GUIDELINEs ON PROSTATE CANCER

(Text update February 2012)

A. Heidenreich (chairman), P.J. Bastian, J. Bellmunt,

M. Bolla, S. Joniau, T.H. van der Kwast, M.D. Mason,
V. Matveev, N. Mottet, T. Wiegel, F. Zattoni
Eur Urol 2008 Jan;53(1):68-80
Eur Urol 2011 Jan;59(1):61-71
Eur Urol 2011 Apr;59(4):572-83

Introduction
Cancer of the prostate (PCa) is currently the second most
common cause of cancer death in men. In developed countries PCa accounts for 15% of male cancers compared with
4% of male cancers in developing countries. Within Europe
exist also large regional differences in the incidence rates of
PCa.
There are three well-established risk factors for PCa: increasing age, ethnic origin, and genetic predisposition. Clinical
data suggest that exogenous risk factors, such as diet, pattern
of sexual behaviour, alcohol consumption, exposure to ultraviolet radiation, and occupational exposure may also play an
important role in the risk of developing PCa.
The introduction of an effective blood test, prostate-specific
antigen (PSA), has resulted in more early-stage prostate cancer diagnosis where potentially curative treatment options
48 Prostate Cancer

can be provided. However, if effective diagnostic procedures

are inappropriately used in elderly men with a short life
span, the issue of over-diagnosis and over-treatment may
occur. Consequently, the same stage of prostate cancer may
require different treatment strategies depending on an individual patients life expectancy.

Staging system
The 7th edition Union Internationale Contre le Cancer
(UICC) 2009 Tumour Node Metastasis (TNM) classification
is used for staging (Table 1).

Table 1: Tumour Node Metastasis (TNM) classification

of cancer of the prostate
T - Primary tumour
TX
T0
T1

T2

Primary tumour cannot be assessed

No evidence of primary tumour
Clinically unapparent tumour not palpable or visible
by imaging
T1a Tumour incidental histological finding in 5%
or less of tissue resected
T1b Tumour incidental histological finding in
more than 5% of tissue resected
T1c Tumour identified by needle biopsy (e.g.
because of elevated PSA level)
Tumour confined within the prostate1
T2a Tumour involves one half of one lobe or less

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T3

T4

T2b Tumour involves more than half of one lobe,

but not both lobes
T2c Tumour involves both lobes
Tumour extends through the prostatic capsule2
T3a Extracapsular extension
(unilateral or bilateral)
T3b Tumour invades seminal vesicle(s)
Tumour is fixed or invades adjacent structures other
than seminal vesicles: external sphinter, rectum,
levator ani and/or pelvic wall

N - Regional lymph nodes3

NX
N0
N1

Regional lymph nodes cannot be assessed

No regional lymph node metastasis
Regional lymph node metastasis

M - Distant metastasis4
M0
M1

No distant metastasis
Distant metastasis
M1a Non-regional lymph node(s)
M1b Bone(s)
M1c Other site(s)

1 Tumour

found in one or both lobes by needle biopsy, but not

palpable or visible by imaging, is classified as T1c.
2 Invasion into the prostatic apex, or into (but not beyond) the
prostatic capsule, is not classified as T3, but as T2.
3 The regional lymph nodes are the nodes of the true pelvis,
which are essentially the pelvic nodes below the bifurcation
of the common iliac arteries. Laterality does not affect the N
classification.
4 When more than one site of metastasis is present, the most
advanced category should be used.

50 Prostate Cancer

Gleason grading system

The most commonly used system for grading PCa is the
Gleason grading system.

Diagnosis and staging

The decision whether to proceed with further diagnostic or
staging work-up is guided by which treatment options are
available to the patient, taking the patients age and comorbidity into consideration. Procedures that will not affect the
treatment decision can usually be avoided.
Synoptic reporting of surgical specimens results in more
transparent and more complete pathology reporting. The use
of a checklist is encouraged and two examples are presented
here.
Checklist for pathology reporting of prostate biopsies
1. Histological type of carcinoma
2. Histological grade (global or highest)
Primary grade
Secondary (= highest) grade
3. Fraction of involved cores
Number of cores involved by carcinoma
Total number of cores
4. Tumour quantification
Percentage of prostatic tissue involved by carcinoma or
total mm of cancer length
5. Tumour extent
Identification of perineural invasion
Identification of extra-prostatic extension
Identification of seminal vesicle invasion
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51

Checklist for processing and pathology reporting of radical

prostatectomy (RP) specimens
1. Processing of RP specimens
Total embedding of a prostatectomy specimen is preferred, either by conventional (quadrant sectioning) or
by whole-mount sectioning
The entire surface of RP specimens should be inked
before cutting in order to evaluate the surgical margin
status
The apex should be separately examined using the cone
method with sagittal or radial sectioning
2. Histological type
3. Histological grade
Primary (predominant) grade
Secondary grade
Tertiary grade (if exceeding > 5% of PCa volume)
Global Gleason score
Approximate percentage of Gleason grade 4 or 5
(optional)
4. Tumour quantification (optional)
Percentage of prostatic tissue involved
Tumour size of dominant nodule (if identified), greatest
dimension in mm
5. Pathological staging (pTNM)
Presence of extraprostatic extension (focal or extensive),
specify sites
Presence of seminal vesicle invasion
Presence of lymph node metastases, number of retrieved
lymph nodes and number of positive lymph nodes
6. Surgical margins
Presence of carcinoma at margin
52 Prostate Cancer

 If present, specify site(s) and extra- or intra-prostatic

invasion
7. Other
If identified, presence of angioinvasion
Location (site, zone) of dominant tumour (optional)
Perineural invasion (optional)
If present, specify extra- or intra-prostatic invasion

A short summary of the guidelines on diagnosis and staging

of PCa are presented in Table 2.

Guidelines for the diagnosis and staging of PCa

Diagnosis of PCa

GR

1.

An abnormal digital rectal examination (DRE)

result or elevated serum PSA measurement
could indicate PCa. The exact cut-off level of
what is considered to be a normal PSA value
has yet to be determined, but values of approximately < 2-3 ng/mL are often used for younger
men.

2.

The diagnosis of PCa depends on histopathological (or cytological) confirmation.

Biopsy and further staging investigations are

only indicated if they affect the management of
the patient.

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3.

4.

Transrectal ultrasound (TRUS)-guided systemic

biopsy is the recommended method in most
cases of suspected PCa. At least 8 systemic,
laterally directed, cores are recommended, with
perhaps more cores in larger volume prostates.

Transition zone biopsies are not recommended

in the first set of biopsies due to low detection
rates.

One set of repeat biopsies is warranted in cases

with persistent indication for PCa (abnormal
DRE, elevated PSA or histopathological findings
suggestive of malignancy at the initial biopsy).

Overall recommendations for further (three

or more) sets of biopsies cannot be made; the
decision must be made based on an individual
patient.

Transrectal peri-prostatic injection with a local

A
anaesthetic can be offered to patients as effective
analgesia when undergoing prostate biopsies.
Staging of PCa

1.

Local staging (T-staging) of PCa should be

based on magnetic resonance (MR) imaging.
Further information is provided by the number
and sites of positive prostate biopsies, the
tumour grade and the level of serum PSA.

54 Prostate Cancer

2.

Despite its high specificity in the evaluation

of extraprostatic extension (EPE) and seminal
vesicle invasion or involvement (SVI), TRUS is
limited by poor contrast resolution, resulting
in low sensitivity and a tendency to understage
PCa. Even with the advent of colour- and power
Doppler to assist in identifying tumour vascularity, the accuracy of TRUS in local staging
remains inadequate. In comparison with DRE,
TRUS and computed tomography (CT), MR
imaging demonstrates higher accuracy for the
assessment of uni- or bi-lobar disease (T2), EPE
and SVI (T3), as well as the invasion of adjacent structures (T4). The addition of dynamic
contrast-enhanced MR imaging (DCE-MRI)
can be helpful in equivocal cases. The addition
of magnetic resonance spectroscopic imaging
(MRSI) to MRI also increases accuracy and
decreases inter-observer variability in the evaluation of EPE.

Lymph node status (N-staging) is only important when potentially curative treatment is
planned. Patients with stage T2 or less, PSA
<20 ng/mL and a Gleason score < 6 have a
lower than 10% likelihood of having node
metastases and can be spared nodal evaluation.

Given the significant limitations of pre-operative imaging in the detection of small metastases (<5 mm), pelvic lymph node dissection
(PLND) remains the only reliable staging method in clinically localised PCa.

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3.

Currently, it seems that only methods of histological detection of lymph node metastases with
high sensitivity, such as sentinel lymph node
dissection or extended PLND, are suitable for
lymph node staging in PCa.

Skeletal metastasis (M-staging) is best assessed

by bone scan. This may not be indicated in
asymptomatic patients if the serum PSA level is
< 20 ng/mL in the presence of well or moderately differentiated tumours.

In equivocal cases, 11C-choline-, 18F-flouridePET/CT or whole body MRI are an option.

Treatment of prostate cancer

An overview of the treatment options for patients with PCa,
subdivided by stage at diagnosis, is presented in Table 3. Due
to a lack of randomised controlled trials in PCa, one therapy
option cannot be considered superior to another. However,
based on the currently available literature, the recommendations presented in Table 3 can be made.

56 Prostate Cancer

Guidelines for the primary treatment of PCa

Stage
Treatment
T1a
Watchful
waiting

T1bT2b

Comment
Standard treatment for
Gleason score < 6 and 7 adenocarcinomas and < 10-year life
expectancy.
Active surveil- In patients with > 10-year life
lance
expectancy, re-staging with
TRUS and biopsy is recommended.
Radical pros- Optional in younger patients
with a long life expectancy,
tatectomy
especially for Gleason score
> 7 adenocarcinomas
Radiotherapy Optional in younger patients
with a long life expectancy,
in particular in poorly differentiated tumours. Higher
complication risks after TURP,
especially with interstitial
radiation.
Hormonal
Not an option.
Combination Not an option.
Active surveil- Treatment option in patients
with cT1c-cT2a, PSA
lance
< 10 ng/mL, biopsy Gleason
score < 6, < 2 biopsies positive, < 50% cancer involvement of each biopsy.
Patients with a life expectancy
< 10 years.

GR
B

A
C
B

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T1aT2c

Patients with a life expectancy > 10 years once they are

informed about the lack of
survival data beyond 10 years.
Patients who do not accept
treatment-related complications.
Radical pros- Optional in patients with pT1a A
tatectomy
PCa.
Standard treatment for
patients with a life expectancy
> 10 years who accept treatment-related complications.
Radiotherapy Patients with a life expectancy B
> 10 years who accept treatment-related complications.
Patients with contraindications for surgery.
Unfit patients with 5-10 years
of life expectancy and poorly
differentiated tumours (combination therapy is recommended; see below).
B
Brachytherapy Low-dose rate brachytherapy
can be considered for low risk
PCa patients with a prostate
volume < 50 mL and an IPSS
< 12.

58 Prostate Cancer

Hormonal

Combination

T3T4

Watchful
waiting

Radical prostatectomy

Symptomatic patients, who

need palliation of symptoms,
unfit for curative treatment.
Anti-androgens are associated
with a poorer outcome compared to active surveillance
and are not recommended.
For high-risk patients, neoadjuvant hormonal treatment
and concomitant hormonal
therapy plus radiotherapy
results in increased overall
survival.
Option in asymptomatic
patients with T3, well-differentiated and moderately-differentiated tumours, and a life
expectancy < 10 years who are
unfit for local treatment.
Optional for selected patients
with T3a, PSA < 20 ng/mL,
biopsy Gleason score < 8 and
a life expectancy > 10 years.
Patients have to be informed
that RP is associated with an
increased risk of positive surgical margins, unfavourable
histology and positive lymph
nodes and that, therefore,
adjuvant or salvage therapy
such as radiation therapy or
androgen deprivation might
be indicated.

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Radiotherapy

Hormonal

Combination

60 Prostate Cancer

T3 with > 5-10 years of life

expectancy. Dose escalation
of > 74 Gy seems to be of
benefit. A combination with
hormonal therapy can be recommended (see below).
Symptomatic patients, extensive T3-T4, high PSA level
(> 25-50 ng/mL), PSADoubling Time (DT) < 1 year.
Patient-driven, unfit patients.
Hormone monotherapy is not
an option for patients who are
fit enough for radiotherapy.
Overall survival is improved
by concomitant and adjuvant
hormonal therapy (3 years)
combined with external beam
radiation.
NHT plus radical prostatectomy: no indication.

N+,
M0

Watchful
waiting

Radical prostatectomy

Radiotherapy

Hormonal

Combination
M+

Watchful
waiting

Radical prostatectomy

Asymptomatic patients.
Patient-driven (PSA
<20-50ng/mL), PSA DT > 12
months. Requires very close
follow-up.
Optional for selected patients
with a life expectancy of > 10
years as part of a multimodal
treatment approach.
Optional in selected patients
with a life expectancy of > 10
years, combination therapy
with adjuvant androgen deprivation for 3 years is mandatory.
Standard adjuvant therapy in
more than 2 positive nodes to
radiation therapy or radical
prostatectomy as primary local
therapy. Hormonal therapy
should only be used as monotherapy in patients who are
unfit for any type of local
therapy.
No standard option.
Patient-driven.
No standard option. May have
worse survival/more complications than with immediate
hormonal therapy. Requires
very close follow-up.
Not a standard option.

B
B

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61

Radiotherapy

Hormonal

Not an option for curative

C
intent; therapeutic option in
combination with androgen
deprivation for treatment of
local cancer-derived symptoms.
Standard option. Mandatory in A
symptomatic patients.

For more detailed information and discussion on second-line

therapy, please see the full text version of the guidelines.

Follow-up of prostate cancer patients

Determination of serum PSA, disease-specific history and
DRE are the cornerstones in the follow-up of PCa patients.
Routine imaging procedures in stable patients are not recommended and should only be used in specific situations.

Guidelines for follow-up after treatment with

curative intent

GR

In asymptomatic patients, a disease-specific history

B
and a serum PSA measurement supplemented by DRE
are the recommended tests for routine follow-up.
These should be performed at 3, 6 and 12 months
after treatment, then every 6 months until 3 years, and
then annually.
After RP, a serum PSA level > 0.2 ng/mL can be asso- B
ciated with residual or recurrent disease.
After radiation therapy, a rising PSA level > 2 ng/mL
B
above the nadir PSA, rather than a specific threshold
value, is the most reliable sign of persistent or recurrent disease.
62 Prostate Cancer

Both a palpable nodule and a rising serum PSA level

can be signs of local disease recurrence.
Detection of local recurrence by TRUS and biopsy is
only recommended if it will affect the treatment plan.
In most cases TRUS and biopsy are not necessary
before second-line therapy.
Metastasis may be detected by pelvic CT/MRI or bone
scan. In asymptomatic patients, these examinations
may be omitted if the serum PSA level is < 20 ng/mL.
Routine bone scans and other imaging studies are not
recommended in asymptomatic patients. If a patient
has bone pain, a bone scan should be considered irrespective of the serum PSA level.

B
B

Guidelines for follow-up after hormonal treatment GR

Patients should first be evaluated at 3 and 6 months
after treatment initiation. Tests should at least include
serum PSA measurement, DRE, serum testosterone
and careful evaluation of symptoms in order to assess
the treatment response and side-effects.
If patients undergo intermittent androgen deprivation,
PSA and testosterone should be monitored at 3 month
intervals during the treatment pause.
Follow-up should be tailored to the individual patient,
according to symptoms, prognostic factors and the
treatment given.
In patients with stage M0 disease with a good treatment response, follow-up is scheduled every 6
months, and should include at least a disease-specific
history, DRE and serum PSA measurement.

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In patients with stage M1 disease with a good treatment response, follow-up is scheduled for every 3 to 6
months. Follow-up should include at least a diseasespecific history, DRE and serum PSA measurement,
frequently supplemented with haemoglobin, serum
creatinine and alkaline phosphatase measurements.
Patients (especially with M1b status) should be
advised about the clinical signs that could suggest spinal cord compression.
Where disease progression occurs, or if the patient
does not respond to the treatment given, follow-up
needs to be individualised.
Routine imaging of stable patients is not recommended.

Treatment of relapse after curative therapies

An effort should be made to distinguish between the probability of local failure only versus distant (+/- local) failure.
Initial pathology, how long after primary therapy the PSArelapse occurs and how fast the PSA-value is rising can all aid
in the distinction between local and distant failure. Poorly
differentiated tumour, early PSA-relapse and a short PSAdoubling time are all signs of distant failure. Treatment can
then be guided by the presumed site of failure, the patients
general condition and personal preferences. Imaging studies
are of limited value in patients with early PSA-relapse only.

64 Prostate Cancer

Guidelines for second-line therapy after curative

treatments

GR

B
Patients with presumed local failure
only may be candidates for salvage
radiotherapy. This should be given
with at least 64 Gy and preferably
before PSA has risen above
0.5 ng/mL. Other patients are best
offered a period of active surveillance
(active monitoring), with possible
hormonal therapy later on.
C
Selected patients may be candidates
Presumed
for salvage RP and they should be
local failure
informed about the high risk of comafter radioplications, such as incontinence and
therapy
erectile dysfunction.
Salvage prostatectomy should only be
performed in experienced centres.
Other patients are best offered a
period of active surveillance (active
monitoring), with possible hormonal
therapy later on.
Presumed dis- There is some evidence that early
B
tant failure
hormonal therapy may be of benefit
in +/- local failure, delaying progression, and possibly achieving a survival
benefit in comparison with delayed
therapy. The results are controversial.
Local therapy is not recommended
except for palliative reasons.
Presumed
local failure
after radical
prostatectomy

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Treatment of relapse after hormonal therapy

Castration-refractory PCa (CRPC) is usually a debilitating
disease, often affecting elderly patients. A multidisciplinary
approach is required with input from medical oncologists,
radiation oncologists, urologists, nurses, psychologists and
social workers. In most cases the decision whether to treat or
not is made based on counselling of the individual patient,
which limits the role of guidelines.

Guidelines for secondary hormonal management in GR

patients with CRPC
Anti-androgen therapy should be stopped once PSA
B
progression is documented.
C
No clear-cut recommendation can be made for the
most effective drug for secondary hormonal manipulations because data from randomised trials are scarce.
However, abiraterone and MDV3100 may address this
issue once final data from the prospective randomised
Phase III clinical trials are analysed.
Comment: An eventual anti-androgen withdrawal effect
should become apparent 4-6 weeks after the discontinuation
of flutamide or bicalutamide.

66 Prostate Cancer

Guidelines for cytotoxic therapy in patients with

CRPC
Patients with CRPC should be counselled, managed
and treated in a multidisciplinary team.
In non-metastatic CRPC, cytotoxic therapy should
only be used in a clinical trial setting.
In patients with a PSA rise only, two consecutive
increases of PSA serum levels above a previous reference level should be documented.
Prior to treatment, testosterone serum levels should be
below 32 ng/dL.
Prior to treatment, PSA serum levels should be
>2ng/mL to assure correct interpretation of therapeutic efficacy.
Potential benefits of cytotoxic therapy and expected
side-effects should be discussed with each individual
patient.
In patients with metastatic CRPC who are candidates
for cytotoxic therapy, docetaxel at 75 mg/m2 every 3
weeks is the drug of choice since it has shown a significant survival benefit.
In patients with symptomatic osseous metastases
due to CRPC, either docetaxel or mitoxantrone with
prednisone or hydrocortisone are viable therapeutic
options. If not contraindicated, docetaxel is the preferred agent based on the significant advantage in pain
relief.
In patients with relapse following first-line docetaxel
chemotherapy, based on the results of prospective
randomised clinical phase III trials, Cabazitaxel and
Abiraterone are regarded as first-choice option for
second-line treatment.

GR

B
B

B
B

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Second-line docetaxel may be considered in previously responding docetaxel-treated patients. Otherwise

treatment is to be tailored to the individual patients.
In case patients are not eligible for cabazitaxel or abiraterone, docetaxel is an option.

Guidelines for palliative management of patients

with CRPC

GR

Patients with symptomatic and extensive osseous

metastases cannot benefit from medical treatment
with regard to life prolongation.
Management of these patients has to be directed at
improving quality of life and providing pain reduction.
Effective medical management with the highest efficacy and a low frequency of side-effects is the major
goal of therapy.
Bisphosphonates (e.g. zoledronic acid) should be
offered to patients with skeletal masses to prevent
osseous complications. However, the benefits must be
balanced against the toxicity of these agents, in particular, jaw necrosis must be avoided.
Palliative treatments, such as radionuclides, external
beam radiotherapy and adequate use of analgesics,
should be considered early on in the management of
painful osseous metastases.
Spinal surgery or decompressive radiotherapy are
emergency surgeries which have to be considered for
patients with neurological symptoms thought to be
critical.

68 Prostate Cancer

Summary
Prostate cancer is a complex disease, in which many aspects
of the disease itself and the affected patient must be considered before decisions regarding diagnostic work-up, treatment and follow-up can be made.

This short booklet text is based on the more comprehensive EAU guidelines
(ISBN 978-90-79754-83-0), available to all members of the European
Association of Urology at their website, http://www.uroweb.org.

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