Guidelines

EAU Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis,

and Local Treatment with Curative Intent—Update 2013

Axel Heidenreich a,*, Patrick J. Bastian b, Joaquim Bellmunt c, Michel Bolla d, Steven Joniau e,Theodor van der Kwast f, Malcolm Mason g, Vsevolod Matveev h, Thomas Wiegel i,F. Zattoni j, Nicolas Mottet k

a Department of Urology, RWTH University Aachen, Aachen, Germany; b Department of Urology, Klinikum Golzheim, Dusseldorf, Germany; c Department of

Medical Oncology, University Hospital Del Mar, Barcelona, Spain; d Department of Radiation Therapy, C.H.U. Grenoble, Grenoble, France; e Department of

Urology, University Hospital, Leuven, Belgium; f Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands; g Department of Oncology

and Palliative Medicine, Velindre Hospital, Cardiff, UK; h Department of Urology, Russian Academy of Medical Science, Cancer Research Center, Moscow,

Russia; i Department of Radiation Oncology, University Hospital Ulm, Ulm, Germany; j Department of Urology, Santa Maria Della Misericordia Hospital,

Udine, Italy; k Department of Urology, Clinique Mutaliste de la Loire, Saint Etienne, France

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 1 2 4 – 1 3 7

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Article info

Article history:Accepted September 26, 2013Published online ahead ofprint on October 6, 2013

Keywords:

Prostate cancer

EAU guidelines

Review

Diagnosis

Treatment

Follow-up

Radical prostatectomy

Radiation therapy

Androgen deprivation

Abstract

Context: The most recent summary of the European Association of Urology (EAU) guidelines onprostate cancer (PCa) was published in 2011.Objective: To present a summary of the 2013 version of the EAU guidelines on screening, diagnosis,and local treatment with curative intent of clinically organ-confined PCa.Evidence acquisition: A literature review of the new data emerging from 2011 to 2013 has beenperformed by the EAU PCa guideline group. The guidelines have been updated, and levels of evidenceand grades of recommendation have been added to the text based on a systematic review of theliterature, which included a search of online databases and bibliographic reviews.Evidence synthesis: A full version of the guidelines is available at the EAU office or online (www.uroweb.org). Current evidence is insufficient to warrant widespread population-based screening byprostate-specific antigen (PSA) for PCa. Systematic prostate biopsies under ultrasound guidance andlocal anesthesia are the preferred diagnostic method. Active surveillance represents a viable optionin men with low-risk PCa and a long life expectancy. A biopsy progression indicates the need foractive intervention, whereas the role of PSA doubling time is controversial. In men with locallyadvanced PCa for whom local therapy is not mandatory, watchful waiting (WW) is a treatmentalternative to androgen-deprivation therapy (ADT), with equivalent oncologic efficacy. Activetreatment is recommended mostly for patients with localized disease and a long life expectancy,with radical prostatectomy (RP) shown to be superior to WW in prospective randomized trials.Nerve-sparing RP is the approach of choice in organ-confined disease, while neoadjuvant ADTprovides no improvement in outcome variables. Radiation therapy should be performed with�74 Gyin low-risk PCa and 78 Gy in intermediate- or high-risk PCa. For locally advanced disease, adjuvantADT for 3 yr results in superior rates for disease-specific and overall survival and is the treatment ofchoice. Follow-up after local therapy is largely based on PSA and a disease-specific history, withimaging indicated only when symptoms occur.Conclusions: Knowledge in the field of PCa is rapidly changing. These EAU guidelines on PCasummarize the most recent findings and put them into clinical practice.Patient summary: A summary is presented of the 2013 EAU guidelines on screening, diagnosis, andlocal treatment with curative intent of clinically organ-confined prostate cancer (PCa). Screeningcontinues to be done on an individual basis, in consultation with a physician. Diagnosis is by prostatebiopsy. Active surveillance is an option in low-risk PCa and watchful waiting is an alternative toandrogen-deprivation therapy in locally advanced PCa not requiring immediate local treatment.Radical prostatectomy is the only surgical option. Radiation therapy can be external or delivered byway of prostate implants. Treatment follow-up is based on the PSA level.

# 2013 Published by Elsevier B.V. on behalf of European Association of Urology.

* Corresponding author. Universitatsklinikum Aachen, Department of Urology, Pauwelsstr. 30,Aachen, 52074, Germany. Tel. +49 241 808 9374; Fax: +49 241 808 2441.E-mail address: aheidenreich@ukaachen.de (A. Heidenreich).

0302-2838/$ – see back matter # 2013 Published by Elsevier B.V. on behalf of European Association of Urology.http://dx.doi.org/10.1016/j.eururo.2013.09.046

1. Introduction

The most recent summary of the European Association of

Urology (EAU) guidelines on prostate cancer (PCa) was

published in 2011 [1]. The aim of this paper is to present a

summary of the 2013 update of the EAU guidelines on PCa.

To facilitate evaluating the quality of the information

provided, level of evidence (LE) and grade of recommenda-

tion (GR) have been inserted according to the general

principles of evidence-based medicine [2].

2. Epidemiology

In Europe, PCa is the most common solid neoplasm, with an

incidence rate of 214 cases per 1000 men, outnumbering

lung and colorectal cancer [3]. PCa affects elderly men more

often and therefore is a bigger health concern in developed

countries. Approximately 15% of male cancers are PCa in

developed countries, compared with 4% of male cancers in

developing countries [4]. There are large regional differ-

ences in incidence rates of PCa, with a range from 68.8 per

1000 in Malta to 182 per 1000 in Belgium [4].

3. Risk factors

The factors that determine the risk of developing clinical

PCa are not well known, although three well-established

risk factors have been identified: increasing age, ethnic

origin, and heredity. If one first-line relative has the disease,

the risk is at least doubled. If two or more first-line relatives

are affected, the risk increases by 5–11 times [5].

Approximately 9% of individuals with PCa have true

hereditary PCa, defined as three or more relatives affected

or at least two relatives who have developed early-onset

disease, that is, disease before 55 yr of age.

Exogenous factors, such as food consumption, pattern of

sexual behavior, alcohol consumption, exposure to ultra-

violet radiation, chronic inflammation [6], and occupational

exposure, might also be involved in the development of

clinical PCa. None of the prospective randomized trials

performed has produced level 1 evidence to justify

recommending lifestyle changes. However, the prospective

randomized Selenium and Vitamin E Cancer Prevention

Trial (SELECT) included 35 533 men with prostate-specific

antigen (PSA)�4 ng/ml and randomized the men in the four

arms to be treated with either selenium, vitamin E,

selenium plus vitamin E, or placebo, with a reduction in

the development of PCa as the primary end point [7]. After a

follow-up of 7 yr, a significantly elevated risk of PCa was

observed in the vitamin E treatment arm (hazard ratio [HR]:

1.17; 95% confidence interval [CI], 1.004–1.136; p = 0.008).

Treatment with selenium was not found to prevent PCa, but

there was no significant increase in the development of PCa.

4. Classifications

The Union Internationale Contre le Cancer 2010 TNM

classification is used throughout these guidelines [8].

The Gleason score is the recommended methodology for

grading PCa. According to current international convention,

the (modified) Gleason score of cancers detected in a

prostate biopsy consists of the Gleason grade of the

dominant (most extensive) carcinoma component plus

the highest grade, regardless of its extent—there is no 5%

rule [9]. In radical prostatectomy (RP) specimens, both the

primary and secondary Gleason grades are to be reported.

The presence of the tertiary grade and its approximate

proportion of the cancer volume should also be reported.

5. Prostate cancer screening

There is currently no evidence for introducing widespread

population-based screening programs for early PCa detec-

tion in all men [10] (LE: 2). To evaluate the efficacy of PCa

screening, two large randomized trials have been pub-

lished: the Prostate, Lung, Colorectal and Ovary (PLCO) trial

in the United States and the European Randomized Study

of Screening for Prostate Cancer (ERSPC) in Europe [11,12]

(LE: 1b).

The PLCO cancer-screening trial randomly assigned

76 693 men to receive either annual screening with PSA

and digital rectal examination (DRE) or standard care as the

control [11]. After 7 yr of follow-up, the incidence of death

per 10 000 person-years was 2.0 (50 deaths) in the screened

group and 1.7 (44 deaths) in the control group (rate ratio:

1.13). The PLCO project team concluded that PCa-related

mortality in screen-detected individuals was very low and

not significantly different between the two study groups

(LE: 1b).

The ERSPC trial included a total of 162 243 men between

55 and 69 yr of age [12]. The men were randomly assigned

to a group offered PSA screening at an average of once every

4 yr or to an unscreened control group. During a median

follow-up of 9 yr, the cumulative incidence of PCa was 8.2%

in the screened group and 4.8% in the control group [10].

The absolute risk difference was 0.71 deaths per 1000 men.

This result means that 1410 men would need to be screened

and 48 additional cases of PCa would need to be treated

to prevent 1 death from PCa (LE: 1b). In an update of the

ERSCP trial, after a mean follow-up of 11 yr, the number of

men needing to be screened decreased to 1055, and the

number needing treatment decreased to 37 [13]. In an update

of the Goteborg section of the ERSPC trial, which included

20 000 men, the authors reported a relative risk (RR)

reduction of 50% in PCa mortality after a median follow-up

of 14 yr. However, this finding was accompanied by a

substantial risk of overdiagnosis [14]. Based on these data,

the real benefit of the ESRPC trial will be evident only after

10–15 yr of follow-up, particularly because of the impact of

the 41% reduction in metastasis in the screening arm.

In a recent retrospective analysis, the PCa incidence, PCa

metastasis, and cause of death were compared between a

group of 11 970 men who were included in the intervention

arm of the ERSCP trial and a control population of 133 287

unscreened men during an 8-yr observation period [11].

The RR of PCa metastasis in the screened compared with

the control population was 0.47 ( p < 0.001). The RR of

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 1 2 4 – 1 3 7 125

PCa-specific mortality was also significantly lower in the

screening arm (0.63, p = 0.008). The absolute mortality

reduction was 1.8 deaths per 1000 men.

Both trials have received considerable attention and

comments, which were addressed extensively in the

previous edition of the EAU guidelines on PCa [1].

Based on the results of these two large randomized trials,

most, if not all, of the major urologic societies have

concluded that at present, widespread mass screening for

PCa is not appropriate. Rather, early detection (opportunis-

tic screening) should be offered to the well-informed man

(see also section 6). Two key questions remain open and

empirical: (1) At what age should early detection start? (2)

What is the interval for PSA and DRE?

The decision to undergo early PSA testing should be

shared between the patient and his physician based on

information balancing the test’s advantages and disadvan-

tages. A position paper of the EAU recently suggested a

baseline PSA determination at age 40, on which the

subsequent screening interval may then be based [12]

(GR: B). A screening interval of 8 yr might be enough in men

with initial PSA levels�1 ng/ml [12–14]. Further PSA testing

is not necessary in men >75 yr and with a baseline PSA

�3 ng/ml because of their very low risk of dying from PCa

[15]. This type of risk-adapted screening has been supported

by a case–control study comprising 21 277 men (27–52 yr)

who provided a baseline PSA in 1974–1984 and 4922 men

who were invited to provide a second PSA 6 yr later [16].

There was an association between the risk of death from PCa

and the baseline PSA: 44% (95% CI, 34–53) of deaths occurred

in men with a PSA concentration in the highest 10th

percentile of the distribution of concentrations at ages 45–

49 (�1.6 mg/l), with a similar proportion for the highest 10th

percentile at ages 51–55 (�2.4 mg/l: 44%; 95% CI, 32–56).

Although a 25- to 30-yr risk of PCa metastasis could not be

ruled out by concentrations below the median at ages 45–49

(0.68 mg/l) or 51–55 (0.85 mg/l), the 15-yr risk remained low

at 0.09% (95% CI, 0.03–0.23) at 45–49 yr and 0.28% (95% CI,

0.11–0.66) at 51–55 yr, suggesting that longer intervals

between screening would be appropriate in this group.

6. Diagnosis and staging of prostate cancer

The main tools to diagnose PCa include DRE, serum

concentration of PSA, and transrectal ultrasound (TRUS)-

guided biopsy. In approximately18% of all patients, PCa is

detected by a PCa-suggestive finding on DRE alone, regard-

less of the PSA level [17] (LE: 2a). A suspect DRE in patients

with a PSA level of�2 ng/ml has a positive predictive value of

5–30% [18] (LE: 2a). A PSA cut-off of 3 or 3.1 mg/l should be

considered for World Health Organization–calibrated assays

to achieve the same sensitivity and specificity profile found

with a cut-off of 4 mg/l in traditionally calibrated assays [19].

The cut-offs for the ratio of free to total PSA (%fPSA) can be

retained.

The level of PSA is a continuous parameter: The higher

the value, the more likely is the existence of PCa. The finding

that many men may harbor PCa despite low levels of serum

PSA has been underscored by recent results from a US

prevention study [20] (Table 1) (LE: 2a). Table 1 gives the

rate of PCa in relation to serum PSA for 2950 men in the

placebo arm and with normal PSA values.

Several modifications of serum PSA value have been

described, which may improve the specificity of PSA in the

early detection of PCa. These modifications include PSA

density, PSA density of the transition zone, age-specific

reference ranges, and PSA molecular forms.

In a prospective multicenter trial, PCa was found on

biopsy in 56% of men with %fPSA <0.10 but in only 8% of

men with %fPSA >0.25 [10] (LE: 2a). These data have been

confirmed in a recent screening test including 27 730 men

with a serum PSA concentration between 2.1 and 10 ng/ml

[21]. Using %fPSA, the number of unnecessary biopsies

decreased significantly and the detection rate of PCa

increased significantly, so %fPSA should be routinely

considered in every patient with suspicious findings.

The concepts of PSA velocity (PSA-V) and PSA doubling

time (PSA-DT) have limited use in the diagnosis of PCa

because of several unresolved issues. Prospective studies

have not shown that these measurements can provide

additional information compared with PSA alone [22,23].

In contrast to the serum markers previously discussed,

the biomarker PCA3 is measured in urine sediment obtained

after prostatic massage [24]. Determination of this PCa-

specific RNA is experimental. At a population level, this

method appears to be helpful, but its impact at the level of

the individual patient remains highly questionable. So far,

none of the biomarkers can be used to counsel an individual

patient on the need to perform a prostate biopsy to rule out

PCa. The molecular marker may help in the decision-making

process with regard to a repeat biopsy in men with a

negative first biopsy but a persistent suspicion of PCa

[25,26]. Men with a positive follow-up biopsy had

significantly higher PCA3 scores compared with men with

a negative second biopsy (69.5 vs 37.7, p < 0.001). In men

with %fPSA <10%, the PCA3 score was identified as a

significant predictor of PCa. However, in men with %fPSA of

10–20% and >20%, the percentage of positive biopsies rose

from 17.8% to 30.6% and from 23.9% to 37%, respectively, if a

PCA3 score >30 was used.

Ultrasound-guided transrectal or transperineal laterally

directed 18G core biopsy has become the standard way to

obtain material for histopathologic examination [27,28].

The need for prostate biopsies should be determined on the

basis of the PSA level, a suspicious DRE, the patient’s

biologic age, potential comorbidities, and the therapeutic

consequences. The first elevated PSA level should not

Table 1 – Risk of prostate cancer in relation to low prostate-specific antigen values

PSA level, ng/ml Risk of PCa, %

0–0.5 6.6

0.6–1 10.1

1.1–2 17.0

2.1–3 23.9

3.1–4 26.9

PSA = prostate-specific antigen; PCa = prostate cancer.

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 1 2 4 – 1 3 7126

prompt an immediate biopsy. The level should be verified

after a few weeks by the same assay under standardized

conditions, except for high PSA values (>20 ng/ml), after

prostatitis has been excluded.

At a glandular volume of 30–40 ml, at least 10–12 cores

should be sampled [29] (LE: 2a). More than 12 cores are not

significantly more conclusive [29] (LE: 1a). Oral or

intravenous quinolones are state-of-the-art preventive

antibiotics, with ciprofloxacin superior to ofloxacin [30]

(LE: 1b). In the last few years, increased resistance to

quinolones has been reported [31] and has been associated

with a rise in severe infectious complications after biopsy

[32]. Based on these findings, the need to obtain culture

results of prebiopsy rectal swabs to identify the most

appropriate antibiotic has been raised by recent studies.

Ultrasound-guided periprostatic block is state of the art [33]

(LE: 1b). On baseline biopsies, the sample sites should be as

far posterior and lateral in the peripheral gland as possible.

Additional biopsy cores should be obtained from suspect

areas by DRE or using TRUS.

Indications for repeat biopsies are rising and/or persis-

tently elevated PSA, suspicious DRE, atypical small acinar

proliferation, and multifocal high-grade prostatic intrae-

pithelial neoplasia (PIN) [34] (LE: 2a). The optimal timing is

still uncertain. The later the repeat biopsy is done, the

higher the detection rate [34]. If clinical suspicion for PCa

persists in spite of negative prostate biopsies, multipara-

metric magnetic resonance imaging (MRI) may be used to

investigate the possibility of an anteriorly located PCa,

followed by TRUS- or MRI-guided biopsies of the suspicious

area [35,36]. The role of transperineal prostate biopsies is

discussed controversially, since there is no statistically

significant evidence of benefit compared with transrectal

biopsies.

Diagnosis of PCa is based on histologic examination [37].

Ancillary staining techniques (eg, basal cell staining) and

additional (deeper) sections should be considered if a

suspect glandular lesion is identified [37].

For each biopsy site, the proportion of biopsies positive

for carcinoma and the Gleason score using the system

adopted in 2005 [38,39] should be reported. A diagnosis of

Gleason score �4 should not be given on prostate biopsies

[31]. The proportion (percentage) or length (in millimeters)

of tumor involvement per biopsy [37,38] and, if present,

extraprostatic extension should be recorded. The presence

of high-grade PIN and perineural invasion are usually

reported.

The extent of a single, small focus of adenocarcinoma

that is located in only one of the biopsies should be clearly

stated (eg, <1 mm or <1%), as it might be an indication for

further diagnostic work-up of the specimen or a rebiopsy

before selecting therapy [38].

The decision to proceed with further diagnostic or

staging work-up is guided by which treatment options are

available to the patient, taking the patient’s preference,

age, and comorbidity into consideration [40–45]. Proce-

dures that do not affect the treatment decision can

usually be avoided. A short summary of the guidelines

on diagnosis and staging of PCa is presented in Tables 2

and 3.

7. Primary local treatment of prostate cancer

The therapeutic management of PCa, even clinically

localized disease, has become increasingly complex because

of the various stage-specific therapeutic options available. It

is therefore advisable to do the following:

� Counsel patients with low-risk PCa (PSA <10 ng/ml and

biopsy Gleason score 6 and cT1c–cT2a) or intermediate-

risk PCa (PSA 10.1–20 ng/ml or biopsy Gleason score 7 or

cT2b–c) in an interdisciplinary setting with a urologist

and a radiation oncologist.

� Discuss neoadjuvant and adjuvant treatment options in

patients with high-risk PCa (PSA <20 ng/ml or biopsy

Gleason score 8–10 or �cT3a) in a multidisciplinary

tumor board.

� Thoroughly document which guidelines have been used

for the decision-making process if no multidisciplinary

approach was possible.

Table 2 – Guidelines for the diagnosis of prostate cancer

Guideline GR

1. An abnormal DRE result or elevated serum PSA measurement could indicate PCa. The exact cut-off level for what is considered to be

a normal PSA value has not been determined, but values of approximately <2–3 ng/ml are often used for younger men.

C

2. The diagnosis of PCa depends on histopathologic confirmation. B

Biopsy and further staging investigations are indicated only if they affect the management of the patient. C

3. TRUS-guided systemic biopsy with �10 systemic, laterally directed cores is recommended, with perhaps more cores in prostates

with a volume >40 ml.

B

Transition zone biopsies are not recommended in the first set of biopsies because of low detection rates. C

One set of repeat biopsies is warranted in cases with persistent indication for prostate biopsy (abnormal DRE, elevated PSA, ASAP,

multifocal PIN).

B

Recommendations for further (three or more) sets of biopsies cannot be made; the decision must be made based on the individual

patient.

C

4. Transrectal periprostatic injection with a local anesthetic agent is to be offered to patients as effective analgesia when undergoing

prostate biopsies.

A

5. Oral or intravenous quinolones are state-of-the-art preventive antibiotics, although increasing frequencies of resistance have to be

considered.

A

ASAP = atypical small acinar proliferation in the prostate; DRE = digital rectal examination; GR = grade of recommendation; PIN = prostatic intraepithelial

neoplasia; PCa = prostate cancer; PSA = prostate-specific antigen; TRUS = transrectal ultrasound.

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 1 2 4 – 1 3 7 127

7.1. Low-risk prostate cancer

7.1.1. Active surveillance

Active surveillance (AS) represents a suitable therapy for

patients who might also be offered a curative approach.

Such patients with (very low risk) PCa are initially not

treated but are followed and treated with a curative intent if

progression or the threat of progression occurs during

follow-up. AS was conceived with the aim of reducing the

ratio of overtreatment in patients with clinically confined

low-risk PCa based on early data [46,47] demonstrating that

men with well-differentiated PCa have a 20-yr PCa-specific

survival rate of 80–90%.

The most advanced cohort to date, reported by Klotz

et al. [48], included 450 patients with clinical stage T1c or

T2a, PSA <10 ng/ml, and Gleason score �6 (PSA <15), with

patients >70 yr of age having a Gleason score �7 (3 + 4).

Initially, six biopsies were performed, followed by the usual

extended 12-core protocol during the study. At a median

follow-up of 6.8 yr, the 10-yr overall survival was 68%. At

10 yr, the disease-specific survival was 97.2%, with 62% of

men still alive on AS. Subsequently, 30% of patients

underwent a radical treatment for the following reasons:

48% for a PSA-DT <3 yr, 27% for Gleason score progression

on repeat biopsies, and 10% because of patient preference. A

variety of additional studies on AS in clinically organ-

confined disease have now been published [49] and have

confirmed a low rate of progression and cancer-specific

death in well-selected patients with very-low-risk disease.

However, an extended follow-up is necessary to obtain

definitive results. Thus, AS might mean no treatment at all

for patients>70 yr or patients with a life expectancy>10 yr,

while AS in younger patients might mean a possible

treatment delayed for years. The repeated biopsies that

are part of AS might then become important for their

potential adverse effect on nerve preservation if surgery is

subsequently considered.

Different series have identified several eligibility criteria

for potential AS patients [49]:

� Clinically confined PCa (T1–T2)

� Gleason score �6

� Three or fewer biopsies involved with cancer

� �50% of each biopsy involved with cancer

� PSA <10 ng/ml.

Different criteria were applied to define cancer progression

[49], although most groups used the following criteria:

� APSA-DT with a cut-off ranging between �2 and �4 yr

� Gleason score progression to �7 at rebiopsy, at intervals

ranging from 1 to 4 yr

� PSA progression >10 ng/ml.

However, the role of PSA-DT in identifying the need for

intervention has recently been challenged [50–52]. In a

cohort of 290 men who underwent AS for low-risk PCa, 35%

of the men developed biopsy progression (Gleason score

�7, more than two positive cores, or >50% core involve-

ment). The PSA-DT was not significantly associated with

biopsy progression ( p = 0.83), nor was the PSA-V ( p = 0.06).

In another study, 36% of men under AS demonstrated

disease progression on rebiopsy [51]. The 5-yr progression-

free probability was 82% for patients with a negative first

repeat biopsy, compared with 50% for patients with

a positive rebiopsy [52]. Both trials underline the need

for surveillance rebiopsies at 1 and 4 yr to adequately

monitor men under AS, independent of the results of PSA-

DT [53].

7.1.2. Radical prostatectomy

RP is the only surgical treatment for localized PCa. The

treatment has shown a cancer-specific survival benefit in a

subset of patients compared with WW in two prospective

randomized trials [54,55]. No such trials are available for

the alternative treatment options. Most of the recruited

patients had low- to intermediate-risk PCa and did not harbor

screen-detected PCa, so these data cannot be automatically

translated into daily routine clinical practice.

Between 1989 and 1999, the Scandinavian Prostate

Cancer Group Study Number 4 (SPCG-4) randomized

695 patients with clinical stage T1–T2 to WW or RP [54].

This study began after PSA screening had been introduced

into clinical practice but was diagnosing only 5% of men with

PCa. After a median follow-up of 12.8 yr, this study showed a

significant decrease in cancer-specific mortality, overall

Table 3 – Guidelines for staging of prostate cancer

Guideline GR

1. Local staging (T staging) of PCa is based on MRI. Further information is provided by the number and sites of positive prostate

biopsies, the tumor grade, and the level of serum PSA.

C

For local staging, TRUS should not be used, since it has low sensitivity and a tendency to understage PCa. C

2. Lymph node status (N staging) need be assessed only when potentially curative treatment is planned.

Patients with stage �T2, PSA <10 ng/ml, a Gleason score �6, and <50% positive biopsy cores have a <10% likelihood of having node

metastases and can be spared nodal evaluation.

B

In clinically localized intermediate- and high-risk PCa, staging must be done by pelvic lymph node dissection, since it is the only

reliable staging method, given the significant limitations of preoperative imaging in the detection of small (<5-mm) metastases.

B

3. Skeletal metastasis (M staging) is best assessed by bone scan. This procedure may not be indicated in asymptomatic patients if the

serum PSA level is <20 ng/ml in the presence of well-differentiated or moderately differentiated tumors.

B

In equivocal cases, 18F-fluorodeoxyglucose PET or PET/CT could be of value, especially to differentiate active metastases and

healing bones.

C

CT = computed tomography; GR = grade of recommendation; MRI = magnetic resonance imaging; PCa = prostate cancer; PET = positron emission tomography;

PSA = prostate-specific antigen; TRUS = transrectal ultrasound.

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 1 2 4 – 1 3 7128

mortality, metastatic risk progression, and local progression

in patients treated with RP compared with WW (LE: 1b).

Subgroup analysis showed that the difference was not

modified by PSA level (<10 or>10 ng/ml) or by the Gleason

score (�7) at the time of diagnosis. However, the patient’s

age at the time of randomization had a profound impact,

with the benefit in overall survival and metastasis-free

survival being seen only in men <65 yr of age. A further

subgroup analysis by Vickers et al. [56] demonstrated a

wide variation in individualized predictions of surgery

benefit, depending on age and tumor characteristics. At

65 yr, the absolute 10-yr risk reduction in PCa mortality

attributable to RP ranged from 4.5% to 17.2% for low-risk

compared with high-risk patients, respectively. The use of

surgery was associated with minimal benefit much beyond

the age of 70 yr. These findings suggest that it is hard to

justify surgery in patients with Gleason 6, T1 disease or in

patients much older than 70 yr. Conversely, surgery seems

to benefit patients with Gleason 8 or Gleason 7 stage T2.

These findings are limited by the fact that estimates from

SPCG-4 have to be applied cautiously to contemporary

patients.

The Prostate Cancer Intervention Versus Observation

Trial recruited 731 men with clinically organ-confined PCa

(cT1c–2cN0M0, PSA <50 ng/ml, age <75 yr, life expectancy

>10 yr) to treatment with either RP or WW [55]. Only 50% of

men had a nonpalpable PCA, compared with 12% of patients

in the SPCG-4 trial [20]. After a mean follow-up of 10 yr,

there were no statistically significant differences between

both treatment arms in mortality (47% vs 49.9%, respec-

tively; p = 0.22) and PCa-specific survival (5.8% vs 8.4%,

respectively; p = 0.09). There were also no statistically

significant differences concerning overall survival between

both treatment groups when considering patient age,

Gleason score, performance status, and Charlson comorbid-

ity score. Only patients with a pretreatment PSA serum

concentration >10 ng/ml or high-risk PCA experienced a

significant benefit in overall survival, with an RR reduction

in mortality of 33% ( p = 0.02) and 31% ( p < 0.01), respec-

tively. The pooled analysis identified an RR reduction and an

absolute risk reduction of 31% and 10.5%, in patients with

intermediate- or high-risk PCa, respectively ( p < 0.01).

Patients who underwent RP also experienced a statistically

significant reduction in the development of bone metasta-

ses (4.7% vs 10.6%, p < 0.01).

In conclusion, a benefit of RP compared with WW was

achieved only in patients with an intermediate or high risk

of progression who were <65 yr, whereas RP in classic low-

risk PCa patients did not demonstrate an advantage with

regard to overall survival and metastasis-specific survival.

The benefits of this trial are limited because survival

estimates can be applied only cautiously to contemporary

patients.

Nerve-sparing RP represents the approach of choice in all

men with normal erectile function and organ-confined

disease. Robot-assisted laparoscopic RP (RALP) is displacing

RP as the gold standard surgical approach for clinically

localized PCa in the United States and is also being

increasingly used in Europe. This trend has occurred despite

the lack of high-quality evidence to support its superiority

over more established treatment modalities. Recent in-

depth systematic reviews of the literature have compared

the results of retropubic RP and RALP. Positive surgical

margin rates are at least equivalent to robot-assisted RP

(RARP), but firm conclusions about biochemical recurrence

and other oncologic end points are difficult to draw because

of the relatively short follow-up in the published literature

and limited experience with RARP in locally advanced PCa.

RARP may offer advantages in postoperative recovery for

urinary continence and erectile function, although most

published studies addressing these outcomes have meth-

odological limitations [57–60].

The need for and the extent of pelvic lymphadenectomy

are discussed controversially. The risk of lymph node

involvement is low in men with low-risk PCa and <50%

positive biopsy cores [61–63].

Guidelines and recommendations for RP are given in

Table 4.

7.1.3. Radiation therapy and low-dose-rate brachytherapy

Three-dimensional conformal radiation therapy (3D-CRT)

remains the gold standard in external-beam radiation

therapy (EBRT) in many countries and institutions. How-

ever, image-guided intensity-modulated radiation therapy

(IMRT), which is an optimized form of 3D-CRT using

implanted fiducial markers in the prostate, should become

the standard treatment of choice based on 11 published

studies including 4559 patients with clinically localized PCA

[64]. IMRT is being more widely used because of its ability

to escalate dosage without increasing acute and/or late

Table 4 – Guidelines and recommendations for radical prostatectomy

Indications LE

Patients with low- and intermediate-risk localized PCa (cT1a–T2b and Gleason score 6–7 and PSA �20) and a life expectancy >10 yr 1b

Optional

Patients with stage T1a disease and a life expectancy >15 yr or Gleason score 7 3

Selected patients with low-volume, high-risk, localized PCa (cT3a or Gleason score 8–10 or PSA >20 ng/ml) 3

Highly selected patients with very high-risk localized PCa (cT3b–T4N0 or any TN1) in the context of multimodality treatment 3

Short-term (3-mo) or long-term (9-mo) neoadjuvant therapy with gonadotrophin releasing–hormone analogs is not recommended in

the treatment of clinically localized low-risk or high-risk PCa.

1a

Nerve-sparing surgery may be attempted in preoperatively potent patients with low risk for extracapsular disease (T1c and Gleason

score <7 and PSA <10 ng/ml).

3

Unilateral nerve-sparing procedures are an option in stage T2a–T3a disease. 4

LE = level of evidence; PCa = prostate cancer; PSA = prostate-specific antigen.

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 1 2 4 – 1 3 7 129

toxicity. A dose of �74 Gy is recommended in low-risk PCa

because it results in significantly higher biochemical

disease-free survival compared with a dosage of <72 Gy

(69% vs 63%, respectively; p = 0.046) [65].

Transperineal brachytherapy as a monotherapy is a safe

and effective technique for low-risk PCa, with consensus on

the following eligibility criteria [66]:

� Stage cT1c–T2aN0M0

� A Gleason score �7a assessed on at least 12 random

biopsies

� An initial PSA level of �10 ng/ml

� �50% of biopsy cores involved with cancer

� A prostate volume of <50 ml

� A good International Prostate Symptom Score (�17)

� No previous transurethral resection of the prostate.

Results of permanent implants have been reported from

different institutions, with median follow-up ranging

between 36 and 120 mo [67]. Recurrence-free survival

after 5 and 10 yr was reported to range from 71% to 93% and

from 65% to 85%, respectively.

In well-selected patients with intermediate-risk PCa,

long-term data of low-dose-rate brachytherapy are prom-

ising, with 94% biochemical disease-free survival at 5 yr

[68].

The incidence of grade 3 toxicity is <5%. Erectile

dysfunction develops in approximately 40% of patients

after 3–5 yr. In a recent retrospective analysis, Hunter

et al. evaluated the long-term toxicity of low-dose-rate

brachytherapy [69] after 10 yr and identified a cumula-

tive incidence of gastrointestinal (GI) and genitourinary

(GU) toxicities of grade �2 in 1.7% and 4.3% of patients,

respectively. Invasive procedures to treat urethral

strictures, subvesical obstruction, or radiation-induced

proctitis or recurrent bleeding had to be performed in

3.4% and 1.7% of patients with GU or GI toxicities,

respectively.

Guidelines and recommendations for the use of defini-

tive radiation therapy (RT) are listed in Table 5.

7.2. Intermediate- and high-risk prostate cancer

7.2.1. Radical prostatectomy

There is no consensus regarding the optimal treatment of

men with high-risk, clinically localized PCa. Decisions on

whether to select surgery as local therapy should be based

on the best available clinical evidence, and RP is a

reasonable first step in selected patients with a low tumor

volume.

Management of high-risk localized PCa must be dis-

cussed in an interdisciplinary team, since a multimodal

approach will probably be needed because of the high

likelihood of positive surgical margins (33.5–66% of

patients) and the presence of positive lymph nodes

(7.9–49% of patients) [70–75]. Of patients primarily treated

by surgery, 56–78% eventually require adjuvant or salvage

RT or hormonal therapy [71,73].

Overstaging of cT3 PCa is relatively frequent and occurs

in 13–27% of cases [73,74]. Patients with pT2 disease and

those with specimen-confined pT3 disease have similarly

good biochemical and clinical progression-free survival

[71,73]. Nerve-sparing RP can be performed safely in

clinically localized high-risk PCa, provided that intra-

operative frozen sections are taken without compromising

the oncologic and functional outcomes [76].

Biochemical progression-free survival varies between

38% and 51% at 10 yr if patients are treated with RP as

monotherapy. However, in the total cohort of patients with

high-risk, clinically localized PCa, excellent 5-, 10-, and

Table 5 – Guidelines and recommendations for definitive radiation therapy

Guideline/recommendation LE GR

In localized PCa (T1c–T2cN0M0), 3D-CRT with or without IMRT is recommended even for young patients who refuse surgical intervention. 2 B

For high-risk patients, long-term ADT before and during RT is recommended, as it results in increased overall survival. 2a B

In patients with locally advanced PCa (T3–T4N0M0) who are fit enough to receive EBRT, the recommended treatment is EBRT plus

long-term ADT. The use of ADT alone is inappropriate.

1b A

Transperineal interstitial brachytherapy with permanent implants is an option for patients with cT1–T2a, Gleason score �7a, PSA �10 ng/ml,

prostate volume �50 ml, without a previous TURP and with a good IPSS.

2b B

Immediate postoperative external irradiation after RP for patients with pathologic tumor stage T3N0M0 improves biochemical and clinical

disease-free survival.

1 A

In patients with pathologic tumor stage T3N0M0, immediate postoperative external irradiation after RP may improve biochemical and

disease-free survival, with the highest impact in cases with positive surgical margins.

1b A

In patients with pathologic tumor stage T2–T3N0M0, salvage irradiation is indicated in cases of persisting PSA or biochemical failure with

rising PSA levels �0.5 ng/ml. Salvage RT might be initiated, even at low PSA levels of 0.1–0.2 ng/ml, if a continuous PSA increase

has been documented.

3 B

In patients with locally advanced PCa, T3–T4N0M0,concomitant and adjuvant hormonal therapy for a total duration of 3 yr, with

external-beam radiation for patients with WHO 0–2 performance status, is recommended, as it improves overall survival.

1b A

In a subset of patients with T2–T3N0M0 and Gleason score 2–6, short-term ADT before and during RT can be recommended, as it may

favorably influence overall survival.

1b A

In patients with very-high-risk PCa, c–pN1M0, and no severe comorbidities, the therapeutic role of pelvic external irradiation and

immediate long-term ADT is unclear; the adjuvant treatment options have to be discussed on an individual basis, taking into consideration

the age of the patient, comorbidities, and biology of the cancer.

3 B

ADT = androgen deprivation therapy; 3D-CRT = three-dimensional conformal radiation therapy; EBRT = external-beam radiation therapy; GR = grade of

recommendation; IMRT = intensity-modulated radiation therapy; IPSS = International Prostate Symptom Score; LE = level of evidence; PCa = prostate cancer;

PSA = prostate-specific antigen; RP = radical prostatectomy; RT = radiation therapy; TURP = transurethral resection of the prostate; WHO = World Health

Organization.

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 1 2 4 – 1 3 7130

15-yr cancer-specific survival rates of 95%, 90%, and 79%,

respectively, have been published, including all patients

who also underwent adjuvant and salvage procedures

[77,78].

PCa with markedly elevated PSA serum concentrations is

not a contraindication for RP. Spahn et al. published the

largest multicenter surgical series to date, including

712 patients with PSA >20 ng/ml, and reported a cancer-

specific survival rate of 90% and 85% at 10- and 15-yr

follow-up, respectively [77]. In the same analysis, they

demonstrated that the combination of PSA >20 ng/ml with

cT3 stage and/or biopsy Gleason score 8–10 significantly

lowered the cancer-specific survival rate. More recently,

Gontero and coworkers described a subanalysis of the same

patient cohort [78]. The 10-yr cancer-specific survival rate

was 80%, 85%, and 91% in patients with PSA>100, 50.1–100,

and 20.1–50 ng/ml, respectively. However, most patients

with PSA levels>100 ng/ml are likely to be harboring occult

metastatic disease and must be informed about the high

likelihood of adjuvant or salvage therapy in a postoperative

multimodality approach.

RP for clinical T3 cancer requires sufficient surgical

expertise to keep the level of morbidity acceptable and to

improve the oncologic outcome [77,78]. In men with

intermediate- and high-risk PCa, an extended pelvic lymph

node dissection (ePLND) should always be performed [63]

to obtain optimal information about the extent of lymph

node involvement for use in counseling patients concerning

the potential need for adjuvant treatment options. The true

therapeutic benefit of ePLND, however, is still unclear.

The indication for RP in all previously described stages

assumes the absence of clinically detectable nodal

involvement. Nevertheless, the combination of RP and

early androgen-deprivation therapy (ADT) in microscopic

pN+ PCa has been shown to achieve a 10-yr cancer-specific

survival rate of 80%. A retrospective observational study

has shown a dramatic improvement in cancer-specific

survival and overall survival in favor of completed RP

compared with abandoned RP in patients who were found

to be N+ at the time of surgery. These results suggest that

RP may have a survival benefit and that the abandonment

of RP in N+ cases may not be justified [79]. These findings

have been corroborated in a contemporary retrospective

analysis [80]. RP resulted in superior survival of patients

with N+ PCa after controlling for lymph node tumor

burden. The findings from these studies support the role of

RP as an important component of multimodal strategies

for N+ PCa.

The incidence of tumor progression is lower in patients

with fewer positive lymph nodes and in patients with

microscopic invasion only [81]. In patients who prove to be

pN+ after RP, early ADT has been shown to significantly

improve cancer-specific survival and overall survival in a

prospective randomized trial [82]. However, this trial

included mostly patients with high-volume nodal disease

and multiple adverse tumor characteristics. It is not known

if adjuvant ADT in patients with minimal nodal involvement

will result in the same positive results. The most recent

update on the Early Prostate Cancer trial and a recent

retrospective analysis of the Surveillance Epidemiology and

End Results data bank found no statistically significant

difference in overall survival between the adjuvant ADT and

non-ADT groups [83,84].

Follow-up of PSA and delayed start of ADT in patients

with rising PSA level is therefore an acceptable option in

selected cases. It is interesting to note that maximal local

control with RT of the prostatic fossa appears to be

beneficial in PCa patients with pN+ after RP who are

treated adjuvantly with continuous ADT [85]. However, this

finding is based on the data of one retrospective matched

pair analysis; data are awaited from prospective trials such

as Radiotherapy and Androgen Deprivation in Combination

After Local Surgery (RADICALS).

7.2.2. Adjuvant external-beam radiation therapy for pT3 or pTxR1

prostate cancer

Three prospective randomized trials have assessed the role of

immediate postoperative RT. Although different in inclusion

criteria, all trials concluded that immediate postoperative RT

significantly improved 5-yr clinical or biologic survival by

approximately 20% ( p < 0.0001) [86–88]. Immediate post-

operative RT proved to be well tolerated, with a risk of grade

3–4 urinary toxicity in �3.5% of patients.

The updated results of the SWOG 8794 trial [88] with a

median follow-up of 11.5 yr found that adjuvant RT

significantly improved 15-yr metastasis-free survival com-

pared with WW (46% vs 38%, p = 0.036) and overall survival

(47% vs 37%, p = 0.053), which may be the result of uneven

group compositions with different competing mortality risks

[89]. However, long-term data from the European Organiza-

tion for Research and Treatment of Cancer (EORTC) trial with

a mean follow-up of 10.6 yr did not demonstrate a significant

benefit concerning overall survival (80.7% vs 76.9%, respec-

tively) and metastasis-free survival (11.3% vs 11.0%, respec-

tively) [90]. Only progression-free survival (58.9% vs 39.4%,

respectively) and local failure (16.5% vs 7.0%, respectively)

were significantly improved. The frequency of severe

(Radiation Therapy Oncology Group [RTOG] grade �3)

RT-induced toxicity was higher in the group of adjuvant

RT compared with WW (5.3% vs 2.5%, p = 0.052), but this rate

was reduced to <1% with 3D-CRT [87]). Therefore, the

indication for adjuvant RT should be made with caution and

should be discussed in an interdisciplinary tumor board.

Thus, for patients with a high risk of local failure after RP

because of positive margins and/or invasion of the seminal

vesicles and negative PSA, two options can be offered within

the framework of informed consent: (1) immediate RT with

66.6 Gy to the surgical bed [91,92] on recovery of urinary

function or (2) clinical and biologic monitoring followed by

salvage RT with�66 Gy, ideally when the PSA rises but does

not exceed 0.5 ng/ml [91–93]. However, salvage RT might

be initiated at lower PSA serum levels, even in the range of

0.1–0.3 ng/ml, once a continuous PSA progression has been

documented.

7.2.3. Radiation therapy

For intermediate-risk PCa, there are three treatment options

based on the patient’s age, comorbidities, and sexual health:

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 1 2 4 – 1 3 7 131

1. EBRT with dose escalation from 76 to 81 Gy, which in

many series has shown a significant impact on 5-yr

progression-free survival [94,95]

2. A combination of EBRT plus low- or high-dose brachy-

therapy

3. Short-term (4–6-mo) ADT combined with a conventional

dose (70 Gy) of EBRT.

For high-risk localized PCa, the combination of EBRT with

ADT is highly recommended, as shown by phase 3

randomized trials [96,97], which display a significant

improvement in overall survival. This recommendation

holds true even if higher doses of EBRT are currently used to

treat high-risk disease.

Nabid et al. [98] reported the results of a phase 3 trial in

high-risk PCa comparing the effectiveness and safety of

short-duration compared with longer-duration ADT fol-

lowed by external irradiation. A total of 630 N0-X M0

patients were included: T1c–T2a–b with Gleason score >7

and/or baseline PSA >20 ng/ml, or T3–4 stages. Patients

were randomly allocated to ADT treatment for 18 mo

(320 patients) or 36 mo (310 patients). ADT consisted of a

luteinizing hormone–releasing hormone agonist with 1 mo

of antiandrogen, started 4 mo before 3D-CRT delivering

44 Gy to the pelvic lymph nodes and 70 Gy to the prostate.

The median age was 71 yr (range: 65–74). With a 77-mo

median follow-up, the 10-yr overall survival was 63.6%

(36-mo treatment arm) compared with 63.2% (18-mo

treatment arm) ( p = 0.429), and the 10-yr specific survival

was 87.2% in both treatment arms. In this trial, T1c–T2a–b

stages represented 75.4%, and T3–4 stages represented only

24.6%, while in the EORTC trial 22863 (which was the

reference of this study), the percentage of T3–4 was 89.6%. It

would therefore be wise to restrict these results to high-risk

localized PCa and to consider that 18 mo of ADT could

represent a new treatment standard in combination with

high-dose, high-precision external irradiation.

For locally advanced PCa, the data of the EORTC-22961

trial demonstrate a 4.7% benefit in overall survival after a

median follow-up of 5.2 yr in favor of 3-yr ADT compared

with short-term ADT [99]. The RTOG 92–02 study compared

4 mo of neoadjuvant ADT with 4 mo of neoadjuvant ADT

plus an additional 24 mo of adjuvant ADT in 1554 men with

T2c–T4 PCa and reported improvements in local progres-

sion, disease-free survival, biochemical survival, and

metastasis-free survival in the adjuvant ADT group [100].

However, an overall survival benefit was restricted to men

with a Gleason score of 8–10 in the subgroup analysis.

Therefore, concomitant (with or without neoadjuvant) and

adjuvant ADT for 3 yr is mandatory and represents the

current standard in the radiotherapeutic management of

high-risk PCa.

Various prospective randomized trials have evaluated

the oncologic efficacy of ADT with or without EBRT

[101–103]. The SPCG-7 trials included 875 men with locally

advanced PCa who were randomly assigned to endocrine

treatment or to ADT plus EBRT at a dose of �70 Gy [101].

After a median follow-up of 7.6 yr, the cancer-specific

mortality was significantly higher in the ADT arm compared

with the ADT plus EBRT arm (23.9% vs 11.9%), as was the

mortality (39.4% vs 29.6%) and the PSA failure rate (74.7% vs

25.5%) ( p < 0.0001). A Canadian study randomized 1205

men with locally advanced PCa to receive ADT or ADT with

EBRT at a dose of 65–69 Gy [102]. After a median follow-up

of 6 yr, the addition of EBRT significantly reduced the risk of

death (HR: 0.77; p = 0.033), with a 10-yr cumulative

disease-specific death rate of 15% compared with 23%. A

French study randomized 263 patients with locally

advanced PCa to receive ADT or ADT plus EBRT [103]. At

a minimum follow-up of 5 yr, the combined treatment

achieved significantly superior results with regard to

progression-free survival (60.9% vs 8.5%, p = 0.001), loco-

regional progression (9.7% vs 29%, p = 0.0002), and meta-

static progression (3% vs 10.8%, p = 0.018).

Patients must be informed about potential late GU or GI

toxicity and about the impact of irradiation on erectile

function. Late toxicity was analyzed using a dose of 70 Gy in

the prospective EORTC randomized trial 22863, graded

according to a modified RTOG scale. Eighty-six patients

(22.8%) had grade >2 urinary or intestinal complications or

leg edema, 72 of whom had grade 2 (moderate) toxicity;

10 patients had grade 3 (severe) toxicity; and 4 patients

died because of grade 4 (fatal) toxicity. Although there were

four late treatment-related deaths (1%), the long-term

toxicity was limited, with a grade 3 or 4 late complication

rate of <5% being reported.

8. Irradiation to the pelvic lymph nodes

There is no firm evidence base for prophylactic whole-

pelvic irradiation (46–50 Gy), since randomized trials have

failed to show a benefit in high-risk cases [104–107]. The

use of ePLND may be needed to improve the selection of

patients who may be able to benefit from pelvic lymph node

irradiation. The results of pelvic lymphadenectomy, partic-

ularly in young patients, will enable radiation oncologists to

tailor both the planning target volume and the duration of

ADT—specifically, no pelvic irradiation for pN0 patients, but

pelvic irradiation for pN1 patients with long-term ADT. The

benefits of high-dosage pelvic nodal irradiation using IMRT

merit further investigation in a phase 2 trial. One such trial

is currently recruiting through the RTOG study, while a

second randomized phase 2 trial is ongoing in the United

Kingdom.

9. Proton-beam and carbon ion–beam therapy

Proton-beam therapy is a promising but costly treatment

for PCa. Although there are theoretical physical advantages,

this therapy has so far been shown to be only comparably

safe and effective when compared with the alternatives and

not necessarily superior [108].

The Proton Radiation Oncology Group 9509 trial

randomly assigned 393 men with clinically localized PCa

to receive EBRT with 70.2 Gy compared with 79.2 Gy of

combined photon and proton radiation [109] in a dose-

escalation trial. At a median follow-up of 9.4 yr, the

estimated 10-yr biochemical progression rate for patients

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 1 2 4 – 1 3 7132

receiving a standard dose was 32%, compared with 17% for

patients receiving a high dose ( p < 0.001). Prostate Cancer

Symptom Indexes did not differ significantly between the

two groups with regard to urinary obstruction/irritation

(23.3 vs 24.6, p = 0.36), urinary incontinence (10.6 vs 9.7,

p = 0.99), bowel problems (7.7 vs 7.9, p = 0.70), and sexual

dysfunction (68.2 vs 65.9, p = 0.65), respectively. However,

a prospective randomized trial using equivalent doses of

IMRT and photon radiation is needed to evaluate the

oncologic efficacy of photon RT, which has only recently

become available.

The guidelines and recommendations for definitive RT

are given in Table 5.

10. Follow-up of prostate cancer patients

Patients diagnosed with PCa who undergo local treatment

with curative intent are usually followed for �10 yr or until

high age makes follow-up superfluous. Determination of

serum PSA, together with a disease-specific history, is

supplemented by DRE and by imaging studies if locally

recurrent disease is suspected.

11. Alternative local treatment options for prostate

cancer

Besides RP, EBRT, and/or brachytherapy, cryosurgical

ablation of the prostate (CSAP) and high-intensity focused

ultrasound (HIFU) have emerged as alternative therapeutic

options in patients with clinically localized PCa who are not

suitable for RP [110–112].

Crouzet et al. [111] analyzed the oncologic and

functional outcomes of the largest patient cohort, which

included 803 patients with low-, intermediate-, and high-

risk PCa in 40.2%, 46.3%, and 13.5% of patients, respectively.

Mean follow-up was 42 � 33 mo. The overall and cancer-

specific survival rates at 8 yr were 89% and 99%, respectively.

The metastasis-free survival rate at 8 yr was 97%. The 5- and

7-yr biochemical-free survival rates (Phoenix criteria) for

low-, intermediate-, and high-risk patients were 83–75%,

72–63%, and 68–62%, respectively ( p = 0.03); the additional

treatment-free survival rates were 84–79%, 68–61%, and

52–54%, respectively ( p < 0.001).

Currently, data from HIFU are not extensive enough to be

considered in treatment recommendations. Applying the

Grading of Recommendations Assessment, Development

and Evaluation (GRADE) approach, the available evidence

on the efficacy and safety of HIFU in PCa is very low quality,

mainly because of study designs that lack control groups,

and patients must be informed accordingly. Indications

might be (1) low- or intermediate-risk PCa or (2) prostate

volume <40 ml at the time of therapy.

The results of the only randomized trial of EBRT

compared with CSAP in patients with clinically localized

PCa were published recently, with promising results [113].

A total of 244 men with low- and intermediate-risk PCa

were assigned to both treatment arms, and all men received

neoadjuvant ADT. After a median follow-up of 100 mo, there

were no differences with regard to disease progression at

36 mo, overall survival, or disease-specific survival. Positive

results might be because of the fact that neoadjuvant ADT

was delivered, and both arms and patient numbers are too

small to draw significant clinical conclusions.

12. Summary

The present text represents a summary. For more detailed

information and a full list of references, refer to the full-text

version. These EAU guidelines (ISBN 978–90–79754–71–7)

are available at the EAU Web site (http://www.uroweb.org/

guidelines/online-guidelines/).

Author contributions: Axel Heidenreich had full access to all the data in

the study and takes responsibility for the integrity of the data and the

accuracy of the data analysis.

Study concept and design: Heidenreich, Mottet.

Acquisition of data: Heidenreich, Bastian, Bellmunt, Bolla, Joniau, van der

Kwast, Mason, Matveev, Wiegel, Zattoni, Mottet.

Analysis and interpretation of data: Heidenreich, Bastian, Bellmunt, Bolla,

Joniau, van der Kwast, Mason, Matveev, Wiegel, Zattoni, Mottet.

Drafting of the manuscript: Heidenreich.

Critical revision of the manuscript for important intellectual content:

Heidenreich, Bastian, Bellmunt, Bolla, Joniau, van der Kwast, Mason,

Matveev, Wiegel, Zattoni, Mottet.

Statistical analysis: None.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Mottet.

Other (specify): None.

Financial disclosures: Axel Heidenreich certifies that all conflicts of

interest, including specific financial interests and relationships and

affiliations relevant to the subject matter or materials discussed in the

manuscript (eg, employment/affiliation, grants or funding, consultan-

cies, honoraria, stock ownership or options, expert testimony, royalties,

or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

Acknowledgment statement: A.H. was chairman of the EAU Prostate

Cancer Guideline Group from 2008 through March 2013. N.M. has been

chairman of the EAU Prostate Cancer Guideline Group since March 2013.

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