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Guidelines

EAU–ESTRO–SIOG Guidelines on Prostate Cancer. Part 1:

Screening, Diagnosis, and Local Treatment with Curative Intent

Nicolas Mottet a,*, Joaquim Bellmunt b,c, Michel Bolla d, Erik Briers e, Marcus G. Cumberbatch f,
Maria De Santis g, Nicola Fossati h,i, Tobias Gross j, Ann M. Henry k, Steven Joniau l,
Thomas B. Lam m,n, Malcolm D. Mason o, Vsevolod B. Matveev p, Paul C. Moldovan q,
Roderick C.N. van den Bergh r, Thomas Van den Broeck l, Henk G. van der Poel s,
Theo H. van der Kwast t, Olivier Rouvière q, Ivo G. Schoots u, Thomas Wiegel v, Philip Cornford w
a
Department of Urology, University Hospital, St. Etienne, France; b Bladder Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA; c Harvard Medical
School, Boston, MA, USA; d Department of Radiation Therapy, CHU Grenoble, Grenoble, France; e Patient Advocate, Hasselt, Belgium; f Academic Urology Unit,
g h
University of Sheffield, Sheffield, UK; University of Warwick, Cancer Research Centre, Coventry, UK; Unit of Urology/Division of Oncology, URI, IRCCS
i j
Ospedale San Raffaele, Milan, Italy; Università Vita-Salute San Raffaele, Milan, Italy; Department of Urology, University of Bern, Inselspital, Bern,
Switzerland; k Leeds Cancer Centre, St. James’s University Hospital, Leeds, UK; University of Leeds, Leeds, UK; l Department of Urology, University Hospitals
Leuven, Leuven, Belgium; m Academic Urology Unit, University of Aberdeen, Aberdeen, UK; n Department of Urology, Aberdeen Royal Infirmary, Aberdeen, UK;
o
Cardiff University, Velindre Hospital, Cardiff, UK; p N.N. Blokhin Cancer Research Center, Moscow, Russia; q Hospices Civils de Lyon, Radiology Department,
Edouard Herriot Hospital, Lyon, France; r Department of Urology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands; s
Department of Urology,
Netherlands Cancer Institute, Amsterdam, The Netherlands; t Department of Pathology, Erasmus Medical Centre, Rotterdam, The Netherlands; u Department
of Radiology and Nuclear Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands; v Department of Radiation Oncology, University
w
Hospital Ulm, Ulm, Germany; Royal Liverpool and Broadgreen Hospitals NHS Trust, Liverpool, UK

Article info Abstract

Article history: Objective: To present a summary of the 2016 version of the European Association of
Accepted August 2, 2016 Urology (EAU) - European Society for Radiotherapy & Oncology (ESTRO) - International
Society of Geriatric Oncology (SIOG) Guidelines on screening, diagnosis, and local
Associate Editor: treatment with curative intent of clinically localised prostate cancer (PCa).
James Catto Evidence acquisition: The working panel performed a literature review of the new data
(2013–2015). The guidelines were updated and the levels of evidence and/or grades of
recommendation were added based on a systematic review of the evidence.
Keywords: Evidence synthesis: BRCA2 mutations have been added as risk factors for early and
Prostate cancer aggressive disease. In addition to the Gleason score, the five-tier 2014 International
Society of Urological Pathology grading system should now be provided. Systematic
Localised
screening is still not recommended. Instead, an individual risk-adapted strategy follow-
EAU-ESTRO-SIOG Guidelines ing a detailed discussion and taking into account the patient’s wishes and life expectancy
Screening must be considered. An early prostate-specific antigen test, the use of a risk calculator, or
Diagnosis one of the promising biomarker tools are being investigated and might be able to limit
Staging the overdetection of insignificant PCa. Breaking the link between diagnosis and treat-
ment may lower the overtreatment risk. Multiparametric magnetic resonance imaging
Treatment using standardised reporting cannot replace systematic biopsy, but robustly nested
Radical prostatectomy within the diagnostic work-up, it has a key role in local staging. Active surveillance
Radiation therapy always needs to be discussed with very low-risk patients. The place of surgery in high-
Androgen deprivation risk disease and the role of lymph node dissection have been clarified, as well as the
management of node-positive patients. Radiation therapy using dose-escalated inten-

* Corresponding author. Department of Urology, University Hospital, St. Etienne, France.

Tel. +33 477828331; Fax: +33 477517179.
E-mail address: [Link]@[Link] (N. Mottet).
[Link]
0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Mottet N, et al. EAU–ESTRO–SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis,
and Local Treatment with Curative Intent. Eur Urol (2016), [Link]
EURURO-6958; No. of Pages 12

2 EUROPEAN UROLOGY XXX (2016) XXX–XXX

sity-modulated technology is a key treatment modality with recent improvement in the

outcome based on increased doses as well as combination with hormonal treatment.
Moderate hypofractionation is safe and effective, but longer-term data are still lacking.
Brachytherapy represents an effective way to increase the delivered dose. Focal therapy
remains experimental while cryosurgery and HIFU are still lacking long-term convincing
results.
Conclusions: The knowledge in the field of diagnosis, staging, and treatment of localised
PCa is evolving rapidly. The 2016 EAU-ESTRO- SIOG Guidelines on PCa summarise the most
recent findings and advice for the use in clinical practice. These are the first PCa guidelines
endorsed by the European Society for Radiotherapy and Oncology and the International
Society of Geriatric Oncology and reflect the multidisciplinary nature of PCa management. A
full version is available from the EAU office and online ([Link]
prostate-cancer/).
Patient summary: The 2016 EAU–ESTRO–SIOG Prostate Cancer (PCa) Guidelines present
updated information on the diagnosis, and treatment of clinically localised prostate cancer.
In Northern and Western Europe, the number of men diagnosed with PCa has been on the
rise. This may be due to an increase in opportunistic screening, but other factors may also be
involved (eg, diet, sexual behaviour, low exposure to ultraviolet radiation). We propose that
men who are potential candidates for screening should be engaged in a discussion with
their clinician (also involving their families and caregivers) so that an informed decision
may be made as part of an individualised risk-adapted approach.
# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

1. Introduction well-established risk factors. If one first-degree relative

has PCa, the risk is at least doubled. It increases by 5–11
The most recent summary of the European Association of times when two or more first-line relatives are affected
Urology (EAU) Guidelines on prostate cancer (PCa) was [8]. About 9% of men with PCa have truly hereditary
published in 2013 [1]. This update is based on structured disease, which is associated with an onset 6–7 yr earlier
yearly literature reviews and systematic review through an than spontaneous cases, but does not differ in other
ongoing process. Evidence levels and grade of recommen- ways. The only exception to this are carriers of the rare
dation have been inserted according to the general BRCA2 germline abnormality, who seem to have an
principles of evidence-based medicine [2]. increased risk of early-onset PCa with aggressive behav-
PCa remains the most common cancer in men in Europe iour [9–11].
(excluding skin cancer). Although the incidence of autopsy-
detected cancers is roughly the same in different parts of the 2. Classification
world, the incidence of clinically diagnosed PCa varies
widely and is highest in Northern and Western Europe The 2009 TNM classification for staging of PCa and the EAU
(>200 per 100 000 men/year) [3]. This is suggested to be a risk group classification are used (Table 1). The latter
consequence of exogenous factors such as diet, chronic classification is based on grouping patients with a similar
inflammation, sexual behaviour, and low exposure to risk of biochemical recurrence after local treatment.
ultraviolet radiation [4]. The International Society of Urological Pathology (ISUP)
Metabolic syndrome has been linked with an increased 2005 modified Gleason score (GS) is the recommended PCa
risk of PCa [5], but there is insufficient evidence to grading system. The biopsy GS consists of the Gleason grade
recommend lifestyle changes or a modified diet to lower of the most extensive pattern plus the highest pattern,
this risk. In hypogonadal men, testosterone therapy is not regardless its extent. In radical prostatectomy (RP) speci-
associated with an increased PCa risk [6]. No drugs or food mens, the GS is determined differently: A pattern compris-
supplements have been approved for PCa prevention. ing 5% of the cancer volume is not incorporated in the GS,
Apart from age and African American origin, a family but its proportion should be reported separately if it is grade
history of PCa (both paternal and maternal [7]) are 4 or 5.

Table 1 – EAU risk groups for biochemical recurrence of localised and locally advanced prostate Cancer

Low-risk Intermediate-risk High-risk

Definition
PSA < 10 ng/mL PSA 10–20 ng/mL PSA > 20 ng/mL any PSA
and GS < 7 or GS 7 or GS >7 any GS
and cT1-2a or cT2b or cT2c cT3–4 or cN+
Localised Localised Localised Locally advanced

GS = Gleason score; PSA = prostate-specific antigen.

Please cite this article in press as: Mottet N, et al. EAU–ESTRO–SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis,
and Local Treatment with Curative Intent. Eur Urol (2016), [Link]
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EUROPEAN UROLOGY XXX (2016) XXX–XXX 3

Table 2 – International Society of Urological Pathology 2014 grade Table 3 – Follow-up data from the European Randomised Study of
groups* Screening for Prostate Cancer study [14]

Gleason score Grade group Years of Number needed Number needed

follow-up to screen* to treat*
6 (3+3 or 3+2 or 2+3 or 2+2) 1
7 (3 + 4) 2 9 1410 48
7 (4 + 3) 3 11 979 35
8 (4+4 or 3+5 or 5+3) 4 13 781 27
9–10 5
*
Number of men needed to screen or treat to avoid the death of disease of
* one man.
Grade groups can now be reported in addition to the overall or global
Gleason score of a prostate biopsy or radical prostatectomy.

The 2014 ISUP Gleason Grading Conference on Gleason useful in reducing the number of unnecessary biopsies.
Grading of Prostate Cancer [12] adopted the concept of None has clearly shown superiority over each other or can
grade groups of PCa to align PCa grading with the grading of be considered as optimal [20].
other carcinomas, eliminate the anomaly that the most Optimal intervals for PSA testing and digital rectal
highly differentiated PCas have a GS 6 and highlight the examination (DRE) follow-up are unknown. A 2-yr interval
clinical differences between GS 7 (3 + 4) and 7 (4 + 3) for men at increased risk, while it could be expanded up to
(Table 2). 8 yr for those not at risk. The age at which to stop early
diagnosis should be based on individual’s life expectancy,
3. Screening and early detection where comorbidity is at least as important as age [21]. Men
who have <15 yr of life expectancy are unlikely to benefit.
Screening for PCa remains one of the most controversial All the available tools will still lead to some overdiagno-
topics in the urologic literature. A Cochrane review [13] sis. Breaking the link between diagnosis and active
suggests that PSA screening is associated with an increased treatment is the only way to decrease the risk of
diagnosis rate (relative risk [RR]: 1.3; 95% confidence overtreatment while maintaining the potential benefit of
interval [CI], 1.02–1.65), the detection of more localised individual early diagnosis for men requesting it (Table 4).
(RR: 1.79; 95% CI, 1.19–2.70) and less advanced disease (T3–
4, N1, M1) (RR: 0.80; 95% CI, 0.73–0.87). However, neither 4. Diagnosis
overall survival (OS; RR: 1.00; 95% CI, 0.96–1.03) nor
cancer-specific survival (CSS) benefit were observed (RR: PCa is usually suspected on the basis of DRE and/or an
1.00; 95% CI, 0.86–1.17). Moreover, screening was associat- elevated PSA. Definitive diagnosis depends on histopatho-
ed with overdiagnosis and overtreatment. All these logic verification. Abnormal DRE is an indication for biopsy,
considerations have led to a strong advice against system- but as an independent variable, PSA is a better predictor of
atic population-based screening in Europe and the United cancer than either DRE or transrectal ultrasound (TRUS).
States. And yet the population-based European Randomised
Study of Screening for Prostate Cancer (ERSPC) showed a
reduction in PCa mortality in the screening arm (RR: 0.8; Table 4 – Guidelines for screening and early detection
95% CI, 0.65–0.98) after a median follow-up of 9 yr. Updated Recommendation LE GR
results from the ERSPC at 13 yr of follow-up showed an
unchanged cancer-specific mortality reduction [14], but the Do not subject men to PSA testing without counselling 3 B
them about the potential risks and benefits.
number needed to screen and to treat to avoid one death Offer an individualised risk-adapted strategy for early 3 B
from PCa decreased and is now below the number needed to detection to a well-informed man with a good
screen in breast cancer trials [15] (Table 3). But an OS benifit performance status and a life expectancy of at least
10–15 yr.
is still lacking. The uptake of the current US Preventive
Offer PSA testing in men at elevated risk of having PCa: 2b A
Services Task Force recommendations has been associated  Men aged >50 yr
with a substantial number of men with aggressive disease  Men aged >45 yr and a family history of PCa
being missed [16]. Finally, a comparison of systematic and  African American men aged >45 yr
 Men with a PSA level >1 ng/ml at age 40 yr
opportunistic screening suggested overdiagnosis and mor-
 Men with a PSA level >2 ng/ml at age 60 yr
tality reduction by systematic screening versus a higher Offer a risk-adapted strategy (based on initial PSA level), 3 C
overdiagnosis with at best a marginal survival benefit after with follow-up intervals of 2 yr for those initially at risk:
opportunistic screening [17].  Men with a PSA level >1 ng/ml at age 40 yr
 Men with a PSA level >2 ng/ml at age 60 yr
Targeting men at higher risk of PCa might reduce the
Postpone follow-up to 8 yr in those not at risk.
number of unnecessary biopsies. These include men aged Decide on the age at which early diagnosis of PCa should 3 A
>50 yr (>45 yr in African American men) or with a family be stopped based on life expectancy and performance
history of PCa. In addition men with a PSA >1 ng/ml at age status; men who have a life expectancy <15 yr are
unlikely to benefit.
40 yr and >2 ng/ml at age 60 yr [18,19] are at increased risk
of PCa metastasis or death several decades later. Risk GR = grade of recommendation; LE = level of evidence; PCa = prostate
cancer; PSA = prostate-specific antigen.
calculators developed from cohort studies may also be

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and Local Treatment with Curative Intent. Eur Urol (2016), [Link]
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4 EUROPEAN UROLOGY XXX (2016) XXX–XXX

PSA is a continuous parameter, with higher levels indicating Table 5 – Indications for rebiopsy after a negative biopsy and the
associated risk to find a prostate cancer
greater likelihood of PCa, precluding an optimal PSA
threshold for detecting nonpalpable but clinically signifi- Indication Associated PCa risk
cant PCa. A limited PSA elevation alone should be confirmed
Rising and/or persistently elevated PSA –
after a few weeks under standardised conditions (ie, no Suspicious DRE 5–30%
ejaculation, manipulations, and urinary tract infections) in Atypical small acinar proliferation 40%
the same laboratory before considering a biopsy. The (ie, atypical glands suspicious for cancer)
Extensive (ie, 3 biopsy sites) high-grade PIN 30%
empiric use of antibiotics in an asymptomatic patient
Few atypical glands immediately adjacent to 50%
should not be undertaken [22]. high-grade PIN
The free-to-total PSA ratio stratifies the risk of PCa in Intraductal carcinoma as a solitary finding >90% (mainly
men with 4–10 ng/ml total PSA and a previous negative high-grade PCa)
Positive mpMRI 34–68%
biopsy but may be affected by several preanalytical and
clinical factors (eg, instability of free PSA at 4 8C and room DRE = digital rectal examination; mpMRI = multiparametric magnetic
temperature, variable assay characteristics, and large resonance imaging; PCa = prostate cancer; PIN = prostatic intraepithelial
neoplasia; PSA = prostate-specific antigen.
concomitant benign prostatic hyperplasia [BPH]). Novel
assays for risk stratification measuring a panel of kallikreins
including the Prostate Health Index test and the four-
kallikrein score test are intended to reduce the number of
unnecessary biopsies in men with a PSA between 2 and of detection of insignificant PCa (sensitivity 0.44 vs 0.83).
10 ng/ml. Prospective multicentre studies demonstrated However, this benefit was restricted to the repeated biopsy
that both tests outperformed free-to-total PSA for PCa subgroup [32]. Two more recent randomised controlled
detection [23,24]. A formal comparison of these new tests is trials (RCTs) restricted to the initial biopsy yielded
lacking. contradictory results regarding the added value of MRI-
Tbx combined with systematic biopsies [33,34]. Major
limitations of mpMRI are its interobserver variability and
5. Prostate biopsy the heterogeneity in the definitions of positive and negative
examinations. The first version of the Prostate Imaging
TRUS-guided biopsy using an 18G biopsy needle and a Reporting and Data System (PI-RADS) scoring system failed
periprostatic block is the standard of care. When the same to improve interobserver variability as compared with
number of cores are taken, both transrectal and transper- subjective scoring [35]. An updated version (PI-RADS v2)
ineal approaches have comparable detection rates [25,26]. needs to be evaluated further [36].
Ten- to 12-core biopsies should be taken, bilateral from
apex to base, as far posterior and lateral as possible from the
6. Staging of prostate cancer
peripheral gland. Additional cores should be obtained from
DRE/TRUS suspect areas. Oral or intravenous quinolones are
The decision to proceed with a further staging work-up is
state-of-the-art preventive antibiotics, in spite of the
guided by which treatment options are available, taking
increased resistance to quinolones, which is associated
into account the patient’s preference and comorbidity. A
with a rise in severe infectious complications [27]. Other
summary of the guidelines is presented in Table 6.
biopsy complications include haematospermia (37%), hae-
maturia lasting >1 d (14.5%), and rectal bleeding lasting 2
d (2.2%). Each biopsy site should be reported individually,
including its location, the ISUP 2005 GS, and extent. ISUP Table 6 – Guidelines for staging of prostate cancer
2014 grade should be given as a global grade, taking into
Risk group LE GR
account the Gleason grades of cancer foci in all biopsy sites.
If identified, intraductal carcinoma, lymphovascular inva- Any risk group staging
sion, perineural invasion, and extraprostatic extension must Do not use CT and TRUS for local staging 2a A
Low-risk localised PCa
each be reported. Table 5 summarises the indications for Do not use additional imaging for staging purposes 2a A
repeat biopsy following an initial negative biopsy. Intermediate-risk PCa
Many single-centre studies suggest that multiparametric In predominantly Gleason pattern 4, metastatic screening, 2a A*
magnetic resonance imaging (mpMRI) can reliably detect include at least cross-sectional abdominopelvic imaging
(s.a. CT/MRI) and a bone scan for staging purposes
aggressive tumours with a negative predictive value (NPV) In predominantly Gleason pattern 4, use prostate mpMRI 2b A
and positive predictive value ranging from 63% to 98% and for local staging
from 34% to 68%, respectively [28]. The combination of High-risk localised PCa or high-risk locally advanced PCa
Use prostate mpMRI for local staging 2b A
systematic and targeted biopsies (MRI-Tbx) may also better
Perform metastatic screening including at least cross-sectional 2a A
predict the final GS [29]. As a result, some authors proposed abdominopelvic imaging and a bone-scan
performing systematic mpMRI before a prostate biopsy
CT = computed tomography; GR = grade of recommendation; LE = level of
[30,31]. One meta-analysis suggested that MRI-Tbx had a evidence; mpMRI = multiparametric magnetic resonance imaging; MRI =
higher detection rate of clinically significant PCa compared magnetic resonance imaging; PCa = prostate cancer; TRUS = transrectal
with TRUS biopsy (sensitivity 0.91 vs 0.76) and a lower rate ultrasound.

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and Local Treatment with Curative Intent. Eur Urol (2016), [Link]
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EUROPEAN UROLOGY XXX (2016) XXX–XXX 5

7. Primary local treatment unclear. Strategies how to incorporate mpMRI within this
follow-up are evolving but are not yet established. The
Management decisions should be made after all options decision to switch to an active treatment is based on a
have been discussed with a multidisciplinary team (includ- change in the inclusion criteria (T stage and biopsy results).
ing urologists, radiation oncologists, medical oncologists, The use of a PSA change (especially a PSA doubling time <3
pathologists, and radiologists), and after the balance of yr) remains contentious based on its weak link with grade
benefits and side effects of each therapy modality has been progression. Active treatment may also be triggered upon a
considered together with the patient. patient’s request [44].

8. Active surveillance and watchful waiting 9. Radical prostatectomy

Active surveillance (AS) aims to reduce overtreatment in The goal of RP is eradication of PCa while preserving
men with very low-risk PCa, without compromising continence and, whenever possible, potency. It is the only
opportunities for cure, whereas watchful waiting (WW) is treatment for localised PCa to show a benefit for OS and CSS,
a conservative management for frail patients until the compared with WW. Patients should not be denied this
possible development of clinical progression leading to procedure on the grounds of age alone [21] provided they
symptomatic treatment. The major differences between have at least 10 yr of life expectancy and are aware that
these two modalities are detailed in Table 7. increasing age is linked to increased incontinence risk.
Mortality from untreated screen-detected PCa in Nerve-sparing RP can be performed safely in most men with
patients with GS 5–7 can be as low as 7% at 15 yr follow- localised PCa. High risk of extracapsular disease, such as any
up [37]. An RCT was unable to show an OS and CSS cT2c or cT3 or any GS >7, are usual contraindications. An
difference at 10 yr between RP and WW in 731 men with externally validated nomogram predicting side-specific
screen-detected clinically organ-confined PCa [38]. Only extracapsular extension can help guide decision making
patients with intermediate risk or with a PSA >10 ng/ml [45]. mpMRI may be helpful for selecting a nerve-sparing
had a significant OS benefit from RP (hazard ratio [HR]: approach because it has good specificity (0.91; 95% CI, 0.88–
0.69 [0.49–0.98] and 0.67 [0.48–0.94], respectively). A 0.93) but low sensitivity (0.57; 95% CI, 0.49–0.64) for
population-based analysis in 19 639 patients aged 65 yr detecting microscopic pT3a stages [46]. But the experience
who were not given curative treatment found that in men of the radiologist remains of paramount importance.
having a Charlson Comorbidity Index score 2, tumour Lower rates of positive surgical margins for high-volume
aggressiveness had little impact on OS at 10 yr [39]. These surgeons suggest that experience and careful attention to
data highlight the potential role of WW in some patients surgical details can improve surgical cancer control [47] and
with an individual life expectancy <10 yr. lower the complication rate.
A systematic review summarised the available data on There is still no evidence that one surgical approach is
AS [40]. There is considerable variation between studies better than another (open, laparoscopic, or robotic), as
regarding patient selection, follow-up policies, and when highlighted in a formal systematic review. Robot-assisted
active treatment should be instigated. Selection criteria for prostatectomy is associated with lower perioperative
AS include clinical T1c or T2a, PSA <10 ng/ml, and PSA morbidity and a reduced positive margins rate compared
density <0.15 ng/ml per ml (even if still controversial [41]), with laparoscopic prostatectomy, although there is consid-
fewer than two to three positive cores with <50% cancer erable methodological uncertainty. No formal differences
involvement of every positive core, GS 6. Extraprostatic exist in cancer-related continence or erectile dysfunction
extension or lymphovascular invasion should not be outcomes [48].
considered for AS [42]. Rebiopsy to exclude Gleason
sampling error is considered important [41], and mpMRI 9.1. Pelvic lymph node dissection
has a major role based on its high NPV value for lesion
upgrading and to exclude anterior prostate lesions [43]. Fol- The individual risk of finding positive lymph nodes can be
low-up in AS is based on repeat biopsy [41], serial PSA estimated using externally validated preoperative nomo-
measurements, and DRE, the optimal schedule remaining grams such as that described by Briganti [49]. A risk of nodal

Table 7 – Definitions of active surveillance and watchful waiting

Active surveillance Watchful waiting

Treatment intent Curative Palliative

Follow-up Predefined schedule Patient specific
Assessment/Markers used DRE, PSA, rebiopsy, mpMRI Not predefined
Life expectancy >10 yr <10 yr
Aim Minimise treatment-related toxicity without compromising survival Minimise treatment-related toxicity
Comments Only for low-risk patients Can apply to patients at all stages

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

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6 EUROPEAN UROLOGY XXX (2016) XXX–XXX

metastases >5% is an indication to perform an extended Retrospective case series demonstrated a CSS at 10 and
nodal dissection (ePLND). This includes removal of the 15 yr between 85% and 92% and 62% and 84%, respectively;
nodes overlying the external iliac artery and vein, the nodes 10-yr OS ranged between 76% and 77% [58]. The overall
within the obturator fossa located cranially and caudally to heterogeneity of this high-risk group was highlighted by a
the obturator nerve, the nodes medial and lateral to the large retrospective multicentre cohort of 1360 high-risk
internal iliac artery, and the nodes overlying the common patients treated with RP in a multimodal approach [58]. At
iliac artery and vein up to the ureteral crossing. It is 10 yr, a 91.3% CSS was observed. CSS was 95% for those
recommended that for each region the nodes should be sent having only one risk factor (ie, GS >7, cT category higher
separately for pathologic analysis. With this template, 75% than cT2, or PSA >20 ng/ml), 88% for those having a cT3–4
of all anatomic landing sites are cleared, resulting in and a PSA >20 ng/ml, and reduced to 79% if all three risk
improved pathological staging compared with a limited factors were present.
pelvic lymph node dissection, but at the cost of three-fold
higher complication rates (19.8% vs 8.2%), mainly related to 9.5. Side effects of radical prostatectomy
significant lymphoceles [50].
In men with pN+ PCa, early adjuvant androgen- Postoperative incontinence and erectile dysfunction (ED)
deprivation therapy (ADT) was shown to achieve a 10-yr are common problems following RP. There is no major
CSS rate of 80% [51]. Improving local control with pelvic difference based on the surgical approach with an overall
radiation therapy (RT) combined with ADT appeared to be continence rate between 89% and 100% when a robotic
beneficial in pN1 PCa patients treated with an ePLND. Men procedure was conducted compared to 80–97% for the
with minimal-volume nodal disease (fewer than three retropubic approach [59].
lymph nodes) and GS 7–10 and pT3–4 or R1 as well as men A prospective controlled nonrandomised trial of patients
with three to four positive nodes were more likely to benefit treated in 14 centres was published recently. At 12 mo after
from combined ADT and RT after surgery [52]. robotic surgery, 21.3% were incontinent, as were 20.2% after
open. The adjusted OR was 1.08 (95% CI, 0.87–1.34). ED was
9.2. Low-risk prostate cancer observed in 70.4% after robotic and 74.7% after open. The
adjusted OR was 0.81 (95% CI, 0.66–0.98) [60].
The decision to offer RP should be based on the probabilities
of clinical progression, side effects, and potential survival 10. Definitive radiation therapy
benefit. No lymph node dissection is needed.
Dose-escalated intensity-modulated radiation therapy
9.3. Intermediate-risk localised prostate cancer (IMRT), with or without image-guided RT, is the gold
standard for external-beam radiation therapy (EBRT)
Data from SPCG-4 [53] and a preplanned subgroup analysis because it is associated with less toxicity compared to
(PIVOT) [36] highlight the benefit of RP compared to WW. three-dimensional conformal radiation therapy (3D-CRT)
The risk of having positive nodes is 3.7–20.1% [49]. An techniques [61]. However, whatever the technique and
ePLND should be performed if the estimated risk for pN+ their degree of sophistication, quality assurance plays a
exceeds 5% [49]. In all other cases, nodal dissection can be major role in the planning and delivery of RT.
omitted while accepting a low risk of missing positive RCTs have shown that escalating the dose into the range
nodes. 74–80 Gy leads to a significant improvement in 5-yr
biochemical-free survival [62–65]. In men with intermedi-
9.4. High-risk and locally advanced prostate cancer ate- or high-risk PCa, there is also evidence to support an OS
benefit from a nonrandomised but well-conducted propen-
Patients with high-risk and locally advanced PCa are at an sity matched retrospective analysis covering a total of 42
increased risk of PSA failure, need for secondary therapy, 481 patients [66].
metastatic progression, and death from PCa. Provided that Biological modelling suggests that PCa may be sensitive
the tumour is not fixed and not invading the urethral to an increased dose per fraction resulting in the
sphincter, RP combined with an ePLND is a reasonable first investigation in RCTs of hypofractionation (HFX) in local-
step in a multimodal approach. The estimated risk for pN+ is ised disease. The largest reported randomised trial, using
15–40% [49]. Regarding each individual high-risk factor in IMRT in predominantly intermediate-risk localised PCa,
patients treated with a multimodal approach, a GS 8–10 (CHHiP trial) demonstrates 60 Gy in 20 fractions (3 Gy/
prostate-confined lesion has a good prognosis after RP. In fraction) is non-inferior to 74 Gy in 37 fractions with 5-yr
addition, frequent downgrading exists between the biopsy recurrence free rates of 90%. A third arm using 57 Gy in
and the specimen GS [54]. At 10- and 15-yr follow-up, the 19 fractions (3 Gy/fraction) was not demonstrated to be
CSS is up to 88% and 66%, respectively [55,56]. A PSA non-inferior in terms of biochemical control. No significant
>20 ng/ml is associated with a CSS at 10 and 15 yr ranging differences in the proportion or cumulative incidence of 5-
between 83% and 91% and 71% and 85%, respectively [55– yr toxicity were found when using the 3 Gy per fraction
57]. Surgery has traditionally been discouraged for cT3N0 schedules [67]. Other trials have demonstrated increased
PCa, mainly because of the increased risk of positive toxicity with HFX. In the RTOG 0415 study, 70 Gy in
margins and lymph node metastases and/or distant relapse. 28 fractions (2.5 Gy/fraction) was investigated in low risk

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PCa patients. Late Grade 2 GI and GU toxicities of 18.2% and long-term ADT, as shown by the STAMPEDE trial, in which
26.2% were noted with HFX compared to 11.4% and 20.5% the use of RT improved failure-free survival in men with N+
using conventional fractionation [68]. Patient reported PCa [77].
toxicity outcomes are awaited. Another randomised trial,
using a higher dose per fraction of 3.4 Gy delivered to a total 10.6. Postoperative external-beam radiation therapy after
dose of 64.6 Gy (HYPRO trial), has demonstrated increased radical prostatectomy
G3 and higher late urinary toxicity particularly in patients
with pre-existing urinary symptoms [69]. HFX delivered Extracapsular invasion and positive surgical margins are
with fewer treatments can increase the convenience for the associated with a risk of local recurrence and progression.
patient and lower costs for the health care system, but only Adjuvant RT was associated with improved biochemical
evidence based fractionation schedules should be used progression-free survival in three RCTs [78–80], although
outside of clinical trials. only SWOG 8794 [80] suggested improved OS. Thus for
HFX requires meticulous quality assurance, excellent patients classified as pT3 pN0 with a high risk of local failure
image guidance, and close attention to organ-at-risk dose with positive margins (highest impact), pT3a and/or pT3b
constraints to minimise the long-term toxicity risk. Extreme with a postoperative PSA <0.1 ng/ml, two options can be
HFX (5–10 Gy per fraction) in which radiation is delivered in offered in the framework of informed consent. Either
five to seven fractions should still be considered as immediate EBRT to the surgical bed after recovery of urinary
investigational. function or monitoring followed by early salvage RT before
the PSA exceeds 0.5 ng/ml [81].
10.1. Low-risk prostate cancer
10.7. Side effects of definitive radiation therapy
Offer dose-escalated IMRT (74–78 Gy) without ADT.
The Memorial Sloan Kettering Cancer Center group reported
10.2. Intermediate-risk prostate cancer data on late toxicity from their experience in 1571 patients
with T1–T3 disease treated with either 3D-CRT or IMRT at
Patients suitable for ADT should be given combined dose- doses between 66 Gy and 81 Gy, with a median follow-up of
escalated IMRT (76–78 Gy) with short-term ADT (4–6 mo) 10 yr [61]. The use of IMRT significantly reduced the risk of
[70]. For patients unsuitable for ADT (eg, due to comorbid- late grade 2 or higher gastrointestinal (GI) toxicity to 5%
ities) or unwilling to accept ADT (eg, to preserve their sexual compared with 13% with 3D-CRT. The incidence of grade 2
health), the recommended treatment is IMRT at a dose of late genitourinary (GU) toxicity was 20% in patients treated
76–80 Gy or a combination of IMRT and brachytherapy. with 81 Gy IMRT versus 12% with lower doses. The overall
incidences of late grade 3 toxicity were 1% and 3% for GI and
10.3. Localised high-risk prostate cancer GU toxicity, respectively.
Systematic review and meta-analysis of observational
The high risk of relapse outside the irradiated volume studies comparing patients exposed or unexposed to
makes it mandatory to use a combined modality approach, radiotherapy in the course of treatment for PCa demon-
consisting of dose-escalated IMRT, possibly including the strate an increased risk of developing second cancers for
pelvic lymphatics and long-term ADT, generally for 2 to 3 yr. bladder (OR: 1.39), colorectal (OR: 1.68), and rectum (OR:
The duration of ADT has to take into account performance 1.62) with similar risks over lag times of 5 and 10 yr.
status, comorbidities, and the number of poor prognostic Absolute risks over 10 yr are small (1–4%) but should be
factors. discussed with younger men in particular [82].

10.4. Locally advanced prostate cancer: T3–4 N0, M0 11. Brachytherapy

The standard of care for patients T3–4 N0, M0 locally Low-dose rate (LDR) brachytherapy uses permanent radio-
advanced PCa is IMRT combined with long-term ADT for at active seeds implanted into the prostate and is an option for
least 2 to 3 yr as it results in better OS [71–73]. The those with low-risk disease and selected cases with
combination is clearly better than EBRT or ADT mono- intermediate-risk disease (low-volume GS 3 + 4), prostate
therapy [74]. In both high-risk localised and locally volume <50 cm3, and an IPSS 12 [83]. Up to 85% relapse-
advanced PCa, an upfront combination with docetaxel only free survival at 10 yr is demonstrated [84]. LDR as a boost
improves relapse-free survival, with no survival benefit at with EBRT can be used to dose escalate radiation in
9 yr [75]. intermediate- and high-risk patients. Although seen as a
low-impact treatment modality, some patients experience
10.5. Lymph node irradiation significant urinary complications following implantation,
such as urinary retention (1.5–22%), postimplantation
In men with cN0 PCa, RCTs failed to show a benefit from transurethral resection of the prostate (TURP) (8.7% of
prophylactic pelvic nodal irradiation (46–50 Gy) in high- cases), and incontinence (0–19%) [85]. Careful selection of
risk cases [76]. In men with cN1 or pN1 the outcome of RT patients using uroflowmetry can avoid these significant
alone is poor, and these patients should receive RT plus side effects [86]. Previous TURP for BPH increases the risk of

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8 EUROPEAN UROLOGY XXX (2016) XXX–XXX

Table 8 – Summary of the main findings regarding treatment of nonmetastatic prostate cancer

Recommendation LE GR

Management decisions should be made after all treatments have been discussed in a multidisciplinary team 4 A*
Offer RP to patients with low- and intermediate-risk PCa and a life expectancy >10 yr 1b A
Nerve-sparing surgery may be attempted in preoperatively potent patients with low risk for extracapsular disease 2b B
(T1c, GS <7, and PSA <10 ng/ml, or refer to Partin tables/nomograms)
In intermediate- and high-risk disease, use mpMRI as a decision tool to select patients for nerve-sparing procedures 2b B
Offer RP in a multimodality setting to patients with high-risk localised PCa and a life expectancy >10 yr 2a A
Offer RP in a multimodality setting to selected patients with locally advanced (cT3a) PCa and a life expectancy >10 yr 2b B
Offer RP in a multimodality setting to highly selected patients with locally advanced PCa (cT3b–4 N0 or any T N1) 3 C
Do not offer NHT before RP 1a A
Do not offer adjuvant HT for pN0 1a A
Offer adjuvant ADT for node positive (pN+) 1b A
Offer EBRT using IMRT to all risk groups 2a A
In patients with low-risk PCa, without a previous TURP, with a good IPSS and a prostate volume <50 ml, offer LDR brachytherapy 2a A
In low risk PCa, use a total dose of 74–78 Gy 1a A
In intermediate- risk PCa use a total dose of 76–78 Gy, in combination with short-term ADT (4–6 mo) 1b A
In patients with high-risk localised PCa, use a total dose of 76–78 Gy in combination with long-term ADT (2–3 yr) 1b A
In patients with locally advanced cN0 PCa, offer radiation therapy in combination with long-term ADT (2–3 yr) 1a A
In patients with cN1 PCa, offer pelvic external irradiation in combination with immediate long-term ADT 2b B
Offer adjuvant ADT for pN1 after ePLND 1b A
Discuss adjuvant ADT with additional radiation therapy for pN1 after ePLND 2b A
Offer observation (expectant management) for pN1 after ePLND when two or fewer nodes show microscopic involvement with a 2b B
PSA <0.1 ng/ml and absence of extranodal extension
In patients with pT3N0M0 PCa and an undetectable PSA following RP, discuss adjuvant EBRT because it at least improves 1a A
biochemical-free survival
Inform patients with pT3N0M0 PCa and an undetectable PSA following RP about salvage irradiation as an alternative to adjuvant 2b A
irradiation when PSA increases
Only offer cryotherapy and HIFU within a clinical trial 3 B
Do not offer focal therapy of the prostate outside a clinical trial 3 A

ADT = androgen-deprivation therapy; EBRT = external beam radiation therapy; ePLND = extended pelvic lymph node dissection; GR = grade of
recommendation; GS = Gleason score; HIFU = high-intensity focussed ultrasound; HT = hormone therapy; IMRT = intensity-modulated radiation therapy;
IPSS = International Prostate Symptom Score; LDR = low-dose rate; LE = level of evidence; mpMRI = multiparametric magnetic resonance imaging;
NHT = neoadjuvant hormone therapy; PCa = prostate cancer; PSA = prostate-specific antigen; RP = radical prostatectomy; TURP = transurethral resection of
the prostate.
*
Upgraded following Panel consensus.

postimplantation incontinence and urinary morbidity. ED Cryosurgery might be considered for patients with an
develops in about 40% of the patients after 3–5 yr. organ-confined PCa or minimal tumour extension beyond
High-dose rate (HDR) brachytherapy uses a radioactive the prostate, prostate volumes <40 ml, PSA <20 ng/ml, and
source temporarily introduced into the prostate to deliver GS <7.
radiation. HDR brachytherapy can be delivered in single or A systematic review compared cryotherapy versus RP
multiple fractions and is often combined with EBRT of at and EBRT [89]. Data from 3995 patients across 19 studies
least 45 Gy as a method of dose escalation in intermediate- were included. In the short term, there was conflicting
or high-risk PCa. Quality-of-life changes are similar to high- evidence relating to cancer-specific outcomes. The 1-yr
dose EBRT alone [87]. HDR brachytherapy as monotherapy disease-free survival was worse for cryotherapy than for
has been pioneered in a small number of centres with low either EBRT or RP. None of the other cancer-specific
published toxicity and high biochemical control rates but outcomes including OS showed any significant differences.
currently mature data are not available on the optimal The high risk of bias across studies precludes any clear
treatment schedule [88]. conclusions.
High-intensity focussed ultrasound (HIFU) of the
12. Alternative local treatment options prostate was compared in a systematic review [89]
with RP and EBRT as primary treatment for localised
Besides RP, EBRT, and brachytherapy, other modalities have PCa. Data from 4000 patients across 21 studies were
emerged as therapeutic options in patients with clinically included. HIFU had a significantly worse disease-free
localised PCa. However patients with a life expectancy >10 survival at 1 yr compared with EBRT. The differences
yr should be fully informed that there are limited data on were no longer significant at 3 yr. The biochemical result
the long-term outcome for cancer control beyond 10 yr. was in contrast to OS at 4 yr, which was higher when
Recently, focal therapy has been developed, with the aim to using HIFU. The quality of the evidence was poor, due to
ablate tumours selectively while sparing the neurovascular high risks of bias across studies precluding any clear
bundles, sphincter, and urethra. Based on the available data conclusion. The overall PCa Guidelines are summarised in
[89], it should still be considered as fully experimental. Table 8.

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EUROPEAN UROLOGY XXX (2016) XXX–XXX 9

13. Conclusions Sanofi, and Janssen. He receives company honoraria from Astellas,
Amgen, Bayer, Sanofi, Janssen, and Ipsen, participates in trials for
Astellas, Bayer, and Janssen, receives fellowships and travel grants from
The present text represents a summary of the 2016 EAU-
Astellas, Amgen, Bayer, Sanofi, Janssen, Ipsen, and Pfizer. Thomas B. Lam
ESTRO-SIOG PCa Guidelines. For more detailed information
is a company consultant for Pfizer, GSK, Astellas, and Ipsen, receives
and a full list of references, refer to the full-text version company speaker honoraria from Pfizer, GSK, Astellas, and Ipsen.
(ISBN 978-90-79754-71-7), available at the EAU Web site Malcolm D. Mason is a company consultant for Bristol-Myers Squibb,
([Link] Janssen, Bayer, Sanofi, and Dendreon, and he receives company speaker
honoraria from Takeda and Bayer. Seva Matveev participates in trials for
Astellas, Pfizer, and Novartis, and receives company speaker honoraria
Author contributions: Nicolas Mottet had full access to all the data in the from Sanofi and Astellas. Henk G. van der Poel is a company consultant
study and takes responsibility for the integrity of the data and the for Intuitive Surgical and participates in trials for Astellas and Steba
accuracy of the data analysis. Biotech. He receives grants/research support from Astellas. Olivier
Rouvière is a company consultant for EDAP-TMS, Bracco, and Philips. He
Study concept and design: Mottet, Cornford.
receives company speaker honoraria from EDAP-TMS and Bracco and
Acquisition of data: Mottet, Bolla, De Santis, Henry, Joniau, Lam, Mason,
participates in trials for EDAP-TMS and Bracco. Thomas Wiegel receives
Matveev, Moldovan, van den Bergh, Van den Broeck, van der Poel, van
company speaker honoraria from Astellas, Takeda, Hexal, Ipsen, Janssen-
der Kwast, Rouvière, Wiegel, Cornford.
Cilac, and Ferring. Philip Cornford is a company consultant for Astellas,
Analysis and interpretation of data: Mottet, Bolla, Briers, De Santis, Henry,
Ipsen and Ferring. He receives company speaker honoraria from Astellas,
Joniau, Lam, Mason, Matveev, Moldovan, van den Bergh, van der Poel,
Janssen, Ipsen and Pfizer and participates in trials from Ferring, and
van der Kwast, Rouvière, Wiegel, Cornford.
receives fellowships and travel grants from Astellas and Janssen. Marcus
Drafting of the manuscript: Mottet.
G. Cumberbatch, Nicola Fossati, Tobias Gross, Ann M. Henry, Paul L.
Critical revision of the manuscript for important intellectual content:
Moldovan, Ivo G. Schoots, Roderick C.N. van den Bergh, Thomas Van den
Mottet, Bellmunt, Bolla, Briers, Cumberbatch, De Santis, Fossati, Gross,
Broeck, and Theo van der Kwast have nothing to disclose.
Henry, Joniau, Lam, Mason, Matveev, Moldovan, van den Bergh, Van den
Broeck, van der Poel, van der Kwast, Rouvière, Schoots, Wiegel, Cornford. Funding/Support and role of the sponsor: None.
Statistical analysis: None.
Obtaining funding: None. References
Administrative, technical, or material support: None.
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Please cite this article in press as: Mottet N, et al. EAU–ESTRO–SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis,
and Local Treatment with Curative Intent. Eur Urol (2016), [Link]