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

One RCT on dose escalation (70.2 vs. 79.2 Gy) has incorporated protons for the boost doses of either 19.8 or 28.8 Gy. This trial shows improved outcome with the higher dose, but it cannot be used as evidence for the superiority of proton therapy per se [527]. Thus, unequivocal information that shows an advantage of protons over IMRT photon therapy is still not available. Studies from the SEER database and from Harvard describing toxicity and patient-reported outcomes do not point to an inherent superiority for protons [583,584]. In terms of longer-term gastrointestinal (GI) toxicity, proton therapy might even be inferior to IMRT [584].

A RCT comparing equivalent doses of proton-beam therapy with IMRT is underway. Meanwhile, proton therapy must be regarded as a promising, but experimental, alternative to photon-beam therapy.

6.1.3.3.Brachytherapy

6.1.3.3.1.Low-dose rate (LDR) brachytherapy

Low-dose rate brachytherapy uses radioactive seeds permanently implanted into the prostate. There is a consensus on the following eligibility criteria for LDR monotherapy [585]: Stage cT1b-T2a N0, M0; ISUP grade 1 with < 50% of biopsy cores involved with cancer or ISUP grade 2 with < 33% of biopsy cores involved with cancer; an initial PSA level of < 10 ng/mL; a prostate volume of < 50 cm3; an International Prostatic Symptom Score (IPSS) < 12 and maximal flow rate > 15 mL/min on urinary flow tests [586].

The only available RCT comparing RP and brachytherapy as monotherapy was closed due to poor accrual [587]. Outcome data are available from a number of large population cohorts with mature follow-up [588-595]. The biochemical disease-free survival for ISUP grade 1 patients after 5 and 10 years has been reported to range from 71% to 93% and 65% to 85%, respectively [588-595]. A significant correlation has been shown between the implanted dose and biochemical control [596]. A D90 (dose covering 90% of the prostate volume) of > 140 Gy leads to a significantly higher biochemical control rate (PSA < 1.0 ng/mL) after 4 years (92 vs. 68%). There is no benefit in adding neoadjuvant or adjuvant ADT to LDR monotherapy [588].

Low-dose rate brachytherapy can be combined with EBRT in intermediate-/high-risk patients (see Section 6.2.3.2.3).

6.1.3.3.2.High-dose rate brachytherapy

High-dose rate (HDR) brachytherapy uses a radioactive source temporarily introduced into the prostate to deliver radiation. The technical differences are outlined in Table 6.1.11. The use of published guidelines is strongly recommended [597]. High-dose rate brachytherapy can be delivered in single or multiple fractions and is often combined with EBRT of at least 45 Gy [598]. A single RCT of EBRT (55 Gy in 20 fractions) vs. EBRT (35.75 Gy in 13 fractions), followed by HDR brachytherapy (17 Gy in two fractions over 24 hours) has been reported [599]. In 218 patients with organ-confined PCa the combination of EBRT and HDR brachytherapy showed a significant improvement in the biochemical disease-free rate (p = 0.04) at 5 and 10 year (75% and 46% compared to 61% and 39%). However, a very high, uncommon, rate of early recurrences was observed in the EBRT arm alone, even after 2 years, possibly due to a dose lower than the current standard used [599]. A systematic review of non-RCTs has suggested outcomes with EBRT plus HDR brachytherapy are superior to brachytherapy alone, but this needs confirmation in a prospective RCT [600].

Fractionated HDR brachytherapy as monotherapy can be offered to patients with low- and intermediate-risk PCa, who should be informed that results are only available from limited series in very experienced centres [601,602]. Five-year PSA control rates over 90% are reported, with late grade 3+ GU toxicity rates < 5% and no or very minimal grade 3+ GI toxicity rates [601,602].

Table 6.1.11: Difference between LDR and HDR brachytherapy

6.1.3.4.Acute side-effects of external beam radiotherapy and brachytherapy

Gastrointestinal and urinary side-effects are common during and after EBRT. In the EORTC 22991 trial, approximately 50% of patients reported acute GU toxicity of grade 1, 20% of grade 2, and 2% grade 3. In the same trial, approximately 30% of patients reported acute grade 1 GI toxicity, 10% grade 2, and less than 1% grade 3. Common toxicities included dysuria, urinary frequency, urinary retention, haematuria, diarrhoea, rectal bleeding and proctitis [537]. In addition, general side-effects such as fatigue are common. It should be noted that the incidence of acute side-effects is greater than that of late effects (see Section 8.2.2.1), implying that most acute effects resolve. In a RCT of conventional dose EBRT vs. EBRT and LDR brachytherapy the incidence of acute proctitis was reduced in the brachytherapy arm, but other acute toxicities were equivalent [603]. Acute toxicity of HDR brachytherapy has not been documented in a RCT, but retrospective reports confirm lower rates of GI toxicity compared with EBRT alone and grade 3 GU toxicity in 10%, or fewer, patients, but a higher incidence of urinary retention [604]. Similar findings are reported using HFX; in a pooled analysis of 864 patients treated using extreme HFX and stereotactic radiotherapy, declines in urinary and bowel domains were noted at 3 months, which returned to baseline, or better, by 6 months [605].

6.1.4.Hormonal therapy

6.1.4.1.Introduction

6.1.4.1.1.Different types of hormonal therapy

Androgen deprivation can be achieved by either suppressing the secretion of testicular androgens or inhibiting the action of circulating androgens at the level of their receptor. These two methods can be combined to achieve what has been known as complete (or maximal or total) androgen blockade (CAB) using the old-fashioned anti-androgens [606].

6.1.4.1.1.1.Testosterone-lowering therapy (castration)

6.1.4.1.1.1.1.Castration level

The castration level is < 50 ng/dL (1.7 nmol/L), which was defined more than 40 years ago when testosterone testing was less sensitive. Current methods have shown that the mean value after surgical castration is 15 ng/dL [607]. Therefore, a more appropriate level should be defined as < 20 ng/dL (1 nmol/L). This definition is important as better results are repeatedly observed with lower testosterone levels compared to 50 ng/dL [608-610]. However, the castrate level considered by the regulatory authorities and in clinical trials addressing castration in PCa is still the historical < 50 ng/dL (1.7 mmol/L).

6.1.4.1.1.1.2.Bilateral orchiectomy

Bilateral orchiectomy, or subcapsular pulpectomy, is still considered the primary treatment modality for ADT. It is a simple, cheap and virtually complication-free surgical procedure. It is easily performed under local anaesthesia and it is the quickest way to achieve a castration level, which is usually reached within less than twelve hours. It is irreversible and therefore does not allow for intermittent treatment [611].

6.1.4.1.1.2.Oestrogens

Treatment with oestrogens results in testosterone suppression and is not associated with bone loss [612]. Early studies tested oral diethylstilboestrol (DES) at several doses. Due to severe side-effects, especially thromboembolic complications, even at lower doses these drugs are not considered as standard first-line treatment [613-615].

6.1.4.1.1.3.Luteinising-hormone-releasing hormone agonists

Long-acting LHRH agonists are currently the main forms of ADT. These synthetic analogues of LHRH, are delivered as depot injections on a 1-, 2-, 3-, 6-monthly, or yearly, basis. The first injection induces a transient rise in luteinising hormone (LH) and follicle-stimulating hormone (FSH) leading to the 'testosterone surge' or 'flare-up' phenomenon, which starts two to three days after administration and lasts for about one week. This may lead to detrimental clinical effects (the clinical flare) such as increased bone pain, acute bladder outlet obstruction, obstructive renal failure, spinal cord compression, and cardiovascular death due to hypercoagulation status [616]. Patients at risk are usually those with high-volume, symptomatic, bony disease. Concomitant therapy with an anti-androgen decreases the incidence of clinical flare but does not completely remove the risk.

Anti-androgen therapy is usually continued for 4 weeks but neither the timing nor the duration of anti-androgen therapy are based on strong evidence. In addition, the long-term impact of preventing 'flare-up' is unknown [617,618].

Chronic exposure to LHRH agonists results in the down-regulation of LHRH-receptors, suppressing LH and FSH secretion and therefore testosterone production. A castration level is usually obtained within 2 to 4 weeks [619]. Although there is no formal direct comparison between the various compounds, they are considered to be equally effective [620]. No survival difference with orchiectomy has been reported, despite the lack of high quality trials [621].

The different products have practical differences that need to be considered in everyday practice, including the storage temperature, whether a drug is ready for immediate use or requires reconstitution, and whether a drug is given by subcutaneous or intramuscular injection.

6.1.4.1.1.4.Luteinising-hormone-releasing hormone antagonists

Luteinising-hormone releasing hormone antagonists immediately bind to LHRH receptors, leading to a rapid decrease in LH, FSH and testosterone levels without any flare. The practical shortcoming of these compounds is the lack of a long-acting depot formulation with, so far, only monthly formulations being available.

Degarelix is a LHRH antagonist. The standard dosage is 240 mg in the first month, followed by monthly injections of 80 mg. Most patients achieve a castrate level at day three [619]. An extended follow-up has been published, suggesting a better PSA PFS compared to monthly leuprorelin [622]. A systematic review did not show major difference between agonists and degarelix and highlighted the paucity of on-treatment data beyond 12 months as well as the lack of survival data [623]. Its definitive superiority over the LHRH analogues remains to be proven.

6.1.4.1.1.5.Anti-androgens

These oral compounds are classified according to their chemical structure as:

• steroidal, e.g. cyproterone acetate (CPA), megestrol acetate and medroxyprogesterone acetate;
• non-steroidal or pure, e.g. nilutamide, flutamide and bicalutamide.

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

6.1.4.1.1.5.1.Steroidal anti-androgens

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

6.1.4.1.1.5.1.1.Cyproterone acetate

Cyproterone acetate was the first licensed anti-androgen, but the least studied. Its most effective dose as monotherapy is still unknown. Although CPA has a relatively long half-life (31-41 hours), it is usually administered in two or three fractionated doses of 100 mg each. In one RCT, CPA showed a poorer OS when compared with LHRH analogues [624]. An underpowered RCT comparing CPA monotherapy with flutamide in M1b PCa did not show any difference in disease-specific and OS at a median follow-up of 8.6 years [625]. Other CPA monotherapy studies suffer from methodological limitations preventing firm conclusions.

6.1.4.1.1.5.2.Non-steroidal anti-androgens

Non-steroidal anti-androgen monotherapy does not suppress testosterone secretion and it is claimed that libido, overall physical performance and bone mineral density (BMD) are frequently preserved [626]. Non-androgen-related pharmacological side-effects differ between agents. Bicalutamide shows a more favourable safety and tolerability profile than flutamide and nilutamide [627]. All three agents share the potential for liver toxicity (occasionally fatal), requiring regular monitoring of patients' liver enzymes.

6.1.4.1.1.5.2.1.Nilutamide

Nilutamide monotherapy has not been compared to castration and is not licensed for monotherapy. Direct drug-related side-effects are visual disturbances (i.e. delayed adaptation to darkness), alcohol intolerance, nausea, and of note, severe interstitial pneumonitis (potentially life-threatening). As a consequence it is rarely used.

6.1.4.1.1.5.2.2.Flutamide

Flutamide has been studied as monotherapy. Flutamide is a pro-drug, and the half-life of the active metabolite is 5 to 6 hours, requiring a three times daily dose. The recommended total daily dose is 750 mg. The non-androgen-related pharmacological side-effect of flutamide is diarrhoea.

6.1.4.1.1.5.2.3.Bicalutamide

The dosage licensed for use in CAB is 50 mg/day, and 150 mg for monotherapy. The androgen pharmacological side-effects are mainly gynaecomastia (70%) and breast pain (68%). However, bicalutamide monotherapy offers clear bone protection compared with LHRH analogues and probably LHRH antagonists [626,628].

6.1.4.1.1.6.New compounds

Once on ADT, the development of castration-resistance (CRPC) is only a matter of time. It is considered to be mediated through two main overlapping mechanisms: androgen-receptor (AR)-independent and AR-dependent mechanisms (see Section 6.5 - Castrate-resistant PCa). In CRPC, the intracellular androgen level is increased compared to androgen sensitive cells, and an over-expression of the AR has been observed, suggesting an adaptive mechanism [629]. This has led to the development of several new compounds targeting the androgen axis. Abiraterone acetate and enzalutamide are both approved for mCRPC. Abiraterone acetate has also been approved for hormone-sensitive PCa, combined with ADT. Apalutamide, darolutamide and enzalutamide have been approved for M0 CRPC at high risk of further metastases [630,631].

6.1.4.1.1.6.1.Abiraterone acetate

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

6.1.4.1.1.6.2.Enzalutamide

Enzalutamide is a novel non-steroidal anti-androgen with a higher affinity for the AR receptor than bicalutamide. While previous non-steroidal anti-androgens still allow transfer of ARs to the nucleus, enzalutamide also blocks AR transfer and therefore suppresses any possible agonist-like activity.

6.1.4.1.1.6.3.Apalutamide

Apalutamide is a novel non-steroidal anti-androgen with similar properties as enzalutamide and an identical mechanism of action.

6.1.4.1.1.6.4.Darolutamide

Darolutamide is a novel non-steroidal anti-androgen with, compared to the other new anti-androgens, structurally unique properties and distinct pharmacokinetics. In particular it does not cross the blood-brain barrier, has a high affinity for AR and a low affinity for GABA receptors, and therefore a lower potential for drug-drug interactions. It has been approved by the FDA and the EMA.

6.1.5.Investigational therapies

6.1.5.1.Background

Besides RP, EBRT and brachytherapy, other modalities have emerged as potential therapeutic options in patients with clinically localised PCa [632-635]. In this section, both whole gland and focal treatment will be considered, looking particularly at high-intensity focused US (HIFU), cryotherapeutic ablation of the prostate (cryotherapy) and focal photodynamic therapy, as sufficient data are available to form the basis of some initial judgements. Other options, such as radiofrequency ablation and electroporation, among others, are considered to be in the early phases of evaluation [636]. In addition, a relatively newer development is focal ablative therapy [636,637], whereby lesion-targeted ablation is undertaken in a precise, organ-sparing manner. All these modalities have been developed as minimally invasive procedures with the aim of providing equivalent oncological safety, reduced toxicity and improved functional outcomes.

6.1.5.2.Cryotherapy

Cryotherapy uses freezing techniques to induce cell death by dehydration resulting in protein denaturation, direct rupture of cellular membranes by ice crystals and vascular stasis and microthrombi, resulting in stagnation of the microcirculation with consecutive ischaemic apoptosis [632-635]. Freezing of the prostate is ensured by the placement of 17 gauge cryo-needles under TRUS guidance, placement of thermosensors at the level of the external sphincter and rectal wall, and insertion of a urethral warmer. Two freeze-thaw cycles are used under TRUS guidance, resulting in a temperature of -40°C in the mid-gland and at the neurovascular bundle. Currently, third and fourth generation cryotherapy devices are mainly used. Since its inception, cryotherapy has been used for whole-gland treatment in PCa either as a primary or salvage treatment option.

The main adverse effects of cryosurgery are ED (18%), urinary incontinence (2-20%), urethral sloughing (0-38%), rectal pain and bleeding (3%) and recto-urethral fistula formation (0-6%) [638]. There is a lack of prospective comparative data regarding oncological outcomes of whole-gland cryosurgery as a curative treatment option for men with localised PCa, with most studies being non-comparative single-arm case series with short follow-up periods [638].

6.1.5.3.High-intensity focused ultrasound

High-intensity focused ultrasound consists of focused US waves, emitted from a transducer, that cause tissue damage by mechanical and thermal effects as well as by cavitation [639]. The goal of HIFU is to heat malignant tissues above 65°C so that it is destroyed by coagulative necrosis. High-intensity focused US is performed under general or spinal anaesthesia, with the patient lying in the lateral or supine position. High-intensity focused US has previously been widely used for whole-gland therapy. The major adverse effects of HIFU include acute urinary retention (10%), ED (23%), urethral stricture (8%), rectal pain or bleeding (11%), recto-urethral fistula (0-5%) and urinary incontinence 10%) [638]. Disadvantages of HIFU include difficulty in achieving complete ablation of the prostate, especially in glands larger than 40 mL, and in targeting cancers in the anterior zone of the prostate. Similar to cryosurgery, the lack of any long-term prospective comparative data on oncological outcomes prevents whole-gland HIFU from being considered as a reasonable alternative to the established curative treatment options [638].

6.1.5.4.Focal therapy

During the past two decades, there has been a trend towards earlier diagnosis of PCa as a result of greater public and professional awareness, leading to the adoption of both formal and informal screening strategies. The effect of this has been to identify men at an earlier stage with smaller tumours that occupy only 5-10% of the prostate volume, with a greater propensity for unifocal or unilateral disease [640-642]. Most focal therapies to date have been achieved with ablative technologies: cryotherapy, HIFU, photodynamic therapy, electroporation, and focal RT by brachytherapy or CyberKnife® Robotic Radiosurgery System technology (Accuray Inc., Sunnyvale, CA, USA). The main purpose of focal therapy is to ablate tumours selectively whilst limiting toxicity by sparing the neurovascular bundles, sphincter and urethra [643-645].

A previous systematic review and network meta-analysis [638] on ablative therapy in men with localised PCa performed a sub-group analysis of focal therapy vs. RP and EBRT. Nine case series reporting on focal therapy were identified (5 studies reporting on focal cryosurgical ablation of the prostate [CSAP], three studies on focal HIFU, and one study reported on both). For focal CSAP vs. RP or EBRT, no statistically significant differences were found for BCR at 3 years. For focal HIFU vs. RP or EBRT, there were neither comparable data on oncological-, continence- nor potency outcomes at one year, or more. More recently, Valerio et al. [637] performed a systematic review to summarise the evidence regarding the effectiveness of focal therapy in localised PCa. Data from 3,230 patients across 37 studies were included, covering different energy sources including HIFU, CSAP, photodynamic therapy, laser interstitial thermotherapy, focal brachytherapy, irreversible electroporation and radiofrequency ablation. The overall quality of the evidence was low, due to the majority of studies being single-centre, non-comparative and retrospective in design, heterogeneity of definitions, approaches, follow-up strategies, outcomes, and duration of follow-up. Although the review suggests that focal therapy has a favourable toxicity profile in the short to medium-term, its oncological effectiveness remains unproven due to lack of reliable comparative data against standard interventions such as RP and EBRT.

In order to update the evidence base, a systematic review incorporating a narrative synthesis was performed by the panel, including comparative studies assessing focal ablative therapy vs. radical treatment, AS or alternative focal ablative therapy, published in English between January 1st 2010 and May 31st 2019. Primary outcomes included oncological outcomes, adverse events and functional outcomes. A total of 707 abstracts were screened; 12 articles were eligible for full text screening, and ultimately only 4 articles (3 studies) were eligible for inclusion [646-649]. Azzouzi et al. [646] and Gill et al. [647] reported on a RCT comparing focal therapy using padeliporfin-based vascular-targeted photodynamic therapy (PDT) vs. AS in men with very low-risk PCa. The study found, at a median follow-up of 24 months, less patients progressed in the PDT arm compared with the AS arm (adjusted HR: 0.34, 95% CI: 0.24-0.46), and needed less radical therapy (6% vs. 29%, p < 0.0001). In addition, more men in the PDT arm had a negative prostate biopsy at two years than men in the AS arm (adjusted RR: 3.67, 95% CI: 2.53-5.33). Updated results were published in 2018 [647], showing that these benefits were maintained after four years. Nevertheless, limitations of the study include inappropriately comparing an intervention designed to destroy cancer tissue in men with low-risk PCa against an intervention primarily aimed at avoiding unnecessary treatment in men with low-risk PCa, and an unusually high observed rate of disease progression in the AS arm (58% in two years). Furthermore, more patients in the AS arm chose to undergo radical therapy without a clinical indication, and this may have introduced confounding bias. Finally, the AS arm did not undergo any confirmatory biopsy nor any mpMRI scanning, which is not representative of contemporary practice. Two further studies identified in the review were non-randomised comparative studies. Albisinni et al. was a small retrospective matched-pair study comparing focal HIFU vs. RALRP; Tourinho-Barbosa et al. was a retrospective cohort study comparing focal HIFU vs. focal cryotherapy for patients with low- or intermediate-risk localised PCa. The certainty of the evidence relating to both studies was low due to the retrospective and unmatched nature of the data.

Given the lack of robust comparative data on medium to long-term oncological outcomes for focal therapy against curative interventions (i.e. RP or EBRT), significant uncertainties remain in regard to focal therapy as a proven alternative to either AS or radical therapy. Consequently, robust prospective trials reporting standardised outcomes [650] are needed before recommendations in support of focal therapy for routine clinical practice can be made [636,650,651]. For now, focal therapy should only be performed within the context of a clinical trial setting or well-designed prospective cohort study.

6.1.6.General guidelines for active treatment

6.1.7.Discussing treatment options

Management decisions should be made after all treatments have been discussed in a multidisciplinary team (including urologists, radiation oncologists, medical oncologists pathologists and radiologists), and after the balance of benefits and side-effects of appropriate therapy modalities has been considered together with the patient. The following paragraphs will only address active modalities where the aim is to try to be "curative" in patients where that is appropriate.

6.2.Treatment by disease stages

6.2.1.Treatment of low-risk disease

6.2.1.1.Active surveillance

The main risk for men with low-risk disease is over-treatment (see Sections 6.1.1.2 and 6.1.1.4) and therefore AS should be considered for all such patients.

6.2.1.1.1.Active surveillance - inclusion criteria

Selection criteria for AS are limited by a lack of prospective RCTs. As a consequence, the EAU-EANM-ESTRO-ESUR-SIOG Prostate Cancer Guideline Panel undertook an international collaborative study involving healthcare practitioners and patients to develop consensus statements for deferred treatment with curative intent for localised PCa, covering all domains of AS (DETECTIVE Study) [7]. The criteria most often published include: ISUP grade 1, a clinical T1c or T2a, a PSA < 10 ng/mL and a PSA density < 0.15 ng/mL/cc [387,652]. The latter threshold remains controversial [652,653]. These criteria were supported by the DETECTIVE consensus. There was no agreement around the maximum number of cores that can be involved with cancer or the maximum percentage core involvement although there was recognition that T2c disease and extensive disease on mpMRI should exclude men from AS.

DETECTIVE did agree that men with favourable ISUP 2 cancer (PSA < 10 ng/mL, clinical stage [< cT2a] and a low number of positive cores) should also be considered for deferred treatment [7]. In this setting, re-biopsy within 6 to 12 months to exclude sampling error is mandatory [652,654] even if this could be modified in the future [655]. A systematic review and meta-analysis found three clinico-pathological variables which were significantly associated with reclassification, which were; PSA density, > 2 positive cores, and African-American race [656].

The DETECTIVE consensus group were clear that those with ISUP 3 disease should not be considered. In addition, a previous pathology consensus group suggested excluding men from AS when any of the following features were present: predominant ductal carcinoma (including pure intraductal carcinoma), sarcomatoid carcinoma, small cell carcinoma, EPE or LVI in needle biopsy [657] and perineal invasion [658] and this view was supported.

6.2.1.1.2.Biological markers

Biological markers, including urine PCA3, transmembrane protease, serine 2-TMPRSS2-ERG fusion, or PSA isoforms appear promising, as does genomics on the tissue sample itself [659-661]. However, further data will be needed before such markers can be used in standard clinical practice [167].

6.2.1.1.3.Imaging for treatment selection

In men eligible for AS based upon systematic biopsy findings alone, mpMRI can detect suspicious lesions inducing reclassification at confirmatory biopsy [662,663]. However, systematic biopsy retains substantial added value at confirmatory biopsy.

A recent meta-analysis evaluated the proportion of men eligible for AS based on systematic TRUS-guided biopsy in whom the cancer was upgraded by MRI-TBx (17%) and systematic biopsy (20%) at confirmatory biopsy [664]. Ten per cent of patients were upgraded by both biopsy methods, meaning MRI-TBx upgraded an additional 7% (95% CI: 5-10%) of men, whilst systematic biopsy upgraded an additional 10% (95% CI: 8-14%) of men. Even if the analysed series used different definitions for csPCa (and thus for cancer upgrading), MRI-TBx and systematic biopsy appear to be complementary to each other, both missing a significant proportion of cancer upgrading or reclassification. Therefore, combining the two biopsy techniques seems the best way to select patients for AS at confirmatory biopsy.

The Active Surveillance Magnetic Resonance Imaging Study (ASIST) randomised men on AS scheduled for confirmatory biopsy to either 12-core systematic biopsy or to MRI with targeted biopsy (when indicated) combined with systematic biopsy, up to 12 cores in total, avoiding oversampling in the MRI arm [665]. The initial report showed little benefit from targeted biopsy. However, after 2 years of follow-up, use of MRI before confirmatory biopsy resulted in fewer failures of surveillance (19% vs. 35%, p = 0.017) and in fewer patients progressing to ISUP > 2 cancer (9.9% vs 23%, p = 0.048) [666].

Upgrading at 1-year confirmatory biopsy by saturation biopsy (24 cores) in combination with MRI-targeted biopsy (2 cores) was investigated in two subgroups of men eligible for AS [662]. Upgrading in men who were eligible for active surveillance, based on initial 12-core systematic biopsy findings, occurred in 59% (93/157), in contrast to 19% (22/116) upgrading in men eligible based on initial 12-core systematic and MRI-targeted biopsy (p < 0.001).

At the DECTECTIVE consensus meeting it was agreed that men eligible for AS after combined systematic- and MRI-targeted biopsy do not require a confirmatory biopsy [7].

6.2.1.1.4.Monitoring during active surveillance

The follow-up strategy is based on serial DRE (at least once yearly), PSA (at least once, every 6 months) and repeated biopsy [7]. Several authors have reported data on sequential mpMRI evaluation, summarised in a review [667], the overall upgrading from ISUP 1 to ISUP > 2 PCa was 30% (81/269), following combined targeted and standard biopsies. Upgrading occurred in 39% of patients with MRI showing progression and in 21% of patients with MRI showing stable findings or regression. However, in a recent study not included in this review, an association between mpMRI progression and pathological upgrade was not observed [668]. Data is more limited on unchanged negative mpMRI. In a small study on 75 men included within PRIAS, with an mpMRI at baseline, 46 (61%) had a negative mpMRI. Twenty-six percent (12/46) were reclassified at 12 months by systematic biopsies; however, this reclassification was based on volume ISUP grade 1 in five, and on upgrading to ISUP grade 2 cancers in 7 men [669]. Two other studies on serial negative MRI showed upgrading to ISUP grade 2 in only 2% (1/56) [663] and 5% (2/41) [668].

Data on the combination of serial mpMRI and PSA as a trigger for re-biopsy are even more limited. Using mpMRI and PSA changes as the sole triggers for re-biopsy would have detected only 14/20 (70%) of progressions and resulted in 15 additional biopsy procedures which failed to show pathological progression [670]. Protocol based re-biopsy, without mpMRI or PSA changes, however, detected pathological progressions in 6 out of 87 (6.9%) men. In another study of serial mpMRI in AS, PSA velocity was significantly associated with subsequent requirement for radical therapy in patients with no visible lesions (negative MRI). PSA doubling time was significant in patients with visible lesions (positive MRI). The AUC of PSA velocity for prediction of progression in MRI-negative patients was 0.85 (95% CI: 0.75-0.94); for PSA doubling time in MRI-positive patients, the AUC was 0.65 (95% CI: 0.52-0.78). In patients with no visible lesions on first MRI, a cut-off of 0.5 ng/mL/year in PSA velocity had a sensitivity of 89% (8/9 progressions identified) and a specificity of 75% for progression to radical therapy.

6.2.1.1.5.Active Surveillance - when to change strategy

Men may remain on AS whilst they continue to consent, have a life expectancy of > 10 years and the disease remains indolent. Patient anxiety about continued surveillance occurs in around 10% of patients on AS [671] and was recognised as a valid reason for active treatment [7]. More common is the development of other co-morbidities which may result in a decision to transfer to a WW strategy.

A PSA change alone (especially a PSA-DT < 3 years) is a less powerful indicator to change management based on its weak link with grade progression [672,673]. As a consequence, this should instead trigger further investigation. There was clear agreement in the DETECTIVE consensus meeting that a change in PSA should lead to repeat-mpMRI and biopsy. It was also agreed that changes on follow-up mpMRI needed a confirmatory biopsy before considering active treatment. However, there was no agreement on the histopathology criteria (neither the extent of core involvement nor the number of cores involved) required to trigger a change in management [7].

6.2.1.2.Guidelines for the treatment of low-risk disease

6.2.2.Treatment of Intermediate-risk disease

When managed with non-curative intent, intermediate-risk PCa is associated with 10-year and 15-year PCSM rates of 13.0% and 19.6%, respectively [674].

6.2.2.1.Active Surveillance

In the ProtecT trial, up to 22% of the randomised patients in the AM arm had ISUP grade > 1 and 10% a PSA > 10 ng/mL [386]. A Canadian consensus group proposes that low volume ISUP grade 2 (< 10% Gleason pattern 4) may also be considered for AS. These recommendations have been endorsed by the American Society of Clinical Oncology ASCO [675] and the recent DETECTIVE consensus meeting [7] for those with a PSA < 10 ng/mL and low core positivity. However, data is less consistent. It is clear that the presence of any grade 4 pattern is associated with a 3-fold increased risk of metastases although from a low baseline, compared to ISUP grade 1, while a PSA up to 20 ng/mL might be an acceptable threshold [654,676,677]. In addition, it is likely that mpMRI and targeted biopsies will detect small focuses of Gleason 4 cancer that might have been missed with systematic biopsy. Therefore, care must be taken when explaining this treatment strategy especially in patients with the longest life expectancy.

6.2.2.2.Surgery

Patients with intermediate-risk PCa should be informed about the results of two RCTs (SPCG-4 and PIVOT) comparing RRP vs. WW in localised PCa. In the SPCG-4 study, death from any cause (RR: 0.71; 95% CI: 0.53-0.95), death from PCa (RR: 0.38; 95% CI: 0.23-0.62) and distant metastases (RR: 0.49; 95% CI: 0.32-0.74) were significantly reduced in intermediate-risk PCa at 18 years. In the PIVOT trial, according to a pre-planned subgroup analysis among men with intermediate-risk tumours, RP significantly reduced all-cause mortality (HR: 0.69 [95% CI: 0.49-0.98]), but not death from PCa (0.50; 95% CI: 0.21-1.21) at 10 years. The risk of having positive LNs in intermediate-risk PCa is between 3.7-20.1% [678]. An eLND should be performed in intermediate-risk PCa if the estimated risk for pN+ exceeds 5% [427]. In all other cases eLND can be omitted, which means accepting a low risk of missing positive nodes.

6.2.2.3.Radiation therapy

6.2.2.3.1.Recommended external beam radiation therapy for intermediate-risk PCa

Patients suitable for ADT can be given combined IMRT with short-term ADT (4-6 months) [679-681]. For patients unsuitable for ADT (e.g. due to comorbidities) or unwilling to accept ADT (e.g. to preserve their sexual health), the recommended treatment is IMRT or VMAT at an escalated dose (76-80 Gy) or a combination of IMRT or VMAT and brachytherapy (see Section 6.2.3.2.3).

6.2.2.3.2.Brachytherapy monotherapy

Low-dose rate brachytherapy can be offered to highly selected patients (ISUP grade 2 with < 33% of biopsy cores involved with cancer), provided they fulfil all the other criteria. Fractionated HDR brachytherapy as monotherapy can be offered to selected patients with intermediate-risk PCa although they should be informed that results are only available from small series in very experienced centres. Five-year PSA control rates over 90% are reported, with late grade 3+ GU toxicity rates < 5% and no, or very minimal, grade 3+ GI toxicity rates [601,682]. There are no direct data to inform on the use of ADT in this setting.

6.2.2.4.Other options for the primary treatment of intermediate-risk PCa (experimental therapies)

A prospective study on focal therapy using HIFU on patients with localised intermediate-risk disease was recently published [651], but the data was derived from an uncontrolled, single-arm case series. There is a paucity of high certainty data for either whole-gland or focal ablative therapy in the setting of intermediate-risk disease. Consequently, neither whole-gland treatment nor focal treatment can be considered as standard therapy for intermediate-risk patients, and if offered it should only be in the setting of clinical trials [636].

Data regarding the use of ADT monotherapy for intermediate-risk disease have been inferred indirectly from EORTC 30891 [678], which was a RCT comparing deferred ADT vs. immediate ADT in 985 patients with T0-4 N0-2 M0 disease. The trial showed a small but statistically significant difference in OS in favour of immediate ADT monotherapy but there was no significant difference in CSS, predominantly because the risk of cancer-specific mortality was low in patients with PSA < 8 ng/mL. Consequently, the use of ADT monotherapy for this group of patients is not considered as standard, even if they are not eligible for radical treatment.

6.2.2.5.Guidelines for the treatment of intermediate-risk disease

6.2.3.Treatment of high-risk localised disease

Patients with high-risk PCa are at an increased risk of PSA failure, need for secondary therapy, metastatic progression and death from PCa. Nevertheless, not all high-risk PCa patients have a uniformly poor prognosis after RP [683]. When managed with non-curative intent, high-risk PCa is associated with 10-year and 15-year PCSM rates of 28.8 and 35.5%, respectively [674]. There is no consensus regarding the optimal treatment of men with high-risk PCa.

6.2.3.1.Radical prostatectomy

Provided that the tumour is not fixed to the pelvic wall, or there is no invasion of the urethral sphincter, RP is a reasonable option in selected patients with a low tumour volume. Extended PLND should be performed in all high-risk PCa cases undergoing RP as the estimated risk for positive LNs is > 5% [427]. Patients should be aware pre-operatively that surgery may be part of multi-modal treatment.

6.2.3.1.1.ISUP grade 4-5

The incidence of organ-confined disease is 26-31% in men with an ISUP grade > 4 on systematic biopsy. A high rate of downgrading exists between the biopsy ISUP grade and the ISUP grade of the resected specimen [684]. Several retrospective case series have demonstrated CSS rates over 60% at 15 years after RP in the context of a multi-modal approach (adjuvant or salvage ADT and/or RT) for patients with a biopsy ISUP grade 5 [350,410,685,686].

6.2.3.1.2.Prostate-specific antigen > 20 ng/mL

Reports in patients with a PSA > 20 ng/mL who underwent surgery as initial therapy within a multi-modal approach demonstrated a CSS at 15 years of over 70% [350,410,417,687-689].

6.2.3.1.3.Radical prostatectomy in cN0 patients who are found to have pathologically confirmed lymph node invasion (pN1)

cN0 patients who undergo RP but who were found to have pN1 were reported to have an overall CSS and OS of 45% and 42%, respectively, at 15 years [690-696]. However, this is a very heterogeneous patient group and further treatment must be individualised based on risk factors (see Section 6.2.5.2).

6.2.3.2.External beam radiation therapy

6.2.3.2.1.Recommended external beam radiation therapy treatment policy for high-risk localised PCa

For high-risk localised PCa, use a combined modality approach, consisting of dose-escalated IMRT or VMAT, plus long-term ADT. The duration of ADT has to take into account PS, comorbidities and the number of poor prognostic factors. It is important to recognise that in several studies, EBRT plus short-term ADT did not improve OS in high-risk localised PCa [569,570,572], and long-term ADT (at least 2 to 3 years) is currently recommended for these patients.

6.2.3.2.2.Lymph node irradiation in cN0

There is no high level evidence for prophylactic whole-pelvic irradiation, since RCTs have failed to show that patients benefit from prophylactic irradiation (46-50 Gy) of the pelvic LNs in high-risk cases [697-699]. In the RTOG 94-13 study [572], there were no PFS differences between patients treated with whole-pelvic or prostate-only RT, but interactions between whole-pelvic RT and the duration of ADT were reported following the subgroup analysis. Furthermore, in most trials dealing with high-risk PCa, a whole pelvis field was considered standard of care. The benefits of pelvic nodal irradiation using IMRT or VMAT merit further investigation in RCTs as conducted by the RTOG or the UK NCRI group. Performing an ePLND in order to decide whether or not pelvic RT is required (in addition to combined prostate EBRT plus long-term ADT) remains purely experimental in the absence of high level evidence.

6.2.3.2.3.Low-dose rate brachytherapy boost

In men with intermediate- or high-risk PCa, LDR brachytherapy boost with supplemental EBRT and hormonal treatment [700] may be considered. Dose-escalated EBRT (total dose of 78 Gy) has been compared with EBRT (total dose 46 Gy) followed by LDR brachytherapy boost (prescribed dose 115 Gy) in intermediate-risk and high-risk patients in a randomised trial with 12 months of ADT in both arms [701]. The LDR boost resulted in 5- and 7-year PSA PFS increase (89% and 86%, respectively, compared to 84% and 75%). This improvement came with an increase in late grade 3+ urinary toxicity (18% compared to 8%) [702]. Toxicity was mainly due to urethral strictures and incontinence and great care should be taken during treatment planning.

6.2.3.3.Options other than surgery and radiotherapy for the primary treatment of localised PCa

Currently there is a lack of evidence supporting any other treatment option or focal therapy in localised high-risk PCa.

6.2.3.4.Guidelines for radical treatment of high-risk localised disease

6.2.4.Treatment of locally advanced PCa

No standard treatment can be defined in the absence of high level evidence. But a local treatment combined with a systemic one provides the best outcome, provided the patient is ready and fit enough to receive both. The optimal local treatment is still a matter of debate [703]. Randomised controlled trials are only available for EBRT.

6.2.4.1.Surgery

Surgery for locally advanced disease as part of a multi-modal therapy has been reported [684,704,705]. However, the comparative oncological effectiveness of RP as part of a multi-modal treatment strategy vs. upfront EBRT with ADT for locally advanced PCa remains unknown, although a prospective phase III RCT (SPCG-15) comparing RP (with or without adjuvant or salvage EBRT) against primary EBRT and ADT among patients with locally advanced (T3) disease is currently recruiting [706]. Data from retrospective case series demonstrated over 60% CSS at 15 years and over 75% OS at 10 years [682,684,704,705,707-710]. For cT3b-T4 disease, PCa cohort studies showed 10-year CSS of over 87% and OS of 65% [711-713]. The indication for RP in all previously described stages assumes the absence of clinically detectable nodal involvement (cN0). In case of suspected positive LNs during RP (initially considered cN0), the procedure should not be abandoned since RP may have a survival benefit in these patients. Intra-operative frozen section analysis is not justified in this case [462]. Only limited evidence exists supporting RP for cN+ patients. Moschini et al. compared the outcomes of 50 patients with cN+ with those of 252 patients with pN1, but cN0 at pre-operative staging. cN+ was not a significant predictor of CSS [714]. An ePLND is considered standard if a RP is planned.

6.2.4.2.Radiotherapy for locally advanced PCa

In locally advanced disease, RCTs have clearly established that the additional use of long-term ADT combined with RT produces better OS than ADT or RT alone (see Section 6.1.3.1.4 and Tables 6.1.9 and 6.1.10). In clinical or pathological node-positive disease, RT monotherapy is associated with poor outcomes [574], and these patients should receive RT plus long-term ADT. A subgroup analysis from RTOG 85-31 with a median follow-up period of 6.5 years, showed that 95 of the 173 pN1 patients who received pelvic RT with immediate HT had better 5-year (54%) and 9-year (10%) PFS rates vs. 33% and 4%, respectively, for radiation alone (p < 0.0001). Multivariate analysis showed that this combination had a statistically significant impact on OS [568]. These findings were also confirmed by the control arm of the STAMPEDE trial (HR: 0.48 [95% CI: 0.29-0.79]) in a non-randomised comparison [715].

6.2.4.3.Treatment of cN1 PCa

The treatment of cN+ PCa was evaluated in a systematic review including 5 studies. Papers addressing LND-proven pelvic nodal metastases after RP for cN0M0 disease and publications including cM+ patients were excluded from the review [716-721].

The findings suggest an advantage in both OS and CSS after local treatment (RT or RP) combined with ADT, as compared to ADT alone, but none of the included studies were RCTs and neither of the two local treatment approaches proved superior in this setting.

6.2.4.4.Options other than surgery and radiotherapy for primary treatment

6.2.4.4.1.Investigational therapies

Currently cryotherapy, HIFU or focal therapies have no place in the management of locally advanced PCa.

6.2.4.4.2.Androgen deprivation therapy monotherapy

The deferred use of ADT as single treatment modality has been answered by the EORTC 30891 trial [678]. Nine hundred and eighty-five patients with T0-4 N0-2 M0 PCa received ADT alone, either immediately or after symptomatic progression or occurrence of serious complications. After a median follow-up of 12.8 years, the OS favoured immediate treatment (HR: 1.21 [95% CI: 1.05-1.39]). Surprisingly, no different disease-free or symptom-free survival was observed, raising the question of survival benefit. In locally advanced T3-T4 M0 disease unsuitable for surgery or RT, immediate ADT may only benefit patients with a PSA > 50 ng/mL and a PSA-DT < 12 months [678,722], or those that are symptomatic. The median time to start deferred treatment was 7 years. In the deferred treatment arm, 25.6% died without needing treatment.

6.2.4.4.3.Adjuvant androgen ablation in pN1 disease

6.2.4.4.3.1.Adjuvant androgen ablation alone

The combination of RP and early adjuvant HT in pN+ PCa has been shown to achieve a 10-year CSS rate of 80% and has been shown to significantly improve CSS and OS in prospective RCTs [723,724]. However, these trials included mostly patients with high-volume nodal disease and multiple adverse tumour characteristics and the findings may not apply to men with less extensive nodal metastases.

6.2.4.4.3.2.Adjuvant radiotherapy combined with ADT in pN1 disease

In a retrospective multicentre cohort study, maximal local control with RT to the prostatic fossa appeared to be beneficial in PCa patients with pN1 after RP, treated "adjuvantly" (within 6 months after surgery irrespective of PSA) with continuous ADT. The beneficial impact of adjuvant RT on survival in patients with pN1 PCa was highly influenced by tumour characteristics. Men with low-volume nodal disease (< 3 LNs), ISUP grade 2-5 and pT3-4 or R1, as well as men with 3 to 4 positive nodes were more likely to benefit from RT after surgery, while the other subgroups were not [725].

These results were confirmed by a US National Cancer Database analysis based on 5,498 patients [726]. Another US National Cancer Database study including 8,074 pN1 patients reports improved OS after ADT + EBRT (including pelvic LNs) vs. observation and vs. ADT alone, in all men with single or multiple adverse pathological features. Men without any adverse pathological features did not benefit from immediate adjuvant therapy [727].

In a series of 2,596 pN1 patients receiving ADT (n = 1,663) or ADT plus RT (n = 906), combined treatment was associated with improved OS, with a HR of 1.5 for ADT alone [728]. In a SEER retrospective population-based analysis, adding RT to RP showed a non-significant trend to improved OS but not PCa-specific survival, but data on the extent of additional RT is lacking in this study [716]. Radiotherapy should be given to the pelvic lymphatics and the prostatic fossa [725,729-731]. No data is available regarding adjuvant EBRT without ADT.

6.2.4.5.Guidelines for radical treatment of locally-advanced disease

6.2.5.Adjuvant treatment after radical prostatectomy

6.2.5.1.Introduction

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

6.2.5.2.Risk factors for relapse

ISUP score > 2 or patients classified as pT3 pN0 after RP due to positive margins (highest impact), capsule rupture and/or invasion of the seminal vesicles are at high risk of relapse which can be as high as 50% after 5 years [732]. Irrespective of the pT stage, the number of removed nodes [733-740], tumour volume within the LNs and capsular perforation of the nodal metastases are predictors of early recurrence after RP for pN1 disease [741]. A LN density (defined as the percentage of positive LNs in relation to the total number of analysed/removed LNs) over 20% was found to be associated with poor prognosis [742]. Finally the number of involved nodes seems to be a major factor for predicting relapse [735,736,743], the threshold being considered to be less than 3 positive nodes from an ePLND [425,735,743]. However, prospective data are needed before defining a definitive threshold value.

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

Four prospective RCTs have assessed the role of immediate post-operative RT (adjuvant RT [ART]), demonstrating an advantage (endpoint, development of BCR) in high-risk patients (e.g. pT2/pT3 with positive surgical margins and GS 8-10) post-RP (Table 6.2.5.1). In the ARO 96-02 trial, 80% of the pT3/R1/GS 8-10 patients randomised to observation developed BCR within 10 years. It must be emphasised that PSA was undetectable at inclusion only in the ARO 96-02 trial, representing a major limitation in interpretation, as patients with a detectable PSA would now be considered for salvage therapy rather than adjuvant radiotherapy (ART) [744]. Therefore, for patients at increased risk of local relapse, who present with a PSA level of < 0.1 ng/mL, two options can be offered in the framework of informed consent.

These are:

• Immediate ART to the surgical bed after recovery of urinary function, during the first 6 months post-surgery [744-746];

or

• Clinical and biological monitoring followed by salvage radiotherapy (SRT) before the PSA exceeds 0.5 ng/mL [747,748] (see Section 6.3.5.1 on Salvage EBRT).

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

*See Section 6.3.5.1 for delayed (salvage) post-radical prostatectomy external irradiation.

BCR = biochemical recurrence; FU = follow-up; mo = months; n = number of patients; n.s. = not significant; PSA = prostate-specific antigen; RP = radical prostatectomy; SM = surgical margin. Preliminary data from RAVES and RADICALS, as well as a meta-analysis combining all findings have been reported, suggesting that SRT and ART offer similar outcomes for event-free survival [750-752]. Full publications are needed before any further conclusions can be drawn. Until then, ART remains a recommended treatment option in highly selected patients with combined high-risk features, such as pT3/R1/GS 8-10.

6.2.5.4.Adjuvant androgen ablation

6.2.5.4.1.Adjuvant androgen ablation in men with N0 disease

Adjuvant androgen ablation with bicalutamide 150 mg daily did not improve PFS in localised disease while it did for locally advanced disease after RT. However this never translated to an OS benefit [753]. A systematic review showed a possible benefit for PFS, but not OS for adjuvant androgen ablation [522].

6.2.5.5.Adjuvant chemotherapy

The TAX3501 trial comparing the role of leuprolide (18 months) with and without docetaxel (6 cycles) ended prematurely due to poor accrual. A recent phase III RCT comparing adjuvant docetaxel against surveillance after RP for locally advanced PCa showed that adjuvant docetaxel did not confer any oncological benefit [754]. Consequently, adjuvant chemotherapy after RP should only be considered in a clinical trial [755].

6.2.5.6.Guidelines for adjuvant treatment options after radical prostatectomy

6.2.5.7.Guidelines for non-curative or palliative treatments in prostate cancer

6.2.6.Persistent PSA after radical prostatectomy

6.2.6.1.Introduction

Between 5 and 20% of men continue to have detectable or persistent PSA after RP (when defined in the majority of studies as detectable post-RP PSA of > 0.1 ng/mL within 4 to 8 weeks of surgery) [756,757]. It may result from persistent local disease, pre-existing metastases or residual benign prostate tissue.

6.2.6.2.Natural history of persistently elevated PSA after RP

Several studies (See table 6.2.6.1) have shown that persistent PSA after RP is associated with more advanced disease (such as positive surgical margins (PSM), pathologic stage > T3a, positive nodal status and/or pathologic ISUP grade > 3) and poor prognosis. Initially defined as > 0.1 ng/mL, improvements in the sensitivity of PSA assays now allow for the detection of PSA at much lower levels.

Moreira et al. demonstrated that failure to achieve a PSA of less than 0.03 ng/mL within 6 months of surgery was associated with an increased risk of BCR and overall mortality [758,759]. However,