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:
http://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 2019 document presents a full update of the 2018 PCa Guidelines publication.

1.4.2.Summary of changes

The literature for the complete document has been assessed and updated, where relevant. Evidence summaries and recommendations have been amended throughout the current document and several new sections have been added.

• Section 5.2.4 – The role of multiparametric magnetic resonance imaging (mpMRI) in clinical diagnosis, has been completely revised, also including data from a recent Cochrane review [1]. As a result new recommendations for imaging have been provided throughout these guidelines.

5.2.4.8 Summary of evidence and guidelines for diagnostic imaging

Summary of evidence	LE
Systematic biopsy is an acceptable approach if mpMRI is unavailable.	3

Recommendations for all patients	LE	Strength rating
Do not use mpMRI as an initial screening tool.	3	Strong
Adhere to PI-RADS guidelines for mpMRI acquisition and interpretation.	3	Strong

Recommendations in biopsy-naïve patients	LE	Strength rating
Perform mpMRI before prostate biopsy.	1a	Weak
When mpMRI is positive (i.e. PI-RADS > 3), combine targeted and systematic biopsy.	2a	Strong
When mpMRI is negative (i.e. PI-RADS < 2), and clinical suspicion of prostate cancer is low, omit biopsy based on shared decision making with the patient.	2a	Weak

Recommendations in patients with prior negative biopsy	LE	Strength rating
Perform mpMRI before prostate biopsy.	1a	Strong
When mpMRI is positive (i.e. PI-RADS > 3), perform targeted biopsy only.	2a	Weak
When mpMRI is negative (i.e. PI-RADS < 2), and clinical suspicion of prostate cancer is high, perform systematic biopsy based on shared decision making with the patient.	2a	Strong

5.3.5 Guidelines for staging of prostate cancer

Any risk group staging	LE	Strength rating
Use pre-biopsy mpMRI for staging information.	2a	Weak

• The literature for Section 5.4 – Evaluation of health status and life expectancy, has been updated, resulting in an additional recommendation.

5.4.5 Guidelines for evaluating health status and life expectancy

Recommendations	Strength rating
Use individual life expectancy, health status, and comorbidity to guide PCa management.	Strong

• Due to the comprehensive revision of all imaging sections, recommendations for imaging for a number of text sections have been changed, or added to.

6.2.1.1.3.3 Guidelines for imaging in men on active surveillance

Recommendations in men on active surveillance	LE	Strength rating
Perform multiparametric magnetic resonance imaging before a confirmatory prostate biopsy, if not done before the first biopsy.	1a	Strong
Perform the combination of targeted biopsy (of any PI-RADS > 3 lesion) and systematic biopsy at confirmatory biopsy.	2a	Weak

6.2.1.4 Guidelines for the treatment of low-risk disease

Recommendations	Strength rating
Active surveillance (AS)
Perform multiparametric magnetic resonance imaging before a confirmatory biopsy, if not done before the first biopsy.	Strong
Perform the combination of targeted biopsy (of any PI-RADS > 3 lesion) and systematic biopsy at confirmatory biopsy.	Weak

6.2.2.5 Guidelines for the treatment of intermediate-risk disease

Recommendations	Strength rating
Radiotherapeutic treatment
For external-beam radiation therapy (EBRT), use a total dose of 76-78 Gy or moderate hypofractionation (60 Gy/20 fx in four weeks or 70 Gy/28 fx in six weeks), in combination with short-term neoadjuvant plus concomitant androgen deprivation therapy (ADT) (four to six months).	Strong
Other therapeutic options
Do not offer ADT monotherapy to intermediate-risk asymptomatic men unable to receive any local treatment.	Strong

• A new text Section 6.2.6 - Persistent PSA after radical prostatectomy, has been added.

6.2.6.6 Recommendations for the management of persistent PSA after radical prostatectomy

Recommendations	Strength rating
Offer a prostate-specific membrane antigen positron emission tomography (PSMA PET) scan to men with a persistent PSA > 0.2 ng/mL to exclude metastatic disease.	Weak
Treat men with no evidence of metastatic disease with salvage radiotherapy and additional hormonal therapy.	Weak

6.3.4.4 Guidelines for imaging in patients with biochemical recurrence

Prostate-specific antigen (PSA) recurrence after radical prostatectomy	LE	Strength rating
Perform PSMA PET/CT if the PSA level is > 0.2 ng/mL and if the results will influence subsequent treatment decisions.	2b	Weak
In case PSMA PET/CT is not available, and the PSA level is > 1 ng/mL, perform Fluciclovine PET/CT or Choline PET/CT imaging if the results will influence subsequent treatment decisions.		Weak
PSA recurrence after radiotherapy
Perform prostate multiparametric magnetic resonance imaging to localise abnormal areas and guide biopsies in patients fit for local salvage therapy.	3	Strong
Perform PSMA PET/CT (if available) or fluciclovine PET/CT or choline PET/CT in patients fit for curative salvage treatment.	2b	Strong

• Section 6.3 - Management of PSA-only recurrence after treatment with curative intent, has been completely revised, introducing the concept of patient stratification into EAU low- and high-risk recurrence groups based on the findings of a systematic review (SR). New recommendations have been provided.

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

Local salvage treatment	Strength rating
Recommendations for biochemical recurrence after radical prostatectomy
Offer active surveillance and possibly delayed salvage radiotherapy (SRT) to patients with biochemical recurrence and classified as EAU low-risk group at relapse who may not benefit from intervention.	Strong
Treat patients with a PSA rise from the undetectable range with SRT. Once the decision for SRT has been made, SRT (at least 66 Gy) should be given as soon as possible.	Strong
Offer pN0 patients undergoing SRT hormonal therapy (with bicalutamide 150 mg for two years, or LHRH agonists for up to two years).	Weak
Do not offer hormonal therapy to every pN0 patient treated with SRT.	Strong

• Based on the complete update of Section 6.4 - Metastatic prostate cancer, new recommendations have been included.

6.4.9 Guidelines for the first-line treatment of metastatic disease

Recommendations	Strength rating
Offer surgery and/or local radiotherapy to any patient with M1 disease and evidence of impending complications such as spinal cord compression or pathological fracture.	Strong
Offer castration combined with prostate radiotherapy to patients whose first presentation is M1 disease and who have low volume of disease by CHAARTED criteria.	Weak
Offer castration alone, with or without an anti-androgen, to patients unfit for, or unwilling to consider, castration combined with docetaxel or abiraterone acetate plus prednisone or prostate radiotherapy.	Strong

6.5.14 Guidelines for non-metastatic castrate-resistant disease

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

8.3.2.1 Guidelines for quality of life in men undergoing systemic treatments

Recommendations	Strength rating
Advise men on androgen deprivation therapy to maintain a healthy weight and diet, to stop smoking and have yearly screening for diabetes and hypercholesterolemia. Supplementation with vitamin D and calcium is advised.	Strong

Specific sections of the text have been updated based on SR questions prioritised by the Guidelines Panel. These reviews were performed using standard Cochrane SR methodology;
http://www.cochranelibrary.com/about/about-cochrane-systematic-reviews.html:

• Section 6.3 - Management of PSA-only recurrence after treatment with curative intent [2].

2.METHODS

2.1.Data identification

For the 2019 PCa Guidelines, new and relevant evidence has been identified, collated and appraised through a structured assessment of the literature.

A broad and comprehensive literature search, covering all sections of the PCa Guidelines was performed. The search was limited to studies representing only high levels of evidence (i.e. SRs with meta-analysis, randomised controlled trials (RCTs), and prospective comparative studies) published in the English language. Databases searched included Medline, EMBASE and the Cochrane Libraries, covering a time frame between May 10th 2017 and May 2nd 2018. After deduplication, a total of 1,124 unique records were identified, retrieved and screened for relevance. A total of 169 new publications were added to the 2019 PCa Guidelines.

Additional searches were done for the ‘imaging sections’ across the PCa Guidelines, addressing all imaging modalities in use for the diagnosis and follow-up of prostate cancer patients. A total of 1,255 new papers were identified and assessed. Detailed search strategies are available online:
http://uroweb.org/guideline/prostate-cancer/?type=appendices-publications.

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.

Additional information can be found in the general Methodology section of this print, and online at the EAU website; http://www.uroweb.org/guideline/.

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 SRs have all been peer-reviewed.

2.3.Future goals

Results of ongoing and new SRs will be included in the 2020 update of the PCa Guidelines:

• A SR of oncological effectiveness and harms of primary local interventions for high-risk localised and locally advanced PCa [7];
• 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.

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 SR of autopsy studies reported a prevalence of PCa at age < 30 years of 5% (95% 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]. For men with relatives with PCa their age-specific increased risk of PCa can be estimated. The probability of high-risk PCa at age 65 was 11.4% (vs. a population risk of 1.4%) in men whose father and two brothers had been diagnosed with PCa in a Swedish population-based study [14]. Prostate-specific antigen testing mainly inflates detection of, less relevant, any-risk PCa.

Only a small subpopulation of men with PCa (~9%) have 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]. Men with one first-degree relative diagnosed with PCa have a relative risk (RR) of 1.8 of having PCa, whereas men with a father and brother or two brothers diagnosed with PCa have a RR of 5.51 and 7.71, respectively [15].

Hereditary PCa is associated with a six to seven year earlier disease onset but the disease aggressiveness and clinical course does not seem to differ in other ways [13,16]. Men of African descent show a higher incidence of PCa and generally have a more aggressive course of disease [17].

Specific ancestry-specific risk loci have been identified [18]. Of the underlying determinants of genomic diversity and mechanisms between genetic and environmental factors, much remains unknown. Genome-wide association studies have identified more than 100 common susceptibility loci contributing to the risk for PCa [19-21]. Furthermore, among men with metastatic PCa, an incidence of 11.8% was found for germline mutations in genes mediating DNA-repair processes [22]. 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 [23,24]. Prostate cancer screening trials targeting BRCA mutation carriers are ongoing [25]. BRCA mutation carriers were reported to have worse outcome when compared to non-carriers after local therapy [26].

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 [27]. 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 [28]. However, currently there are no 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) [29,30].

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) [31]. 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) [32]. The ongoing Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial assesses metformin use in advanced PCa [33].

3.2.2.1.2.Cholesterol/statins

A meta-analysis of fourteen 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 [34]. Results of the REDUCE study also did not show a preventive effect of statins on PCa risk [32].

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) [35]. This effect seems mainly explained by environmental determinants of height/body mass index (BMI) rather than genetically elevated height or BMI [36].

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

Alcohol	High alcohol intake, but also total abstention from alcohol has been associated with a higher risk of PCa and PCa-specific mortality [37]. A meta-analysis shows a dose-response relationship with PCa [38].
Dairy	A weak correlation between high intake of protein from dairy products and the risk of PCa was found [39].
Fat	No association between intake of long-chain omega-3 poly-unsaturated fatty acids and PCa was found [40]. A relation between intake of fried foods and risk of PCa may exist [41].
Tomatoes (lycopenes / carotenes)	A trend towards a favourable effect of tomato intake (mainly cooked) and lycopenes on PCa incidence has been identified in meta-analyses [42,43]. Randomised controlled trials comparing lycopene with placebo did not identify a significant decrease in the incidence of PCa [44].
Meat	A meta-analysis did not show an association between red meat or processed meat consumption and PCa [45].
Phytoestrogens	Phytoestrogen intake was significantly associated with a reduced risk of PCa in a meta-analysis [46].
Soy (phytoestrogens (isoflavones / coumestans))	Total soy food intake has been associated with reduced risk of PCa, but also with increased risk of advanced disease [47,48].
Vitamin D	A U-shaped association has been observed, with both low- and high vitamin-D concentrations being associated with an increased risk of PCa, and more strongly for high-grade disease [49,50].
Vitamin E / Selenium	An inverse association of blood, but mainly nail selenium levels (reflecting long-term exposure) with aggressive PCa have been found [51,52]. Selenium and Vitamin E supplementation were, however, found not to affect PCa incidence [53].

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 [54-56]. 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 [57]. 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 [58].

3.2.2.4.Other potential risk factors

Balding was associated with a higher risk of PCa death [59]. Gonorrhoea was significantly associated with an increased incidence of PCa (OR: 1.31; 95% CI: 1.14-1.52) [60]. 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 [61]. Current cigarette smoking was associated with an increased risk of PCa death (relative risk [RR] 1.24; 95% CI: 1.18-1.31) [62]. 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 [63]. Men positive for human papillomavirus-16 may be at increased risk [64].

A number of other factors previously linked to an increased risk of PCa have been disproved including vasectomy [65] and self-reported acne [66]. There are conflicting data about the use of aspirin or non-steroidal anti-inflammatory drugs and the risk of PCa and mortality [67,68].

Ultraviolet radiation exposure decreased the risk of PCa (hazard ratio [HR]: 0.91; 95% CI: 0.88-0.95) [69]. A review found a small but protective association of circumcision status with PCa [70]. Higher ejaculation frequency (> 21 times a month vs. four to seven times) has been associated with a 20% lower risk of PCa [71].

However, the associations 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

Summary of evidence

Prostate cancer is a major health concern in men, with incidence mainly dependent on age.

Genetic factors are associated with risk of (aggressive) PCa but ongoing trials will need to define the clinical applicability of screening for genetic susceptibility to PCa.

A variety of exogenous/environmental factors may have an impact on PCa incidence and the risk of progression.

Selenium or vitamin-E supplements have no beneficial effect in preventing PCa.

In hypogonadal men, testosterone supplements do not increase the risk of PCa.

Recommendation	Strength rating
No specific preventive or dietary measures are recommended to reduce the risk of developing prostate cancer.	Strong

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) [72] and the EAU risk group classification, which is essentially based on D’Amico’s classification system for PCa, are used (Table 4.3) [73]. The latter classification is based on the grouping of patients with a similar risk of biochemical recurrence after RP or external beam radiotherapy (EBRT).

Table 4.1: Clinical Tumour Node Metastasis (TNM) classification of PCa [72]

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

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

2When 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 [72].

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 [74,75]. 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 [75,76] 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 [77].

Table 4.2: International Society of Urological Pathology 2014 grades

Gleason score	ISUP grade
2-6	1
7 (3+4)	2
7 (4+3)	3
8 (4+4 or 3+5 or 5+3)	4
9-10	5

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

Definition
Low-risk	Intermediate-risk	High-risk
PSA < 10 ng/mL	PSA 10-20 ng/mL	PSA > 20 ng/mL	any PSA
and GS < 7 (ISUP grade 1)	or GS 7 (ISUP grade 2/3)	or GS > 7 (ISUP grade 4/5)	any GS (any ISUP grade)
and cT1-2a	or cT2b	or cT2c	cT3-4 or cN+
Localised			Locally advanced

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

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 [76].

Emerging clinical data support this distinction between favourable- and unfavourable-risk patient categories within the intermediate-risk group [77,78].

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 [79]. Mortality due to PCa has decreased in most Western nations but the magnitude of the reduction varies between countries. The reduced mortality rate seen recently in the USA is considered to be partly due to a widely adopted aggressive PCa screening policy [80].

Currently, screening for PCa is one of the most controversial topics in the urological literature [81]. Three large prospective RCTs published data on screening in 2009 [82-84] resulting in conflicting positions and policy papers. Some authors argue that following the current American Urological Association (AUA) guidelines [85] or the 2012 US Preventive Services Task Force (USPSTF) recommendations for screening [86-88] may lead to a substantial number of men with aggressive disease being missed [89,90]. 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 [91], from a previous grade of ‘D’ [88,91,92]. 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 [93]. The potential impact of this topic would necessitate the highest level of evidence produced through a systematic literature search of all published trials or cohorts summarised in a meta-analysis. Subgroup analyses of cohorts that are part of large trials, or mathematical projections alone, cannot provide the quality of evidence needed to appropriately address this clinical question.

A Cochrane review published in 2013 [94], which has since been updated [95], 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 five 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).

Moreover, screening was associated with minor and major harms such as over-diagnosis and over-treatment. Surprisingly, the diagnostic tool (i.e. biopsy) was not associated with any mortality in the selected papers, which is in contrast with other known data [55,56].

The impact on the patient’s overall QoL is still unclear, although screening has never been shown to be detrimental at population level [96-98]. Nevertheless, all these findings have led to strong advice against systematic population-based screening in all countries, including those in Europe.

Since 2013, the European Randomized Study of Screening for Prostate Cancer (ERSPC) data have been updated with thirteen years of follow up (see Table 5.1) [99]. 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 and to treat is decreasing, and is now below the number needed to screen observed in breast cancer trials [100].

Table 5.1: Follow-up data from the ERSPC study [99]

Years of follow-up	Number needed to screen	Number needed to treat
9	1,410	48
11	979	35
13	781	27

5.1.2.Early detection

An individualised risk-adapted strategy for early detection might be offered to a well-informed man with at least ten to fifteen years of life expectancy. It is important to carefully identify the patient taking into account the potential balances and harms involved. However, this approach 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.

Men at elevated risk of having PCa are those > 50 years [101] or at age > 45 years with a family history of PCa (either paternal or maternal [102]), or African-Americans [103]. 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 [104,105]. The long-term survival and QoL benefits of such an approach remain to be proven at a population level. In 2014, as for breast cancer, a genetic abnormality associated with an increased risk has been shown prospectively i.e. BRCA2 [25,78].

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 [106]. Informed men requesting an early diagnosis should be given a PSA test and undergo a DRE [107]. 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 ten-year PCa-specific survival compared to standard care in a large RCT in a primary care setting [108]. A risk-adapted strategy might be a consideration, based on the initial PSA level. This could be every two years for those initially at risk, or postponed up to eight to ten 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 [109]. 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 fifteen-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 [110].

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 [111,112] or kallikreins as incorporated in the Phi or 4Kscore tests [113,114] 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 [115].
• 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 [116].

5.1.3.Guidelines for screening and early detection

Recommendations	LE	Strength rating
Do not subject men to prostate-specific antigen (PSA) testing without counselling them on the potential risks and benefits.	3	Strong
Offer an individualised risk-adapted strategy for early detection to a well-informed man with a good performance status (PS) and a life-expectancy of at least ten to fifteen years.	3	Strong
Offer early PSA testing in well-informed men at elevated risk of having PCa: men > 50 years of age; men > 45 years of age and a family history of PCa; African-Americans > 45 years of age.	2b	Strong
Offer a risk-adapted strategy (based on initial PSA level), with follow-up intervals of two years for those initially at risk: men with a PSA level of > 1 ng/mL at 40 years of age; men with a PSA level of > 2 ng/mL at 60 years of age; Postpone follow-up to eight years in those not at risk.	3	Weak
Stop early diagnosis of PCa based on life expectancy and PS; men who have a life-expectancy of < fifteen years are unlikely to benefit.	3	Strong

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 or specimens from transurethral resection of the prostate (TURP) or prostatectomy for benign prostatic enlargement (BPE).

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 [117]. A suspect DRE in patients with a PSA level < 2 ng/mL has a positive predictive value (PPV) of 5-30% [118]. An abnormal DRE is associated with an increased risk of a higher ISUP grade and is an indication for biopsy [119,120].

5.2.2.Prostate-specific antigen

The use of PSA as a serum marker has revolutionised PCa diagnosis [121]. 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) [122].

There are no agreed standards defined for measuring PSA [123]. It is a continuous parameter, with higher levels indicating greater likelihood of PCa. Many men may harbour PCa despite having low serum PSA [124]. 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 [125].

Table 5.2.1: Risk of PCa in relation to low PSA values [124]

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

5.2.2.1.PSA density

Prostate-specific antigen density is the level of serum PSA divided by the TRUS-determined 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) [126];
• PSA doubling time (PSA-DT): which measures the exponential increase in serum PSA over time [127].

Prostate specific antigen velocity and PSA-DT may have a prognostic role in treating PCa [128], 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. These measurements do not provide additional information compared with PSA alone [129-132].

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) [133]. 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 [134]. A SR including fourteen studies found a pooled sensitivity of 70% in men with a PSA of 4-10 ng/mL [135]. 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

A few 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 [114,136-138]. In a head-to-head comparison both tests performed equally [139].

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 detection of PCa in men with elevated PSA as it shows significant increases in the area under the receiver-operator characteristic curve for positive biopsies [140-143].

PCA3 score increases with PCa volume, but there are conflicting data about whether it independently predicts the ISUP grade, and its use for monitoring in active surveillance (AS) is, as yet, not confirmed [144]. 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 [145]. 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 [146].

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 [147].

TMPRSS2-ERG fusion, a fusion of the trans-membrane protease serine 2 (TMPRSS2) and the ERG gene can be detected in 50% of PCas [148]. When detection of TMPRSS2-ERG in urine was added to PCA3 expression and serum PSA (Mi(chigan)Prostate Score [MiPS]), cancer prediction improved [149]. Exosomes secreted by cancer cells may contain mRNA diagnostic for high-grade PCa [150,151]. 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 six 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 [152]. In the screening population of the ERSPC study the use of both PCA3 and 4K panel has added value to the risk calculator but the differences in AUC were less than 0.03 [111]. 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 [153]. Upfront mpMRI may likely affect the utility of above-mentioned biomarkers (see Section 5.2.4)

5.2.2.6.Guidelines for risk-assessment of asymptomatic men

Recommendation	LE	Strength rating
To avoid unnecessary biopsies, offer further risk-assessment to asymptomatic men with a normal digital rectal examination (DRE) and a prostate-specific antigen (PSA) level between 2-10 ng/mL prior to performing a prostate biopsy. Use one of the following tools: risk-calculator; imaging; an additional serum or urine-based test.	3	Strong

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 [154]. Risk stratification is a potential tool for reducing unnecessary biopsies [154].

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]) [155,156]. Empiric use of antibiotics in an asymptomatic patient in order to lower the PSA should not be undertaken [157].

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 magnetic resonance imaging (MRI), are comparable between the two approaches [158], 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 [159].

Transurethral resection of the prostate should not be used as a tool for cancer detection [160].

5.2.4.The role of imaging in clinical diagnosis

5.2.4.1.Transrectal ultrasound (TRUS) and ultrasound-based techniques

Grey-scale TRUS is not reliable at detecting PCa [161]. Thus, there is no evidence that US-targeted biopsies can replace systematic biopsies. New sonographic modalities such as sonoelastography and contrast-enhanced US are still under investigation and not ready for routine use.

5.2.4.2.Multiparametric magnetic resonance imaging (mpMRI)

5.2.4.2.1.mpMRI performance in detecting ISUP grade > 2 PCa

Correlation with RP specimens shows that mpMRI, associating T2-weighted imaging with at least one functional imaging technique (DWI, DCE, H1-spectroscopy), has good sensitivity for the detection and localisation of ISUP grade > 2 cancers (see Table 5.2.4.1) [162-164]. 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 [1]. 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. As a result, mpMRI is increasingly used to localise suspicious areas that could be targeted by so-called magnetic resonance imaging-targeted biopsies (MRI-TBx).

Table 5.2.4.1: PCa detection rates (%) by mpMRI for tumour volume and ISUP grade group in radical prostatectomy specimen [162]

ISUP grade group	Tumour volume (mL)
	< 0.5	0.5-2	> 2
ISUP grade 1	21-29%	43-54%	67-75%
ISUP grade 2-3	63%	82-88%	97%
ISUP grade > 4	80%	93%	100%

5.2.4.2.2.mpMRI performance in detecting ISUP grade group 1 PCa

Multiparametric magnetic resonance imaging 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 (see Table 5.2.4.1) [162]. 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 [1].

5.2.4.2.3.Does MRI-TBx 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-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 [1]. 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. This confirms previous SRs that suggested that MRI-TBx significantly outperformed systematic biopsy in detecting clinically significant (cs)PCa in patients with prior negative systematic biopsy, but not in biopsy-naïve men [165,166].

Three prospective multicentre RCTs 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) [167]. 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) [168]. 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]) [1]. 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) [169]. 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 outperforms 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; it is not significant in all series, but 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 [1]. In the PRECISION and 4M trials, the detection rate of ISUP grade 1 patients was significantly lower in the MRI-TBx group (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 [167,169]. 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 (secondary objective, 5.6% vs. 19.5%, p < 0.0001, detection ratio of 0.29) [168]. 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 negative mpMRI undergo systematic biopsy; 2) the ‘MR pathway’, in which patients with a positive mpMRI undergo only MRI-TBx, and patients with negative mpMRI are not biopsied at all.

Many studies evaluated combined systematic and targeted biopsy in the same patients and could therefore assess the added value of each technique (i.e. the percentage of patients diagnosed by only one biopsy technique). Data from a Cochrane meta-analysis of these studies and from the MRI-FIRST and 4M trials suggest that the added value of MRI-TBx for detecting ISUP grade > 2 cancers is higher than that of systematic biopsy (see Table 5.2.4.2).

Table 5.2.4.2: Added values of targeted and systematic biopsies for ISUP grade ≥ 2 and ≥ 3 cancer detection

		ISUP > 2			ISUP > 3
ISUP grade		Cochrane meta-analysis* [1]	MRI-FIRST trial* [168]	4M trial [169]	Cochrane meta-analysis* [1]	MRI-FIRST trial* [168]	4M trial [169]
Biopsy-naïve	Added value of MRI-TBx	6.3% (4.8-8.2)	7.6% (4.6-11.6)	7.0% (ND)	4.7% (3.5-6.3)	6.0% (3.4-9.7)	3.2% (ND)
	Added value of systematic biopsy	4.3% (2.6-6.9)	5.2% (2.8-8.7)	5.0% (ND)	2.8% (1.7-4.8)	1.2% (0.2-3.5)	4.1% (ND)
	Overall prevalence	27.7% (23.7-32.6)	37.5% (31.4-43.8)	30% (ND)	15.5% (12.6-19.5)	21.1% (16.2-26.7)	15% (ND)
Prior negative biopsy	Added value of MRI-TBx	9.6% (7.7-11.8)	-	-	6.3% (5.2-7.7)	-	-
	Added value of systematic biopsy	2.3% (1.2-4.5)	-	-	1.1% (0.5-2.6)	-	-
	Overall prevalence	22.8% (20.0-26.2)	-	-	12.6% (10.5-15.6)	-	-

* 95% CI.

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

In Table 5.2.4.2, the 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, approximately 10% of ISUP grade > 2 PCa and 9% of ISUP grade > 3 PCa are missed.

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) [1]. 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 [1]. 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 [167-169].

5.2.4.2.7.Other considerations

5.2.4.2.7.1.mpMRI reproducibility

Despite the use of the PIRADSv2 scoring system [170], mpMRI inter-reader reproducibility remains moderate at best [171-174], which currently limits its broad use by non-dedicated radiologists. In a community hospital that started a prostate mpMRI programme in 2010, cancer detection rates improved and false positives decreased with the implementation of PIRADSv2 scoring and multidisciplinary meetings using pathological correlation and feedback [175]. It is still too early to predict whether quantitative approaches and computer-aided diagnostic systems will improve the characterisation of lesions seen at mpMRI [176-178].

5.2.4.2.7.2.Targeted biopsy accuracy and reproducibility

Magnetic resonance imaging-targeted biopsies 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 [179-183]. However, the accuracy of most systems have largely been evaluated on phantoms, and data on the accuracy and reproducibility in real-life patients are limited [183]. One study, using an elastic US/MR fusion and intraprostatic fiducials, showed a median 3D registration error of 3.8-5.6 mm depending on the operator’s experience. The error tended to be higher at the apex and in the anteroposterior direction [184].

Clinically significant PCa not detected by the ‘MR 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). The PRECISION trial found a marked difference between targeted and systematic biopsies (detection ratio: 1.46), a finding the MRI-FIRST trial could not reproduce (detection ratio: 1.08). PRECISION allowed four targeted cores per lesion, while MRI-FIRST allowed only three, which might explain these findings. In a retrospective study of 211 patients with a unilateral mpMRI lesion, targeted biopsy alone detected 73.5% of all csPCa (ISUP grade > 2); combining targeted biopsy with systematic biopsy of the lobe with the MRI lesion detected 96% of all csPCas and combined targeted and systematic biopsy of the contralateral lobe only identified 81.6% of csPCas [185]. 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, but there is currently no data on the minimum number of targeted cores to be obtained as a function of the prostate volume, lesion size and location. In addition, the inter-operator reproducibility of MRI-TBx is still unclear.

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 risk of disease [186]. Prostate-specific antigen density [187-189] or risk-calculators [190] can select patients with a high risk of csPCa in whom mpMRI NPV is low, and who may still benefit from systematic biopsies even if the mpMRI is negative. 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 outperform predictors such as the ERSPC calculator in the selection of patients who may benefit from systematic and/or MRI-TBx [191-197].

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 ‘MR 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. 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 its 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 [168,185]. Therefore, there is a crucial need to improve these methods, or at least to define the minimum number of targeted cores that need to be obtained from each lesion, as a function of its size, location and prostate volume. Without standardisation of mpMRI interpretation and of MRI-TBx technique, the ‘MR pathway’ may lead to suboptimal care outside large-volume (expert) centres.

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.Summary of evidence and guidelines for imaging

Summary of evidence	LE
Systematic biopsy is an acceptable approach if mpMRI is unavailable.	3

Recommendations for all patients	LE	Strength rating
Do not use mpMRI as an initial screening tool.	3	Strong
Adhere to PI-RADS guidelines for mpMRI acquisition and interpretation.	3	Strong

Recommendations in biopsy naïve patients	LE	Strength rating
Perform mpMRI before prostate biopsy.	1a	Weak
When mpMRI is positive (i.e. PI-RADS > 3), combine targeted and systematic biopsy.	2a	Strong
When mpMRI is negative (i.e. PI-RADS < 2), and clinical suspicion of prostate cancer is low, omit biopsy based on shared decision making with the patient.	2a	Weak

Recommendations in patients with prior negative biopsy	LE	Strength rating
Perform mpMRI before prostate biopsy.	1a	Strong
When mpMRI is positive (i.e. PI-RADS > 3), perform targeted biopsy only.	2a	Weak
When mpMRI is negative (i.e. PI-RADS < 2), and clinical suspicion of prostate cancer is high, perform systematic biopsy based on shared decision making with the patient.	2a	Strong

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 [117,118];
• atypical small acinar proliferation (i.e. atypical glands suspicious for cancer), 31-40% PCa risk on repeat biopsy [198,199];
• extensive (multiple biopsy sites, i.e. > 3) high-grade prostatic intraepithelial neoplasia (HGPIN), ~30% PCa risk [199,200];
• a few atypical glands immediately adjacent to high-grade prostatic intraepithelial neoplasia (i.e. PINATYP), ~50% PCa risk [201];
• intraductal carcinoma as a solitary finding, > 90% risk of associated high-grade PCa [202];
• 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 [145]. 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 [203]. 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 the widespread use of mpMRI in the repeat-biopsy setting.

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

Name of test	Test substrate	Molecular	FDA approved
Progensa	DRE urine	lncRNA PCA3	yes
SelectMDX	DRE urine	mRNA HOXC6, DLX1	no
PHI	Serum	Total, free and p2PSA	yes
4Kscore Test	Serum/plasma	Total, free, intact PSA, hK2	no
ConfirmMDX	Benign prostate biopsy	Methylated APC, RASSF1 and GSTP1	no

*Isolated high-grade prostatic intraepithelial neoplasia (PIN) in one or two biopsy sites is no longer an indication for repeat biopsy [204].

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 [205]. 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 [206].

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 by DRE/TRUS. Sextant biopsy is no longer considered adequate. At least eight systematic biopsies are recommended in prostates with a size of about 30 cc [207]. Ten to twelve core biopsies are recommended in larger prostates, with > twelve cores not being significantly more conclusive [208,209].

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 [210]. Increased quinolone resistance is associated with a rise in severe post-biopsy infection [211,212]. 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 six 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 [159]. For transperineal biopsy, which avoids rectal flora, a single dose of intravenous cephazolin only is sufficient [213,214].

5.2.6.3.Local anaesthesia prior to biopsy

Ultrasound-guided periprostatic block is recommended [215]. It is not important whether the depot is apical or basal. Intrarectal instillation of local anaesthesia is inferior to periprostatic infiltration [216]. Local anaesthesia can also be used effectively for mpMRI-targeted transperineal biopsy [217]. 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. Targeted biopsies can then be taken via a brachytherapy grid or a freehand needle-guiding device [217-219].

5.2.6.4.Complications

Complications of TRUS biopsy are listed in Table 5.2.3 [220]. Severe post-procedural infections were initially reported in < 1% of cases, but have increased as a consequence of antibiotic resistance [221]. Low-dose aspirin is no longer an absolute contraindication [222]. A SR found favourable infection rates for transperineal compared to TRUS biopsies with similar rates of haematuria, haematospermia and urinary retention [223]. A meta-analysis of 4,280 men randomised between transperineal vs. TRUS biopsies in thirteen 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 [158].

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

Complications	Percentage of patients affected
Haematospermia	37.4
Haematuria > 1 day	14.5
Rectal bleeding < 2 days	2.2
Prostatitis	1.0
Fever > 38.5°C	0.8
Epididymitis	0.7
Rectal bleeding > 2 days +/− surgical intervention	0.7
Urinary retention	0.2
Other complications requiring hospitalisation	0.3

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% [224]. 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 [225].

5.2.6.7.Fine-needle aspiration biopsy

Fine-needle aspiration biopsy is no longer recommended.

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 [226]. 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 [227,228]. To optimise detection of small lesions, paraffin blocks should be cut at three levels and intervening unstained sections kept for immunohistochemistry [225].

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 [229-231]. Diagnostic uncertainty is resolved by intradepartmental or external consultation [229]. Table 5.2.7.1 lists the recommended terminology for reporting prostate biopsies [227].

Table 5.2.7.1: Recommended terminology for reporting prostate biopsies [227]

Recommended terminology	LE	Strength rating
Benign/negative for malignancy; if appropriate, include a description	3	Strong
Active inflammation
Granulomatous inflammation
High-grade prostatic intraepithelial neoplasia (PIN)
High-grade PIN with atypical glands, suspicious for adenocarcinoma (PINATYP)
Focus of atypical glands/lesion suspicious for adenocarcinoma/atypical small acinar proliferation, suspicious for cancer
Adenocarcinoma
Intraductal carcinoma

Each biopsy site should be reported individually, including its location (in accordance with the sampling site) and histopathological findings, which include the histological type and the ISUP 2014 grade [75].
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. Gleason score 7[3+4]) or 3 (i.e. Gleason score 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. Gleason score 8[4+4]). Recent publications demonstrated that global ISUP grade is somewhat superior in predicting prostatectomy ISUP grade [232] and BCR [233].

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 [234] and PCa-specific survival [235].

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 [236-238]. 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 [239]. An extent of > 50% of adenocarcinoma in a single core is used in some AS protocols as a cut off [240] 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

The Prolaris test (Myriad Genetics) measures the expression of 31 cell-cycle associated genes in biopsy-derived PCa tissue and may be of clinical use to determine whether a patient needs curative treatment or may have his treatment deferred [241]. A SR on the topic concluded that cell-cycle-associated gene expression can be helpful in predicting BCR risk after local treatment and may alter clinical decision-making but the economic impact on healthcare systems remains to be determined [242].

Similarly, Oncotype Dx® is a RNA-based test based on twelve carcinoma-associated genes and five reference genes which can be applied to carcinoma tissue in prostate biopsies to determine the aggressiveness of the carcinoma. Both tests were shown in prospective studies to provide prognostic information in men with clinically localised PCa, additional to conventional clinico-pathological parameters, including ISUP grade and PSA level. The results of prospective multicentre studies are awaited before a recommendation can be made regarding their routine application.

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 [243].

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 [244]. 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 [74]. 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

Recommendations	LE	Strength rating
Ensure total embedding, by conventional (quadrant) or whole-mount sectioning.	3	Strong
Ink the entire surface before cutting, to evaluate the surgical margin.	3	Strong
Examine the apex and base separately, using the cone method with sagittal or radial sectioning.	3	Strong

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 [245].

Table 5.2.7.1: Mandatory elements provided by the pathology report

Histopathological type: > 95% of PCa represents conventional (acinar) adenocarcinoma.

Grading according to ISUP grade (or not applicable if therapy-related changes).

Tumour (sub)staging and surgical margin status: location and extent of EPE, presence of bladder neck invasion, laterality of EPE or seminal vesicle invasion, location and extent of positive surgical margins.

Additional information may be provided on multifocality, and diameter/volume and zonal location of the dominant tumour.

Table 5.2.7.2: Example checklist: reporting of prostatectomy specimens

Histopathological type

Type of carcinoma, e.g. conventional acinar, or ductal

Histological grade

Primary (predominant) Gleason grade Secondary Gleason grade Tertiary Gleason grade (if applicable) Global ISUP grade Approximate percentage of Gleason grade 4 or 5

Tumour quantitation (optional)

Percentage of prostate involved Size/volume of dominant tumour nodule

Pathological staging (pTNM)

If extraprostatic extension is present: indicate whether it is focal or extensive; specify sites; indicate whether there is seminal vesicle invasion. If applicable, regional lymph nodes: location; number of nodes retrieved; number of nodes involved.

Surgical margins

If carcinoma is present at the margin: specify sites.

Other

Presence of lymphovascular/angio-invasion Location of dominant tumour Presence of intraductal carcinoma/cribriform architecture

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 [75]. The ISUP grade is incorporated in nomograms that predict disease-specific survival (DSS) after prostatectomy [246].

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 Gleason score < 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) [247].

5.2.7.4.4.Definition of extraprostatic extension

Extraprostatic extension is defined as carcinoma mixed with periprostatic 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 [248].

There are no internationally accepted definitions of focal or microscopic, vs. non-focal or extensive EPE. Some describe focal as a few glands [249] or extension as < 1 per high-power field (HPF) [250], whereas others measure the depth of extent in millimetres [251].

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 [252,253] 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 [254].

5.2.7.4.5.PCa volume

The independent prognostic value of PCa volume in RP specimens has not been established [250,255-258]. Nevertheless, a cut-off of 0.5 mL is traditionally used to distinguish insignificant from clinically relevant cancer [255]. 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 [259].

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 [256] 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 [260].

Surgical margin is separate from pathological stage, and a positive margin is not evidence of EPE [261]. There is insufficient evidence to prove a relationship between margin extent and recurrence risk [250]. However, some indication must be given of the multifocality extent of margin positivity, such as the linear extent in mm of involvement: focal, < 1 mm vs. extensive, > 1 mm [262], or number of blocks with positive margin involvement. Gleason score at the positive margin was found to correlate with outcome, and should be reported [263].

5.2.8.Guidelines for the clinical diagnosis of prostate cancer

Recommendations	LE	Strength rating
In symptomatic men, base the initial decision to perform a biopsy on prostate-specific antigen testing and digital rectal examination.	2b	Strong
Perform transrectal prostate needle biopsies under antibiotic protection.	1b	Strong
Use a local anaesthetic by periprostatic infiltration for transrectal prostate needle biopsies.	1a	Strong
Do not offer transition zone sampling at initial biopsies due to low detection rates.	2b	Weak
Ensure that prostate core biopsies from different sites are submitted separately for processing and pathology reporting.	3	Strong
Use the International Society of Urological Pathology (ISUP) 2014 system for grading of PCa.	2a	Strong
Do not use transurethral resection of the prostate as a tool for cancer detection.	2a	Strong

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 [264]. Transrectal US-derived techniques (e.g. 3D-TRUS, colour Doppler) cannot differentiate between T2 and T3 tumours with sufficient accuracy to be recommended for staging [197,265,266].

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 [267]. Multiparametric MRI cannot detect microscopic EPE. Its sensitivity increases with the radius of extension within periprostatic 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 [268]. 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 [269].

The use of high field strength (3 Tesla) or functional imaging in addition to T2-weighted imaging improves sensitivity for EPE or SVI detection [267], but the experience of the reader remains of paramount importance [270] and the inter-reader agreement remains moderate with kappa values ranging from 0.41 to 0.68 [271]. Multiparametric MRI, although not perfect for local staging, may improve the prediction of the pathological stage when combined with clinical data [272,273]. Other MRI-derived parameters such as the tumour volume or the contact length of the tumour with the capsule [274-276], or the ISUP grade obtained through MRI-TBx [277] could further improve the local staging.

Given its low sensitivity for focal (microscopic) EPE, mpMRI is not recommended for local staging in low-risk patients [272,278,279]. 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 [280,281]. Computed tomography and MRI sensitivity is less than 40% [282,283]. Among 4,264 patients, 654 (15.3%) of whom had positive LNs at LND, CT was positive in only 105 patients (2.5%) [280]. In a multicentre database of 1,091 patients who underwent pelvic LN dissection, CT sensitivity and specificity were 8.8% and 98%, respectively [284]. Detection of microscopic LN invasion by CT is < 1% in patients with ISUP grade < 4 cancer, PSA < 20 ng/mL, or localised disease [285-287].

Diffusion-weighted MRI may detect metastases in normal-sized nodes, but a negative diffusion-weighted MRI cannot rule out the presence of LN metastases [281,288].

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 [289]. 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 [290]. 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 outperforming contrast-enhanced CT [291]. However, comparisons between choline PET/CT and diffusion-weighted MRI yielded contradictory results, with PET/CT sensitivity found to be superior [292], similar [293,294] or inferior [290] 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 6.1.2.1.1).

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

68Ga- or 18F-labelled prostate-specific membrane antigen PET/CT (PSMA 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 non-prostatic expression of PSMA in other malignancies, sarcoidosis or benign bone diseases may cause incidental false-positive findings [295-298].

Preliminary assessment of PSMA PET/CT showed promising sensitivity for LN involvement. A meta-analysis of five retrospective studies using histological correlation as reference standard and performed in an initial staging and/or recurrence setting reported combined sensitivities and specificities of 86% (95% CI: 37-98%) and 86% (95% CI: 3-100%) at patient level, and 80% (95% CI: 66-89%) and 97% (95% CI: 92-99%) at lesion level, [299] using LND as reference. A multicentre prospective study has recently compared PSMA PET/CT and LN dissection findings in 51 high-risk patients with negative 99mTc bone scan. At patient level, PSMA PET/CT sensitivity and specificity were 53% and 86%, respectively. The mean maximal length of metastases within LNs detected and missed by PSMA PET/CT was 13.1 ± 7.7 mm and 3.9 ± 2.7 mm respectively [300]. Another prospective single-centre study also found that metastatic LNs missed by PSMA PET/CT were on average < 5 mm [301]. 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 a ISUP grade between 1 and 3 showed significantly lower tracer uptake than tumours with a ISUP grade > 4. Similarly, patients with PSA levels > 10 ng/mL showed significantly higher uptake than those with PSA levels < 10 ng/mL [302].

Comparison between PSMA PET/CT and mpMRI yielded similar results in a group of 42 consecutive patients with intermediate- to high-risk PCa [303]. Another prospective trial reported superior sensitivity of PSMA PET/CT as compared to mpMRI for nodal staging of 36 high-risk PCas [304]. Therefore, PSMA PET/CT has higher sensitivity for LN metastases as compared to abdominal contrast-enhanced CT or choline PET/CT; however, small LN metastases 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 [305]. 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 [306]. 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 [280]. In two studies, a major Gleason pattern of 4 was found to be a significant predictor of positive bone scan [307,308].

Bone scanning should be performed in symptomatic patients, independent of PSA level, ISUP grade or clinical stage [280].

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 [309,310]. However, unlike choline PET/CT, 18F-NaF PET does not detect LN metastases, and is less cost-effective compared to bone scan [309].

It remains unclear whether choline PET/CT is more sensitive than bone scan, but it has higher specificity, with fewer indeterminate bone lesions [289,311,312].

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 [313,314]. Whole-body MRI is also more sensitive and specific than combined bone scan, targeted radiography and abdominopelvic CT [315]. 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 [305].

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 SR including twelve 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) [316]. Table 5.3.1 reports the data of the five studies including histopathologic correlation.

Table 5.3.1: PSMA PET/CT results in primary staging alone [316]

Study	Sensitivity (per lesion)	Specificity (per lesion)	PPV (per lesion)	NPV (per lesion)
Budaus	33 %	100 %	100 %	69 %
Herlemann	84 %	82%	84 %	82 %
Van Leeuwen	58 %	100 %	94 %	98 %
Maurer	74 %	99 %	95 %	94 %
Rahbar	92 %	92 %	96 %	85 %

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 [317]; management changes occurred in 21% of patients.

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 associating 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 [318].

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 submitted to aggressive local and metastases-directed therapies [319].

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 [320].

5.3.5.Guidelines for staging of prostate cancer

Any risk group staging	LE	Strength rating
Do not use computed tomography and transrectal ultrasound for local staging.	2a	Strong
Use pre-biopsy mpMRI for staging information.	2a	Weak
Low-risk localised disease
Do not use additional imaging for staging purposes.	2a	Strong
Intermediate-risk disease
In ISUP grade > 3, include at least a cross-sectional abdominopelvic imaging and bone-scan for metastatic screening.	2a	Weak
High-risk localised disease/locally advanced disease
Perform metastatic screening including at least cross-sectional abdominopelvic imaging and a bone-scan.	2a	Strong

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 [321,322].

Active treatment mostly benefits patients with intermediate- or high-risk PCa and longest expected survival. In localised disease, over ten 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. AS [323]. 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) [324]. External beam radiotherapy shows similar cancer control regardless of age, assuming a dose of > 72 Gy when using intensity-modulated or image-guided RT [325].

Older men with a high incidence of PCa may be under-treated despite the high overall mortality rates [326,327]. Of all PCa-related deaths 71% occur in men aged > 75 years [328], probably due to the higher incidence of advanced disease and death from PCa despite higher death rates from competing causes [329-331]. 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 [332].

5.4.2.Life expectancy

Life expectancy tables for European men are available at: http://appsso.eurostat.ec.europa.eu/nui/show.do?dataset=demo_mlexpec&amp;lang=en. Individual 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 six meters). For men at age 75, ten-year survival ranged from 19% < 0.4 m/s to 87%, for > 1.4 m/s [333].

Figure 5.4.1: Predicted Median Life Expectancy by Age and Gait Speed for males* [333].

*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) [334]. Healthy patients with a G8 score > 14 or frail patients with reversible impairment after resolution of their geriatric problems should receive the same treatment as younger patients. Disabled patients with irreversible impairment should receive adapted treatment. Patients who are too ill should receive only palliative treatment (Figure 1) [334]. Patients with a G8 score < 14 should undergo a full geriatric evaluation as this score is associated with three-year mortality, assessing comorbidity, nutritional status, and cognitive and physical functions, to determine if the impairment is reversible [335].

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 [336,337]. 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 [336]. Measures for comorbidity include: Cumulative Illness Score Rating-Geriatrics (CISR-G) [338,339] (Table 5.4.2) and Charlson Comorbidity Index (CCI) [340].

5.4.3.2.Nutritional status

Malnutrition can be estimated from body weight during the previous three months (good nutritional status < 5% weight loss; risk of malnutrition: 5-10% weight loss; severe malnutrition: > 10% weight loss) [341].

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 [342-344].

5.4.3.4.Physical function

Measures for overall physical functioning include: Karnofsky score and ECOG scores [345]. 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) [346-348].

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 ten years is most commonly used as a threshold for benefit of local treatment. Older men may be undertreated. Resolution of impairments in frail men allows a similar urological approach as in fit patients.

Table 5.4.1: G8 screening tool (adapted from [349])

	Items	Possible responses (score)
A	Has food intake declined over the past 3 months due to loss of appetite, digestive problems, chewing, or swallowing difficulties?	0 = severe decrease in food intake
		1 = moderate decrease in food intake
		2 = no decrease in food intake
B	Weight loss during the last 3 months?	0 = weight loss > 3 kg
		1 = does not know
		2 = weight loss between 1 and 3 kg
		3 = no weight loss
C	Mobility?	0 = bed or chair bound
		1 = able to get out of bed/chair but does not go out
		2 = goes out
D	Neuropsychological problems?	0 = severe dementia or depression
		1 = mild dementia
		2 = no psychological problems
E	BMI? (weight in kg)/(height in m2)	0 = BMI < 19
		1 = BMI 19 to < 21
		2 = BMI 21 to < 23
		3 = BMI ≥ 23
F	Takes more than three prescription drugs per day?	0 = yes
		1 = no
G	In comparison with other people of the same age, how does the patient consider his/her health status?	0.0 = not as good
		0.5 = does not know
		1.0 = as good
		2.0 = better
	Age	0: > 85
		1: 80-85
		2: < 80
	Total score	0-17

Figure 5.4.1: Decision tree for health status screening (men > 70 years)* [334]

*Reproduced with permission of Elsevier, from Droz J-P, et al. Eur Urol 2017:72(4); 521 [334].

Mini-COGTM = cognitive test; ADL = activities of daily living; CIRS-G = cumulative illness rating score-geriatrics; CGA = comprehensive geriatric assessment.

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

1	Cardiac (heart only)
2	Hypertension (rating is based on severity; affected systems are rated separately)
3	Vascular (blood, blood vessels and cells, marrow, spleen, lymphatics)
4	Respiratory (lungs, bronchi, trachea below the larynx)
5	ENT (eye, ear, nose, throat, larynx)
6	Upper GI (esophagus, stomach, duodenum. Biliar and parcreatic trees; do not include diabetes)
7	Lower GI (intestines, hernias)
8	Hepatic (liver only)
9	Renal (kidneys only)
10	Other GU (ureters, bladder, urethra, prostate, genitals)
11	Musculo-Skeletal-Integumentary (muscles, bone, skin)
12	Neurological (brain, spinal cord, nerves; do not include dementia)
13	Endocrine-Metabolic (includes diabetes, diffuse infections, infections, toxicity)
14	Psychiatric/Behavioural (includes dementia, depression, anxiety, agitation, psychosis)
	All body systems are scores on a 0 - 4 scale. - 0: No problem affecting that system. - 1: Current mild problem or past significant problem. - 2: Moderate disability or morbidity and/or requires first line therapy. - 3: Severe problem and/or constant and significant disability and/or hard to control chronic problems. - 4: Extremely severe problem and/or immediate treatment required and/or organ failure and/or severe functional impairment.
Total score 0-52

5.4.5.Guidelines for evaluating health status and life expectancy

Recommendations	Strength rating
Use individual life expectancy, health status, and comorbidity in PCa management.	Strong
Systematically screen the health status of older men (> 70 years) diagnosed with PCa.	Strong
Use the Geriatric-8 and mini-COG tools for health status screening.	Strong
Perform a full specialist geriatric evaluation in patients with a G8 score < 14.	Strong
Consider standard treatment in frail patients with reversible impairments (after resolution of geriatric problems) similar to fit patients, if life expectancy is > 10 years.	Weak
Offer adapted treatment to patients with irreversible impairment.	Weak
Offer palliation to patients with poor health status.	Weak

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 ten years is considered mandatory for any benefit from local treatment. 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, watchful waiting (WW) with symptom-guided treatment is appropriate in order to maintain QoL [350]. In addition, many men with low-risk screening-detected localised PCa will not benefit from curative treatment [351]. Mortality from untreated screen-detected PCa in patients with ISUP grade 1-2 might be as low as 7% at fifteen years follow-up [351]. 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 [352]. 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 [351]

	Active surveillance	Watchful waiting
Treatment intent	Curative	Palliative
Follow-up	Predefined schedule	Patient-specific
Assessment/markers used	DRE, PSA, re-biopsy, mpMRI	Not predefined
Life expectancy	> 10 years	< 10 years
Aim	Minimise treatment-related toxicity without compromising survival	Minimise treatment-related toxicity
Comments	Low-risk patients	Can apply to patients with all stages

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 would represent a ‘very light’ AS strategy with less stringent surveillance criteria in terms of clinical follow-up, imaging and repeat biopsies [353].

Several cohorts have investigated AS in organ-confined disease, the findings of which were summarised in a SR [354]. More recently, the largest prospective series of men with low-risk PCa managed by AS was published [355]. 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 ‘re-classified’ during follow-up, most of whom require 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 [352]. These will be discussed further in section 6.2.1.

Table 6.1.2: Active surveillance in screening-detected prostate cancer

Studies	n	Median FU (mo)	pT3 in RP patients	10-year OS (%)	10-year CSS (%)
Van As, et al. 2008 [356]	326	22	8/18 (44%)	98	100
Carter, et al. 2007 [350]	407	41	10/49 (20%)	98	100
Adamy, et al. 2011 [357]	533-1,000	48	4/24 (17%)	90	99
Soloway, et al. 2010 [358]	99	45	0/2	100	100
Roemeling, et al. 2007 [359]	278	41	-	89	100
Khatami, et al. 2007 [360]	270	63	-	n.r.	100
Klotz, et al. 2015 [361]	993	77	-	85	98.1
Tosoian, et al. 2015 [355]	1,298	60	-	93	99.9
Total	4,204-4,671	46.5	-	93	100

* 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.Introduction

Studies on WW have included patients with up to 25 years of follow-up, with endpoints of OS and CSS. Several series have shown a consistent CSS rate of 82-87% at ten years [362-367], and 80-95% for T1/T2 and ISUP grade < 2 [368]. In three studies with data beyond fifteen years, the DSS was 80%, 79% and 58% [364,366,367], and two reported twenty-year CSS rates of 57% and 32%, respectively [364,366]. 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 ten-year CSS rates of 91%, 90% and 74%, respectively, correlating with data from the pooled analysis [368]. Observation was most effective in men aged 65-75 years with low-risk PCa [369].

In an analysis at ten 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 ten 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 ten years, especially for well- or moderately-differentiated lesions [336]. This highlights the importance of checking the CCI before considering a biopsy.

6.1.1.3.2.Outcome of watchful waiting compared with active treatment

The SPCG-4 study randomised patients to either WW or RP (Table 6.1.3) [324] 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) [370] 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 [371]. 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 ten years), compared with more contemporary series.

Table 6.1.3: Outcome of SPCG-4 at fifteen years follow-up [324]

	RP (n = 348) (%)	Watchful waiting (n = 348) (%)	Relative risk (95% CI)	p-value
Disease-specific mortality	14.6	20.7	0.62	0.010
Overall mortality	46.1	57.2	0.75 (0.61-0.92)	0.007
Metastatic progression	21.7	33.4	0.59 (0.45-0.79)	< 0.001
Local progression	21.5	49.3	0.34 (0.26-0.45)	n.r.

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 [353]. In this AM schedule, patients with a PSA rise of more than 50% in twelve 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 were mainly intermediate risk. After ten 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 ten 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 ten years, no data is available as yet, and AS is possibly safer, 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 ten years individual life expectancy, AM or WW are probably very good options.

6.1.2.Radical prostatectomy

The goal of RP by any approach is the eradication of cancer, while whenever possible, preserving continence and potency [372]. The procedure involves removing the entire prostate with its capsule intact and seminal vesicles, followed by undertaking vesico-urethral anastomosis. Since its description in 1905, the technique has evolved. An estimation of life expectancy is paramount in counselling a patient about surgery [362] (see Section 5.4 – Evaluating health status and life expectancy). 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

Study	Acronym	Population	Year of treatment	Median FU (mo)	Risk category	CSS (%)
Bill-Axelson, et al. 2018 [373]	SPCG-4	Pre-PSA era	1989-1999	283	Low risk and Intermediate risk	80.4 (at 23 yr.)
Wilt, et al. 2017 [370]	PIVOT	Early years of PSA testing	1994-2002	152	Low risk Intermediate risk	95.9 91.5 (at 19.5 yr.)
Hamdy, et al. 2016 [353]	ProtecT	Screened population	1999-2009	120	Mainly low- and intermediate risk	99 (at 10 yr.)

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

6.1.2.1.Surgical techniques

Prostatectomy can be performed by open, laparoscopic or robot-assisted (RARP) approaches. In a randomised phase III trial, RARP was shown to have reduced admission times and blood loss but not early (twelve weeks) functional or oncological outcomes [374]. An updated analysis with follow-up at 24 months did not reveal any significant differences in functional outcomes between the approaches [375]. Increased surgical experience has lowered the complication rates of RP and improved cancer cure [366-369]. 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 [376-378]. There is a lack of studies comparing the different surgical modalities for these longer-term outcomes [365,370,371,379]. A first SR 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 [380]. There was no evidence of differences in urinary incontinence at twelve months and there was insufficient evidence to draw conclusions on differences in cancer-related, patient-driven or erectile dysfunction (ED) outcomes. Another SR and meta-analysis included two small RCTs comparing RARP vs. LRP [381]. 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 [382]. Therefore, no surgical approach can be recommended over another.

6.1.2.1.1.Pelvic lymph node dissection

A recent SR demonstrated that performing pelvic lymph node dissection (PLND) during RP failed to improve oncological outcomes, including survival [383]. However, it is generally accepted that extended pelvic LN dissection (eLND) provides important information for staging and prognosis which cannot be matched by any other currently available procedure [383]. The individual risk of finding positive LNs can be estimated using pre-operative tools. A recent SR and meta-analysis found similar diagnostic accuracy in predicting LN invasion between the Briganti, Partin and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms [384]. However, only a few of these tools are based on eLND templates. A risk of nodal metastases over 5% (Briganti nomogram [385,386] or Roach formula [387] which has been shown to be almost as good as the nomogram) is an indication to perform nodal sampling by an extended nodal dissection [388-390]. 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 [391]. However, there is currently no consensus on the recommended minimum number of LNs which should be retrieved, due to the lack of standardisation of techniques in tissue harvesting and processing.

6.1.2.1.2.Sentinel node biopsy analysis

The rationale for a sentinel node biopsy (SNB) is based on the concept that a sentinel node is the first to be involved by migrating tumour cells. Therefore, when this node is negative, it is possible to avoid an ePLND. There is heterogeneity and variation in techniques in relation to SNB (e.g. the optimal tracer), but a multi-disciplinary collaborative endeavour attempted to standardise definitions, thresholds and strategies in relation to techniques of SNB using consensus methods [392]. Indeed SNB has been shown to have a sensitivity of 95.2% and NPV of 98.0% for detecting men with metastases at eLND in a SR [393]. 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.

6.1.2.1.3.Nerve-sparing surgery

Nerve-sparing RP can be performed safely in most men with localised PCa [394,395]. Relative contraindications are patients in whom there is a high risk of extracapsular disease, such as any cT2c or cT3 PCa or any ISUP grade > 3 on biopsy. An externally validated nomogram predicting side-specific extracapsular extension can help guide decision making [396,397]. If any doubt remains regarding residual tumour, the surgeon should remove the neurovascular bundle (NVB). Alternatively, the use of intra-operative frozen-section analysis or imaging with pre-operative mpMRI can help guide these decisions [398,399].

6.1.2.1.4.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 [400]. It 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 eight 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.

6.1.2.1.5.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 [401]. As a consequence there is no role for performing frozen section of suspicious LNs.

6.1.2.2.Comparing effectiveness of radical prostatectomy vs. other interventions for localised disease

6.1.2.2.1.Radical prostatectomy vs. 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 [324]. When comparing RP against WW [370] or against AM [353], no statistically significant benefit in OS at ten 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.

6.1.2.2.2.Radical prostatectomy vs. radiotherapy

ProtecT compared RP vs. AM vs. EBRT (combined with six months of ADT) [353]. At a median follow-up of ten years, there were no differences between surgery vs. EBRT in all oncological outcomes.

6.1.2.3.Acute 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 robotic-assisted laparoscopic prostatectomy (RALP). Recent SRs have documented complication rates after RALP [380,402-405], and can be compared with contemporaneous reports after radical retropubic prostatectomy (RRP) [406]. From these reports, the mean continence rates at twelve months were 89-100% for patients treated with RALP and 80-97% for patients treated with RRP. There is, as yet, no evidence from retrospective studies on differences in urinary incontinence at twelve months and there was insufficient evidence to draw conclusions on differences in cancer-related, patient-driven or ED outcomes. The major limitations of the included studies were the retrospective study design and the use of different assessment tools preventing comparison between techniques and series. Recently, a prospective, controlled, non-RCT of patients undergoing RP in fourteen centres using RALP or RRP was published. At twelve 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) [407]. A RCT comparing RALP and RRP reported outcomes at twelve weeks in 326 patients and functional outcomes at two years [374]. 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).

Table 6.1.5: Intra-and peri-operative complications of retropubic RP and RALP (Adapted from [380])

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

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

6.1.2.3.1.Early complications of extended lymph node dissection

Pelvic eLND increases morbidity in the treatment of PCa [383]. 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 [408]. 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%) [409,410]. Briganti et al. [411] 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.

6.1.3.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 (IMRT) 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 [412]. 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 five-year biochemical relapse [413-419]. 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 [420]. In everyday practice, a minimum dose of > 74 Gy is recommended for EBRT plus hormonal therapy (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% [416,419,421-434].

Table 6.1.6: Randomised trials of dose escalation in localised PCa

Trial	n	PCa condition	Radiotherapy Dose	Follow-up (median)	Outcome	Results
MD Anderson study 2011 [414]	301	T1-T3, N0, M0, PSA 10 ng/mL vs. PSA > 10 ng/mL	70 vs.78 Gy	9 yr.	DSM vs. other cause of death	High risk/PSA > 10 16% DSM at 70 Gy 4% DSM at 78 Gy (p = 0.05) Higher risk 15% DSM at 70 Gy 2% DSM at 78 Gy (p = 0.03)
PROG 95-09 2010 [415]	393	T1b-T2b PSA 15 ng/mL 75%	70.2 vs.79.2 Gy including proton boost 19.8 vs. 28.8 Gy	8.9 yr.	10-year ASTRO BCF	All patients: 32% BF at 70.2 Gy 17% BF at 79.2 Gy (p < 0.0001) Low-risk patients: 28% BF at 70.2 Gy 7% BF at 79.2 Gy (p < 0.0001)
MRC RT01 2014 [435]	843	T1b-T3a, N0, M0 PSA < 50 ng/mL neoadjuvant HT	64 vs. 74 Gy	10 yr.	BFS; OS	43% BFS at 64 Gy 55% BFS at 74 Gy (p = 0.0003) 71% OS both groups (p = 0.96)
Dutch randomised phase III trial 2014 [419]	664	T1b-T4 143 pts. with (neo) adjuvant HT	68 vs. 78 Gy	110 mo.	Freedom biochemical (Phoenix) and/or clinical failure at 10 yr.	43% FFF at 68 Gy 49% FFF at 78 Gy (p = 0.045)
GETUG 06 2011 [418]	306	T1b-T3a, N0, M0 PSA < 50 ng/mL	70 vs. 80 Gy	61 mo.	BCF (ASTRO)	39% BF at 70 Gy 28% BF at 80 Gy
RTOG 0126 2018 [413]	1,532	T1b-T2b ISUP grade 1 + PSA 10-20 ng/mL or ISUP grade 2/3 + PSA < 15 ng/mL	70.2 vs. 79.2 Gy	100 mo.	OS DM BCF (ASTRO)	75% OS at 70.2 Gy 76% OS at 79.2 Gy 6% DM at 70.2 Gy 4% DM at 79.2 Gy (p = 0.05) 47% BCF at 70.2 Gy 31% BCF at 79.2 Gy (p < 0.001; Phoenix, p < 0.001)

(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 [436]. A meta-analysis of 25 studies including > 14,000 patients concluded that because PCa has a slow proliferation rate, hypofractionated RT could be more effective than conventional fractions of 1.8-2 Gy [437]. Hypofractionation (HFX) has the added advantage of being more convenient for the patient and cheaper for the health care system.

Several studies report on HFX applied in various techniques and, in part, also including HT [438-446]. An SR 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 [447]. 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

Study/Author	n	Risk, ISUP grade, or NCCN	ADT	RT Regimen	BED, Gy	Median FU, mo	Outcome
Lee, et al. 2016 [442]	550 542	low risk	None	70 Gy/28 fx 73.8 Gy/41 fx	80 69.6	70	5 yr. DFS 86.3% (n.s.) 5 yr. DFS 85.3%
Dearnaley, et al. CHHiP 2012 [438] and 2016 [443]	1077/19 fx 1074/20 fx 1065/37 fx	15% low 73% intermediate 12% high	3-6 mo. before and during EBRT	57 Gy/19 fx 60 Gy/20 fx 74 Gy/37 fx	73.3 77.1 74	62	5 yr. BCDF 85.9% (19 fx) 90.6% (20 fx) 88.3% (37 fx)
Aluwini, et al. 2015 [441], 2016 [444,445]	403 392	30% ISUP grade 1 45% ISUP grade 2-3, 25% ISUP grade 4-5	None	64.6 Gy/19 fx 78 Gy/39 fx	90.4 78	60	5 yr. RFS 80.5% (n.s.) 5 yr. RFS 77.1%
Catton, et al. 2017 [446]	608	intermediate risk 53% T1c 46% T2a-c	None	60 Gy/20 fx	77.1	72	5 yr. BCDF both arms 85% HR: 0.96 (n.s)
	598	9% ISUP grade 1 63% ISUP grade 2 28% ISUP grade 3		78 Gy/39 fx 78

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

Extreme HFX has been defined as radiotherapy with > 3.4 Gy per fraction [448]. It requires IGRT and stereotactic body radiotherapy (SBRT). Table 6.1.8 gives 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 [447,449,450]. 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 extreme hypofractionation for intact localised PCa

Reference	n	med FU (mo)	Risk-Group	Regimen (TD/fx)	Outcome
Freeman, et al. 2014 [451]	1,743	-	41% low 42% intermediate 10% high 7% data missing	35-40 Gy/4-5 fx (8% SBRT-boost 19.5-21.8 Gy/3 fx after 45-50 Gy EBRT)	FFBF 92% at 2 yr. 99% low risk 97-85% intermediate 87% high risk
Katz, et al. 2014 [452]	515	72	63% low 30% intermediate 7% high	35-36.25 Gy/5 fx	FFBF at 7 yr. 96% low risk 89% intermediate 69% high risk

EBRT = external beam radiotherapy in standard fractionation; FFBF = freedom from biochemical failure; FU = follow-up; fx = number fractions; mo = months; n = number of patients; TD = total dose; SBRT = stereotactic body radiotherapy; y = year.

6.1.3.1.4.Neoadjuvant or adjuvant hormone therapy plus radiotherapy

The combination of RT with luteinising-hormone-releasing hormone (LHRH) ADT has definitively proven its superiority compared with RT alone followed by deferred ADT on relapse, as shown by phase III RCTs [453-457] (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 three 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

Trial	TNM stage	n	Trial	ADT	RT	Effect on OS
RTOG 85-31 2005 [454]	T3 or N1 M0	977	EBRT ± ADT	Orchiectomy or LHRH agonist 15% RP	65-70 Gy RT	Significant benefit for combined treatment (p = 0.002) seems to be mostly caused by patients with ISUP grade 2-5
RTOG 94-13 2007 [458]	T1c-4 N0-1 M0	1292	ADT timing comparison	2 mo. neoadjuvant plus concomitant vs. 4 mo. adjuvant suppression	Whole pelvic RT vs. prostate only; 70.2 Gy	No significant difference between neoadjuvant plus concomitant vs. adjuvant androgen suppression therapy groups (interaction suspected)
RTOG 86-10 2008 [455]	T2-4 N0-1	456	EBRT ± ADT	Goserelin plus flutamide 2 mo. before, plus concomitant therapy	65-70 Gy RT	No significant difference at 10 yr.
D’Amico AV, et al. 2008 [456]	T2 N0 M0 (localised unfavourable risk)	206	EBRT ± ADT	LHRH agonist plus flutamide for 6 mo.	70 Gy 3D-CRT	Significant benefit (HR: 0·55, 95% CI: 0.34-0.90, p = 0.01) that may pertain only to men with no or minimal comorbidity
RTOG 92-02 2008 [459]	T2c-4 N0-1 M0	1554	Short vs. prolonged ADT	LHRH agonist given for 2 yr. as adjuvant after 4 mo. as neoadjuvant	65-70 Gy RT	p = 0.73, p = 0.36 overall; significant benefit (p = 0.044) (p = 0.0061) in subset with ISUP grade 4-5
EORTC 22961 2009 [460]	T1c-2ab N1 M0, T2c-4 N0-1 M0	970	Short vs. prolonged ADT	LHRH agonist for 6 mo. vs. 3 yr.	70 Gy 3D-CRT	Better result with 3 yr. treatment than with 6 mo. (3.8% improvement in survival at 5 yr.)
EORTC 22863 2010 [453]	T1-2 poorly differentiated and M0, or T3-4 N0-1 M0	415	EBRT ± ADT	LHRH agonist for 3 yr. (adjuvant)	70 Gy RT	Significant benefit at 10 yr. for combined treatment (HR: 0.60, 95% CI: 0.45-0.80, p = 0.0004).
TROG 96-01 2011 [457]	T2b-4 N0 M0	802	Neoadjuvant ADT duration	Goserelin plus flutamide 3 or 6 mo. before, plus concomitant suppression	66 Gy 3D-CRT	No significant difference in OS reported; benefit in PCa-specific survival (HR: 0.56, 95% CI: 0.32-0.98, p = 0.04) (10 yr.: HR: 0.84, 0.65-1.08, p = 0.18)
RTOG 99-10 2015 [461]	intermediate risk (94% T1-T2, 6% T3-4)	1579	Short vs. prolonged ADT	LHRH agonist 8 + 8 vs. 8 + 28 wk.	70.2 Gy 2D/3D	67 vs. 68%, p = 0.62, confirms 8 + 8 wk. LHRH as a standard

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

Trial	Year	TNM stage	n	Trial	ADT	RT	Effect on OS
SPCG-7/ SFUO-3 2016 [462]	2016	T1b-2 WHO Grade 1-3, T3 N0 M0	875	ADT ± EBRT	LHRH agonist for 3 mo. plus continuous flutamide	70 Gy 3D-CRT vs. no RT	34% (95% CI: 29-39%) vs. 17% (95% CI: 13-22% CSM at 12 (15) yr. favouring combined treatment (p < 0.0001 for 15-yr. results) NCIC CTG PR.3/MRC
PRO7/NCIC 2011 [464] and 2015 [465]	2015	T3-4 (88%), PSA > 20 ng/mL (64%), ISUP grade 4-5 (36%) N0 M0	1,205	ADT ± EBRT	Continuous LHRH agonist	65-70 Gy 3D-CRT vs. no RT	10-yr. OS = 49% vs. 55% favouring combined treatment HR: 0.7, p < 0.001)
Mottet N, et al. 2012 [466]	2012	T3-4 N0 M0	273 264	ADT ± EBRT	LHRH agonist for 3 yr.	70 Gy 3D-CRT vs. no RT	Significant reduction of clinical progression; 5-yr. OS 71.4% vs. 71.5%

ADT = androgen deprivation therapy; CSM = cancer-specific mortality; EBRT = external beam radiotherapy; HR = hazard ratio; LHRH = luteinising hormone-releasing hormone; mo = months; n = number of patients; OS = overall survival; RT = radiotherapy; 3D-CRT = three-dimensional conformal radiotherapy.

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

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 [467]. The prostate dose ranged from 64.8 to 86.4 Gy; doses beyond 81 Gy were delivered during the last ten 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 three months for low-risk patients and six months for intermediate-risk and high-risk patients, starting at three months before RT. The ten-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 six 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 [426].

2.DART01/05 GICOR which shows that two years of adjuvant ADT combined with high-dose RT improved biochemical control and OS in high-risk patients [468].

3.EORTC trial 22991 which shows that six months ADT improves biochemical and clinical DFS whatever the dose (70, 74, 78 Gy) in intermediate-risk and low-volume high-risk localised PCa [469].

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 [415]. 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